TW202440113A - Method of treating early breast cancer - Google Patents

Abstract

The present disclosure relates to the adjuvant treatment of HR+/HER2- stage II or III early breast cancer in adult patients. The method includes administering ribociclib (a CDK4/6 inhibitor) in combination with endocrine therapy.

Description

Treatment for early-stage breast cancer

Breast cancer (BC) is the most commonly diagnosed cancer worldwide, with an estimated 1.7 million new cases of BC and 522,000 deaths attributable to the disease in 2012 (CA Cancer J Clin 65:87-108, 2015). The incidence of BC varies across ethnic groups and regions around the world, ranging from 27 per 100 000 in Central Africa and East Asia to 92 per 100 000 in North America (GLOBOCAN: Estimated Cancer Incidence, Mortality and Prevalence Worldwide 2012 [Internet] [cited June 26, 2018], https://publications.iarc.fr/Databases/Iarc-Cancerbases/GLOBOCAN-2012-Estimated-Cancer-Incidence-Mortality-And-Prevalence-Worldwide-In-2012-V1.0-2012). In the United States, BC is projected to be the most commonly diagnosed cancer in 2018, with an estimated 268,670 new cases and 41,400 deaths (CA Cancer J Clin 68:7-30, 2018). An estimated 458,337 cases of BC were reported in European countries in 2012 (Eur J Cancer Oxf Engl 1990 49:1374-1403, 2013). BC is uncommon in men, reported in approximately 1% of all BC cases, but its incidence is increasing (Breast Cancer Res Treat 137:465-470, 2013).

The vast majority of newly diagnosed BC cases are early breast cancer (EBC), which is confined to the breast tissue and regional lymphatics and may be treatable with locoregional treatments such as surgery and radiation therapy. According to data collected between 1975 and 2012 by the Surveillance, Epidemiology, and End Results (SEER) program, 93% of diagnosed cases were EBC, with 62% of cases confined to breast tissue and 31% located in breast tissue and regional lymph nodes (SEER Cancer Statistics Review, 1975–2015 [Internet]. National Cancer Institute, Bethesda, MD, 2018, https://seer.cancer.gov/csr/1975_2015/).

In addition to primary surgical therapy, treatment of EBC usually includes other anti-tumor therapies, such as radiation therapy and adjuvant or neoadjuvant systemic therapy. Although many EBC patients can achieve disease-free survival with surgical resection and radiation therapy, micrometastatic disease often causes distant recurrence, which is also the main cause of death in EBC patients (BMC Med 13:195, 2015). According to a meta-analysis of nearly 150,000 women in 200 randomized clinical trials by the EBC Trialists’ Collaborative Group (EBCTCG), during the 5-year follow-up period, approximately 36% and 20% of EBC patients without any adjuvant systemic therapy will experience recurrence and BC-related death, respectively (Lancet Lond Engl 365:1687-1717, 2005). In addition, patients with hormone receptor (HR)-positive EBC still experience recurrence and BC-related death 5 years after surgery, with only 45% of patients reporting freedom from recurrence at 15 years of follow-up.

Adjuvant systemic therapy for EBC patients includes cytotoxic therapy, biological therapy, and endocrine therapy, which can reduce locoregional and distant recurrences, reduce BC-induced mortality, and improve overall survival (OS) (Lancet Lond Engl 365:1687-1717, 2005). Whether and how to choose adjuvant systemic therapy depends on the individual risk of recurrence and may be influenced by some clinical, pathological, and genomic predictive and prognostic factors of the tumor and the patient (such as tumor stage, histopathological grade, tumor HR status, human epidermal growth factor receptor 2 (HER2) status, multigene test recurrence score, proliferation markers such as Ki67, menopausal status, patient comorbidities, age, etc.). Using these factors, the risk of postoperative recurrence of EBC can be classified as low, moderate, or high (BMC Med 13:195, 2015). Although there is no consensus on the definition of these risk groups, in general, patients with smaller tumors, no regional lymph node metastases, low tumor grade, HR-positive and HER2-negative status, and a low relapse genomic score have a lower risk of relapse (i.e., 5-year relapse rate of 5%-10%). These patients are often considered for adjuvant endocrine therapy (ET) rather than chemotherapy because the clinical benefit of the latter is relatively low. On the other hand, patients with multiple regional lymph node metastases, high tumor grade, HER2-positive status, or a high relapse genomic score have a higher risk of relapse. Such patients are usually considered for adjuvant chemotherapy (and HER2-targeted agents for HER2-positive BC) and, if the tumor exhibits HR, adjuvant ET (usually given after completion of chemotherapy).

An estimated 75% of BC express steroid hormone receptors (estrogen receptor [ER] and/or progesterone receptor [PgR]), and therefore these patients may benefit from adjunctive ET with tamoxifen or an aromatase inhibitor (AI) (letrozole, anastrozole, or exemestane) (J Clin Oncol Off J Am Soc Clin Oncol 28:2784-2795, 2010). ET, unlike chemotherapy, reduces the risk of recurrence and BC death in HR-positive EBC (Lancet London 365:1687-1717, 2005).

Current clinical guidelines (see Ann Oncol Off J Eur Soc Med Oncol 26 Suppl 5:v8-30, 2015; and National Comprehensive Cancer Network. Breast Cancer (2019, 1st ed.) [Internet]. NCCN, 2019 [cited May 6, 2019], https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf) recommend adjuvant ET for HR-positive EBC: •   For premenopausal women: 1.1.    5–10 years of tamoxifen therapy with or without ovarian suppression, or 1.2. 5 years of AI therapy with ovarian suppression (see N Engl J Med 379:122-137, 2018) •   For postmenopausal women: 1.3.    Initial AI therapy for 5 years (or up to 10 years) based on the results of the MA.17R trial (see N Engl J Med 375:209-219, 2016), or 1.4.    Initial tamoxifen therapy for 2-3 years followed by AI therapy (total duration up to 5 years, or up to 5 years of AI therapy), or 1.5.    Tamoxifen therapy for approximately 5 years followed by AI therapy for 5 years, or 1.6.   Tamoxifen therapy for up to 10 years (Ann Oncol Off J Eur Soc Med Oncol 26 Suppl 5:v8-30, 2015; National Comprehensive Cancer Network. Breast Cancer (2019, 1st ed.) [Internet]. NCCN, 2019 [cited May 6, 2019], https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf) •   For men: Limited data suggest that tamoxifen or a combination of an AI and a gonadotropin-releasing hormone (GnRH) agonist should be the first choice for ET in HR-positive, HER2-negative EBC (Breast Cancer Res Treat 151:141-147, 2015).

WO2015/022609 A1 (incorporated herein by reference) discloses combination therapy for treating cancer, including EBC. Some EBC patients may still relapse, especially those with adverse clinical, pathological and genomic features. Among EBC patients who are HR-positive, HER2-negative, and have multiple (≥4) regional lymph node metastases (roughly equivalent to anatomical stage III group in the AJCC 8th edition breast cancer staging), approximately 25%-30% of patients will relapse within 5 years of using ET containing AI (Lancet London Engl 365:1687-1717, 2005). Despite ET for 5 years, only 48% of these patients remained free of distant recurrence within 20 years, and almost half of them died of BC within 20 years (N Engl J Med 377:1836-1846, 2017). Although patients with 1-3 regional lymph node metastases (generally corresponding to anatomic stage II in the AJCC 8th edition breast cancer staging system) may have a lower risk of recurrence than patients in anatomic stage III, 31% of these patients still had distant recurrence despite ET, and 28% still died of BC within 20 years (N Engl J Med 377:1836-1846, 2017).

Adjuvant therapy for HR+ HER2- EBC remains limited. Although similar adjuvant therapies used for patients with HR+ HER2- advanced or metastatic breast cancer have been tried, the results obtained from this approach have varied. In one example, the cdk4/6 inhibitor abemaciclib was initially approved for the treatment of patients with HR+ HER2- advanced or metastatic breast cancer (either alone or in combination with endocrine therapy) and was subsequently shown to be effective in the monarchE clinical trial for the treatment of patients with HR+ HER2- high-risk early breast cancer (Johnston et al., 2023. Lancet 24(1), pp. 77-90). In contrast, the cdk4/6 inhibitor palbociclib combined with endocrine therapy showed clinically relevant efficacy in patients with HR+ HER2- metastatic breast cancer (PALOMA3 trial, described in Turner et al., 2015. N Engl J Med 2015;373:209-219), but the results were not confirmed in patients with HR+ HER2- early breast cancer (see PENELOPE-B trial, in which endocrine therapy plus palbociclib did not improve invasive disease-free survival (iDFS) compared with ET plus placebo in patients with HR+ HER2- early breast cancer who had residual invasive disease after completing neoadjuvant chemotherapy (Loibl et al., 2021. Breast Cancer v39(14)). Similarly, the results of the PALLAS trial in patients with HR+ HER2- early breast cancer showed that the combination of palbociclib and endocrine therapy did not improve iDFS compared with endocrine therapy alone (Mayer et al., 2021. Lancet, v22 (2), pp. 212-222).

Therefore, new treatment strategies may improve the clinical outcomes of patients with HR-positive, HER2-negative EBC.

Thus, disclosed herein are methods of treating early breast cancer using the CDK4/6 inhibitor Kisqali® (Riboxil) plus endocrine therapy (ET). The disclosure provides methods of treating patients with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2-) early breast cancer (EBC). The disclosure relies specifically on the results of the NATALEE trial, an aggressive Phase III study of CDK4/6 inhibitors designed to demonstrate consistent benefit in a broad population of patients with Stage II and III HR+/HER2- early breast cancer (EBC) at risk of relapse, including those without lymph node involvement.

The present disclosure is described and exemplified in more detail below.

The present disclosure relates to methods of treating patients with breast cancer (BC). The methods are based, inter alia, on the striking results of the NATALEE clinical trial, which showed that CDK inhibitors combined with endocrine therapy can provide beneficial effects in patients with early-stage breast cancer, such as hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) early-stage breast cancer. A.   Treatment of Early-stage Breast Cancer

One aspect of the disclosure relates to a method of treating breast cancer in an adult patient in need thereof, the method comprising administering to the patient a therapy comprising a combination of a cyclin-dependent kinase (CDK) inhibitor and an endocrine therapy, wherein the breast cancer is early breast cancer (EBC).

EBC is characterized by the localization of cancer cells in breast tissue and regional lymphatic vessels (e.g., forming a tumor). In EBC, cancer cells are not usually detected outside of the breast or axillary lymph nodes. Early breast cancer may be stage 0, I, II, or III cancer (e.g., stage 0, I, IIA, IIB, IIIA, IIIB, or IIIC). Based on its localization, EBC can be distinguished from advanced breast cancer (also called metastatic cancer), in which the cancer has spread to one or more parts of the body, such as the bones, lungs, liver, etc.

In some embodiments, EBC is a breast cancer, such as an adenocarcinoma. EBC may be an invasive cancer. Invasive cancer, also called invasive or invasive ductal carcinoma (IDC), is a type of breast cancer that starts in the milk ducts of the breast and moves into nearby tissues. Over time, IDC can spread (metastasize) to other parts of the body via the lymph nodes or bloodstream. EBC may be a non-invasive cancer, such as ductal carcinoma in situ (DCIS). DCIS may spread in the breast along the milk ducts but will not spread outside the ductal system.

Signs and/or symptoms of early breast cancer may be one or more of the following: a lump in the breast or armpit, thickening or swelling of part of the breast, irritation or dimpling of the breast skin (e.g., peau dimpling), redness or scaly skin in the nipple area of the breast, nipple pulling or pain in the nipple area, nipple discharge (other than breast milk, but including blood), any change in the size or shape of the breast, and/or pain in any part of the breast. Other signs and/or symptoms of early breast cancer may include: the presence of one or more breast cancer cells; the presence of a breast cancer tumor; or the presence of biochemical or genetic markers in a patient's tissues or fluids that indicate the presence of breast cancer (e.g., breast cancer biomarkers in a tissue biopsy or blood sample). The presence of breast cancer may be physically present and may be detected using tests such as ultrasound, mammogram, magnetic resonance imaging, analysis of tissue samples (e.g., biopsy), and/or analysis of body fluid samples (e.g., blood samples). Any known test may be used to detect signs and/or symptoms of cancer. When there are no detectable signs and/or symptoms of cancer, the term "no evidence of disease" (NED or NEOD) may be used.

Breast cancer can be graded based on its histology. Histological grade (or "grade") can refer to the extent to which cancer cells are different from normal cells, which can be distinguished, for example, by how differentiated the cells are. Grade 1 refers to breast cancer cells that are similar to normal breast cells and usually grow slowly. Grade 2 refers to breast cancer cells that may not be similar to normal breast cells and grow rapidly. Grade 3 refers to breast cancer cells that are not similar to normal breast cells and usually grow rapidly. Grade 4 refers to breast cancer cells that are the least similar to normal breast cells and grow and spread faster than lower grade tumors.

Breast cancer is classified according to a staging method. Staging can be pathological (for example, based on a pathologist's study of tumor tissue and any lymph nodes removed during surgery) or clinical (for example, based on a clinician's physical examination, tests, and/or imaging tests).

In general, staging is used to classify breast cancer according to the size of the cancer (such as the primary tumor) and how far the cancer has spread in the body.

One method used to classify breast cancer or tumors according to their stage is the TNM classification or staging method. Using this method, a tumor may be classified as T0 when there is no evidence of tumor, while a classification of T1, T2, T3, or T4 may be used to label the size and invasion of the tumor. Tx may indicate that the tumor cannot be evaluated. N (node) describes the extent to which the cancer has spread to nearby lymph nodes. A tumor may be classified as N0 when it has not spread to the local lymph nodes, while a classification of N1-N3 may be used to indicate lymph node spread.

M (metastatic) describes metastasis (e.g., spread of cancer to other parts of the body). A tumor may be classified as M0 when there is no distant metastasis and as M1 when there is evidence of distant metastasis (Rosen and Sapra, TNM Classification, StatPearls Publishing; Treasure Island (FL), January 2023).

In breast cancer, T1 may be defined as a tumor that is 20 mm or less in diameter. T1a may be defined as a tumor that is larger than 1 mm but not larger than 5 mm in greatest dimension; T1b may be defined as a tumor that is larger than 5 mm but not larger than 10 mm in greatest dimension; and T1c may be defined as a tumor that is larger than 10 mm but not larger than 20 mm in greatest dimension. T2 may be defined as a tumor that is larger than 20 mm but not larger than 50 mm in greatest dimension. T3 may be defined as a tumor that is larger than 50 mm in greatest dimension. T4 may be defined as a tumor of any size that has directly invaded the chest wall and/or skin (e.g., an ulcer or skin nodule). T4a may be invasion of the chest wall. T4b may be defined as edema or ulceration of the skin of the breast, or a satellite nodule of the skin confined to the same breast. T4c may be defined as both T4a and T4b. T4d may be defined as an inflammatory cancer, for example, a cancer characterized by diffuse erythema and edema involving approximately one third or more of the breast skin.

Regional lymph nodes near the breast may include one or more of the following: (1) axillary lymph nodes, interpectoral lymph nodes (Rotter nodes), and lymph nodes along the axillary vein and its branches. Axillary lymph nodes may be level I (lower axillary), level II (middle axillary), or level III (upper axillary); (2) internal mammary lymph nodes; (3) supraclavicular lymph nodes; and (4) internal mammary lymph nodes.

For cancer that has or may have spread to the lymph nodes, N0 means the cancer has not spread to nearby lymph nodes; N1 means the cancer has spread to 1-3 axillary lymph nodes and/or the cancer has been found in an internal mammary lymph node during sentinel lymph node biopsy; N2 means the cancer has spread to 4-9 axillary lymph nodes or has caused enlargement of the internal mammary lymph nodes; and N3 means the cancer has spread to 10 or more axillary lymph nodes, with at least one cancer spread larger than 2 mm, or has spread to the subclavian lymph nodes, with at least one cancer spread larger than 2 mm, or has been found in at least one axillary lymph node, with at least one cancer spread larger than 2 mm. mm) and has enlarged internal mammary lymph nodes, or has spread to 4 or more axillary lymph nodes (at least one of which is larger than 2 mm) and has spread to the internal mammary lymph nodes on a sentinel lymph node biopsy, or has spread to the supraclavicular lymph nodes on the same side of the cancer with at least one cancer larger than 2 mm.

Lymph node classification can be clinical or pathological. Clinical classifications may include cN1, which is defined as metastasis to the ipsilateral level I and II axillary lymph nodes; cN2a, which is defined as metastasis to the ipsilateral level I and II axillary lymph nodes that are fixed to each other (matted); and cN2b, which is defined as metastasis only to the clinically detected ipsilateral internal mammary lymph nodes, and no clinically obvious level I and II axillary lymph nodes. cN3a is defined as metastasis to the ipsilateral infraclavicular (level III axillary) lymph nodes with or without involvement of level I or II axillary lymph nodes; cN3b is defined as metastasis to clinically detected ipsilateral internal mammary lymph nodes and clinically evident axillary lymph nodes; or cN3c is defined as metastasis to the ipsilateral supraclavicular lymph nodes with or without involvement of axillary or internal mammary lymph nodes.

An addition to the TMN classification system is the R classification system, or residual tumor classification system, which can be used to indicate the status of the tumor after treatment. The R classification can indicate how well treatment is working and can be used to predict prognosis. For example, a patient may be diagnosed with a tumor that is classified using the TMN classification system, then treated, and any residual tumor may then be classified according to the R classification system. Using this system, the extent of the tumor resection can be classified as R0, R1, or R2. In R0, there is no residual tumor after surgery, for example, the surgical margins show no residual tumor under a microscope. In R1, there is no residual tumor visible to the naked eye, but the margins under a microscope still show the presence of tumor. In R2, there is still palpable (macroscopic) tumor after surgery.

The TNM classification system predates many of the genetic tests and/or biochemical marker (or “biomarker”) tests that are now routinely used to provide additional predictive or prognostic information about cancer type and may be used in conjunction with these and/or other tests to classify cancer. For example, the TNM classification system may be used in combination with tumor grade, estrogen receptor (ER) status, progesterone receptor (PR) status, and human epidermal growth factor receptor 2 (HER2) status. Examples of such combinations are shown in Table 1 of the following reference: Ann Surg Oncol. 2018 Jul;25(7):1783-1785. doi: 10.1245/s10434-018-6486-6. Epub 2018 Apr 18.

An example of a biomarker used in breast cancer is the nuclear antigen Ki-67. Ki-67 levels in breast cancer cells can be measured using, for example, immunohistochemical staining. The anti-human Ki-67 antibody MIB1 can be used for immunohistochemistry. Ki-67 values are calculated as the percentage of positively labeled malignant cells relative to the total number of malignant cells assessed (Breast Cancer Res Treat. 2013; 139(2): 539-552). In general, Ki-67 expression is associated with high levels of cell proliferation (J Clin Oncol. 2005 Oct 1; 23(28): 7212-20).

Genetic tests (such as multi-gene or multi-parameter expression assays) can be used to evaluate the characteristics of breast cancer, risk of metastasis, and/or risk of recurrence. One exemplary test is the Oncotype DX® test, in which a breast recurrence score ≥ 26 (range 0-100) indicates risk of recurrence. In another exemplary test, the Prosigna®/PAM50 (Prediction Analysis of Microarray 50) test classifies tumors as having low, intermediate, or high risk of metastasis based on the expression level of 50 genes in the tumor. Other exemplary tests include, but are not limited to, the MammaPrint®, EndoPredict®, and Breast Cancer Index® tests, which can be used to determine a risk score for cancer recurrence.

Another way to classify tumors is the "stage group" classification system. This method, which can be used alone or with the TNM classification system and other tests, divides breast cancer into anatomical stage groups (or "stages"). Therefore, breast cancer can be classified according to stage groups (or "anatomical stage groups") 0, I, II, III, or IV. Specifically, the stage group can be 0, Ia, Ib, IIa, IIb, IIIa, IIIb, IIIC, or IV.

Stage 0: Stage zero (0) may describe disease that is confined to the ducts of the breast tissue and has not spread to tissue surrounding the breast. It is also called noninvasive or carcinoma in situ (Tis, N0, M0).

Stage IA can refer to a tumor that is small, aggressive, and has not spread to the lymph nodes (T1, N0, M0).

Stage IB can refer to cancer that has spread to the lymph nodes, and the cancer in the lymph nodes is larger than 0.2 mm but not larger than 2 mm. There may be no evidence of a breast tumor, or the breast tumor is 20 mm or smaller (T0 or T1, N1mi (also called "N1 micrometastasis"), M0).

Stage IIA can refer to cancer that meets any of the following conditions: a. There is no evidence of a breast tumor, but the cancer has spread to 1-3 axillary lymph nodes. It has not spread to distant parts of the body (T0, N1, M0). b. The tumor is 20 mm or smaller and has spread to 1-3 axillary lymph nodes (T1, N1, M0). c. The tumor is larger than 20 mm but not larger than 50 mm and has not spread to axillary lymph nodes (T2, N0, M0).

Stage IIB can refer to any of the following: a. The tumor is larger than 20 mm but not larger than 50 mm and has spread to 1-3 axillary lymph nodes (T2, N1, M0). b. The tumor is larger than 50 mm but has not spread to the axillary lymph nodes (T3, N0, M0).

Stage IIIA can refer to a tumor of any size that has spread to 4-9 axillary lymph nodes or internal mammary lymph nodes. It has not spread to other parts of the body (T0, T1, T2, or T3; N2; M0). Stage IIIA can also refer to a tumor that is larger than 50 mm and has spread to 1-3 axillary lymph nodes (T3, N1, M0).

Stage IIIB can refer to a tumor that has spread to the chest wall or caused swelling or ulcers in the breast, or is diagnosed as inflammatory breast cancer. It may or may not have spread to up to 9 axillary or internal mammary lymph nodes. It has not spread to other parts of the body (T4; N0, N1, or N2; M0).

Stage IIIC can refer to a tumor of any size that has spread to 10 or more axillary lymph nodes, internal mammary lymph nodes, and/or subclavian lymph nodes. It has not spread to other parts of the body (any T, N3, M0).

Stage IV (metastatic) can refer to a tumor of any size that has spread to other organs, such as the bones, lungs, brain, liver, distant lymph nodes, or chest wall (any T, any N, M1). About 6% of metastatic cancers are discovered when the cancer is first diagnosed. This may be called de novo metastatic breast cancer. Most often, metastatic breast cancer is discovered after an earlier diagnosis of early-stage breast cancer.

Recurrent cancer is cancer that has returned after treatment and can be described as local, regional, and/or distant (Breast Cancer: Staging, from Cancer.Net).

Recurrence may be evaluated by medical imaging and confirmed by histology (or cytology, when applicable). Recurrence may be classified as local, regional, or distant recurrence, or as contralateral invasive breast cancer or a second primary non-breast invasive cancer, based on the following guidelines: -   Locally invasive breast cancer recurrence or ipsilateral invasive breast tumor recurrence: Invasive breast cancer involving the same breast as the primary tumor. Ductal and lobular carcinoma in situ and tumors in the contralateral breast and/or contralateral lymph nodes are not considered locally invasive recurrences. Confirmed by histology. -   Regional breast cancer recurrence: Invasive breast cancer in the ipsilateral axilla, regional lymph nodes (all grades), chest wall, or skin of the ipsilateral breast. Tumors in the contralateral breast are not considered regional recurrences. They may be confirmed by histology (preferably) or cytology. -   Distant recurrence: Distant metastasis of breast cancer (bone, distant lymph nodes, visceral organs, CNS, bone marrow, etc.) or any non-local or regional site of invasive breast cancer recurrence. Distant recurrence may be confirmed by histology (preferably) or cytology. o  If bone metastasis is confirmed by bone scan, it may be confirmed by histology (preferably) or radiological imaging (CT, MRI, or FDG-PET-CT) if it cannot be confirmed by biopsy. o  Central nervous system metastases may be confirmed by histology (preferably), cytology, or radiographic imaging (CT or MRI, both with intravenous (IV) contrast) if not confirmed by biopsy. o  All other sites of metastasis may be confirmed by histology (preferably) or cytology unless this procedure would present an unacceptable risk to the patient. -   Contralateral invasive breast cancer: Any invasive breast cancer in the contralateral breast, with or without contralateral lymph node involvement. Contralateral invasive breast cancer must be confirmed by histology. In situ/noninvasive contralateral breast cancer is not included in contralateral invasive breast cancer. - Second primary non-breast invasive cancer: Any second primary non-breast invasive cancer. Second primary non-breast invasive cancers must be confirmed by histology. Carcinoma in situ/non-invasive and basal cell or squamous cell carcinomas of the skin are not considered second primary non-breast invasive cancers.

Table B1 summarizes the anatomical staging groups of the 8th edition of the AJCC [ Table B1 ] Anatomical staging group T- Class N- Category 0 Tis N0 I A T1 N0 IB T0-1 N1mi IIA T0-1 N1 T2 N0 IIB T2 N1 T3 N0 IIIA T0-3 N2 T3 N1 IIIB T4 N0-2 IIIC Any T N3 IV T1-T3 N1-N3 Note that T2, T3, and T4 tumors with lymph node micrometastasis (N1mi) may be staged using the N1 category.

Thus, in some embodiments, the EBC suffered by the adult patient treated using the methods described herein is ductal carcinoma in situ, stage I breast cancer, stage II breast cancer (such as stage IIA breast cancer or stage IIB breast cancer), or stage III breast cancer (such as stage IIIA, stage IIIB, or stage IIIC breast cancer). In some embodiments, the patient has stage II or stage III early breast cancer. In some embodiments, the patient has stage IIA cancer or stage IIB cancer. In some embodiments, the patient has stage IIIA cancer, stage IIIB cancer, or stage IIIC cancer. The patient may be lymph node positive (e.g., cancer has spread to their lymph nodes) or lymph node negative (e.g., cancer has not spread to their lymph nodes). In some embodiments, the treatment methods described herein are performed without regard to the lymph node status of the patient's breast cancer.

In some embodiments, the EBC is a hormone receptor positive (HR+) breast cancer, for example, a breast cancer comprising cells expressing one or more types of hormone receptors. Exemplary hormone receptors can be estrogen receptors (ER), such as ERα or ERβ, and/or progesterone receptors (PR), such as PRA and PRB. The EBC may comprise breast cancer cells expressing estrogen receptors (ER+) or progesterone receptors (PR+) or a combination of estrogen receptors and progesterone receptors (ER+/PR+). In some embodiments, the EBC is ER+/PR-, ER-/PR+, or ER+/PR+.

In certain embodiments, the EBC is human epidermal growth factor receptor 2 (HER2) positive.

Certain embodiments relate to a method for preventing or alleviating signs or symptoms of early breast cancer, the method comprising administering to a patient a treatment comprising reboxil, its free base form or a pharmaceutically acceptable salt thereof in combination with an aromatase inhibitor, preferably letrozole or anastrozole. In some embodiments, reboxil is in its free base form or a pharmaceutically acceptable salt thereof and is administered to the patient on days 1-21 of a 28-day cycle in an amount ranging from 150 mg/day to 450 mg/day. In some embodiments, the aromatase inhibitor is administered daily in a 28-day cycle. B.   CDK inhibitors and endocrine therapy

One aspect of the disclosure relates to a method of treating early-stage breast cancer in an adult patient in need thereof, the method comprising administering to the patient a therapy comprising a combination of a cyclin-dependent kinase (CDK) inhibitor and an endocrine therapy (ET).

Cyclin-dependent kinases (CDKs) are serine/threonine protein kinases that bind to cyclins in cells to form active complexes. In healthy cells, a variety of extracellular and intracellular signals tightly regulate the formation of CDK/cyclin complexes and control their phosphorylation of target proteins involved in cell cycle, such as retinoblastoma (Rb) protein, nuclear lamina proteins, histone H1, and components of mitotic spindle bodies. However, in cancer cells, CDKs may be overactivated, leading to uncontrolled tumor proliferation.

CDK4 and CDK6, which bind to D-cyclin, are exemplary CDKs that have been shown to promote growth of certain breast cancer tumors. In these tumors, D-cyclin is overexpressed, leading to activation of CDK4 and CDK6, which then leads to phosphorylation of Rb, which releases its inhibition of the E2F transcription factor and causes tumor cells to rapidly progress through the cell cycle (Shah et al., Oncology. 2018 May 15;32(5):216-222).

CDK inhibitors have been shown to block unregulated cell growth and division resulting from CDK overactivation and/or cyclin overexpression. For example, inhibitors of the CDK/cyclin complex, particularly CDK4/6, have been used to treat patients with certain types of cancer. The CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib have been approved by regulatory agencies for the treatment of hormone receptor-positive (HR+ or HR-positive) and human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer (Fassi et al., Science. 2022 Jan 14;375(6577):eabc1495). To date, riboxil has been approved by multiple regulatory agencies, including the U.S. Food and Drug Administration (FDA) and the European Commission. The FDA has approved it in combination with: (1) an AI for the treatment of pre-/perimenopausal or postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer as initial endocrine-based therapy; or (2) fulvestrant for the treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer as initial endocrine-based therapy or after disease progression during ET. In Europe, ribociclib is indicated for the treatment of women with HR-positive, HER2-negative locally advanced or metastatic breast cancer in combination with an AI or fulvestrant as initial endocrine-based therapy or in women who have previously received ET. For premenopausal or perimenopausal women, ET can be combined with a luteinizing hormone-releasing hormone agonist.

Therefore, in some embodiments of the present disclosure, the CDK inhibitor used in the methods disclosed herein can be a CDK4/6 inhibitor, for example, an inhibitor of a CDK4/6/cyclin complex. The cyclin can be a D cyclin, for example, cyclin-D1 in a CDK4/cyclin-D1 complex or cyclin-D3 in a CDK6/cyclin-D3 complex.

In some embodiments, the CDK4/6 inhibitor can be a compound described by the following formula A1 or a salt thereof. (A1)

The compound of formula A1 is known by the international non-patented drug name Riboxil. Therefore, in some embodiments, the CDK4/6 inhibitor can be a compound having the international non-patented name Riboxil.

Reboxili can be in the form of its free base or can be a pharmaceutically acceptable salt of Reboxili. The salt can exist alone or in a mixture with a free compound (such as Reboxili), and is preferably a pharmaceutically acceptable salt. Such Reboxili salts are preferably formed from Reboxili compounds having a basic nitrogen atom with organic or inorganic acids, for example as acid addition salts. Suitable inorganic acids are, for example, hydrohalides, such as hydrochloric acid, sulfuric acid, or phosphoric acid. Suitable organic acids are, for example, succinic acid, carboxylic acid or sulfonic acid, such as fumaric acid or methanesulfonic acid. For the purpose of separation or purification, pharmaceutically unacceptable salts, such as picrates or perchlorates, may also be used. For therapeutic use, only pharmaceutically acceptable salts or free compounds (where applicable in the form of pharmaceutical preparations) are employed and are therefore preferred.

In some embodiments, reboxil can be in the form of racemates, non-mirror isomers, mirror isomers and tautomers, as well as corresponding crystal modifications (if any), such as solvates, hydrates and polymorphs.

Reboxili can be in the form of a pharmaceutically acceptable salt, such as a succinate, such as reboxili succinate. The chemical name of reboxili succinate is succinic acid-7-cyclopentyl- N,N -dimethyl-2-{[5-(piperidin-1-yl)pyridin-2-yl]amino} -7H -pyrrolo[2,3 _- d]pyrimidine-6-carboxamide (1: _{1), corresponding to the molecular formula C27H36N8O5 . Its} relative molecular weight is 552.6 g/mol (EMA evaluation report for Kisqali, procedure number EMEA/H/C/004213/0000, dated June 22, 2017).

Oral tablet forms of Reboxili are known in the art (e.g., WO 2016/166703) and have been approved as the KISQALI® product. Various Reboxili salts have been described (e.g., see claim 85 of WO 2022/207788), and the approved KISQALI® product contains Reboxili succinate. The amount of any salt will be adjusted to provide the desired amount of Reboxili (e.g., 254.40 mg of Reboxili succinate is equivalent to 200 mg of Reboxili). Various polymorphs of Riboxil succinate are known (e.g., see WO 2019/040567, WO 2019/082143, WO 2019/150181, WO 2019/166987, WO 2020/225827, WO 2021/038590, etc.). The methods described herein can be implemented using the approved KISQALI® product, for example, together with an approved endocrine therapy.

As described herein, a CDK inhibitor (e.g., a CDK4/6 inhibitor, such as ribociclib or a pharmaceutically acceptable salt thereof, such as ribociclib succinate) can be administered together with an endocrine therapy. In some embodiments of the present disclosure, the endocrine therapy is an aromatase inhibitor.

Endocrine therapy (also called hormone therapy, hormonal therapy, or hormone treatment) has been used to slow or stop the growth of hormone-sensitive cancers (also called hormone-dependent cancers). Hormone-sensitive tumors express receptors for hormones (such as estrogen and/or progesterone), and the hormones can promote the growth of the cancer. Thus, endocrine therapy refers to treatments that (1) interfere with the effects of hormones on cancer cells and/or (2) block the body's ability to produce hormones.

Exemplary compounds that interfere with the effects of hormones on breast cancer cells are selective estrogen receptor modulators (SERMs), which bind to estrogen receptors and prevent estrogen from binding. SERMs can mimic the effects of estrogen. FDA-approved SERMs for the treatment of breast cancer are tamoxifen (Nolvadex®) and toremifene (Fareston®). Other anti-estrogen drugs may bind to estrogen receptors, but instead of mimicking the effects of estrogen, they may target estrogen receptors for destruction. An exemplary anti-estrogen compound is fulvestrant (Faslodex®).

Hormone production can be blocked by ablating the tissue or organ that produces the hormone. For example, in premenopausal women, in whom the ovaries are the main source of estrogen, ovarian ablation (for example, by ovarian removal (also called oophorectomy or oophorectomy) or radiation therapy) can be done to remove or lower estrogen levels.

Alternatively, hormone production can be blocked by administering compounds that inhibit hormone synthesis and/or release. Long-term administration of gonadotropin-releasing hormone (GnRH) agonists may lead to desensitization, thereby inhibiting gonadotropin secretion. In contrast, GnRH antagonists inhibit GnRH signaling and gonadotropin secretion (Reprod Biomed Online [Reproductive Biomedicine Online]. 2002; 5 Supplement 1: 1-7. doi: 10.1016/s1472-6483(11)60210-1). Exemplary GnRH agonists are goserelin (Zoladex®) and leuprorelin (Lupron®), which inhibit the release of estrogen in female ovaries and inhibit the release of testosterone in male testicles. In some embodiments, goserelin is used in the methods disclosed herein.

Another class of compounds that block estrogen production are specifically aromatase inhibitors. Aromatase inhibitors work by inhibiting the action of aromatase, which converts androgens to estrogen through a process called aromatization. Of note, in premenopausal women, the ovaries produce too high levels of aromatase to be blocked by aromatase inhibitors alone. For premenopausal women, aromatase inhibitors may be combined with compounds that inhibit ovarian function (e.g., goserelin or leuprolide). In contrast, postmenopausal women produce estrogen primarily in peripheral tissues rather than in the ovaries, so aromatase inhibitors may be sufficient to suppress estrogen production in these women.

There are two types of aromatase inhibitors: (1) steroidal inhibitors, such as exemestane (Aromasin®), which form a permanent, inactivating bond with aromatase; and (2) nonsteroidal inhibitors (NSAIs), such as anastrozole (Arimidex®) or letrozole (Femara®).

Letrozole is a nonsteroidal competitive inhibitor of the aromatase system. It works by highly selectively inhibiting the conversion of androgens (which are primarily derived from the adrenal glands and are the main source of estrogen in postmenopausal women) to estrogens. Two weeks of treatment with letrozole at a daily dose of 0.1 to 5 mg induces a 75% to 95% decrease in estrogen levels without significant clinical and laboratory toxicity or changes in levels of other hormones in the endocrine system (Lancet London Engl 386:1341-1352, 2015; Cancer 75:2132-2138, 1995).

Anastrozole, like letrozole, is a selective NSAI that significantly reduces serum estradiol concentrations without any detectable effect on adrenal cortical steroids or aldosterone formation.

In some embodiments, the endocrine therapy administered with a CDK inhibitor (e.g., a CDK4/6 inhibitor, such as ribociclib or a pharmaceutically acceptable salt thereof, such as ribociclib succinate) is an aromatase inhibitor, such as anastrozole or letrozole. In some embodiments, the therapy further comprises a gonadotropin-releasing hormone agonist, such as goserelin.

Exemplary aromatase inhibitors are described in Breast Cancer Res Treat 2007 Oct; 105(Suppl 1):7-17.

The aromatase inhibitor may be a non-steroidal aromatase inhibitor described by one of the following formulae or a pharmaceutically acceptable salt thereof. Formula (B1) Formula (C1) Formula (D1) Formula (E1)

In some embodiments, the aromatase inhibitor can be letrozole. The aromatase inhibitor can be a pharmaceutically acceptable salt of letrozole. The chemical name of letrozole is 4,4'-(1H-1,2,4-triazol-1-ylmethylene)dibenzonitrile. Letrozole is freely soluble in dichloromethane, slightly soluble in ethanol, and almost insoluble in water. Its molecular weight is 285.31 g/mol, its empirical formula is C ₁₇ H ₁₁ N ₅ , and its melting point ranges from 184°C to 185°C.

In some embodiments, letrozole may be in the form of a racemate, a non-mirror isomer, a mirror isomer or a tautomer, as well as corresponding crystal modifications (if any), such as solvates, hydrates and polymorphs.

In some embodiments, the aromatase inhibitor can be anastrozole or a pharmaceutically acceptable salt thereof. The chemical name of anastrozole is α,α,α',α'-tetramethyl-5-(1H-1,2,4-triazol-1-ylmethyl)-isophthalic diacetonitrile. Anastrozole is freely soluble in methanol, acetone, ethanol and tetrahydrofuran, and is very soluble in acetonitrile. Its molecular weight is 293.374 g/mol, its empirical formula is C ₁₇ H ₁₉ N ₅ , and its melting point ranges from 80°C to 86°C. In some embodiments, anastrozole can be in the form of a solvate, a hydrate or a polymorph.

In some embodiments, endocrine therapy may include an aromatase inhibitor (e.g., letrozole or anastrozole) for postmenopausal women. For premenopausal women or men, endocrine therapy may include an aromatase inhibitor (e.g., letrozole or anastrozole) and may further include a compound that suppresses gonadal function (e.g., a GnRH agonist such as goserelin).

The GnRH agonist may be a compound according to the following formula or a pharmaceutically acceptable salt thereof: Formula (F1)

In some embodiments, the aromatase inhibitor can be goserelin or a pharmaceutically acceptable salt thereof. Goserelin is sold under the trade name Zoladex®. Its molecular weight is 1269.433 g/mol and its empirical formula is C ₅₉ H ₈₄ N ₁₈ O ₁₄ . In some embodiments, goserelin can be in the form of a solvate, a hydrate, or a polymorph. C. Administration - Dosage and Treatment Schedule

Another aspect of the disclosure relates to a method of treating early-stage breast cancer in an adult patient in need thereof, the method comprising administering to the patient a therapy comprising a dose of a cyclin-dependent kinase (CDK) inhibitor in combination with a dose of an endocrine therapy.

In some embodiments, the CDK inhibitor is a CDK4/6 inhibitor, such as ribociclib or a pharmaceutically acceptable salt thereof (such as ribociclib succinate), and the endocrine therapy is an aromatase inhibitor, such as letrozole. In some embodiments, the endocrine therapy is letrozole.

In clinical trials in patients with advanced BC, riboxil at a dose of 600 mg/day on days 1 to 21 of a 28-day cycle has been shown to be tolerable and effective when combined with ET (N Engl J Med 375:1738-1748, 2016). However, because HR-positive, HER2-negative EBC may relapse later, with events that may occur as early as one year after surgery and may persist for at least 15 years after diagnosis, longer durations of treatment may also be beneficial for EBC. In some embodiments, riboxil (in combination with ET) may be administered at doses lower than 600 mg/day. For example, riboxil (or a pharmaceutically acceptable salt thereof, such as riboxil succinate) may be administered at a dose of about 400 mg/day. This exemplary dosage may be administered at 2 x 200 mg/day.

In some embodiments, reboxili (or a pharmaceutically acceptable salt thereof, such as reboxili succinate) can be administered at a dose of about 400 mg/day. The dose of reboxili or a pharmaceutically acceptable salt thereof (such as reboxili succinate) can be administered once a day in the form of a tablet, for example, as 2 x 200 mg tablets (it should be understood that the two tablets can be taken simultaneously or sequentially in a single daily dosing). The dose can be administered as an oral solution. The dose can be administered orally (by mouth). In some embodiments, the dose of reboxili (or a pharmaceutically acceptable salt thereof, such as reboxili succinate) is about 200 mg/day. This dose can be administered in the form of a tablet (e.g., 1 x 200 mg tablet). The dose can be administered orally (by mouth). The dose may be a flat fixed dose, for example not based on body weight or body surface area.

For example, dosage adjustments can be made to administer less than about 400 mg/day of reboxili or a pharmaceutically acceptable salt thereof (e.g., reboxili succinate). For example, about 350 mg/day, about 300 mg/day, about 250 mg/day, about 200 mg/day, or about 150 mg/day of reboxili or a pharmaceutically acceptable salt thereof (e.g., reboxili succinate) can be administered. In some embodiments, a dose of about 200 mg/day is administered after an earlier dose of 400 mg/day has been administered. In some embodiments, the dose is administered in tablet form (e.g., 1 x 200 mg tablet). A dose of about 200 mg/day can be administered orally. Thus, patients who have previously received a dose of about 400 mg of ribociclib or a pharmaceutically acceptable salt thereof (e.g., ribociclib succinate) (e.g., 2 x 200 mg tablets taken orally) can be switched to receiving a dose of about 200 mg/day (e.g., 1 x 200 mg tablet taken orally). The dose can be taken once daily (e.g., 1 x 200 mg tablet once daily, or 2 x 200 mg tablets once daily).

For patients who are intolerant to a dose of about 400 mg/day, a dose adjustment may be made. For example, a patient who receives a dose of about 400 mg/day of ribociclib (or a pharmaceutically acceptable salt thereof, such as ribociclib succinate) and develops one or more of thrombocytopenia, decreased absolute neutrophil count (ANC), febrile neutropenia, anemia, hepatotoxicity (e.g., as indicated by bilirubin levels and/or AST and ALT enzyme levels), drug-induced liver injury, cardiac abnormalities (e.g., as measured by QT interval), interstitial lung disease/pneumonitis, and/or other adverse events may receive an adjusted dose of about 200 mg/day of ribociclib (or a pharmaceutically acceptable salt thereof, such as ribociclib succinate).

Therefore, the dosage of reboxili (or a pharmaceutically acceptable salt thereof, such as reboxili succinate) may range from about 150 mg/day to about 450 mg/day. The dosage may be about 150 mg/day, about 200 mg/day, about 250 mg/day, about 300 mg/day, about 350 mg/day, or about 450 mg/day. The dosage may be taken once daily.

In some embodiments, the dose of reboxili (or a pharmaceutically acceptable salt thereof, e.g., reboxili succinate) is not about 600 mg/day.

In some embodiments, the aromatase inhibitor is letrozole. The dose of letrozole can be selected based on data indicating the patient's disease-free survival (e.g., clinical data; which can be combined with data on adverse reactions (e.g., renal and/or hepatic impairment)) to determine an effective dose. The dose can be selected by testing the efficacy and tolerability of individual patients.

The dosage of letrozole can range from about 1 mg/day to about 4 mg/day. For example, the dosage of letrozole can be about 1 mg/day, about 1.25 mg/day, about 1.5 mg/day, about 1.75 mg/day, about 2 mg/day, about 2.25 mg/day, about 2.5 mg/day, about 2.75 mg/day, about 3 mg/day, about 3.25 mg/day, about 3.5 mg/day, about 3.75 mg/day, or about 4 mg/day. In some embodiments, the dosage of letrozole is about 2.5 mg/day. The dosage can be a stable fixed dosage, such as not calculated by body weight or body surface area.

The dosage of letrozole can be administered orally (e.g., by mouth). Thus, any dosage described above can be administered, such as a dosage of about 2.5 mg/day of letrozole. The dosage of letrozole can be administered orally. The dosage can be administered in the form of a tablet. The dosage can be taken once daily.

In certain embodiments, the aromatase inhibitor is anastrozole. The dose of anastrozole can be selected based on data indicating the patient's disease-free survival (e.g., clinical data; which can be combined with data on adverse reactions (e.g., renal and/or hepatic impairment)) to determine an effective dose. The dose can be selected by testing the efficacy and tolerability of individual patients.

The dosage of anastrozole ranges from about 0.5 mg/day to about 1.5 mg/day. For example, the dosage of anastrozole can be about 0.5 mg/day, about 0.75 mg/day, about 1 mg/day, about 1.25 mg/day, or about 1.50 mg/day. In some embodiments, the dosage of anastrozole is about 1 mg/day.

The dosage of anastrozole can be administered orally (e.g., by mouth). Thus, any dosage described above can be administered, such as an dosage of anastrozole of about 1 mg/day. The dosage of anastrozole can be administered orally. The dosage can be administered in the form of a tablet. The dosage can be taken once daily.

In addition to reboxili (or a pharmaceutically acceptable salt thereof, such as reboxili succinate) (e.g., about 400 mg/day or about 200 mg/day) and letrozole (about 2.5 mg/day) or anastrozole (about 1 mg/day), the patient may also receive a gonadotropin-releasing hormone agonist, such as goserelin. For example, premenopausal female patients and male patients may receive a dose of goserelin. The dose of goserelin may be selected based on data (e.g., clinical data) indicating efficacy in patients or by testing efficacy and tolerability in individual patients.

The dosage of goserelin can range from about 2 mg to about 5 mg. The dosage of goserelin can be about 2 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3 mg, about 3.25 mg, about 3.5 mg, about 3.75 mg, about 4 mg, about 4.25 mg, about 4.5 mg, about 4.75 mg, or about 5 mg. In some embodiments, the dosage of goserelin is about 3.4 mg, 3.5 mg, 3.6 mg, or 3.7 mg. In some embodiments, the dosage of goserelin is 3.6 mg. The dosage can be a stable fixed dosage, for example, not calculated by body weight or body surface area.

The dose of goserelin can be administered subcutaneously. The dose can be administered subcutaneously at intervals ranging from 2 weeks to 4 weeks.

In one embodiment, goserelin is administered subcutaneously in a dose of 3.6 mg.

The compounds may be administered separately, for example, when the compounds are administered by different routes of administration and/or according to different treatment schedules. If administered separately, the compounds may be administered simultaneously or sequentially. In an illustrative example, two compounds are administered to a patient in two separate doses, but on the same day as one another. In this example, the two compounds may be administered simultaneously, or may be administered at different times. The compounds may be administered separately in two or more separate unit doses (e.g., where a unit dose is the amount of the compound administered to a patient in a single dose) and/or unit dosage forms.

The compounds can be administered together in combination. The compounds can be administered together in a single pharmaceutical composition, for example, the compounds can be administered together in a single dose (eg, a unit dose). The unit dosage form can also be a fixed combination.

In some embodiments, a dose of ribociclib (or a pharmaceutically acceptable salt thereof, such as ribociclib succinate) (about 400 mg/day or about 200 mg/day) and a dose of endocrine therapy (e.g., letrozole (a dose of about 2.5 mg/day) or anastrozole (a dose of about 1 mg/day)) are administered together. Typically, the dose can be administered at the same time each day, such as in the morning. The dose can be administered in the afternoon or evening. In some embodiments, the dose is not administered in the evening.

Another aspect of the disclosure relates to a method of treating early-stage breast cancer in an adult patient in need thereof, the method comprising administering to the patient a therapy comprising a dose of a cyclic protein-dependent kinase (CDK) inhibitor in combination with a dose of an endocrine therapy according to a treatment schedule.

In some embodiments, the treatment schedule includes a treatment cycle of about 28 days. In this cycle, the CDK inhibitor can be administered once daily on days 1 to 21 of the 28-day cycle, followed by a 7-day discontinuation of the CDK inhibitor, during which the endocrine therapy is continued to be administered once daily. Thus, endocrine therapy (e.g., letrozole or anastrozole) can be administered every day of the 28-day cycle.

Thus, in some embodiments, the CDK inhibitor is ribociclib (or a pharmaceutically acceptable salt thereof, such as ribociclib succinate) administered at a dose of about 400 mg/day (or about 200 mg/day), and the endocrine therapy is letrozole administered at a dose of about 2.5 mg/day or anastrozole administered at a dose of about 1 mg/day, wherein the ribociclib (or a pharmaceutically acceptable salt thereof, such as ribociclib succinate) is administered once daily on days 1 to 21 of a 28-day cycle, and then ribociclib (or a pharmaceutically acceptable salt thereof, such as ribociclib succinate) is discontinued for 7 days (days 22-28 of the cycle), and letrozole or anastrozole is administered continuously once daily during the 28-day period (e.g., every day of the 28-day cycle). Reboxili (or a pharmaceutically acceptable salt thereof, such as reboxili succinate) can be administered orally, for example, in the form of tablets. Letrozole or anastrozole can be administered orally, for example, in the form of tablets.

For patients where the treatment further comprises administration of goserelin (e.g., at a dose of about 3.6 mg), it may be administered once in a 28-day cycle. Goserelin may be administered once every 2-4 weeks (e.g., every 4 weeks). In some embodiments, goserelin is administered on day 1 (± 3 days) of each 28-day cycle. Goserelin may be administered on day -3, day -2, day -1, day 1, day 2, or day 3 of a 28-day cycle.

Treatment can be administered for at least about 12 months. Treatment can be administered for at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 42 months, at least about 48 months, at least about 54 months, at least about 60 months, or longer. In some embodiments, ribociclib and letrozole are administered for at least about 48 months (about 4 years) or at least about 60 months (about 5 years). In some embodiments, treatment is administered for at least 36 months.

Exemplary dosage and treatment schedules are shown in Table B1.1. [Table B1.1]. Exemplary dosage and treatment schedules Experimental treatment Drug forms and routes of administration Dosage Frequency and / or schedule Riboxil (LEE011 200 mg) Oral tablets 400 mg Once daily on days 1 to 21 of each 28-day cycle Letrozole 2.5 mg Oral tablets 2.5 mg Give continuously once a day Anastrozole 1 mg Oral tablets 1 mg Give continuously once a day Goserelin 3.6 mg Implants, in prefilled syringes and for subcutaneous use 3.6 mg Days 1 ± 3 of each 28-day cycle

In some embodiments, the patient has not received a loading dose prior to treatment. In some embodiments, the patient has received a loading dose prior to treatment. For example, the patient may have received a loading dose of ribociclib (e.g., or a ribociclib salt, such as ribociclib succinate) and/or an endocrine therapy (e.g., letrozole or anastrozole).

A loading dose can be an initial dose of a drug that can be given at the beginning of or before the start of a course of treatment and then stepped down to a different, typically lower dose (e.g., a therapeutic or maintenance dose). A loading dose can be a single dose or a short-term regimen of a compound administered to a subject to rapidly increase the blood concentration level of a drug. Suitably, the short-term regimen used herein will be: 1 to 14 days; e.g., 1 to 7 days; e.g., 1 to 3 days; e.g., three days; e.g., two days; e.g., one day. In some embodiments, a "loading dose" can increase the blood concentration of a drug to a therapeutically effective level. In some embodiments, a "loading dose" can be combined with a therapeutic dose of a drug to increase the blood concentration of a drug to a therapeutically effective level. A "loading dose" can be administered once a day, or more than once a day (e.g., up to 4 times a day). In some embodiments, a loading dose can be used for drug molecules that have a long half-life or slow elimination in the body.

In some embodiments, treatment continues until the patient has no remaining signs and/or symptoms of breast cancer. In some embodiments, treatment continues until the patient has no detectable cancer and/or no signs (e.g., indications) of a recurrence of the cancer. In some embodiments, treatment is restarted if the patient exhibits one or more signs of a recurrence of the cancer. In some embodiments, treatment continues until the cancer recurs. Signs and/or symptoms of cancer and cancer recurrence can be determined by monitoring the patient in the months and years following treatment using tests such as physical examinations, scans and/or imaging of the cancer site (e.g., X-rays, CT scans, mammograms), and blood tests. In an illustrative example, the different follow-up modalities may be mammography, clinical examination, whole-body or local MRI, and/or CT scans. According to guidelines from the National Cancer Information Network, breast cancer patients may have (1) a history and physical examination 1-4 times per year for 5 years, as clinically indicated, (2) a mammogram every 12 months, and (3) no laboratory or imaging tests to screen for metastases in the absence of clinical signs and symptoms suggestive of recurrent disease. When cancer is not detected, the patient may be presumed to be treated, but observation for disease recurrence is necessary.

In some embodiments, treatment as disclosed herein may be administered to patients who no longer have detectable signs and/or symptoms of cancer but may still be at risk of cancer recurrence. Such patients may be treated for a period of time, such as a time range of at least about 3 months to at least about 10 years, such as 3 months, 6 months, 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, or 10 years or any time period therebetween. During this period, the patient may be monitored for cancer recurrence, such as based on clinical examination, mammography, scanning, imaging, sample collection (e.g., tissue biopsy), and/or blood tests. Patients who have no detectable signs and/or symptoms of cancer during this time period may stop treatment as described herein. In some embodiments, the patient may continue treatment for another period of time. In some embodiments, patients whose cancer relapses can stop treatment, for example, to try another treatment option. D.   Patients

Another aspect of the disclosure relates to a method of treating early-stage breast cancer in an adult patient in need thereof, the method comprising administering to the patient a therapy comprising a cyclic protein-dependent kinase (CDK) inhibitor in combination with an endocrine therapy, wherein the adult patient is selected or characterized according to one or more criteria.

Criteria may involve patient demographics, characteristics of the patient's early breast cancer (e.g., type, stage, grade, hormone receptor status, etc.), prior treatment, and/or other criteria described herein. I.    Age

In some embodiments, the patient is an adult, such as 18 years of age or older. In some embodiments, the patient is between about 18 and about 45 years of age. In some embodiments, the patient is between about 45 and about 54 years of age. In some embodiments, the patient is between about 55 and about 64 years of age. In some embodiments, the patient is about 64 years of age or older. The patient may belong to an age category that is younger than the median age of a given EBC patient population, or alternatively, the patient may belong to an age category that is greater than or equal to the median age of the EBC patient population. II.   Gender and Menopausal Status

In some embodiments, the patient is female. In other embodiments, the patient is male. For female patients, the patient's menopausal status may be premenopausal. Alternatively, the female patient's menopausal status may be postmenopausal.

Patients in the postmenopausal state were defined as (1) patients who had undergone bilateral oophorectomy; (2) patients who were 60 years of age or older; (3) patients who were younger than 60 years of age and had been amenorrhea for 12 months or longer (in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression) and whose follicle-stimulating hormone (FSH) and plasma estradiol were within the postmenopausal range based on local normal ranges; or (4) patients who were younger than 60 years of age and were taking tamoxifen or toremifene and whose FSH and plasma estradiol levels were within the postmenopausal range.

Patients who do not meet the criteria for postmenopausal status may be defined as premenopausal. For women in the premenopausal state, amenorrhea may not be a reliable indicator of menopausal status because ovarian function may remain intact or recoverable despite anovulation/amenorrhea. For women with induced amenorrhea with these therapies, serial measurement of FSH and/or estradiol may be used to determine postmenopausal status according to local clinical guidelines. III. Fertility

In some embodiments, the patient is a female of childbearing potential (CBP), defined as being physiologically capable of becoming pregnant.

Women were considered to have CBP unless they had natural (spontaneous) amenorrhea for 12 months or more and had an appropriate clinical profile (i.e., age appropriate, history of vasomotor symptoms) or had undergone surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks before randomization. In the case of oophorectomy alone, women were considered not to have CBP after confirmation by hormone level assessment.

In some embodiments, the patient is a non-pregnant female with CBP.

In some embodiments, the patient is not a pregnant or lactating (lactating) female or a female who plans to become pregnant or lactating during treatment as described herein. IV. Diagnosis of Breast Cancer

In some embodiments, a patient in need of treatment for early-stage breast cancer is a patient who has been diagnosed with early-stage breast cancer. The patient may not have received prior treatment for early-stage breast cancer. The patient may have received prior treatment for early-stage breast cancer, such as surgery, chemotherapy, radiation therapy, and/or hormone therapy, but may still need treatment because the early-stage breast cancer did not respond to prior treatment. In some embodiments, the patient received prior treatment for early-stage breast cancer and the early-stage breast cancer recurred. In some embodiments, the patient received prior treatment for cancer, but the cancer was diagnosed as early-stage breast cancer. In some embodiments, the patient is at risk for developing early-stage breast cancer and/or is at risk for recurrence of early-stage breast cancer. Patients at risk may not have detectable early signs or symptoms of breast cancer but may be at risk due to a previous diagnosis of cancer.

In some embodiments, the patient has received prior treatment for early stage breast cancer (e.g., HR+HER2- Stage II or Stage III early stage breast cancer) and has no detectable signs or symptoms of early stage breast cancer, but is still at risk for recurrence of early stage breast cancer. Risk factors may be associated with the early stage breast cancer that the patient was treated for, with high tumor grade, large tumor size (e.g., greater than 2 mm), and axillary lymph node involvement being associated with a higher risk of recurrence.

In some embodiments, the patient has breast cancer that is diagnosed and/or confirmed (e.g., histologically confirmed) as breast cancer. The cancer may have been diagnosed within 18 months prior to the start of treatment. The cancer may be a unilateral primary invasive adenocarcinoma. The cancer may be a multicentric and/or multifocal tumor. V.   Hormone Receptor (HR) Status and Expression of Human Epidermal Growth Factor Receptor 2 (HER2)

In some embodiments, the patient has hormone receptor positive breast cancer. The breast cancer may be ER and/or PR positive. The breast cancer may be ER+/PR-, ER-/PR+, or ER+/PR+.

In some embodiments, the breast cancer a patient has is a HER2- breast cancer. For example, a breast cancer may be defined as a cancer that has a negative in situ hybridization test result and/or an immunohistochemistry (IHC) status of 0+ or 1+. If the breast cancer has an IHC of 2+, a negative in situ hybridization (FISH, CISH, or SISH) may be used to confirm the HER2- status. VI. Tumor Characteristics

In some embodiments, the patient has breast cancer comprising a tumor belonging to one of the following categories: •   Anatomical stage group III, or •   Anatomical stage group IIB, or •   Anatomical stage group IIA belonging to any of the following: •        N1, or •        N0, where: •      Grade 3, or •      Grade 2.

In some embodiments, there may be additional indicators for classifying breast cancer for patients with tumors belonging to anatomical stage IIA group, N0 and grade 2. For example, the tumor may have a Ki67 percentage of about 20% or greater. In a multi-parameter test, the tumor may have a score that indicates the risk of cancer recurrence and/or spread, for example, a breast recurrence score of ≥ 26 points (on a scale of 0-100) in the Oncotype DX® test, a high risk score in the Prosigna®/PAM50 (Prediction Analysis of Microarray 50) test, a high risk score in the MammaPrint® test, or a high risk score in the EndoPredict® EPclin test.

In some embodiments, the patient has a stage IIA tumor. In some embodiments, the patient has a stage IIB tumor. In some embodiments, the patient has a stage IIIA tumor. In some embodiments, the patient has a stage IIIB tumor. In some embodiments, the patient has a stage IIIC tumor.

In some embodiments, the patient does not have a stage IV tumor, such as a breast cancer tumor that has metastasized distantly beyond the lymph nodes.

In some embodiments, the patient has a tumor with a lymph node status selected from NX, N0, N1, N2, or N3. For example, the patient may have a tumor with an N0 status. Alternatively, the patient may have a tumor with an N1, N2, or N3 status, or a tumor with any of the N1, N2, or N3 statuses.

In some embodiments, the patient has a tumor of the T0 category, Tis category, T1, T2, T3, or T4 category. In some embodiments, the patient has a tumor of the T0 category. The patient may have a tumor of the T1, T2, or T3 category status, or any of the T1, T2, or T3 categories. In some embodiments, the patient has a tumor of the T4 category.

In some embodiments, the patient has a tumor with M stage M0.

In some embodiments, the patient has a tumor with histological grade GX, G1, G2, or G3 (e.g., grade X, grade 1, grade 2, or grade 3). The patient may have a tumor with histological grade 1. The patient may have a tumor with histological grade 2. The patient may have a tumor with histological grade 3.

In certain embodiments, the patient has a tumor with a Ki67 status of less than or equal to 20%. The Ki67 class may be less than or equal to 14%, or the Ki67 class may be greater than 14%. Alternatively, the patient may have a tumor with a Ki67 status of greater than 20%. Ki67 can be measured in an archived sample of a resected tumor from a patient. Ki67 is a proliferation marker in normal and human cell populations that can be used as a clinical marker for breast cancer and a predictive marker for the success of endocrine therapy.

In some embodiments, a patient has a tumor that has been evaluated by a genomic test (e.g., one or more of the Endopredict® test, the Mammaprint® test, the Oncotype DX® test, the Prosigna/PAM50® test, and the Breast Cancer Index® test). The patient may have a risk score for one or more tests that indicates a high risk of cancer recurrence and/or metastasis.

In some embodiments, the tumor has an EndoPredict EPclin® risk score indicating a high risk. In some embodiments, the tumor has a Mammaprint® test result indicating a high risk. In some embodiments, the tumor has a Prosigna/PAM50® test result indicating a high risk. In some embodiments, the tumor has an Oncotype DX Breast Recurrence score greater than or equal to about 26.

Parameters such as histopathological grade, T stage, N stage, M stage, and Ki67 can be determined at the time of initial diagnosis or using surgical specimens.

In some embodiments, the patient has a tumor of the ductal subtype. The patient may have a tumor of the lobular subtype. Alternatively, the patient may have a tumor that is neither a ductal nor a lobular subtype.

In some embodiments, the primary histology of the tumor is selected from invasive ductal carcinoma, not otherwise specified (NOS), invasive lobular carcinoma, medullary carcinoma, mucinous carcinoma, papillary carcinoma, tubular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.

In some embodiments, the patient has a tumor comprising a HER2 ISH result with an IHC score of 0, 1+, 2+, or 3+. The HER2 ISH result can be obtained prior to surgery or from a surgical specimen.

In some embodiments, the patient's hormone receptor status is positive. For example, positive ER status and/or positive PR status. The positive status can be obtained before surgery or from a surgical specimen.

In certain embodiments, a patient has a tumor that has no metastases in the sentinel lymph nodes (e.g., the patient is considered pN0). A patient may have only micrometastases in the sentinel lymph nodes (e.g., the patient is considered pN1mi). A patient may have a T1-2 tumor and have no clinically evident lymph nodes preoperatively, have not received neoadjuvant chemotherapy, have at least one macrometastasis in 1 or 2 sentinel lymph nodes, and/or have no fused lymph nodes or significant extranodal disease at sentinel dissection (e.g., the patient is considered pN1).

In some embodiments, breast cancer is staged by lymph node dissection, such as axillary lymph node dissection (ALND). In some embodiments, breast cancer is staged by sentinel lymph node (SLN) dissection.

In some embodiments, the tumor is located only in the right breast and not in the left breast. Alternatively, the tumor may be located only in the left breast and not in the right breast. In some embodiments, the tumor is bilateral, for example comprising cancer cells in both the right and left breasts. VII.    Body Mass Index

In some embodiments, the patient has a body mass index (BMI) greater than or equal to 25. In some embodiments, the patient has a BMI less than 25. VIII.      Previous treatment for cancer

In some embodiments, the patient has received treatment (also referred to as therapy) for breast cancer prior to receiving the methods described herein.

The prior treatment can be the initial treatment for breast cancer (also called initial therapy, primary therapy or treatment, induction therapy or treatment, or first-line therapy or treatment). In some embodiments, the patient has completed initial treatment for breast cancer before the treatment described herein. Thus, the treatment described herein can be adjunctive treatment following a prior treatment.

In some embodiments, the prior treatment is not the initial treatment, but is given after an initial treatment or other treatment. In these examples, the treatment described herein can be an adjunct to a prior treatment, where the prior treatment itself was given after one or more additional prior treatments for breast cancer.

A prior treatment can itself be an adjunct to an initial treatment. A prior treatment can be a neo-adjunct to an initial treatment. A prior treatment can be a neo-adjunct to a treatment disclosed herein. In some embodiments, a patient completes a prior treatment (e.g., an adjunct and/or neo-adjunct) prior to a treatment disclosed herein.

In other illustrative examples, a prior therapy is a neoadjuvant therapy to an initial therapy. For example, a prior therapy may be administered prior to an initial therapy to shrink a tumor. In some embodiments, both the prior therapy and the initial therapy for which the prior therapy is a neoadjuvant therapy are completed prior to the treatment described herein.

In some embodiments, the prior treatment is a new adjunct to the treatment described herein.

Previous treatment may have been radiation therapy (also called "radiotherapy"), surgery, or chemotherapy.

In some embodiments, the prior treatment is radiation therapy. Radiation therapy can be performed at one or more of the following locations: breast, chest wall, axillary lymph nodes, supraclavicular lymph nodes, and internal mammary lymph nodes.

In some embodiments, the patient has undergone surgical treatment. Thus, the prior treatment may be a surgical removal of cancer cells (e.g., a tumor). For example, the patient may have undergone one or more of a mastectomy, breast-conserving surgery, axillary lymph node dissection, or sentinel lymph node biopsy. In some embodiments, the patient has undergone a mastectomy. In some embodiments, the patient has undergone a breast lumpectomy. In some embodiments, the entire organ or even surrounding structures may be removed to achieve the necessary removal of the cancer (e.g., a tumor). Surrounding normal, healthy tissue (called "surgical margins") may be removed to increase the success rate of the surgery. Thus, in some embodiments, the prior treatment included a complete tumor removal. The cancer may be completely removed, with the final surgical specimen microscopic margins being tumor-free.

In some embodiments, following surgical resection, the cancer may be R0 (e.g., the surgical margins are negative for residual tumor under microscopy).

In some embodiments, a treatment as described herein is administered to a patient as an adjunct to prior surgical treatment. For example, a treatment as described herein may be initiated following a surgical resection in which the tumor is completely removed and the final surgical specimen microscopic margins are tumor-free.

Prior treatment can be chemotherapy. In some embodiments, the patient has received a prior treatment that was chemotherapy. The chemotherapy can be neoadjuvant chemotherapy. For example, neoadjuvant chemotherapy can be administered before another treatment such as surgery, radiation therapy, or administration of another drug. The chemotherapy can be adjuvant chemotherapy. For example, prior treatment can be chemotherapy administered after another treatment such as surgery, radiation therapy, or administration of another drug. The chemotherapy can be neo/adjuvant chemotherapy. In such illustrative examples, the prior treatment (e.g., neoadjuvant chemotherapy and/or adjuvant chemotherapy) occurs before treatment according to the methods described herein.

In some embodiments, the patient has received prior anti-neoplastic chemotherapy, such as anthracyclines or taxanes.

In some embodiments, the patient has received endocrine therapy (ET). ET can be, for example, neoadjuvant therapy and/or adjuvant ET. The patient may have received ET within 12 months prior to starting the methods of the present disclosure. In some embodiments, the patient has received tamoxifen or toremifene as adjuvant ET, wherein the patient has undergone a washout period of 5 half-lives (e.g., 35 days) prior to starting the methods of the present disclosure. The patient may have received an aromatase inhibitor during the washout period.

In some embodiments, the patient has received an endocrine therapy selected from aromatase inhibitors, anti-estrogens, gonadotropin-releasing hormone analogs, or and biological/targeted therapy.

In some embodiments, the patient has received prior treatment, but the breast cancer did not respond to the treatment, for example due to resistance of the breast cancer cells to the drug. In some embodiments, the patient has received prior treatment, but the breast cancer has recurred (or "relapsed").

In some embodiments, the patient has received treatment (also referred to as therapy) for breast cancer prior to receiving the treatment described herein and is in remission. The patient may be in remission from early stage breast cancer (e.g., HR+/HER2- early stage breast cancer). HR+/HER2- early stage breast cancer may be stage II or stage III cancer.

Cancer may be in remission. A patient with cancer may be in remission. In both cases, remission may refer to a decrease or disappearance of physical signs of cancer in a patient following cancer treatment. Remission may be a partial remission, in which the size of the cancer (e.g., cancer cells and/or tumors) or the extent to which it has spread in the body has decreased. For example, a partial remission may reflect a 50% decrease in a measurable parameter of the cancer (e.g., the growth, size, or spread of cancer cells and/or tumors). Remission may be a complete remission, in which physical signs of cancer (e.g., cancer cells and/or tumors) are no longer detected. While in complete remission, there may be no evidence of disease.

While in complete remission, there may be no detectable signs or symptoms of cancer.

Remission may be related to the period of time since the patient had detectable signs or symptoms of cancer. For example, after about 1 month without detectable signs or symptoms of cancer, the patient may be described as being in remission. In some embodiments, the time period is about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 24 months, about 25 months, about 26 months, about 27 months, about 28 months, about 29 months, about 30 months, about 31 months, about 32 months, about 33 months, about 34 months, about 35 months, about 36 months, or longer. In some embodiments, the time period is about 4 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, about 10 years, or longer.

Thus, the treatments described herein can be administered to patients who are in remission. In some embodiments, the patient is in complete remission. In some embodiments, the patient is in partial remission.

In some embodiments, at the start of a treatment described herein, the patient is in complete remission. For example, the patient may have no detectable cancer cells and/or tumors. The patient may have been diagnosed with early-stage breast cancer at a previous time and may have received previous treatments, resulting in cancer no longer being detected. Therefore, the treatments described herein may be administered to patients who have no symptoms of cancer. In some embodiments, the patient may have been diagnosed with HR+/HER2- early-stage breast cancer and received surgical treatment to remove the cancer, and the HR+/HER2- early-stage breast cancer may no longer be detectable. In some embodiments, the patient may be at risk for developing HR+/HER2- breast cancer based on the presence of a previously diagnosed HR+/HER2- breast cancer. For example, a patient may be at risk for recurrence of HR+/HER2- breast cancer based on a previous diagnosis of HR+/HER2- early-stage breast cancer.

In some embodiments, the patient is in partial remission and shows detectable signs of cancer at the start of treatment described herein. In some embodiments, the patient was diagnosed with HR+/HER2- early stage breast cancer and received previous treatment, but the cancer was not completely eliminated and/or the cancer returned. In some embodiments, patients in partial remission may be at risk for regrowth and/or spread of HR+/HER2- breast cancer based on a previous diagnosis of HR+/HER2- early stage breast cancer.

In some embodiments, a treatment described herein prevents the growth of HR+/HER2- breast cancer cells in a patient (e.g., a patient in remission (e.g., in complete remission or in partial remission)).

In some embodiments, the treatment described herein maintains the patient in remission (e.g., in complete remission or in partial remission). Treatment can maintain remission for at least about 3 months, at least about 6 months, at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 42 months, at least about 48 months, at least about 54 months, at least about 60 months, at least about 66 months, at least about 72 months, at least about 78 months, at least about 84 months, at least about 90 months, at least about 96 months, at least about 102 months, at least about 108 months, at least about 114 months, at least about 120 months, or longer.

In some embodiments, treatment reduces recurrence of breast cancer (e.g., early stage breast cancer, such as HR+/HER2- early stage breast cancer). Treatment can reduce recurrence by at least about 3 months, at least about 6 months, at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 42 months, at least about 48 months, at least about 54 months, at least about 60 months, at least about 66 months, at least about 72 months, at least about 78 months, at least about 84 months, at least about 90 months, at least about 96 months, at least about 102 months, at least about 108 months, at least about 114 months, at least about 120 months, or longer.

Breast cancer recurrence may be ipsilateral breast tumor recurrence (IBTR), defined in this article as a breast tumor that appears again in the same (i.e., same side) breast or chest wall. Breast cancer recurrence may be contralateral breast cancer, defined in this article as a primary breast cancer that develops in the opposite (i.e., contralateral) breast at least three months after the first breast cancer.

Thus, in some embodiments, the methods described herein include maintaining remission in an adult patient previously diagnosed with HR+/HER2- stage II or stage III early breast cancer, the method comprising administering to the patient a treatment comprising a dose of riboxil, its free base form, or a pharmaceutically acceptable salt thereof, in combination with an aromatase inhibitor.

In some embodiments, a treatment described herein is an adjunct to a prior treatment (also referred to as an adjuvant therapy). An adjuvant therapy can be given after any prior treatment (e.g., a prior treatment described herein). An adjuvant therapy can be given after more than one prior treatment. For example, a prior treatment can be a neoadjuvant therapy given before an initial treatment (e.g., first-line treatment) such as surgery and subsequent chemotherapy, radiation therapy, and/or endocrine therapy, after which a treatment described herein is administered as an adjuvant therapy.

Thus, in some embodiments, the methods described herein include preventing breast cancer recurrence in adult patients, the method comprising providing adjuvant therapy to patients who have received prior treatment for HR+/HER2- stage II or stage III early breast cancer, wherein the adjuvant therapy comprises administering to the patient 400 mg of riboxil or a pharmaceutically acceptable salt thereof on days 1 to 21 of a 28-day cycle for at least 36 months, in combination with an aromatase inhibitor as defined herein administered daily in a 28-day cycle.

Thus, in some embodiments, the methods described herein include maintaining remission in an adult patient previously diagnosed with HR+/HER2- Stage II or Stage III early breast cancer, the method comprising providing adjuvant therapy to a patient who has received prior treatment for HR+/HER2- Stage II or Stage III early breast cancer, wherein the adjuvant therapy comprises administering to the patient 400 mg of riboxil or a pharmaceutically acceptable salt thereof on days 1 to 21 of a 28-day cycle for at least 36 months, in combination with an aromatase inhibitor as defined herein administered daily in a 28-day cycle.

In some embodiments, adjunctive therapy does not include administration of riboxili at a dose of 600 mg/day.

Another aspect of the disclosure relates to a method of treating an adult patient diagnosed with HR+/HER2- stage II or stage III early breast cancer, the method comprising administering to the patient an adjuvant therapy comprising (i) riboxil administered at a dose ranging from 150 mg/day to 450 mg/day on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily in a 28-day cycle, wherein the method results in an improvement in one or more of the patient's overall survival (OS), distant disease-free survival (DDFS), or relapse-free survival (RFS).

In some embodiments, the early stage breast cancer may no longer be at stage II or stage III when a treatment described herein is initiated. For example, the patient may have received at least one prior treatment for which the treatment described herein was an adjuvant therapy.

Another aspect of the disclosure relates to a method for improving one or more of overall survival (OS), distant disease-free survival (DDFS), or relapse-free survival (RFS) in a patient diagnosed with HR+/HER2- stage II or stage III early breast cancer, the method comprising administering to the patient an adjuvant therapy comprising (i) riboxil at a dose ranging from 150 mg/day to 450 mg/day on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily in a 28-day cycle.

Additional aspects of the disclosure relate to reboxil for use in a method of improving one or more of overall survival (OS), distant disease-free survival (DDFS), or relapse-free survival (RFS) in adult patients diagnosed with HR+/HER2- stage II or stage III early breast cancer, wherein the method comprises administering to the patient an adjuvant therapy comprising (i) administering reboxil at a dose ranging from 150 mg/day to 450 mg/day on days 1-21 of a 28-day cycle, and (ii) administering an aromatase inhibitor daily in a 28-day cycle.

The methods described herein can prevent local and/or regional invasive recurrence of early-stage breast cancer.

Thus, one aspect of the disclosure relates to a method for reducing the risk of locally or regionally invasive recurrence of early breast cancer in an adult patient diagnosed with HR+/HER2- stage II or stage III early breast cancer, the method comprising administering to the patient an adjuvant therapy comprising (i) riboxil in a dose range of from 150 mg/day to 450 mg/day on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily during the 28-day cycle.

One aspect of the present disclosure relates to reboxil for use in a method of reducing the risk of locally or regionally invasive recurrence of early breast cancer in adult patients diagnosed with HR+/HER2- stage II or stage III early breast cancer, wherein the method comprises administering to the patient an adjuvant therapy comprising (i) administering reboxil at a dose ranging from 150 mg/day to 450 mg/day on days 1-21 of a 28-day cycle, and (ii) administering an aromatase inhibitor daily in a 28-day cycle.

The methods described herein can prevent cancer from returning in tissues other than the breast, such as the bone, liver, and lung or pleura.

Thus, additional aspects of the disclosure relate to a method for reducing the risk of aggressive recurrence of early breast cancer in one or more of the bone, liver, and lung or pleura in adult patients diagnosed with HR+/HER2- stage II or stage III early breast cancer, the method comprising administering to the patient an adjuvant therapy comprising (i) riboxil in an amount ranging from 150 mg/day to 450 mg/day on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily in a 28-day cycle.

Additional aspects of the disclosure relate to reboxil for use in a method of reducing the risk of aggressive recurrence of early breast cancer in one or more of the bone, liver, and lung or pleura in adult patients diagnosed with HR+/HER2- stage II or stage III early breast cancer, wherein the method comprises administering to the patient an adjuvant therapy comprising (i) reboxil at a dose ranging from 150 mg/day to 450 mg/day on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily in a 28-day cycle.

Treatment is given without regard to the lymph node status of the breast cancer.

Another aspect of the disclosure relates to a method for reducing the risk of early breast cancer recurrence in an adult patient diagnosed with HR+/HER2- stage II or stage III early breast cancer, the method comprising administering an adjuvant therapy comprising (i) riboxil at a dose ranging from 150 mg/day to 450 mg/day on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily during a 28-day cycle, wherein the treatment is administered without regard to the lymph node status of the breast cancer.

One aspect of the present disclosure relates to reboxilide for use in a method of reducing the risk of early breast cancer recurrence in adult patients diagnosed with HR+/HER2- stage II or stage III early breast cancer, the method comprising administering to the patient an adjuvant therapy comprising (i) administering reboxilide at a dose ranging from 150 mg/day to 450 mg/day on days 1-21 of a 28-day cycle, and (ii) administering an aromatase inhibitor daily during a 28-day cycle, wherein the treatment is administered without regard to the lymph node status of the breast cancer.

For example, breast cancer can have a lymph node status of N0, N1, N2, or N3. Breast cancer can have a lymph node status of N0.

In some embodiments, the early stage breast cancer is stage II, such as stage IIA. In some embodiments, the early stage breast cancer is stage III, such as stage IIIB or stage IIIC.

In certain embodiments, the breast cancer is of the ductal subtype.

In some embodiments, the patient is Asian.

Patients who have received at least one prior treatment for breast cancer may require adjuvant therapy. In some embodiments, the methods described herein are adjuvant therapy because the patient has received at least one prior treatment for breast cancer selected from the group consisting of surgery, chemotherapy, and radiation therapy.

In some embodiments, the patient has not undergone a mastectomy.

In some embodiments, the dosage of reboxili is 400 mg/day. Reboxili can be administered in the form of a salt (preferably reboxili succinate).

In some embodiments, the aromatase inhibitor is letrozole or anastrozole. For example, the aromatase inhibitor can be letrozole, preferably administered at a dose of 2.5 mg/day. The aromatase inhibitor can be anastrozole, preferably administered at a dose of 1 mg/day.

In some embodiments, the dose of ribociclib is 400 mg/day, ribociclib is administered in the form of ribociclib succinate, and the aromatase inhibitor is letrozole or anastrozole, preferably 2.5 mg/day of letrozole or 1 mg/day of anastrozole.

In some embodiments, the patient achieves an improvement in OS, DDFS, and/or RFS, or a reduction in the risk of breast cancer recurrence of at least 36 months.

In some embodiments, the patient has not previously received a CDK4/6 inhibitor.

In some embodiments, the patient has not received tamoxifen, raloxifene, or an aromatase inhibitor to reduce breast cancer risk ("chemoprevention") and/or to treat osteoporosis within 2 years prior to receiving the methods of the disclosure.

In some embodiments, the patient has not received anthracycline therapy before receiving the method of the present disclosure, and the cumulative dose of doxorubicin is 450 mg/m² or more, and the cumulative dose of epirubicin is 900 mg/m² or more.

In some embodiments, the patient does not have a known hypersensitivity reaction to any of the reboxil and/or ET formulations (e.g., the patient does not have a rare genetic problem of galactose intolerance, Lapp lactase deficiency, glucose-galactose malabsorption, or soy allergy).

In some embodiments, the patient receives no other anti-cancer therapy other than adjuvant ET as described herein.

In some embodiments, the patient has not undergone major surgery, chemotherapy, or radiation therapy within 14 days of receiving the methods of the disclosure.

In some embodiments, patients have not recovered from clinical and laboratory acute toxicity related to previous anticancer therapy to NCI CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) version 4.03 ≤ Grade 1 on the day of randomization. Patients with any grade of alopecia, amenorrhea, grade 2 neuropathy, or other toxicities that are not considered to pose a safety risk to the patient are excluded.

In some embodiments, patients do not have concurrent invasive malignancies or prior invasive malignancies that were treated within 2 years prior to randomization. Patients may have been adequately treated for basal cell or squamous cell skin cancer or have undergone curative resection of cervical carcinoma in situ.

In some embodiments, the patient has no known history of human immunodeficiency virus (HIV) infection.

In some embodiments, the patient does not have known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (testing is not mandatory unless required by local regulations).

In some embodiments, the patient does not have clinically significant, uncontrolled cardiac disease and/or cardiac complex abnormalities, including any of the following: •   Documented history of myocardial infarction (MI), angina, symptomatic pericarditis, or coronary artery bypass graft surgery within 6 months prior to initiation of the disclosed methods. •   Documented cardiomyopathy. •   Left ventricular ejection fraction (LVEF) < 50%, as determined by multi-gated acquisition (MUGA) scan or echocardiogram (ECHO). •   QT prolongation syndrome or family history of idiopathic sudden death or congenital QT prolongation syndrome, or any of the following: •     Risk factors for torsade de pointes (TdP), including uncorrected hypocalcemia, hypokalemia, or hypomagnesemia, history of heart failure, or history of clinically significant/symptomatic bradycardia. •     One or more concomitant medications with a known risk of prolonging the QT interval and/or known to cause TdP that cannot be discontinued or replaced by a safe alternative (e.g., within 5 half-lives or 7 days prior to initiating the disclosed method). •     QTcF interval cannot be determined. •   Clinically significant arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, and/or high-grade atrioventricular (AV) block (e.g., bifascicular block, Mobitz type II, and third-degree AV block). •   Uncontrolled arterial hypertension, systolic blood pressure > 160 mmHg.

In some embodiments, the patient has not received any of the following within 7 days prior to receiving the methods of the present disclosure: •   Concomitant medications, herbal supplements, and/or fruits (e.g., grapefruit, pomelo, carambola, lime) and their juices known to be potent inhibitors or inducers of CYP3A4/5. •   Drugs that have a narrow therapeutic window and are primarily metabolized by CYP3A4/5.

In some embodiments, the patient does not consume grapefruit (or grapefruit juice). In some embodiments, the patient does not consume grapefruit, star fruit, and lime (and their juice). In certain embodiments, the patient does not concomitantly use any of boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir, ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, and voriconazole.

In some embodiments, the patient is not currently receiving or has received systemic corticosteroids within ≤ 2 weeks prior to receiving the methods of the present disclosure, or has not fully recovered from the side effects of such treatment. In some embodiments, the patient may be using corticosteroids in the following situations: short-term (< 5 days) systemic corticosteroids; topical application of any duration (e.g., for rash), inhalation spray (e.g., for obstructive airway disease), eye drops, or local injection (e.g., intra-articular).

In some embodiments, the patient does not have a GI disease that impairs GI function or that could significantly alter the absorption of the oral trial therapy (e.g., uncontrolled ulcerative disease, uncontrolled nausea, vomiting, or diarrhea, malabsorption syndrome, or small bowel resection).

In some embodiments, the patient does not have any other concurrent serious and/or uncontrolled medical conditions that may result in an unacceptable safety risk, prohibit the patient from treatment or affect compliance with the regimen (e.g., chronic pancreatitis, chronic active hepatitis, cirrhosis or any other significant liver disease, untreated or uncontrolled active fungal, bacterial or viral infection, active infection requiring systemic antimicrobial therapy, etc.) or limit life expectancy to ≤ 5 years.

In some embodiments, the patient has not participated in treatment with one or more investigational drugs within 30 days or within 5 half-lives of one or more investigational drugs (whichever is longer) prior to receiving the methods of the disclosure. IX. Additional Criteria

In some embodiments, the patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

In some embodiments, the patient has bone marrow and organ function defined by the following values: • Absolute neutrophil count (ANC) ≥ 1.5 × 10 ⁹ /L. • Platelets ≥ 100 × 10 ⁹ /L. • Hemoglobin ≥ 9.0 g/dL. • Estimated glomerular filtration rate (eGFR) according to the Modification of Diet in Nephropathy (MDRD) formula ≥ 30 mL/min/1.73 m ² . • Alanine transaminase (ALT) < 2.5 × upper limit of normal (ULN). • Aspartate transaminase (AST) < 2.5 × ULN. • Serum total bilirubin <ULN; or total bilirubin ≤ 3.0 × ULN or direct bilirubin ≤ 1.5 × ULN in patients with well-documented Geppel syndrome. • International Normalized Ratio (INR) ≤ 1.5 (unless the patient is receiving an anticoagulant and the INR was within the therapeutic range for the intended use of the anticoagulant during the 7 days prior to randomization). • The following laboratory values are within normal limits or corrected to normal limits with supplementation (corrected local laboratory values should be recorded within normal limits): • Potassium • Magnesium • Total Calcium (corrected for serum albumin)

In some embodiments, the patient has a standard 12-lead ECG value of QTcF interval (using Fridericia-corrected QT interval) < 450 msec and a resting heart rate of 50-90 beats/min (determined by ECG) at screening. X.   Region and Race/Ethnicity

In some embodiments, the patient is located in North America. The patient may be located in Europe, such as Western Europe. The patient may be located in Oceania, such as Australia. In some embodiments, the patient is located in Asia. In some embodiments, the patient is located in Africa. In some embodiments, the patient is located in Latin America.

In some embodiments, the patient can be American Indian. In some embodiments, the patient can be Alaska Native. In some embodiments, the patient can be Asian. In some embodiments, the patient can be Black or African American. In some embodiments, the patient can be Native Hawaiian or other Pacific Islander. In some embodiments, the patient can also be White. In some embodiments, the patient can be mixed race. In some embodiments, the patient can be non-Asian. In some embodiments, the patient can be Hispanic or Latino. In some embodiments, the patient is non-Hispanic or Latino. E.   Effect Readings

One aspect of the present disclosure relates to a method of treating early breast cancer in an adult patient in need thereof, the method comprising administering to the patient a treatment comprising a combination of a cyclin-dependent kinase (CDK) inhibitor and an endocrine therapy (ET), wherein the treatment is characterized by an improvement in the patient's condition compared to a patient not receiving the treatment or compared to the patient before the treatment. In some embodiments, the treatment regimen (e.g., the dosage of ribociclib and/or an aromatase inhibitor) is selected to achieve a degree of improvement in the patient's condition compared to a patient not receiving the treatment or compared to the patient before the treatment.

In some embodiments, patients who do not receive the treatment described herein may include patients who do not receive reboxili (or a pharmaceutically acceptable salt thereof, such as reboxili succinate). In some embodiments, patients who do not receive the treatment described herein may include patients who do not receive reboxili (or a pharmaceutically acceptable salt thereof, such as reboxili succinate) in combination with endocrine therapy. For example, a patient may receive endocrine therapy alone without receiving reboxili (or a pharmaceutically acceptable salt thereof, such as reboxili succinate). A patient may receive letrozole alone without receiving reboxili (or a pharmaceutically acceptable salt thereof, such as reboxili succinate). A patient may receive anastrozole alone without receiving reboxili (or a pharmaceutically acceptable salt thereof, such as reboxili succinate). In some embodiments, patients who have not received a treatment as described herein may receive another cancer treatment, wherein the other cancer treatment is not a combination of ribociclib (or a pharmaceutically acceptable salt thereof, such as ribociclib succinate) and endocrine therapy. In some embodiments, patients who have not received a treatment as described herein may be patients who have not received any cancer treatment.

Improvement of the patient's condition may be associated with a reduction in signs and/or symptoms of breast cancer. For example, improvement may include a reduction in breast cancer progression and/or breast cancer recurrence. Improvement may include prevention of breast cancer progression, early breast cancer recurrence, and/or death from breast cancer. Improvement may include reducing the risk of cancer progression, cancer recurrence, and/or death from cancer (or avoiding death).

In some embodiments, the patient's condition improves by maintaining existing signs and/or symptoms of breast cancer. For example, after treatment, the breast cancer may have substantially the same characteristics as before treatment, but the breast cancer has not progressed further or the characteristics have worsened.

In some embodiments, the improvement in the patient's condition is compared to an improvement in an untreated patient. In some embodiments, the untreated patient receives another treatment for early breast cancer. In some embodiments, the untreated patient receives only endocrine therapy alone.

In some embodiments, improvement in a patient's condition may include one or more of reduction in tumor size, prevention of tumor spread, prevention or reduction in breast cancer recurrence, prevention of second primary malignancies, and increased survival rate.

For example, improvement in a patient's condition may include the absence (or reduction) of locoregional recurrence, distant recurrence, ipsilateral and contralateral invasive breast cancer, and second primary non-breast invasive cancers.

In some embodiments, improvement in a patient's condition is associated with measures such as disease-free survival (DFS), invasive disease-free survival (iDFS), overall survival (OS), distant disease-free survival (DDFS), relapse-free survival (RFS), and loco-regional relapse-free survival (LRRFS).

Disease-free survival (DFS) may relate to the length of time a patient lives without local recurrence, contralateral recurrence, distant disease, secondary cancers, or new primary cancers. DFS may be defined as the time from the first date (e.g., the date cancer treatment started or, alternatively, the date cancer treatment ended) to the date the patient showed recurrence of cancer or died.

Invasive disease-free survival (iDFS) can be defined as DFS excluding DCIS as a recurrent event.

Overall survival (OS) may relate to the length of time a patient lives, which may include death from any cause, regardless of whether breast cancer recurs or spreads. OS may be defined as the time from the first date (e.g., the date cancer treatment started, or, alternatively, the date cancer treatment ended) to the date of death from any cause.

Distant disease-free survival (DDFS) may be related to the length of time a patient remains free of cancer recurrence at a distant site (e.g., not in the original breast). DDFS may be defined as the time from the first date (e.g., the date cancer treatment started or, alternatively, the date cancer treatment ended) to the date of the first event of distant recurrence, death (from any cause), or a second primary non-breast invasive cancer (excluding basal cell carcinoma and squamous cell carcinoma of the skin).

Recurrence-free survival (RFS) may be associated with any recurrence (local, regional, or distant) of the original breast cancer, but does not include one or more new cancers. RFS can be defined as the time from the first date (e.g., the date cancer treatment started or, alternatively, the date cancer treatment ended) to the date of the first of locally invasive breast cancer recurrence, regional invasive recurrence, distant recurrence, or death (from any cause).

Locoregional recurrence-free survival (LRRFS) can be defined as the time from the first date (e.g., the date cancer treatment started or, alternatively, the date cancer treatment ended) to the date of the first event of locally (ipsilaterally) invasive breast cancer recurrence, regional invasive recurrence, or death from any cause.

Thus, in some embodiments, the methods of the present disclosure improve one or more of DFS, iDFS, OS, DDFS, RFS, and LRRFS in patients receiving treatment compared to patients not receiving treatment. For example, the improvement in a patient's condition can be a prolongation of the time period between a first date (e.g., the date cancer treatment begins, or, alternatively, the date cancer treatment ends) and the date of an event as defined in any of DFS, iDFS, OS, DDFS, RFS, and LRRFS.

In some embodiments, the improvement in the patient's condition is a decrease in the incidence (or a decrease in the time until the occurrence) of one or more of invasive ipsilateral breast tumor (IBTR) recurrence, loco-regional invasive recurrence, distant recurrence (e.g., presence of metastases), death from breast cancer, death from causes other than breast cancer, death from unknown causes, the presence of invasive contralateral breast cancer, and the presence of a second primary invasive cancer.

For example, treatment may reduce the rate of (or the time until) death from breast cancer, death from causes other than breast cancer, and death from unknown causes.

In some embodiments, the improvement in the patient's condition is a decrease in the incidence (or decreased time until occurrence) of distant recurrence (e.g., presence of metastases), death from breast cancer, death from causes other than breast cancer, death from unknown causes, and the presence of a second primary invasive cancer.

In some embodiments, the improvement in the patient's condition is a decrease in the incidence (or a decrease in the time until occurrence) of invasive ipsilateral breast tumor (IBTR) recurrence, loco-regional invasive recurrence, distant recurrence (e.g., presence of metastases), death from breast cancer, death from causes other than breast cancer, and death from unknown causes.

In some embodiments, the improvement in the patient's condition is a decrease in the incidence (or a decrease in the time until occurrence) of one or more of invasive ipsilateral breast tumor (IBTR) recurrence, loco-regional invasive recurrence, distant recurrence (e.g., presence of metastases), death from breast cancer, death from causes other than breast cancer, and death from unknown causes.

If the patient's improvement in condition is a reduced risk of invasive disease or other cancer-related events, a different indicator may be used to determine risk. In some embodiments, treatment reduces the risk of invasive disease, corresponding to a hazard ratio of less than about 1 when the risk is calculated relative to patients not receiving treatment. For example, the hazard ratio may be less than about 0.9, about 0.8, about 0.7, about 0.6, about 0.5, about 0.4, about 0.3, about 0.2, or about 0.1. For example, the hazard ratio for iDFS can be calculated using a model (e.g., an unstratified and unadjusted Cox model or a stratified and covariate-adjusted Cox model) as described in Appendix A.

In some embodiments, the hazard ratio may be less than or equal to about 0.78. The hazard ratio may be less than or equal to about 0.72.

In some embodiments, the patient has HR+/HER2- stage III early breast cancer, and treatment reduces the risk of aggressive disease, corresponding to a hazard ratio of less than or equal to about 0.74 when the risk is calculated relative to patients not receiving treatment. The hazard ratio may be less than or equal to about 0.76. In some embodiments, treatment reduces the risk of aggressive disease by at least 25%, corresponding to a hazard ratio of 0.75 when the risk is calculated relative to patients not receiving treatment.

In some embodiments, treatment reduces the risk of invasive disease to similar levels in patient subgroups including patients with stage II early breast cancer, patients with stage III early breast cancer, premenopausal female or male patients, and postmenopausal female patients.

In some embodiments, treatment as disclosed herein may achieve the following hazard ratios for a particular patient with HR+/HER2- early breast cancer.

In some embodiments, the patient is female and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than about 0.76 when the risk is calculated relative to patients not receiving treatment.

In some embodiments, the patient is a premenopausal female or male, and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than about 0.72 when the risk is calculated relative to patients not receiving treatment.

In some embodiments, the patient is a postmenopausal woman and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than about 0.78 when the risk is calculated relative to patients not receiving treatment.

In some embodiments, the patient has received prior neo/adjuvant chemotherapy and the treatment reduces the risk of aggressive disease corresponding to a hazard ratio of less than about 0.73 when the risk is calculated relative to patients who did not receive treatment.

In some embodiments, the patient is located in North America, Western Europe, or Oceania, and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than about 0.76 when the risk is calculated relative to patients not receiving treatment.

In some embodiments, the patient is not located in North America, Western Europe, or Oceania, and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than about 0.76 when the risk is calculated relative to patients not receiving treatment.

In some embodiments, the patient has stage II cancer and the treatment reduces the risk of aggressive disease corresponding to a hazard ratio of less than about 0.76 when the risk is calculated relative to patients not receiving treatment.

In some embodiments, the patient has stage III cancer and the treatment reduces the risk of aggressive disease corresponding to a hazard ratio of less than about 0.74 when the risk is calculated relative to patients not receiving treatment.

In some embodiments, the patient has stage IIA cancer and the treatment reduces the risk of aggressive disease corresponding to a hazard ratio of less than about 0.5 when the risk is calculated relative to patients not receiving treatment.

In some embodiments, the patient has stage IIB cancer and the treatment reduces the risk of aggressive disease corresponding to a hazard ratio of less than about 0.93 when the risk is calculated relative to patients not receiving treatment.

In some embodiments, the patient has stage IIIA cancer and the treatment reduces the risk of aggressive disease corresponding to a hazard ratio of less than about 0.79 when the risk is calculated relative to patients not receiving treatment.

In some embodiments, the patient has stage IIIB cancer and the treatment reduces the risk of aggressive disease corresponding to a hazard ratio of less than about 0.68 when the risk is calculated relative to patients not receiving treatment.

In some embodiments, the patient has stage IIIC cancer and the treatment reduces the risk of aggressive disease corresponding to a hazard ratio of less than about 0.69 when the risk is calculated relative to patients who did not receive treatment.

In some embodiments, the patient has received prior adjuvant chemotherapy, and the treatment reduces the risk of aggressive disease corresponding to a hazard ratio of less than about 0.67 when the risk is calculated relative to patients who did not receive treatment.

In some embodiments, the patient has not received prior adjuvant chemotherapy, and the treatment reduces the risk of aggressive disease corresponding to a hazard ratio of less than about 0.81 when the risk is calculated relative to patients who did not receive treatment.

In some embodiments, the patient has received prior neoadjuvant chemotherapy and the treatment reduces the risk of aggressive disease corresponding to a hazard ratio of less than about 0.79 when the risk is calculated relative to patients who did not receive treatment.

In some embodiments, the patient has not received prior neoadjuvant chemotherapy, and the treatment reduces the risk of aggressive disease corresponding to a hazard ratio of less than about 0.72 when the risk is calculated relative to patients not receiving treatment.

In some embodiments, the patient has received prior radiation therapy and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than about 0.74 when the risk is calculated relative to patients who did not receive treatment.

In some embodiments, the patient has not received prior radiation therapy and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than about 0.98 when the risk is calculated relative to patients who did not receive treatment.

In some embodiments, the patient has received prior endocrine therapy, and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than about 0.76 when the risk is calculated relative to patients who did not receive treatment.

In some embodiments, the patient is not receiving endocrine therapy and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than about 0.77 when the risk is calculated relative to patients not receiving treatment.

In some embodiments, the patient has had a prior mastectomy and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than about 0.85 when the risk is calculated relative to patients who did not receive treatment.

In some embodiments, the patient has not undergone a prior mastectomy and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than about 0.55 when the risk is calculated relative to patients who did not receive treatment.

In some embodiments, the patient is Asian and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than about 0.52 when the risk is calculated relative to patients not receiving treatment.

In some embodiments, the patient is not Asian and the treatment reduces the risk of aggressive disease corresponding to a hazard ratio of less than about 0.81 when the risk is calculated relative to patients not receiving treatment.

In some embodiments, the patient is located in Europe and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than about 0.88 when the risk is calculated relative to patients not receiving treatment.

In some embodiments, the patient is located in North America or Australia, and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than about 0.70 when the risk is calculated relative to patients not receiving treatment.

In some embodiments, the patient is located in Asia and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than about 0.34 when the risk is calculated relative to patients not receiving treatment.

In some embodiments, the patient is located in Latin America and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than about 0.69 when the risk is calculated relative to patients not receiving treatment.

In some embodiments, the patient is younger than 45 years of age and the treatment reduces the risk of aggressive disease corresponding to a hazard ratio of less than about 0.68 when the risk is calculated relative to patients not receiving treatment.

In some embodiments, the patient is 45 to 54 years of age and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than about 0.75 when the risk is calculated relative to patients not receiving treatment.

In some embodiments, the patient is 55 to 64 years of age and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than about 0.84 when the risk is calculated relative to patients not receiving treatment.

In some embodiments, the patient is 65 years of age or older and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than about 0.72 when the risk is calculated relative to patients not receiving treatment.

In some embodiments, the patient receives letrozole, and treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than about 0.79 when the risk is calculated relative to patients not receiving treatment.

In some embodiments, the patient receives anastrozole, and treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than about 0.70 when the risk is calculated relative to patients not receiving treatment.

In some embodiments, the patient has ER+/PR+ cancer and treatment reduces the risk of aggressive disease corresponding to a hazard ratio of less than about 0.73 when the risk is calculated relative to patients not receiving treatment.

In some embodiments, the patient has ER+/PR- cancer and treatment reduces the risk of aggressive disease corresponding to a hazard ratio of less than about 0.91 when the risk is calculated relative to patients not receiving treatment.

In some embodiments, the patient has a tumor with a lymph node status of 0, and treatment reduces the risk of aggressive disease corresponding to a hazard ratio of less than about 0.63 when the risk is calculated relative to patients not receiving treatment.

In some embodiments, the patient has a tumor with a lymph node status of N1-N3, and treatment reduces the risk of aggressive disease corresponding to a hazard ratio of less than about 0.77 when the risk is calculated relative to patients not receiving treatment.

In some embodiments, the patient has a tumor in the T1-T3 category and treatment reduces the risk of aggressive disease corresponding to a hazard ratio of less than about 0.74 when the risk is calculated relative to patients not receiving treatment.

In some embodiments, the patient has a tumor of category greater than T3 (e.g., T4), and treatment reduces the risk of aggressive disease corresponding to a hazard ratio of less than about 0.83 when the risk is calculated relative to patients not receiving treatment.

In some embodiments, the patient has a histologic grade 1 tumor and treatment reduces the risk of aggressive disease corresponding to a hazard ratio of less than about 0.78 when the risk is calculated relative to patients not receiving treatment.

In some embodiments, the patient has a histologic grade 1 tumor and treatment reduces the risk of aggressive disease corresponding to a hazard ratio of less than about 0.78 when the risk is calculated relative to patients not receiving treatment.

In some embodiments, the patient has histologic grade 2 tumor and treatment reduces the risk of aggressive disease corresponding to a hazard ratio of less than about 0.75 when the risk is calculated relative to patients not receiving treatment.

In some embodiments, the patient has histologic grade 3 tumor and treatment reduces the risk of aggressive disease corresponding to a hazard ratio of less than about 0.78 when the risk is calculated relative to patients not receiving treatment.

In some embodiments, the patient has a tumor with a Ki67 status of 20% or less, and treatment reduces the risk of aggressive disease corresponding to a hazard ratio of less than about 0.80 when the risk is calculated relative to patients not receiving treatment.

In some embodiments, the patient has a tumor with a Ki67 status greater than 20%, and treatment reduces the risk of aggressive disease corresponding to a hazard ratio of less than about 0.75 when the risk is calculated relative to patients not receiving treatment.

In some embodiments, the patient has a ductal subtype of tumor and the treatment reduces the risk of aggressive disease corresponding to a hazard ratio of less than about 0.68 when the risk is calculated relative to patients not receiving treatment.

In some embodiments, the patient has a non-ductal subtype or a lobular subtype tumor, and the treatment reduces the risk of aggressive disease corresponding to a hazard ratio of less than about 0.89 when the risk is calculated relative to patients not receiving treatment.

In some embodiments, the patient has a BMI of 25 or greater, and treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than about 0.85 when the risk is calculated relative to patients not receiving treatment.

In some embodiments, the patient has a BMI less than 25, and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than about 0.64 when the risk is calculated relative to patients not receiving treatment.

For overall survival, treatment may not have resulted in a shortening of overall survival, corresponding to a hazard ratio of 0.76 when the risk was calculated relative to patients who did not receive treatment.

In some embodiments, treatment does not cause or worsen events such as pneumonia, pulmonary embolism, dyspnea, elevated alanine aminotransferase, elevated aspartate aminotransferase, arthralgia, fatigue, neutropenia, decreased neutrophil count, and/or nausea.

In some embodiments, treatment does not induce or exacerbate symptoms associated with hepatobiliary toxicity, e.g., as measured by elevations in alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, hemoglobin, and/or hemophosphatase.

In some embodiments, the treatment does not cause or worsen conditions associated with myelosuppression (e.g., anemia and/or leukopenia). For example, the treatment does not cause or worsen leukopenia, or result in a decrease in white blood cell counts, lymphopenia, or a decrease in lymphocyte counts.

In some embodiments, treatment does not induce or worsen symptoms associated with myelosuppression (e.g., neutropenia, decreased neutrophil count, thrombocytopenia, decreased platelet count).

In some embodiments, treatment does not prolong the QT interval in the electrocardiogram.

In some embodiments, treatment does not induce or exacerbate symptoms associated with renal toxicity (e.g., increased blood creatinine, decreased glomerular filtration rate, increased blood urea).

In some embodiments, the treatment does not cause or aggravate conditions associated with reproductive toxicity, such as mastitis. F.    A method for treating HR+/HER2- early breast cancer

One aspect of the present disclosure relates to a method for treating HR+/HER2- stage II or stage III early breast cancer in an adult patient in need thereof, the method comprising administering to the patient a treatment comprising a dose ranging from 150 mg/day to 450 mg/day of riboxil (or a pharmaceutically acceptable salt thereof, such as riboxil succinate) administered on days 1-21 of a 28-day cycle in combination with an endocrine therapy (such as an aromatase inhibitor, preferably letrozole or anastrozole) administered daily (e.g., days 1-28) of a 28-day cycle.

Another aspect of the present disclosure relates to a method for preventing or alleviating the signs or symptoms of early breast cancer, comprising administering to a patient a treatment comprising a dose ranging from 150 mg/day to 450 mg/day of riboxil, its free base form or a pharmaceutically acceptable salt thereof on days 1-21 of a 28-day cycle in combination with an aromatase inhibitor administered daily in a 28-day cycle, preferably letrozole or anastrozole.

Another aspect of the present disclosure relates to a method of maintaining remission in an adult patient previously diagnosed with HR+/HER2- stage II or stage III early breast cancer, the method comprising administering to the patient a treatment comprising a dose ranging from 150 mg/day to 450 mg/day of riboxil, its free base form or a pharmaceutically acceptable salt thereof on days 1-21 of a 28-day cycle in combination with an aromatase inhibitor administered daily in a 28-day cycle, the aromatase inhibitor preferably being letrozole or anastrozole.

Yet another aspect of the present disclosure relates to a method for preventing breast cancer recurrence in adult patients, the method comprising providing adjuvant therapy to patients who have received prior treatment for HR+/HER2- stage II or stage III early breast cancer, wherein the adjuvant therapy comprises administering 400 mg of riboxil or a pharmaceutically acceptable salt thereof to the patient on days 1 to 21 of a 28-day cycle for at least 36 months, in combination with an aromatase inhibitor administered daily in a 28-day cycle as defined in any one of embodiments 23 to 28.

In some embodiments, the treatment comprises administering to the patient a treatment comprising about 400 mg/day (or about 200 mg/day) of ribociclib or a pharmaceutically acceptable salt thereof (e.g., ribociclib succinate) administered on days 1 to 21 of a 28-day cycle for 36 months in combination with an endocrine therapy comprising letrozole in an amount ranging from about 1 mg/day to about 4 mg/day or anastrozole in an amount ranging from about 0.5 mg/day to about 1.5 mg/day administered daily (e.g., days 1-28) of a 28-day cycle.

In some embodiments, the treatment comprises administering to the patient a dose of about 400 mg/day (or about 200 mg/day) of ribociclib or a pharmaceutically acceptable salt thereof (e.g., ribociclib succinate) administered on days 1 to 21 of a 28-day cycle for 36 months in combination with endocrine therapy, wherein the endocrine therapy comprises letrozole at a dose of about 2.5 mg/day or anastrozole at a dose of about 1 mg/day administered on days 1-28 of a 28-day cycle.

In some embodiments, treatment reduces one or more of invasive ipsilateral breast tumor (IBTR) recurrence, loco-regional invasive recurrence, distant recurrence (e.g., presence of metastases), death from breast cancer, death from causes other than breast cancer, death from unknown causes, presence of invasive contralateral breast cancer, and presence of second primary invasive cancers.

In some embodiments, treatment reduces the risk of invasive disease, corresponding to a hazard ratio of less than about 1 when the risk is calculated relative to patients not receiving treatment. For example, the hazard ratio for iDFS can be calculated using a model (e.g., an unstratified and unadjusted Cox model or a stratified and adjusted Cox model), as described in Appendix A.

In some embodiments, the hazard ratio may be less than or equal to about 0.78. The hazard ratio may be less than or equal to about 0.72.

In some embodiments, the patient has HR+/HER2- stage III early breast cancer, and treatment reduces the risk of aggressive disease, corresponding to a hazard ratio of less than or equal to about 0.74 when the risk is calculated relative to patients not receiving treatment. The hazard ratio may be less than or equal to about 0.76. In some embodiments, treatment reduces the risk of aggressive disease by at least 25%, corresponding to a hazard ratio of 0.75 when the risk is calculated relative to patients not receiving treatment.

In some embodiments, treatment reduces the risk of invasive disease to similar levels in patient subgroups including patients with stage II early breast cancer, patients with stage III early breast cancer, premenopausal female or male patients, and postmenopausal female patients.

For overall survival, treatment may not have resulted in a shortening of overall survival, corresponding to a hazard ratio of 0.76 when the risk was calculated relative to patients who did not receive treatment.

In some embodiments, the patient is a postmenopausal woman. In some embodiments, the patient is a premenopausal woman or man.

In some embodiments, early stage breast cancer includes stage II tumors. In some embodiments, the tumor may have an anatomical stage of IIA. In some embodiments, the tumor may have an anatomical stage of IIB. In some embodiments, early stage breast cancer includes stage III tumors. In some embodiments, the tumor may have an anatomical stage of IIIA. In some embodiments, the tumor may have an anatomical stage of IIIB. In some embodiments, the tumor may have an anatomical stage of IIIC.

In some embodiments, the patient has received prior neoadjuvant chemotherapy. In some embodiments, the patient has received prior adjuvant chemotherapy.

In some embodiments, the patient has received prior radiation therapy.

In some embodiments, the patient has undergone a mastectomy. In some embodiments, the patient has not undergone a mastectomy.

In some embodiments, the patient is located in North America. In some embodiments, the patient is located in Europe, such as in Western Europe. In some embodiments, the patient is located in Oceania, such as in Australia. In some embodiments, the patient is located in Latin America. In some embodiments, the patient is located in Asia.

In some embodiments, the patient is Asian. In some embodiments, the patient is non-Asian.

In some embodiments, the patient can be American Indian. In some embodiments, the patient can be Alaska Native. In some embodiments, the patient can be Black or African American. In some embodiments, the patient can be Native Hawaiian or other Pacific Islander. In some embodiments, the patient can also be Caucasian. In some embodiments, the patient can be mixed race. In some embodiments, the patient can be non-Asian. In some embodiments, the patient can be Hispanic or Latino. In some embodiments, the patient is non-Hispanic or Latino.

In some embodiments, the patient is 18 years of age or older. The patient may be 18-44 years of age. The patient may be 45-54 years of age. The patient may be 55 to 64 years of age. The patient may be 65 years of age or older.

In some embodiments, the endocrine therapy is a nonsteroidal aromatase inhibitor (NSAI). In some embodiments, the NSAI can be letrozole. In some embodiments, the NSAI can be anastrozole.

In some embodiments, the early stage breast cancer is selected from ER+/PR+, ER-/PR+, and ER+/PR- breast cancer.

In some embodiments, treatment is administered without regard to the lymph node status of the breast cancer.

In some embodiments, the early stage breast cancer has a lymph node status of N0, N1, N2, or N3.

In some embodiments, early stage breast cancer includes tumors of T0 category, T1, T2, T3, or T4 category.

In some embodiments, the early stage breast cancer has a histological grade of G1, G2, or G3 at the time of surgery.

In some embodiments, an early stage breast cancer has a Ki67 status of 20 or less (e.g., from an archived tumor). Alternatively, an early stage breast cancer can have a Ki67 status greater than 20.

In some embodiments, the early stage breast cancer has a ductal histology subtype or a lobular histology subtype.

One aspect of the present disclosure relates to a method for preventing recurrence of breast cancer in an adult patient who has received prior treatment for HR+/HER2- stage II or stage III early breast cancer, the method comprising administering to the patient (i) a dose of riboxil, its free base form or a pharmaceutically acceptable salt thereof and (ii) a dose of an aromatase inhibitor, preferably letrozole or anastrozole.

Another aspect of the disclosure relates to a method for treating an adult patient in remission from HR+/HER2- stage II or stage III early breast cancer, the method comprising administering to the patient (i) a dose of riboxil, its free base form or a pharmaceutically acceptable salt thereof and (ii) a dose of an aromatase inhibitor, preferably letrozole or anastrozole.

Another aspect of the present disclosure relates to a method for treating HR+/HER2- stage II or stage III early breast cancer in an adult patient in need thereof, the method comprising administering to the patient (i) a dose ranging from 150 mg/day to 450 mg/day of ribociclib, its free base form or a pharmaceutically acceptable salt thereof, administered on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor, preferably letrozole or anastrozole, administered daily in a 28-day cycle.

One aspect of the present disclosure relates to a method for treating recurrence of breast cancer in an adult patient who has received at least one prior treatment for HR+/HER2- stage II or III early breast cancer and has no detectable signs or symptoms of breast cancer, the method comprising administering to the patient an adjuvant therapy comprising (i) administering a dose of 400 mg/day of riboxil succinate on days 1 to 21 of a 28-day cycle, and (ii) administering 2.5 mg/day of letrozole or 1 mg/day of anastrozole on each day of the 28-day cycle.

Another aspect of the disclosure relates to a method of treating an adult patient in remission from HR+/HER2- stage II or stage III early breast cancer and in need of adjuvant therapy, the method comprising administering to the patient an adjuvant therapy comprising (i) administering a dose of riboxil succinate on days 1-21 of a 28-day cycle, the total dose of riboxil being 400 mg/day, and (ii) administering a dose of 2.5 mg/day of letrozole or 1 mg/day of anastrozole on each day of the 28-day cycle.

In some embodiments, the patient has a BMI of 25 or more. In some embodiments, the patient has a BMI of less than 25.

Another aspect of the disclosure relates to a method for preventing or alleviating signs or symptoms of early breast cancer, the method comprising administering to a patient a treatment comprising a combination of reboxil, its free base form or a pharmaceutically acceptable salt thereof and an aromatase inhibitor, preferably letrozole or anastrozole. In some embodiments, reboxil is in its free base form or a pharmaceutically acceptable salt thereof and is administered to the patient on days 1-21 of a 28-day cycle in an amount ranging from 150 mg/day to 450 mg/day. In some embodiments, the aromatase inhibitor is administered daily during a 28-day cycle. G. Patients in remission

One aspect of the disclosure relates to a method of treating HR+/HER2- stage II or stage III early breast cancer in an adult patient in remission, the method comprising administering to the adult patient a combination of riboxil and an aromatase inhibitor, whereby the administration maintains remission in the adult patient for at least about 3 months.

Another aspect relates to a method of treating HR+/HER2- stage II or stage III early breast cancer in an adult patient, the method comprising providing adjuvant treatment by administering a combination of reboxil and an aromatase inhibitor, wherein the patient is in complete remission at the start of the adjuvant treatment, and the administration of the combination of reboxil and the aromatase inhibitor maintains the adult patient in complete remission for at least about 3 months.

Administration of a combination of reboxil and an aromatase inhibitor can maintain remission (e.g., complete remission) in adult patients for a period of at least about 3 months. In some embodiments, administration maintains remission in adult patients for at least about 6 months. In some embodiments, administration maintains remission in adult patients for at least about 9 months. In some embodiments, administration maintains remission in adult patients for at least about 12 months. In some embodiments, administration maintains remission in adult patients for at least about 15 months. In some embodiments, administration maintains remission in adult patients for at least about 18 months. In some embodiments, administration maintains remission in adult patients for at least about 21 months. In some embodiments, administration maintains remission in adult patients for at least about 24 months. In some embodiments, administration maintains remission in adult patients for at least about 27 months. In some embodiments, administration maintains remission in adult patients for at least about 30 months. In some embodiments, administration maintains remission in adult patients for at least about 33 months. In some embodiments, administration maintains remission in adult patients for at least about 36 months.

In certain embodiments, reboxil and the aromatase inhibitor are administered for a duration of treatment, and the administration maintains remission in the adult patient for at least the duration of treatment.

For the methods described herein, the dosage and treatment regimen of the combination of ribociclib and an aromatase inhibitor can follow the following exemplary embodiments. In some embodiments, ribociclib is orally administered once daily at a dose of 400 mg on days 1-21 of a 28-day cycle, and an aromatase inhibitor is administered once daily on each day of the 28-day cycle.

Treatment duration is up to three years with a dose of 400 mg of reboxili administered orally once daily on days 1-21 of a 28-day cycle, and an aromatase inhibitor is administered once daily on each day of the 28-day cycle for up to three years. For example, treatment duration is up to five years with a dose of 400 mg of reboxili administered orally once daily on days 1-21 of a 28-day cycle, and an aromatase inhibitor is administered once daily on each day of the 28-day cycle for up to five years.

In some embodiments, a pharmaceutically acceptable salt of reboxili is orally administered in an amount equivalent to 400 mg of reboxili. The pharmaceutically acceptable salt may be reboxili succinate.

In some embodiments, the adult patient has never been treated with riboxili at a dose of 600 mg.

In some embodiments, the adult patient has never been diagnosed with HR+/HER2- advanced or metastatic breast cancer.

Reboxil and an aromatase inhibitor can be administered as adjunctive therapy. In some embodiments, Reboxil is not administered at a dose of 600 mg/day.

The dosage of ribociclib can be administered in the form of tablets. For example, two tablets can be orally administered to adult patients once a day on days 1-21 of a 28-day cycle, repeated during the duration of treatment, and each tablet contains an amount of a pharmaceutically acceptable ribociclib salt equivalent to 200 mg of ribociclib. In some embodiments, the ribociclib salt is ribociclib succinate. In some embodiments, the aromatase inhibitor is letrozole. In some embodiments, the aromatase inhibitor is anastrozole.

In some embodiments, the aromatase inhibitor is letrozole, and the letrozole is administered in a dosage ranging from 1 mg to 4 mg once daily. For example, the aromatase inhibitor can be letrozole, and the letrozole can be administered once daily in a dosage of 2.5 mg/day.

In some embodiments, the aromatase inhibitor is anastrozole, and anastrozole is administered in a dosage ranging from 0.5 mg once daily to 1.5 mg once daily. For example, anastrozole can be administered in a dosage of 1 mg once daily. The method of any one of embodiments 117 to 148, wherein the patient is a postmenopausal female.

In some embodiments, the patient is a premenopausal female or male.

The patient can be a premenopausal woman or man. Some embodiments (e.g., wherein the patient is a premenopausal woman or man) further comprise administering a gonadotropin-releasing hormone agonist to the adult patient. In some embodiments, the gonadotropin-releasing hormone agonist is goserelin. In some embodiments, goserelin is administered in an amount ranging from 2 mg to 5 mg. For example, the dose of goserelin can be 3.6 mg. In some embodiments, goserelin is administered subcutaneously. In some embodiments, goserelin is administered once every 4 weeks.

In some embodiments, the histologic subtype of the breast cancer is ductal subtype or the histologic subtype is lobular subtype.

In some embodiments, the breast cancer is a stage IIA cancer or a stage IIB cancer. For example, the breast cancer can be a stage IIA cancer. The breast cancer can be a stage IIB cancer.

In some embodiments, the breast cancer is a stage IIIA cancer, a stage IIIB cancer, or a stage IIIC cancer. For example, the breast cancer can be a stage IIIA cancer. The breast cancer can be a stage IIIB cancer. The breast cancer can be a stage IIIC cancer.

In some embodiments, treatment is administered without regard to the lymph node status of the breast cancer. In some embodiments, treatment with ribociclib and an aromatase inhibitor is not adjusted based on the lymph node status of early stage breast cancer.

In some embodiments, the breast cancer has a lymph node status selected from N0, N1, N2, and N3. For example, the breast cancer may have a lymph node status of N0. The breast cancer may have a lymph node status of N1-N3. The breast cancer may have a lymph node status of N1. The breast cancer may have a lymph node status of N2. The breast cancer may have a lymph node status of N3.

In some embodiments, the breast cancer comprises one or more cells having a histological grade selected from G1, G2, or G3. For example, a breast cancer may comprise one or more cells having a G1 histological grade. A breast cancer may comprise one or more cells having a G2 histological grade. A breast cancer may comprise one or more cells having a G3 histological grade.

In some embodiments, breast cancer includes tumors classified as T0, T1, T2, T3, or T4. For example, breast cancer may include tumors classified as T1, T2, or T3. Breast cancer may include tumors classified as T0. Breast cancer may include tumors classified as T1. Breast cancer may include tumors classified as T2. Breast cancer may include tumors classified as T3. Breast cancer may include tumors classified as T4.

In some embodiments, the breast cancer has a Ki67 status of 20 or less. In some embodiments, the breast cancer has a Ki67 status of greater than 20.

In some embodiments, prior to administering riboxil and an aromatase inhibitor to an adult patient, the patient underwent surgery for early-stage breast cancer.

In some embodiments, prior to administering riboxil and an aromatase inhibitor to an adult patient, the patient had (1) surgery for early-stage breast cancer and then had (2) chemotherapy.

In some embodiments, prior to administering riboxil and an aromatase inhibitor to an adult patient, the patient had (1) surgery for early-stage breast cancer and then (2) chemotherapy and/or endocrine therapy.

In some embodiments, the endocrine therapy is therapy with a prior aromatase inhibitor. The prior aromatase inhibitor can be letrozole or anastrozole.

In some embodiments, immediately prior to administering ribociclib and an aromatase inhibitor to an adult patient, the patient has undergone surgery for early-stage breast cancer. In some embodiments, the surgery includes complete surgical removal of the cancer. In some embodiments, the surgery is a mastectomy.

In some embodiments, the patient receives a new adjuvant therapy. For example, the new adjuvant therapy can be chemotherapy.

In some embodiments, the adult patient is located in a geographic region selected from North America, Western Europe, or Oceania.

In some embodiments, the patient is Asian.

In some embodiments, the patient is between 18 and 45 years of age. In some embodiments, the patient is between 45 and 54 years of age. In some embodiments, the patient is between 54 and 64 years of age. In some embodiments, the patient is older than 64 years of age.

In some embodiments, wherein the patient has a BMI of 25 or more. In some embodiments, the patient has a BMI of less than 25.

In some embodiments, treatment improves the patient's condition relative to an untreated patient and/or relative to the patient's condition prior to treatment.

In some embodiments, the treatment reduces the risk of invasive disease. For example, the treatment can reduce the risk of invasive disease in an adult patient, corresponding to a hazard ratio of less than 1 when the risk is calculated relative to other patients who have received the same treatment as the adult patient but have not received the ribociclib.

In some embodiments, the treatment reduces the risk of invasive disease in the adult patient, corresponding to a hazard ratio of less than or equal to 0.78, when the risk is calculated relative to other patients who have received the same treatment as the adult patient but have not received the ribociclib.

In some embodiments, the adult patient is a premenopausal female or male, and the treatment reduces the risk of aggressive disease, corresponding to a hazard ratio of less than or equal to 0.72, when the risk is calculated relative to other premenopausal females and males, respectively, who have received the same treatment as the premenopausal female or male, except that they did not receive riboxil.

In some embodiments, the adult patient is diagnosed with HR+/HER2- stage III early breast cancer, and the treatment reduces the risk of aggressive disease in the adult patient, corresponding to a hazard ratio of less than or equal to 0.74, when the risk is calculated relative to other patients who have received the same treatment as the adult patient but have not received the ribociclib.

In some embodiments, an adult patient is diagnosed with HR+/HER2- stage II early breast cancer and is treated to reduce the risk of aggressive disease, corresponding to a hazard ratio of less than or equal to 0.76, when the risk is calculated relative to other patients who have received the same treatment as the adult patient but have not received the ribociclib.

In some embodiments, the adult patient is diagnosed with HR+/HER2- stage III early breast cancer, and treatment reduces the risk of aggressive disease by at least 25%, corresponding to a hazard ratio of 0.75 when the risk is calculated relative to other patients who have received the same treatment as the adult patient but have not received ribociclib.

In some embodiments, treatment reduces the risk of invasive disease to similar levels in patient subgroups including patients with stage II early breast cancer, patients with stage III early breast cancer, premenopausal female or male patients, and postmenopausal female patients.

In some embodiments, treatment does not result in a shortening of overall survival, corresponding to a hazard ratio of 0.76 when the risk is calculated relative to other patients who have received the same treatment as the adult patient but have not received the ribociclib.

In some embodiments, treatment reduces and/or prevents one or more of cancer recurrence, cancer spread, development and/or growth of additional cancers, and risk of death from cancer.

In some embodiments, treatment reduces cancer recurrence, wherein the recurrence is one or more of invasive ipsilateral breast tumor (IBTR) recurrence, loco-regional invasive recurrence, and distant recurrence.

In some embodiments, treatment reduces cancer spread, wherein the cancer spread is invasive contralateral breast cancer or another primary invasive cancer.

Another aspect of the disclosure relates to reboxil or a pharmaceutically acceptable salt thereof and an aromatase inhibitor for use in a method for treating HR+/HER2- stage II or stage III early breast cancer in adult patients, wherein the method is any one of the methods described herein.

Another aspect of the present disclosure relates to the use of reboxil or a pharmaceutically acceptable salt thereof and an aromatase inhibitor in the manufacture of a medicament for treating HR+/HER2- stage II or stage III early breast cancer in adult patients, wherein the medicament is administered by any of the methods described herein.

Another aspect of the disclosure relates to a kit for use in performing a method of treating HR+/HER2- stage II or stage III early breast cancer in an adult patient according to any of the methods described herein. H.   Uses and methods of the kit

In one aspect of the present disclosure, a kit for performing the methods disclosed herein is provided, for example, a kit for performing a method for treating HR+/HER2- stage II or stage III early breast cancer in an adult patient. The kit can be promoted, distributed or sold as a unit for performing the methods of the present invention.

In some embodiments, the kit comprises a dose of ribociclib, its free base form or a pharmaceutically acceptable salt thereof, and a dose of an aromatase inhibitor, such as letrozole or anastrozole. The kit may comprise guidelines and/or instructions, for example, a schedule for administering ribociclib and/or the aromatase inhibitor.

In some embodiments, the kit comprises a dosage range of about 150 mg/day to 450 mg/day of ribociclib, and instructions and/or directions for administering ribociclib on days 1-21 of a 28-day cycle. The kit may further comprise a dosage of an aromatase inhibitor, such as letrozole or anastrozole, for example, about 2.5 mg/day of letrozole or about 1 mg/day of anastrozole, and may further comprise instructions and/or directions for administering the aromatase inhibitor every day of a 28-day cycle.

In some embodiments, the kit comprises a dose of ribociclib succinate (a total dose of ribociclib of 400 mg/day) and a dose of 2.5 mg/day of letrozole or 1 mg/day of anastrozole. The kit may further comprise instructions and/or instructions for administering a dose of ribociclib succinate on days 1-21 of a 28-day cycle and a dose of letrozole or anastrozole on each day of a 28-day cycle.

Exemplary kits may contain more than 1 daily dose, for example, a kit may contain 21 doses of reboxili or its free base form or a pharmaceutically acceptable salt thereof, and 28 doses of an aromatase inhibitor (e.g., letrozole or anastrozole) for administration throughout a 28-day cycle. Other exemplary kits may contain doses of reboxili or its free base form or a pharmaceutically acceptable salt thereof and an aromatase inhibitor (letrozole or anastrozole) for multiple 28-day cycles. I.    Exemplary Implementations

The following embodiments provide treatment methods and medical uses of the present disclosure.

1.     A method for treating HR+/HER2- stage II or stage III early breast cancer in an adult patient in need thereof, the method comprising administering to the patient a treatment comprising a dose ranging from 150 mg/day to 450 mg/day of riboxil, its free base form or a pharmaceutically acceptable salt thereof on days 1-21 of a 28-day cycle in combination with an aromatase inhibitor administered daily in a 28-day cycle, wherein the aromatase inhibitor is preferably letrozole or anastrozole.

2.     A method for preventing or alleviating the signs or symptoms of early breast cancer, the method comprising administering to a patient a treatment comprising riboxil, its free base form or a pharmaceutically acceptable salt thereof in combination with an aromatase inhibitor, preferably letrozole or anastrozole.

3.     The method as described in embodiment 2, wherein the reboxil, its free base form or a pharmaceutically acceptable salt thereof is administered to the patient on days 1-21 of a 28-day cycle in a dose ranging from 150 mg/day to 450 mg/day.

4.     The method of embodiment 2 or 3, wherein the aromatase inhibitor is administered every day in a 28-day cycle.

5.     A method for preventing or alleviating the signs or symptoms of early breast cancer, the method comprising administering to a patient a treatment comprising a dose ranging from 150 mg/day to 450 mg/day of riboxil, its free base form or a pharmaceutically acceptable salt thereof on days 1-21 of a 28-day cycle, in combination with an aromatase inhibitor administered daily in a 28-day cycle, the aromatase inhibitor preferably being letrozole or anastrozole.

6.     The method of any one of embodiments 1 to 5, wherein the patient is in remission from HR+/HER2- stage II or stage III early breast cancer.

7.     A method for maintaining remission in an adult patient previously diagnosed with HR+/HER2- stage II or III early breast cancer, the method comprising administering to the patient a treatment comprising a dose of riboxil, its free base form or a pharmaceutically acceptable salt thereof in combination with an aromatase inhibitor, preferably letrozole or anastrozole.

8.     The method as described in Implementation Method 6 or Implementation Method 7, wherein the relief is complete relief.

9.     The method as described in Implementation Method 6 or Implementation Method 7, wherein the relief is partial relief.

10.   The method of any one of embodiments 1 to 9, wherein the treatment reduces the recurrence of HR+/HER2- stage II or stage III early breast cancer.

11. The method of embodiment 10, wherein the treatment prevents recurrence for at least 3 months.

12. The method of embodiment 11, wherein the treatment prevents recurrence for at least 6 months.

13. The method of embodiment 12, wherein the treatment prevents recurrence for at least 1 year.

14. The method of any one of embodiments 1 to 13, wherein the patient has no signs or symptoms of cancer prior to receiving the treatment.

15.   The method of any one of embodiments 1 to 14, wherein the treatment prevents the growth of HR+/HER2- breast cancer cells.

16.   The method as described in any of embodiments 1 to 15, wherein the treatment is adjunctive therapy.

17. The method as described in any one of embodiments 1 to 16, wherein the reboxili is a pharmaceutically acceptable reboxili salt.

18. The method as described in embodiment 17, wherein the reboxili salt is reboxili succinate.

19. The method as described in any one of embodiments 1 to 18, wherein the dose of Riboxil is 200 mg/day or 400 mg/day.

20. The method of any one of embodiments 1 to 18, wherein the reboxil is not administered in a dose of 600 mg/day.

21. The method as described in any one of embodiments 1 to 19, wherein the reboxili is administered in the form of reboxili succinate, and the total dose of reboxili is 200 mg/day.

22. The method as described in any one of embodiments 1 to 19, wherein the reboxili is administered in the form of reboxili succinate, and the total dose of reboxili is 400 mg/day.

23. A method as described in any one of embodiments 1 to 19, wherein the reboxil is administered at a dose of 400 mg/day for a period of time, followed by administration of 200 mg/day of reboxil.

24. The method of any one of embodiments 1 to 23, wherein the dose of Riboxil is administered orally.

25. The method of any one of embodiments 1 to 24, wherein the dose of Riboxil is administered in the form of a tablet.

26.   The method as described in any one of embodiments 1 to 24, wherein the aromatase inhibitor is letrozole or anastrozole.

27.   The method as described in any one of embodiments 1 to 26, wherein the aromatase inhibitor is administered orally.

28. The method of embodiment 26 or 27, wherein the letrozole is administered in a dosage ranging from 1 mg/day to 4 mg/day.

29. The method as described in embodiment 28, wherein the letrozole is administered in a dose of 2.5 mg/day.

30. The method of embodiment 26 or 27, wherein the anastrozole is administered in a dosage ranging from 0.5 mg/day to 1.5 mg/day.

31. The method as described in embodiment 30, wherein the anastrozole is administered in a dose of 1 mg/day.

32.   The method of any one of embodiments 1 to 31, wherein the treatment comprises a gonadotropin-releasing hormone agonist.

33. The method as described in embodiment 32, wherein the gonadotropin-releasing hormone agonist is goserelin.

34. The method as described in embodiment 33, wherein the goserelin is administered in a dose ranging from 2 mg to 5 mg.

35. The method as described in embodiment 34, wherein the dose of goserelin is 3.6 mg.

36. The method of any one of embodiments 33 to 35, wherein the goserelin is administered subcutaneously.

37. The method of any one of embodiments 33 to 36, wherein goserelin is administered once every 4 weeks.

38. The method as described in any one of embodiments 1 to 31, wherein the patient is a postmenopausal female.

39. The method as described in any one of embodiments 1 to 37, wherein the patient is a premenopausal female or male.

40.   The method of any one of embodiments 1 to 39, wherein the treatment is administered to the patient for at least 12 months.

41. The method of embodiment 40, wherein the treatment is administered to the patient for at least 24 months.

42. The method of embodiment 40 or embodiment 41, wherein the treatment is administered to the patient for at least 36 months.

43. The method of any of embodiments 40 to 41, wherein the treatment is administered to the patient for at least 48 months.

44. The method of any of embodiments 40 to 41, wherein the treatment is administered to the patient for at least 60 months.

45.   The method of any of embodiments 1 to 44, wherein the treatment continues until the patient has no detectable cancer.

46.   The method of any one of embodiments 1 to 45, wherein the breast cancer is ER+ and PR+.

47.   The method of any one of embodiments 1 to 45, wherein the breast cancer is ER- and PR+.

48.   The method of any one of embodiments 1 to 45, wherein the breast cancer is ER+ and PR-.

49.   The method as described in any one of embodiments 1 to 48, wherein the histological subtype of the breast cancer is a ductal subtype or its histological subtype is a lobular subtype.

50.   The method as described in any one of embodiments 1 to 49, wherein the breast cancer is stage IIA cancer or stage IIB cancer.

51. The method as described in embodiment 50, wherein the breast cancer is stage IIA cancer.

52. The method as described in embodiment 50, wherein the breast cancer is stage IIB cancer.

53.   The method as described in any one of embodiments 1 to 49, wherein the breast cancer is stage IIIA cancer, stage IIIB cancer or stage IIIC cancer.

54. The method as described in embodiment 53, wherein the breast cancer is stage IIIA cancer.

55. The method as described in embodiment 53, wherein the breast cancer is stage IIIB cancer.

56. The method as described in embodiment 53, wherein the breast cancer is stage IIIC cancer.

57.   The method of any one of embodiments 1 to 56, wherein the treatment is administered without regard to the lymph node status of the breast cancer.

58.   The method as described in any one of embodiments 1 to 57, wherein the breast cancer has a lymph node status selected from N0, N1, N2 and N3.

59. The method as described in embodiment 57 or 58, wherein the breast cancer has a lymph node status of N0.

60. The method as described in embodiment 57 or 58, wherein the breast cancer has a lymph node status of N1 to N3.

61. The method as described in embodiment 57 or 58, wherein the breast cancer has a lymph node status of N1.

62. The method as described in embodiment 57 or 58, wherein the breast cancer has a lymph node status of N2.

63. The method as described in embodiment 57 or 58, wherein the breast cancer has a lymph node status of N3.

64.   The method of any one of embodiments 1 to 63, wherein the breast cancer comprises one or more cells having a histological grade selected from G1, G2 or G3.

65. The method of embodiment 64, wherein the breast cancer comprises one or more cells with a G1 histological grade.

66. The method of embodiment 64, wherein the breast cancer comprises one or more cells with a G2 histological grade.

67. The method of embodiment 64, wherein the breast cancer comprises one or more cells having a G3 histological grade.

68. The method of any one of embodiments 1 to 67, wherein the breast cancer comprises a tumor of the T0, T1, T2, T3 or T4 class.

69. The method as described in embodiment 68, wherein the breast cancer comprises tumors of T1, T2 or T3 classification.

70. The method as described in embodiment 68, wherein the breast cancer comprises a tumor of T0 category.

71. The method of embodiment 68 or 69, wherein the breast cancer comprises a tumor of T1 classification.

72. The method of embodiment 68 or 69, wherein the breast cancer comprises a tumor of T2 classification.

73. The method of embodiment 68 or 69, wherein the breast cancer comprises a T3 tumor.

74. The method as described in embodiment 68, wherein the breast cancer comprises a T4 class tumor.

75.   The method of any one of embodiments 1 to 74, wherein the breast cancer has a Ki67 status of 20 or less.

76.   The method of any one of embodiments 1 to 74, wherein the breast cancer has a Ki67 status greater than 20.

77. The method of any one of embodiments 1 to 76, wherein prior to the administration, the patient has received a loading dose of (i) riboxil and/or (ii) endocrine therapy.

78.   The method of any of embodiments 1 to 77, wherein the patient has received at least one prior treatment for cancer.

79. The method of implementation method 78, wherein the previous treatment is an adjunct to another previous treatment.

80.   The method as described in implementation method 78 or 79, wherein the previous treatment is surgery.

81. The method of embodiment 80, wherein the surgery comprises complete surgical resection of the cancer.

82. The method as described in embodiment 80 or 81, wherein the surgery is a mastectomy.

83. The method of embodiment 80 or 81, wherein the previous treatment is chemotherapy.

84. The method of implementation method 83, wherein the previous treatment is adjuvant chemotherapy.

85. The method of implementation method 83, wherein the previous treatment is neoadjuvant chemotherapy.

86.   The method as described in embodiment 78 or 79, wherein the previous treatment is endocrine therapy.

87. The method of implementation method 78 or 79, wherein the previous treatment is radiation therapy.

88.   The method of any of embodiments 78 to 87, wherein the patient is unresponsive to the prior treatment.

89.   The method of any one of embodiments 1 to 88, wherein the patient is located in a geographic region selected from North America, Western Europe, or Oceania.

90.   The method as described in any one of embodiments 1 to 89, wherein the patient is Asian.

91.   The method as described in any one of embodiments 1 to 90, wherein the patient is aged between 18 and 45 years old.

92.   The method as described in any of embodiments 1 to 90, wherein the patient is 45 to 54 years old.

93.   The method as described in any of embodiments 1 to 90, wherein the patient is 54 to 64 years old.

94.   The method as described in any of embodiments 1 to 90, wherein the patient is older than 64 years old.

95.   The method of any of embodiments 1 to 94, wherein the patient has a BMI of 25 or greater.

96.   The method of any one of embodiments 1 to 94, wherein the patient has a BMI less than 25.

97. A method as described in any of embodiments 1 to 96, wherein the treatment improves the patient's condition compared to patients not receiving the treatment and/or compared to the patient's condition before treatment.

98. The method of any of embodiments 1 to 97, wherein the treatment reduces the risk of invasive disease.

99. The method of embodiment 98, wherein the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than 1 when the risk is calculated relative to patients not receiving the treatment.

100. The method of embodiment 99, wherein the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than or equal to 0.78 when the risk is calculated relative to patients not receiving the treatment.

101. The method of any one of embodiments 1 to 37 and 39 to 100, wherein the patient is a premenopausal female or male and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than or equal to 0.72 when the risk is calculated relative to patients not receiving the treatment.

102. The method of any one of embodiments 98 to 100, wherein the patient has HR+/HER2- stage III early breast cancer and the treatment reduces the risk of invasive disease, corresponding to a hazard ratio of less than or equal to 0.74 when the risk is calculated relative to patients not receiving the treatment.

103. The method of any one of embodiments 98 to 100, wherein the patient has HR+/HER2- stage II early breast cancer and the treatment reduces the risk of invasive disease, corresponding to a hazard ratio of less than or equal to 0.76 when the risk is calculated relative to patients not receiving the treatment.

104. The method of any one of embodiments 98 to 100, wherein the patient has HR+/HER2- stage III early breast cancer and the treatment reduces the risk of invasive disease by at least 25%, corresponding to a hazard ratio of 0.75 when the risk is calculated relative to patients not receiving the treatment.

105. The method of any one of embodiments 1 to 104, wherein the treatment reduces the risk of invasive disease to similar levels in subgroups of patients including patients with stage II early breast cancer, patients with stage III early breast cancer, premenopausal female or male patients, and postmenopausal female patients.

106. The method of any one of embodiments 1 to 105, wherein the treatment does not result in a shortening of overall survival, corresponding to a hazard ratio of 0.76 when the risk is calculated relative to patients not receiving the treatment.

107. The method of any one of embodiments 1 to 106, wherein the treatment reduces and/or prevents one or more of the risk of cancer recurrence, cancer spread, additional cancer development and/or growth, and death from cancer.

108. The method of embodiment 107, wherein the treatment reduces cancer recurrence, wherein the recurrence is one or more of invasive ipsilateral breast tumor (IBTR) recurrence, loco-regional invasive recurrence, and distant recurrence.

109. The method of embodiment 107 or embodiment 108, wherein the treatment reduces cancer spread, wherein the cancer spread is invasive contralateral breast cancer or another primary invasive cancer.

110. The method of any one of embodiments 1 to 109, wherein the treatment prevents death from cancer.

111. A method for maintaining remission in an adult patient previously diagnosed with HR+/HER2- stage II or stage III early breast cancer, the method comprising administering to the patient a treatment comprising a dose ranging from 150 mg/day to 450 mg/day of riboxil, its free base form or a pharmaceutically acceptable salt thereof on days 1-21 of a 28-day cycle in combination with an aromatase inhibitor administered daily in a 28-day cycle, the aromatase inhibitor preferably being letrozole or anastrozole.

112. A method for preventing recurrence of breast cancer in adult patients, the method comprising providing adjuvant therapy to a patient who has received prior treatment for HR+/HER2- stage II or stage III early breast cancer, wherein the adjuvant therapy comprises administering to the patient 400 mg of riboxil or a pharmaceutically acceptable salt thereof on days 1 to 21 of a 28-day cycle for at least 36 months, in combination with an aromatase inhibitor administered daily in a 28-day cycle as defined in any one of embodiments 26 to 31.

113. The method of embodiment 112, wherein the previous treatment was surgical resection of the cancer.

114. Reboxil or a pharmaceutically acceptable salt thereof and an aromatase inhibitor are used in a method for treating HR+/HER2- stage II or stage III early breast cancer in adult patients, wherein the method is a method as described in any one of embodiments 1 to 112.

115. Use of ribociclib or a pharmaceutically acceptable salt thereof and an aromatase inhibitor in the manufacture of a medicament for treating HR+/HER2- stage II or stage III early breast cancer in adult patients, wherein the medicament is administered by the method described in any one of embodiments 1 to 112.

116. A kit for use in performing a method for treating HR+/HER2- stage II or stage III early breast cancer in an adult patient according to any one of embodiments 1 to 112.

117. A method for treating HR+/HER2- stage II or stage III early breast cancer in an adult patient in remission, the method comprising administering to the adult patient a combination of riboxil and an aromatase inhibitor, whereby the administration maintains remission in the adult patient for at least 3 months.

118. A method for treating HR+/HER2- stage II or III early breast cancer in an adult patient, the method comprising providing adjuvant therapy by administering a combination of riboxil and an aromatase inhibitor, wherein the patient is in complete remission at the start of the adjuvant therapy, and administration of the combination of riboxil and the aromatase inhibitor maintains the adult patient in complete remission for at least 3 months.

119. The method of embodiment 117 or 118, wherein the administration maintains remission (e.g., complete remission) in the adult patient for at least 6 months.

120. The method of embodiment 117 or 118, wherein the administration maintains remission (e.g., complete remission) in the adult patient for at least 9 months.

121. The method of embodiment 117 or 118, wherein the administration maintains remission (e.g., complete remission) in the adult patient for at least 12 months.

122. The method of embodiment 117 or 118, wherein the administration maintains remission (e.g., complete remission) in the adult patient for at least 15 months.

123. The method of embodiment 117 or 118, wherein the administration maintains remission (e.g., complete remission) in the adult patient for at least 18 months.

124. The method of embodiment 117 or 118, wherein the administration maintains remission (e.g., complete remission) in the adult patient for at least 21 months.

125. The method of embodiment 117 or 118, wherein the administration maintains remission (e.g., complete remission) in the adult patient for at least 24 months.

126. The method of embodiment 117 or 118, wherein the administration maintains remission (e.g., complete remission) in the adult patient for at least 27 months.

127. The method of embodiment 117 or 118, wherein the administration maintains remission (e.g., complete remission) in the adult patient for at least 30 months.

128. The method of embodiment 117 or 118, wherein the administration maintains remission (e.g., complete remission) in the adult patient for at least 33 months.

129. The method of embodiment 117 or 118, wherein the administration maintains remission (e.g., complete remission) in the adult patient for at least 36 months.

130. The method of any one of embodiments 117 to 129, wherein reboxil and the aromatase inhibitor are administered for a treatment duration, and the administration maintains the adult patient in remission (e.g., complete remission) for at least the treatment duration.

131. The method of any one of embodiments 117 to 129, wherein a dose of 400 mg of ribociclib is administered orally once daily on days 1-21 of a 28-day cycle, and the aromatase inhibitor is administered once daily on each day of the 28-day cycle.

132. The method of any one of embodiments 117 to 129, wherein a dose of 400 mg of riboxil is administered orally once daily on days 1-21 of a 28-day cycle for up to three years, and the aromatase inhibitor is administered once daily on every day of a 28-day cycle for up to three years.

133. The method of any one of embodiments 117 to 129, wherein a dose of 400 mg of riboxil is administered orally once daily on days 1-21 of a 28-day cycle for up to five years, and the aromatase inhibitor is administered once daily on every day of a 28-day cycle for up to three years.

134. The method of any one of embodiments 117 to 133, wherein the pharmaceutically acceptable salt of riboxili is orally administered in an amount equivalent to 400 mg of riboxili.

135. The method of embodiment 134, wherein the pharmaceutically acceptable salt is reboxili succinate.

136. The method of any one of embodiments 117 to 135, wherein the adult patient has never been treated with 600 mg of riboxil.

137. The method of any one of embodiments 117 to 136, wherein the adult patient has never been diagnosed with HR+/HER2- advanced or metastatic breast cancer.

138. The method of any one of embodiments 117 to 137, wherein reboxil and an aromatase inhibitor are administered as adjunctive therapy.

139. The method of any one of embodiments 117 to 138, wherein the reboxil is not administered at a dose of 600 mg/day.

140. The method of any one of embodiments 117 to 139, wherein the dose of riboxil is administered in the form of a tablet.

141. The method of any one of embodiments 117 to 139, wherein two tablets are orally administered to the adult patient once daily on days 1-21 of a 28-day cycle, repeated during the treatment duration, and each tablet contains an amount of a pharmaceutically acceptable salt of reboxilicon equivalent to 200 mg of reboxilicon.

142. The method according to embodiment 141, wherein the reboxili salt is reboxili succinate.

143. The method of any one of embodiments 117 to 142, wherein the aromatase inhibitor is letrozole.

144. The method of any one of embodiments 117 to 142, wherein the aromatase inhibitor is anastrozole.

145. The method of any one of embodiments 117 to 144, wherein the aromatase inhibitor is letrozole, and the letrozole is administered in an amount ranging from 1 mg to 4 mg once daily.

146. The method of any one of embodiments 117 to 144, wherein the aromatase inhibitor is letrozole, and the letrozole is administered in a dose of 2.5 mg once daily.

147. The method of any one of embodiments 117 to 144, wherein the aromatase inhibitor is anastrozole, and the anastrozole is administered in an amount ranging from 0.5 mg once daily to 1.5 mg once daily.

148. The method of any one of embodiments 117 to 144, wherein the aromatase inhibitor is anastrozole, and the anastrozole is administered in a dose of 1 mg once daily.

149. The method of any one of embodiments 114 to 148, further comprising administering a gonadotropin-releasing hormone agonist to the adult patient.

150. The method of embodiment 149, wherein the gonadotropin-releasing hormone agonist is goserelin.

151. The method of embodiment 150, wherein the goserelin is administered in an amount ranging from 2 mg to 5 mg.

152. The method of embodiment 151, wherein the dose of goserelin is 3.6 mg.

153. The method of any one of embodiments 150 to 152, wherein the goserelin is administered subcutaneously.

154. The method of any one of embodiments 150 to 153, wherein the goserelin is administered once every 4 weeks.

155. The method of any one of embodiments 117 to 148, wherein the patient is a postmenopausal female.

156. The method of any one of embodiments 117 to 154, wherein the patient is a premenopausal female or male.

157. The method of any one of embodiments 117 to 156, wherein the histological subtype of the breast cancer is a ductal subtype or the histological subtype is a lobular subtype.

158. The method of any one of embodiments 117 to 156, wherein the breast cancer is stage IIA cancer or stage IIB cancer.

159. The method of any one of embodiments 117 to 156, wherein the breast cancer is stage IIA cancer.

160. The method of any one of embodiments 117 to 156, wherein the breast cancer is stage IIB cancer.

161. The method of any one of embodiments 117 to 156, wherein the breast cancer is stage IIIA cancer, stage IIIB cancer, or stage IIIC cancer.

162. The method of any one of embodiments 117 to 156, wherein the breast cancer is stage IIIA cancer.

163. The method of any one of embodiments 117 to 156, wherein the breast cancer is stage IIIB cancer.

164. The method of any one of embodiments 117 to 156, wherein the breast cancer is stage IIIC cancer.

165. The method of any one of embodiments 117 to 156, wherein the treatment is administered without regard to the lymph node status of the breast cancer.

166. The method of any one of embodiments 117 to 156, wherein treatment with riboxil and an aromatase inhibitor is not adjusted based on the lymph node status of the early stage breast cancer.

167. The method of any one of embodiments 117 to 156, wherein the breast cancer has a lymph node status selected from N0, N1, N2 and N3.

168. The method of any one of embodiments 117 to 156, wherein the breast cancer has a lymph node status of N0.

169. The method of any one of embodiments 117 to 156, wherein the breast cancer has a lymph node status of N1-N3.

170. The method of any one of embodiments 117 to 156, wherein the breast cancer has a lymph node status of N1.

171. The method of any one of embodiments 117 to 156, wherein the breast cancer has a lymph node status of N2.

172. The method of any one of embodiments 117 to 156, wherein the breast cancer has a lymph node status of N3.

173. The method of any one of embodiments 117 to 156, wherein the breast cancer comprises one or more cells having a histological grade selected from G1, G2 or G3.

174. The method of any one of embodiments 117 to 156, wherein the breast cancer comprises one or more cells having a G1 histological grade.

175. The method of any one of embodiments 117 to 156, wherein the breast cancer comprises one or more cells having a G2 histological grade.

176. The method of any one of embodiments 117 to 156, wherein the breast cancer comprises one or more cells having a G3 histological grade.

177. The method of any one of embodiments 117 to 156, wherein the breast cancer comprises a tumor of T0, T1, T2, T3 or T4 classification.

178. The method of any one of embodiments 117 to 156, wherein the breast cancer comprises a tumor classified as T1, T2 or T3.

179. The method of any one of embodiments 117 to 156, wherein the breast cancer comprises a tumor of T0 classification.

180. The method of any one of embodiments 117 to 156, wherein the breast cancer comprises a tumor of T1 classification.

181. The method of any one of embodiments 117 to 156, wherein the breast cancer comprises a tumor of T2 classification.

182. The method of any one of embodiments 117 to 156, wherein the breast cancer comprises a tumor of T3 classification.

183. The method of any one of embodiments 117 to 156, wherein the breast cancer comprises a T4 classification tumor.

184. The method of any one of embodiments 117 to 156, wherein the breast cancer has a Ki67 status of 20 or less.

185. The method of any one of embodiments 117 to 156, wherein the breast cancer has a Ki67 status greater than 20.

186. The method of any one of embodiments 117 to 185, wherein prior to administering riboxil and an aromatase inhibitor to the adult patient, the patient underwent surgery for early-stage breast cancer.

187. The method of any one of embodiments 117 to 185, wherein prior to administering riboxil and an aromatase inhibitor to the adult patient, the patient underwent (1) surgery for early-stage breast cancer and then (2) chemotherapy.

188. The method of any one of embodiments 117 to 185, wherein prior to administering riboxil and an aromatase inhibitor to the adult patient, the patient underwent (1) surgery for early breast cancer and then (2) chemotherapy and/or endocrine therapy.

189. The method of embodiment 188, wherein the endocrine therapy is therapy using a previous aromatase inhibitor.

190. The method of embodiment 188, wherein the previous aromatase inhibitor is letrozole or anastrozole.

191. The method of any one of embodiments 117 to 185, wherein immediately prior to administering riboxil and an aromatase inhibitor to the adult patient, the patient underwent surgery for early-stage breast cancer.

192. The method of any one of embodiments 186 to 191, wherein the surgery comprises complete surgical resection of the cancer.

193. The method of any one of embodiments 186 to 191, wherein the surgery is a mastectomy.

194. The method of any one of embodiments 186 to 191, wherein the patient has received a neoadjuvant therapy.

195. The method of embodiment 194, wherein the new adjuvant therapy is chemotherapy.

196. The method of any one of embodiments 117 to 195, wherein the adult patient is located in a geographic region selected from North America, Western Europe, or Oceania.

197. The method of any one of embodiments 117 to 195, wherein the patient is Asian.

198. The method of any one of embodiments 117 to 195, wherein the patient is 18 to 45 years old.

199. The method of any one of embodiments 117 to 195, wherein the patient is 45 to 54 years old.

200. The method of any one of embodiments 117 to 195, wherein the patient is 54 to 64 years old.

201. The method of any one of embodiments 117 to 195, wherein the patient is older than 64 years old.

202. The method of any one of embodiments 117 to 195, wherein the patient has a BMI of 25 or greater.

203. The method of any one of embodiments 117 to 195, wherein the patient has a BMI less than 25.

204. The method of any one of embodiments 117 to 203, wherein the treatment improves the patient's condition relative to patients not receiving the treatment and/or relative to the patient's condition before the treatment.

205. The method of any one of embodiments 117 to 203, wherein the treatment reduces the risk of invasive disease.

206. The method of any one of embodiments 117 to 203, wherein the treatment reduces the risk of invasive disease in the adult patient by a hazard ratio of less than 1 when the risk is calculated relative to other patients who have received the same treatment as the adult patient but have not received the ribociclib.

207. The method of any one of embodiments 117 to 203, wherein the treatment reduces the risk of invasive disease in the adult patient, corresponding to a hazard ratio of less than or equal to 0.78 when the risk is calculated relative to other patients who have received the same treatment as the adult patient except that they did not receive the ribociclib.

208. The method of any one of embodiments 117 to 203, wherein the adult patient is a premenopausal female or male, and the treatment reduces the risk of invasive disease, corresponding to a hazard ratio of less than or equal to 0.72, when the risk is calculated relative to other premenopausal females and males, respectively, who have received the same treatment as the premenopausal female or male, except that they did not receive riboxil.

209. The method of any one of embodiments 117 to 203, wherein the adult patient is diagnosed with HR+/HER2- stage III early breast cancer, and the treatment reduces the risk of invasive disease in the adult patient, corresponding to a hazard ratio of less than or equal to 0.74, when the risk is calculated relative to other patients who have received the same treatment as the adult patient but have not received the ribociclib.

210. The method of any one of embodiments 117 to 203, wherein the adult patient is diagnosed with HR+/HER2- stage II early breast cancer and the treatment reduces the risk of aggressive disease, corresponding to a hazard ratio of less than or equal to 0.76 when the risk is calculated relative to other patients who have received the same treatment as the adult patient but have not received the ribociclib.

211. The method of any one of embodiments 117 to 203, wherein the adult patient is diagnosed with HR+/HER2- stage III early breast cancer and the treatment reduces the risk of invasive disease by at least 25%, corresponding to a hazard ratio of 0.75 when the risk is calculated relative to other patients who have received the same treatment as the adult patient but have not received the ribociclib.

212. The method of any one of embodiments 117 to 203, wherein the treatment reduces the risk of invasive disease to similar levels in subgroups of patients including patients with stage II early breast cancer, patients with stage III early breast cancer, premenopausal female or male patients, and postmenopausal female patients.

213. The method of any one of embodiments 117 to 203, wherein the treatment does not result in a shortening of overall survival, corresponding to a hazard ratio of 0.76 when the risk is calculated relative to other patients who have received the same treatment as the adult patient but have not received the ribociclib.

214. The method of any one of embodiments 117 to 203, wherein the treatment reduces and/or prevents one or more of cancer recurrence, cancer spread, the development and/or growth of additional cancers, and the risk of death from cancer.

215. The method of any one of embodiments 117 to 203, wherein the treatment reduces cancer recurrence, wherein the recurrence is one or more of invasive ipsilateral breast tumor (IBTR) recurrence, loco-regional invasive recurrence, and distant recurrence.

216. The method of any one of embodiments 117 to 203, wherein the treatment reduces cancer spread, wherein the cancer spread is invasive contralateral breast cancer or another primary invasive cancer.

217. Riboxil or a pharmaceutically acceptable salt thereof and an aromatase inhibitor are used in a method for treating HR+/HER2- stage II or stage III early breast cancer in adult patients, wherein the method is a method as described in any one of embodiments 117 to 216.

218. Use of ribociclib or a pharmaceutically acceptable salt thereof and an aromatase inhibitor in the manufacture of a medicament for treating HR+/HER2- stage II or stage III early breast cancer in adult patients, wherein the medicament is administered by the method described in any one of embodiments 117 to 216.

219. A kit for use in performing a method for treating HR+/HER2- stage II or stage III early breast cancer in an adult patient according to any one of embodiments 117 to 216.

220. A method for treating an adult patient diagnosed with HER+/HER2- stage II or stage III early breast cancer, the method comprising administering to the patient an adjuvant therapy comprising (i) riboxil at a dose ranging from 150 mg/day to 450 mg/day on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily in a 28-day cycle, wherein the method results in an improvement in one or more of overall survival (OS), distant disease-free survival (DDFS), or relapse-free survival (RFS) in the patient.

221. A method for improving one or more of overall survival (OS), distant disease-free survival (DDFS), or relapse-free survival (RFS) in a patient diagnosed with HR+/HER2- stage II or stage III early breast cancer, the method comprising administering to the patient an adjuvant therapy comprising (i) riboxil at a dose ranging from 150 mg/day to 450 mg/day on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily in a 28-day cycle.

222. A method for reducing the risk of locally or regionally invasive recurrence of early breast cancer in an adult patient diagnosed with HR+/HER2- stage II or stage III early breast cancer, the method comprising administering to the patient an adjuvant therapy comprising (i) riboxil in a dose range of from 150 mg/day to 450 mg/day on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily during the 28-day cycle.

223. A method for reducing the risk of aggressive recurrence of early breast cancer in one or more of the bones, liver, and lung or pleura in an adult patient diagnosed with HR+/HER2- Stage II or III early breast cancer, the method comprising administering to the patient an adjuvant therapy comprising (i) riboxil at a dose ranging from 150 mg/day to 450 mg/day on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily during the 28-day cycle.

224. The method of any one of embodiments 220 to 223, wherein the treatment is administered without regard to the lymph node status of the breast cancer.

225. A method for reducing the risk of early breast cancer recurrence in an adult patient diagnosed with HR+/HER2- stage II or stage III early breast cancer, the method comprising administering to the patient an adjuvant therapy comprising (i) riboxil at a dose ranging from 150 mg/day to 450 mg/day on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily during a 28-day cycle, wherein the treatment is administered without regard to the lymph node status of the breast cancer.

226. The method of any one of embodiments 220 to 225, wherein the breast cancer has a lymph node status of N0, N1, N2 or N3.

227. The method of embodiment 226, wherein the breast cancer has a lymph node status of N0.

228. The method of any one of embodiments 220 to 227, wherein the early breast cancer is stage II, such as stage IIA.

229. The method of any one of embodiments 220 to 227, wherein the early breast cancer is stage III, such as stage IIIB or IIIC.

230. The method of any one of embodiments 220 to 229, wherein the breast cancer is of the ductal subtype.

231. The method of any one of embodiments 220 to 230, wherein the patient is Asian.

232. The method of any one of embodiments 220 to 231, wherein the method is adjuvant therapy because the patient has received at least one prior treatment for breast cancer selected from the group consisting of surgery, chemotherapy, and radiation therapy.

233. The method of embodiment 232, wherein the patient has not undergone a mastectomy.

234. The method of any one of embodiments 220 to 233, wherein the dose of riboxil is 400 mg/day.

235. The method of any one of embodiments 220 to 234, wherein the reboxili is administered in the form of a salt, preferably reboxili succinate.

236. The method of any one of embodiments 220 to 235, wherein the aromatase inhibitor is letrozole or anastrozole.

237. The method of embodiment 236, wherein the aromatase inhibitor is letrozole, preferably administered in a dose of 2.5 mg/day.

238. The method of embodiment 236, wherein the aromatase inhibitor is anastrozole, preferably administered in a dose of 1 mg/day.

239. The method of any one of embodiments 220 to 238, wherein the dose of reboxili is 400 mg/day, the reboxili is administered in the form of reboxili succinate, and the aromatase inhibitor is letrozole or anastrozole, preferably 2.5 mg/day of letrozole or 1 mg/day of anastrozole.

240. The method of any one of embodiments 220 to 239, wherein the patient achieves an improvement in OS, DDFS and/or RFS of at least 36 months or a reduction in the risk of breast cancer recurrence.

241. Reboxil is for use in a method of improving one or more of overall survival (OS), distant disease-free survival (DDFS), or relapse-free survival (RFS) in adult patients diagnosed with HR+/HER2- stage II or stage III early breast cancer, wherein the method comprises administering to the patient an adjuvant therapy comprising (i) reboxil at a dose ranging from 150 mg/day to 450 mg/day on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily in a 28-day cycle.

242. Reboxil is for use in a method of reducing the risk of locally or regionally invasive recurrence of early breast cancer in adult patients diagnosed with HR+/HER2- stage II or III early breast cancer, wherein the method comprises administering to the patient an adjuvant therapy comprising (i) revocili administered at a dose ranging from 150 mg/day to 450 mg/day on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily in a 28-day cycle.

243. Reboxil is for use in a method of reducing the risk of aggressive recurrence of early breast cancer in one or more of the bones, liver, and lung or pleura in adult patients diagnosed with HR+/HER2- Stage II or III early breast cancer, wherein the method comprises administering to the patient an adjuvant therapy comprising (i) reboxil at a dose ranging from 150 mg/day to 450 mg/day on Days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily in a 28-day cycle.

244. Reboxil for use as described in any one of embodiments 241 to 243, wherein the treatment is administered without regard to the lymph node status of the breast cancer.

245. Reboxil is for use in a method of reducing the risk of recurrence of early breast cancer in adult patients diagnosed with HR+/HER2- stage II or stage III early breast cancer, the method comprising administering to the patient an adjuvant therapy comprising (i) reboxil at a dose ranging from 150 mg/day to 450 mg/day on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily during a 28-day cycle, wherein the treatment is administered without regard to the lymph node status of the breast cancer.

246. Reboxil for use as described in any one of embodiments 241 to 245, wherein the breast cancer has a lymph node status of N0, N1, N2 or N3.

247. Reboxil for use as described in embodiment 246, wherein the breast cancer has a lymph node status of N0.

248. Riboxil for use as described in any one of embodiments 241 to 247, wherein the early breast cancer is stage II, such as stage IIA.

249. Riboxil for use as described in any one of embodiments 241 to 247, wherein the early breast cancer is stage III, such as stage IIIB or IIIC.

250. Reboxil for use as described in any one of embodiments 241 to 249, wherein the breast cancer is of the ductal subtype.

251. Reboxil for use according to any one of embodiments 241 to 250, wherein the patient is Asian.

252. Reboxil for use according to any one of embodiments 241 to 251, wherein the method is adjuvant therapy because the patient has received at least one previous treatment for breast cancer selected from the group consisting of surgery, chemotherapy and radiation therapy.

253. Riboxil for use as described in embodiment 252, wherein the patient has not undergone a mastectomy.

254. The method for use according to any one of embodiments 241 to 253, wherein the dosage of Reboxil is 400 mg/day.

255. Reboxili for use according to any one of embodiments 241 to 254, wherein the reboxili is administered in the form of a salt, and the salt is preferably reboxili succinate.

256. Reboxil for use according to any one of embodiments 241 to 255, wherein the aromatase inhibitor is letrozole or anastrozole.

257. Reboxil for use as described in embodiment 256, wherein the aromatase inhibitor is letrozole, preferably administered in a dose of 2.5 mg/day.

258. Reboxil for use as described in embodiment 256, wherein the aromatase inhibitor is anastrozole, preferably administered in a dose of 1 mg/day.

259. The ribociclib for use as described in any one of embodiments 241 to 258, wherein the dosage of ribociclib is 400 mg/day, the ribociclib is administered in the form of ribociclib succinate, and the aromatase inhibitor is letrozole or anastrozole, preferably 2.5 mg/day of letrozole or 1 mg/day of anastrozole.

260. Riboxil for use according to any one of embodiments 241 to 259, wherein the patient achieves an improvement in OS, DDFS and/or RFS of at least 36 months or a reduction in the risk of breast cancer recurrence.

261. Reboxilibe succinate is for use in a method of treating HR+/HER2- Stage II or III early breast cancer in adult patients who have received at least one prior treatment for early breast cancer and who have no signs or symptoms of cancer, wherein the method comprises administering to the patient an adjuvant therapy comprising (i) administration of a dose of 400 mg/day of reboxilibe on days 1 to 21 of a 28-day cycle and (ii) administration of 2.5 mg/day of letrozole or 1 mg/day of anastrozole on each day of the 28-day cycle.

262. Riboxil succinate for use as described in embodiment 261, wherein the adjunctive treatment comprises letrozole at a dose of 2.5 mg/day.

263. Riboxil succinate for use as described in embodiment 261, wherein the adjunctive treatment comprises anastrozole at a dose of 1 mg/day.

264. Riboxil succinate for use as described in any one of embodiments 261 to 263, wherein the breast cancer has a lymph node status of N0, N1, N2 or N3.

265. Riboxil succinate for use as described in embodiment 264, wherein the breast cancer has a lymph node status of N0.

266. Riboxil succinate for use as described in any one of embodiments 261 to 265, wherein the early breast cancer is stage II, such as stage IIA.

267. Riboxil succinate for use as described in any one of embodiments 261 to 265, wherein the early breast cancer is stage III, such as stage IIIB.

268. Riboxil succinate for use as described in any one of embodiments 261 to 265, wherein the early breast cancer is stage III, such as stage IIIC.

269. Reboxil succinate for use as described in any one of embodiments 261 to 268, wherein the breast cancer is of the ductal subtype.

270. Reboxil succinate for use according to any one of embodiments 261 to 269, wherein the patient is Asian.

271. Reboxil succinate for use according to any one of embodiments 261 to 270, wherein the method is adjuvant therapy because the patient has received at least one previous treatment for breast cancer selected from the group consisting of surgery, chemotherapy, endocrine therapy and radiation therapy.

272. Riboxil succinate for use as described in embodiment 271, wherein the patient has not undergone a mastectomy.

273. Riboxil succinate for use as described in any one of embodiments 261 to 272, wherein the method improves the patient's breast cancer overall survival (OS), distant disease-free survival (DDFS) and/or recurrence-free survival (RFS) by at least 36 months; or the method reduces the patient's risk of breast cancer recurrence by at least 36 months.

274. A method for preventing recurrence of breast cancer in an adult patient who has received prior treatment for HR+/HER2- stage II or III early breast cancer, the method comprising administering to the patient (i) an amount of riboxil, its free base form or a pharmaceutically acceptable salt thereof and (ii) an amount of an aromatase inhibitor, preferably letrozole or anastrozole.

275. A method for treating an adult patient in remission from HR+/HER2- stage II or stage III early breast cancer, the method comprising administering to the patient (i) a dose of riboxil, its free base form or a pharmaceutically acceptable salt thereof and (ii) a dose of an aromatase inhibitor, preferably letrozole or anastrozole.

276. A method for treating HR+/HER2- stage II or III early breast cancer in an adult patient in need thereof, the method comprising administering to the patient (i) a dose ranging from 150 mg/day to 450 mg/day of riboxil, its free base form or a pharmaceutically acceptable salt thereof, administered on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor, preferably letrozole or anastrozole, administered daily in a 28-day cycle.

277. The method of any one of embodiments 274 to 276, wherein the reboxili is a pharmaceutically acceptable reboxili salt.

278. The method as described in embodiment 277, wherein the reboxili salt is reboxili succinate.

279. The method of any one of embodiments 274, 275, 277 and 278, wherein the dose of riboxil is not 600 mg/day.

280. The method of any one of embodiments 274 to 278, wherein the dose of riboxil is 200 mg/day or 400 mg/day.

281. The method of embodiment 280, wherein reboxili is administered in the form of reboxili succinate, and the total dose of reboxili is 200 mg/day.

282. The method of embodiment 280, wherein reboxili is administered in the form of reboxili succinate, and the total dose of reboxili is 400 mg/day.

283. The method of embodiment 280, wherein the reboxil is administered at a dose of 400 mg/day for a period of time, followed by administration of reboxil at a dose of 200 mg/day.

284. The method of any one of embodiments 274 to 283, wherein the dose of reboxil is administered orally.

285. The method of any one of embodiments 274 to 284, wherein the dose of riboxil is administered in the form of a tablet.

286. The method of any one of embodiments 274 to 285, wherein the aromatase inhibitor is letrozole or anastrozole.

287. The method of any one of embodiments 274 to 286, wherein the aromatase inhibitor is administered orally.

288. The method of embodiment 286 or 287, wherein the letrozole is administered in an amount ranging from 1 mg/day to 4 mg/day.

289. The method of embodiment 288, wherein the letrozole is administered in a dose of 2.5 mg/day.

290. The method of embodiment 286 or 287, wherein the anastrozole is administered in an amount ranging from 0.5 mg/day to 1.5 mg/day.

291. The method of embodiment 290, wherein the anastrozole is administered in a dose of 1 mg/day.

292. A method for treating recurrence of breast cancer in an adult patient who has received at least one prior treatment for HR+/HER2- stage II or III early breast cancer and has no detectable signs or symptoms of breast cancer, the method comprising administering to the patient an adjuvant therapy comprising (i) riboxil succinate administered on days 1 to 21 of a 28-day cycle at a total dose of 400 mg/day and (ii) letrozole at a dose of 2.5 mg/day or anastrozole at a dose of 1 mg/day administered daily in a 28-day cycle.

293. A method for treating an adult patient who is in remission from HR+/HER2- stage II or stage III early breast cancer and who is in need of adjuvant therapy, the method comprising administering to the patient an adjuvant therapy comprising (i) administering a dose of riboxil succinate on days 1-21 of a 28-day cycle, the total dose of riboxil being 400 mg/day, and (ii) administering a dose of 2.5 mg/day of letrozole or 1 mg/day of anastrozole on each day of the 28-day cycle.

294. The method of any one of embodiments 274 to 293, wherein the treatment further comprises administering a gonadotropin-releasing hormone agonist.

295. The method of embodiment 294, wherein the gonadotropin-releasing hormone agonist is goserelin.

296. The method of embodiment 295, wherein the goserelin is administered in an amount ranging from 2 mg to 5 mg.

297. The method of embodiment 296, wherein the dose of goserelin is 3.6 mg.

298. The method of any one of embodiments 294 to 297, wherein the goserelin is administered subcutaneously.

299. The method of any one of embodiments 294 to 298, wherein the goserelin is administered once every 4 weeks.

300. The method of any one of embodiments 274 to 299, wherein the patient is a postmenopausal female.

301. The method of any one of embodiments 274 to 293, wherein the patient is a premenopausal female or male.

302. The method of any one of embodiments 274 to 301, wherein the treatment is administered to the patient for at least 12 months.

303. The method of embodiment 302, wherein the treatment is administered to the patient for at least 24 months.

304. The method of embodiment 302 or 303, wherein the treatment is administered to the patient for at least 36 months.

305. The method of any one of embodiments 302 to 304, wherein the treatment is administered to the patient for at least 48 months.

306. The method of any one of embodiments 302 to 305, wherein the treatment is administered to the patient for at least 60 months.

307. The method of any one of embodiments 274 to 306, wherein the breast cancer is ER+ and PR+.

308. The method of any one of embodiments 274 to 306, wherein the breast cancer is ER- and PR+.

309. The method of any one of embodiments 274 to 306, wherein the breast cancer is ER+ and PR-.

310. The method of any one of embodiments 274 to 309, wherein the histological subtype of breast cancer is a ductal subtype.

311. The method of any one of embodiments 274 to 310, wherein the histological subtype of the breast cancer is a lobular subtype.

312. The method of any one of embodiments 274 to 311, wherein the breast cancer is stage IIA cancer or stage IIB cancer.

313. The method of embodiment 312, wherein the breast cancer is stage IIA cancer.

314. The method of embodiment 312, wherein the breast cancer is stage IIB cancer.

315. The method of any one of embodiments 274 to 311, wherein the breast cancer is stage IIIA cancer, stage IIIB cancer, or stage IIIC cancer.

316. The method of embodiment 315, wherein the breast cancer is stage IIIA cancer.

317. The method of embodiment 315, wherein the breast cancer is stage IIIB cancer.

318. The method of embodiment 315, wherein the breast cancer is stage IIIC cancer.

319. The method of any one of embodiments 274 to 318, wherein the treatment is administered without regard to the lymph node status of the breast cancer.

320. The method of any one of embodiments 274 to 319, wherein the breast cancer has a lymph node status selected from N0, N1, N2 and N3.

321. The method of embodiment 319 or 320, wherein the breast cancer has a lymph node status of N0.

322. The method of embodiment 319 or 320, wherein the breast cancer has a lymph node status of N1 to N3.

323. The method of embodiment 319 or 320, wherein the breast cancer has a lymph node status of N1.

324. The method of embodiment 319 or 320, wherein the breast cancer has a lymph node status of N2.

325. The method of embodiment 319 or 320, wherein the breast cancer has a lymph node status of N3.

326. The method of any one of embodiments 274 to 325, wherein the breast cancer comprises one or more cells having a histological grade selected from G1, G2 or G3.

327. The method of embodiment 326, wherein the breast cancer comprises one or more cells having a G1 histological grade.

328. The method of embodiment 326, wherein the breast cancer comprises one or more cells having a G2 histological grade.

329. The method of embodiment 326, wherein the breast cancer comprises one or more cells having a G3 histological grade.

330. The method of any one of embodiments 274 to 329, wherein the breast cancer comprises a tumor of T0, T1, T2, T3 or T4 classification.

331. The method of embodiment 330, wherein the breast cancer comprises a tumor classified as T1, T2 or T3.

332. The method of embodiment 330, wherein the breast cancer comprises a tumor of T0 classification.

333. The method of embodiment 330 or embodiment 331, wherein the breast cancer comprises a tumor of T1 classification.

334. The method of embodiment 330 or embodiment 331, wherein the breast cancer comprises a tumor of T2 classification.

335. The method of embodiment 330 or embodiment 331, wherein the breast cancer comprises a T3 tumor.

336. The method of embodiment 330, wherein the breast cancer comprises a T4 tumor.

337. The method of any one of embodiments 274 to 336, wherein the breast cancer has a Ki67 status of 20 or less.

338. The method of any one of embodiments 274 to 336, wherein the breast cancer has a Ki67 status greater than 20.

339. The method of any one of embodiments 274 to 338, wherein prior to administration, the patient has received a loading dose of (i) riboxil and/or (ii) endocrine therapy.

340. The method of any one of embodiments 274 to 291 and 293 to 339, wherein the patient has received at least one prior treatment for cancer.

341. The method of embodiment 292 or embodiment 340, wherein the previous treatment is an adjunct to another previous treatment.

342. The method of implementation 340 or 341, wherein the previous treatment is surgery.

343. The method of embodiment 342, wherein the surgery comprises complete surgical resection of the cancer.

344. The method of embodiment 342 or embodiment 343, wherein the surgery is a mastectomy.

345. The method of embodiment 340 or embodiment 341, wherein the prior treatment is chemotherapy.

346. The method of embodiment 345, wherein the prior treatment is adjuvant chemotherapy.

347. The method of embodiment 345, wherein the previous treatment is neoadjuvant chemotherapy.

348. The method of embodiment 340 or embodiment 341, wherein the previous treatment is endocrine therapy.

349. The method of embodiment 340 or embodiment 341, wherein the previous treatment is radiation therapy.

350. The method of any one of embodiments 292 and 340 to 349, wherein the patient has not responded to previous treatment.

351. The method of any one of embodiments 274 to 350, wherein the patient is located in a geographic region selected from North America, Western Europe, or Oceania.

352. The method of any one of embodiments 274 to 351, wherein the patient is Asian.

353. The method of any one of embodiments 274 to 352, wherein the patient is 18 to 45 years old.

354. The method of any one of embodiments 274 to 352, wherein the patient is 45 to 54 years old.

355. The method of any one of embodiments 274 to 352, wherein the patient is 54 to 64 years old.

356. The method of any one of embodiments 274 to 352, wherein the patient is older than 64 years old.

357. The method of any one of embodiments 274 to 357, wherein the patient has a BMI of 25 or greater.

358. The method of any one of embodiments 274 to 357, wherein the patient has a BMI of less than 25.

359. The method of any one of embodiments 274 to 358, wherein the treatment improves the patient's condition relative to patients not receiving the treatment and/or relative to the patient's condition before the treatment.

360. The method of any one of embodiments 274 to 359, wherein the treatment reduces the risk of invasive disease.

361. The method of embodiment 360, wherein the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than 1 when the risk is calculated relative to patients not receiving the treatment.

362. The method of embodiment 361, wherein the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than or equal to 0.78 when the risk is calculated relative to patients not receiving the treatment.

363. The method of any one of embodiments 274 to 299 and 301 to 362, wherein the patient is a premenopausal female or male and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than or equal to 0.72 when the risk is calculated relative to patients not receiving the treatment.

364. The method of any one of embodiments 360 to 362, wherein the cancer is HR+/HER2- stage III early breast cancer and the treatment reduces the risk of invasive disease, corresponding to a hazard ratio of less than or equal to 0.74 when the risk is calculated relative to patients not receiving the treatment.

365. The method of any one of embodiments 360 to 362, wherein the cancer is HR+/HER2- stage II early breast cancer and the treatment reduces the risk of invasive disease, corresponding to a hazard ratio of less than or equal to 0.76 when the risk is calculated relative to patients not receiving the treatment.

366. The method of any one of embodiments 360 to 362, wherein the cancer is HR+/HER2- stage III early breast cancer and the treatment reduces the risk of invasive disease by at least 25%, corresponding to a hazard ratio of 0.75 when the risk is calculated relative to patients not receiving the treatment.

367. The method of any one of embodiments 360 to 366, wherein the treatment reduces the risk of invasive disease to similar levels in subgroups of patients including patients with stage II early breast cancer, patients with stage III early breast cancer, premenopausal female or male patients, and postmenopausal female patients.

368. The method of any one of embodiments 274 to 367, wherein the treatment does not result in a shortening of overall survival, corresponding to a hazard ratio of 0.76 when the risk is calculated relative to patients not receiving the treatment.

369. The method of any one of embodiments 274 to 368, wherein the treatment reduces and/or prevents one or more of cancer recurrence, cancer spread, the development and/or growth of additional cancers, and the risk of death from cancer.

370. The method of embodiment 369, wherein the treatment reduces cancer recurrence, wherein the recurrence is one or more of invasive ipsilateral breast tumor (IBTR) recurrence, loco-regional invasive recurrence, and distant recurrence.

371. The method of embodiment 369, wherein the treatment reduces cancer spread, wherein the cancer spread is invasive contralateral breast cancer or another primary invasive cancer.

372. The method of any of embodiments 274 to 371, wherein the treatment prevents death from cancer. J.    Further exemplary embodiments

Further treatment methods and uses of Reboxil are provided in the following embodiments.

1.     A method for treating an adult patient diagnosed with HER+/HER2- stage II or stage III early breast cancer, the method comprising administering to the patient an adjuvant therapy comprising (i) riboxil at a dose ranging from 150 mg/day to 450 mg/day on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily in a 28-day cycle, wherein the method results in an improvement in one or more of the patient's overall survival (OS), distant disease-free survival (DDFS), or relapse-free survival (RFS).

2.     A method for improving one or more of overall survival (OS), distant disease-free survival (DDFS), or relapse-free survival (RFS) in a patient diagnosed with HR+/HER2- stage II or stage III early breast cancer, the method comprising administering to the patient an adjuvant therapy comprising (i) riboxil at a dose ranging from 150 mg/day to 450 mg/day on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily in a 28-day cycle.

3.     A method for reducing the risk of locally or regionally invasive recurrence of early breast cancer in an adult patient diagnosed with HR+/HER2- stage II or stage III early breast cancer, the method comprising administering to the patient an adjuvant therapy comprising (i) riboxil at a dose ranging from 150 mg/day to 450 mg/day on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily in a 28-day cycle.

4.     A method for reducing the risk of aggressive recurrence of early breast cancer in one or more of the bones, liver, and lung or pleura in adult patients diagnosed with HR+/HER2- Stage II or III early breast cancer, the method comprising administering to the patient an adjuvant therapy comprising (i) riboxil at a dose ranging from 150 mg/day to 450 mg/day on Days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily in a 28-day cycle.

5.     The method of any of claims 1 to 4, wherein the treatment is administered without regard to the lymph node status of the breast cancer.

6.     A method for reducing the risk of early breast cancer recurrence in adult patients diagnosed with HR+/HER2- Stage II or Stage III early breast cancer, the method comprising administering an adjuvant therapy comprising (i) riboxil at a dose ranging from 150 mg/day to 450 mg/day on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily in a 28-day cycle, wherein the treatment is administered without regard to the lymph node status of the breast cancer.

7.     The method of any one of claims 1 to 6, wherein the breast cancer has a lymph node status of N0, N1, N2 or N3.

8.     The method of claim 7, wherein the breast cancer has a lymph node status of N0.

9.     The method as described in any of claims 1 to 8, wherein the early breast cancer is stage II, such as stage IIA.

10.   The method of any one of claims 1 to 8, wherein the early breast cancer is stage III, such as stage IIIB or stage IIIC.

11.   The method of any of claims 1 to 10, wherein the breast cancer is of the ductal subtype.

12.   The method of any of claims 1 to 11, wherein the patient is Asian.

13.   The method of any of claims 1 to 12, wherein the method is adjuvant therapy because the patient has received at least one prior treatment for breast cancer selected from the group consisting of surgery, chemotherapy, and radiation therapy.

14. The method of claim 13, wherein the patient has not undergone a mastectomy.

15.   The method of any one of claims 1 to 14, wherein the dose of riboxil is 400 mg/day.

16. The method of any one of claims 1 to 15, wherein the reboxil is administered in the form of a salt, and the salt is preferably reboxil succinate.

17.   The method of any one of claims 1 to 16, wherein the aromatase inhibitor is letrozole or anastrozole.

18. The method of claim 17, wherein the aromatase inhibitor is letrozole, preferably administered in a dose of 2.5 mg/day.

19. The method of claim 17, wherein the aromatase inhibitor is anastrozole, preferably administered in a dose of 1 mg/day.

20.   The method as described in any one of claims 1 to 19, wherein the dose of reboxili is 400 mg/day, the reboxili is administered in the form of reboxili succinate, and the aromatase inhibitor is letrozole or anastrozole, preferably 2.5 mg/day of letrozole or 1 mg/day of anastrozole.

21. The method of any of claims 1 to 20, wherein the patient achieves an improvement in OS, DDFS and/or RFS of at least 36 months or a reduction in the risk of breast cancer recurrence.

22.   Reboxil is for use in a method of improving one or more of overall survival (OS), distant disease-free survival (DDFS), or relapse-free survival (RFS) in adult patients diagnosed with HR+/HER2- Stage II or III early breast cancer, the method comprising administering to the patient an adjuvant therapy comprising (i) reboxil at a dose ranging from 150 mg/day to 450 mg/day on Days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily in a 28-day cycle.

23.   Reboxil is for use in a method of reducing the risk of locally or regionally invasive recurrence of early breast cancer in adult patients diagnosed with HR+/HER2- Stage II or III early breast cancer, the method comprising administering to the patient an adjuvant therapy comprising (i) reboxil at a dose ranging from 150 mg/day to 450 mg/day on Days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily in a 28-day cycle.

24.   Reboxil is for use in a method of reducing the risk of aggressive recurrence of early breast cancer in one or more of the bones, liver, and lung or pleura in adult patients diagnosed with HR+/HER2- Stage II or III early breast cancer, and the method is an adjuvant treatment, which method comprises administering to the patient an adjuvant treatment comprising (i) revocili at a dose ranging from 150 mg/day to 450 mg/day on Days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily in a 28-day cycle.

25.   Reboxil for use as described in any of claims 22 to 24, wherein the treatment is administered without regard to the lymph node status of the breast cancer.

26.   Reboxil is for use in a method of reducing the risk of recurrence of early breast cancer in adult patients diagnosed with HR+/HER2- Stage II or III early breast cancer, the method comprising administering to the patient an adjuvant therapy comprising (i) reboxil at a dose ranging from 150 mg/day to 450 mg/day on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily during a 28-day cycle, wherein the treatment is administered without regard to the lymph node status of the breast cancer.

27.   Reboxil for use as described in any of claims 22 to 26, wherein the breast cancer has a lymph node status of N0, N1, N2 or N3.

28.   Reboxil for use as described in claim 27, wherein the breast cancer has a lymph node status of N0.

29.   Riboxil for use as described in any of claims 22 to 28, wherein the early breast cancer is stage II, such as stage IIA.

30.   Riboxil for use as described in any of claims 22 to 28, wherein the early breast cancer is stage III, such as stage IIIB or IIIC.

31.   Reboxil for use as described in any of claims 22 to 30, wherein the breast cancer is of the ductal subtype.

32.   Reboxil for use as described in any of claims 22 to 31, wherein the patient is Asian.

33.   Reboxil for use as described in any of claims 22 to 32, wherein the method is adjuvant therapy because the patient has received at least one prior treatment for breast cancer selected from the group consisting of surgery, chemotherapy, and radiation therapy.

34.   Riboxil for use as described in claim 33, wherein the patient has not undergone a mastectomy.

35.   Reboxil for use as described in any of claims 22 to 34, wherein the dose of Reboxil is 400 mg/day.

36.   Reboxili for use as described in any one of claims 22 to 35, wherein the reboxili is administered in the form of a salt, and the salt is preferably reboxili succinate.

37.   Reboxil for use as described in any of claims 22 to 36, wherein the aromatase inhibitor is letrozole or anastrozole.

38.   Reboxil for use as described in claim 37, wherein the aromatase inhibitor is letrozole, preferably administered in a dose of 2.5 mg/day.

39.   Reboxil for use as described in claim 37, wherein the aromatase inhibitor is anastrozole, preferably administered in a dose of 1 mg/day.

40.   Reboxili for use as described in any one of claims 22 to 39, wherein the dose of Reboxili is 400 mg/day, the Reboxili is administered in the form of Reboxili succinate, and the aromatase inhibitor is letrozole or anastrozole, preferably 2.5 mg/day of letrozole or 1 mg/day of anastrozole.

41.   Riboxil for use as described in any of claims 22 to 40, wherein the patient achieves at least 36 months of improvement in OS, DDFS and/or RFS or a reduction in the risk of breast cancer recurrence. K.   More exemplary embodiments

More treatment methods and uses of Reboxil are provided in the following embodiments.

1.     Reboxilibe succinate is for use in a method of treating HR+/HER2- Stage II or III early breast cancer in adult patients who have received at least one prior treatment for early breast cancer and who have no signs or symptoms of cancer, wherein the method comprises administering to the patient an adjuvant therapy comprising (i) administering a dose of reboxilibe succinate on days 1 to 21 of a 28-day cycle, with a total dose of 400 mg/day of reboxilibe, and (ii) administering a dose of 2.5 mg/day of letrozole or 1 mg/day of anastrozole on each day of the 28-day cycle.

2.     Riboxil succinate for use as described in embodiment 1, wherein the adjuvant treatment includes letrozole at a dose of 2.5 mg/day.

3.     Riboxil succinate for use as described in embodiment 1, wherein the adjuvant treatment includes anastrozole at a dose of 1 mg/day.

4.     Riboxil succinate for use as described in any one of embodiments 1 to 3, wherein the breast cancer has a lymph node status of N0, N1, N2 or N3.

5.     Riboxil succinate for use as described in embodiment 4, wherein the breast cancer has a lymph node status of N0.

6.     Riboxil succinate for use as described in any one of embodiments 1 to 5, wherein the early breast cancer is stage II, such as stage IIA.

7.     Riboxil succinate for use as described in any one of embodiments 1 to 5, wherein the early breast cancer is stage III, such as stage IIIB.

8.     Riboxil succinate for use as described in any one of embodiments 1 to 5, wherein the early breast cancer is stage III, such as stage IIIC.

9.     Riboxil succinate for use as described in any one of embodiments 1 to 8, wherein the breast cancer is of the ductal subtype.

10.   Riboxil succinate for use as described in any one of embodiments 1 to 9, wherein the patient is Asian.

11.   Riboxil succinate for use as described in any one of embodiments 1 to 10, wherein the method is adjuvant therapy because the patient has received at least one previous treatment for breast cancer selected from the group consisting of surgery, chemotherapy, endocrine therapy and radiation therapy.

12.   Riboxil succinate for use as described in embodiment 11, wherein the patient has not undergone a mastectomy.

13.   Riboxil succinate for use as described in any one of embodiments 1 to 12, wherein the method improves the patient's overall survival (OS), distant disease-free survival (DDFS) and/or recurrence-free survival (RFS) of breast cancer by at least 36 months; or the method reduces the risk of breast cancer recurrence in the patient by at least 36 months. L.   Additional exemplary embodiments

Additional treatment methods and uses of reboxil are provided in the following embodiments.

1.     A method for preventing recurrence of breast cancer in an adult patient who has received prior treatment for HR+/HER2- stage II or III early breast cancer, the method comprising administering to the patient (i) a dose of riboxil, its free base form or a pharmaceutically acceptable salt thereof and (ii) a dose of an aromatase inhibitor, preferably letrozole or anastrozole.

2.     A method for treating an adult patient in remission from HR+/HER2- stage II or stage III early breast cancer, the method comprising administering to the patient (i) a dose of riboxil, its free base form or a pharmaceutically acceptable salt thereof and (ii) a dose of an aromatase inhibitor, preferably letrozole or anastrozole.

3.     A method for treating HR+/HER2- stage II or III early breast cancer in an adult patient in need thereof, the method comprising administering to the patient (i) a dose ranging from 150 mg/day to 450 mg/day of riboxil, its free base form or a pharmaceutically acceptable salt thereof, administered on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor, preferably letrozole or anastrozole, administered daily in a 28-day cycle.

4.     The method as described in any one of embodiments 1 to 3, wherein the reboxili is a pharmaceutically acceptable reboxili salt.

5.     The method as described in embodiment 4, wherein the reboxili salt is reboxili succinate.

6.     The method as described in any of embodiments 1, 2, 4 and 5, wherein the dose of Riboxil is not 600 mg/day.

7.     The method as described in any one of embodiments 1 to 5, wherein the dose of Riboxil is 200 mg/day or 400 mg/day.

8.     The method as described in embodiment 7, wherein reboxili is administered in the form of reboxili succinate, and the total dose of reboxili is 200 mg/day.

9.     The method as described in embodiment 7, wherein reboxili is administered in the form of reboxili succinate, and the total dose of reboxili is 400 mg/day.

10. The method as described in embodiment 7, wherein the reboxil is administered at a dose of 400 mg/day for a period of time, followed by administration of 200 mg/day of reboxil.

11.   The method as described in any one of embodiments 1 to 10, wherein the dose of Riboxil is administered orally.

12.   The method as described in any one of embodiments 1 to 11, wherein the dose of Riboxil is administered in the form of a tablet.

13.   The method as described in any one of embodiments 1 to 12, wherein the aromatase inhibitor is letrozole or anastrozole.

14.   The method as described in any one of embodiments 1 to 13, wherein the aromatase inhibitor is administered orally.

15. The method of embodiment 13 or 14, wherein the letrozole is administered in a dosage ranging from 1 mg/day to 4 mg/day.

16. The method as described in embodiment 15, wherein the letrozole is administered in a dose of 2.5 mg/day.

17. The method of embodiment 13 or 14, wherein the anastrozole is administered in a dosage ranging from 0.5 mg/day to 1.5 mg/day.

18. The method as described in embodiment 17, wherein the anastrozole is administered in a dose of 1 mg/day.

19. A method for treating recurrence of breast cancer in an adult patient who has received at least one prior treatment for HR+/HER2- stage II or III early breast cancer and has no detectable signs or symptoms of breast cancer, the method comprising administering to the patient an adjuvant therapy comprising (i) a dose of 400 mg/day of riboxil succinate administered on days 1 to 21 of a 28-day cycle and (ii) 2.5 mg/day of letrozole or 1 mg/day of anastrozole administered daily in a 28-day cycle.

20. A method for treating an adult patient who is in remission from HR+/HER2- stage II or stage III early breast cancer and who is in need of an adjuvant therapy, the method comprising administering to the patient an adjuvant therapy comprising (i) administering a dose of riboxil succinate on days 1-21 of a 28-day cycle, with a total dose of riboxil succinate of 400 mg/day, and (ii) administering a dose of 2.5 mg/day of letrozole or 1 mg/day of anastrozole on each day of the 28-day cycle.

21.   The method of any one of embodiments 1 to 20, wherein the treatment comprises administering a gonadotropin-releasing hormone agonist.

22. The method as described in embodiment 21, wherein the gonadotropin-releasing hormone agonist is goserelin.

23. The method as described in embodiment 22, wherein the goserelin is administered in a dose ranging from 2 mg to 5 mg.

24. The method as described in embodiment 23, wherein the dose of goserelin is 3.6 mg.

25. The method of any one of embodiments 22 to 24, wherein the goserelin is administered subcutaneously.

26. The method of any one of embodiments 22 to 25, wherein goserelin is administered once every 4 weeks.

27. The method as described in any one of embodiments 1 to 20, wherein the patient is a postmenopausal female.

28. The method as described in any one of embodiments 1 to 26, wherein the patient is a premenopausal female or male.

29.   The method of any one of embodiments 1 to 28, wherein the treatment is administered to the patient for at least 12 months.

30. The method of embodiment 29, wherein the treatment is administered to the patient for at least 24 months.

31. The method of embodiment 29 or embodiment 30, wherein the treatment is administered to the patient for at least 36 months.

32. The method of any of embodiments 29 to 31, wherein the treatment is administered to the patient for at least 48 months.

33. The method of any of embodiments 29 to 32, wherein the treatment is administered to the patient for at least 60 months.

34.   The method as described in any one of embodiments 1 to 33, wherein the breast cancer is ER+ and PR+.

35.   The method as described in any one of embodiments 1 to 33, wherein the breast cancer is ER- and PR+.

36.   The method as described in any one of embodiments 1 to 33, wherein the breast cancer is ER+ and PR-.

37.   The method as described in any one of embodiments 1 to 36, wherein the histological subtype of breast cancer is a ductal subtype.

38.   The method as described in any one of embodiments 1 to 37, wherein the histological subtype of the breast cancer is a lobular subtype.

39. A method as described in any one of embodiments 1 to 38, wherein the breast cancer is stage IIA cancer or stage IIB cancer.

40. The method as described in embodiment 39, wherein the breast cancer is stage IIA cancer.

41. The method as described in embodiment 39, wherein the breast cancer is stage IIB cancer.

42. A method as described in any one of embodiments 1 to 38, wherein the breast cancer is stage IIIA cancer, stage IIIB cancer or stage IIIC cancer.

43. The method as described in embodiment 42, wherein the breast cancer is stage IIIA cancer.

44. The method as described in embodiment 42, wherein the breast cancer is stage IIIB cancer.

45. The method as described in embodiment 42, wherein the breast cancer is stage IIIC cancer.

46.   The method of any one of embodiments 1 to 45, wherein the treatment is administered without regard to the lymph node status of the breast cancer.

47.   The method as described in any one of embodiments 1 to 46, wherein the breast cancer has a lymph node status selected from N0, N1, N2 and N3.

48. The method as described in embodiment 46 or 47, wherein the breast cancer has a lymph node status of N0.

49. The method as described in embodiment 46 or 47, wherein the breast cancer has a lymph node status of N1 to N3.

50. The method as described in embodiment 46 or 47, wherein the breast cancer has a lymph node status of N1.

51. The method as described in embodiment 46 or 47, wherein the breast cancer has a lymph node status of N2.

52. The method as described in embodiment 46 or 47, wherein the breast cancer has a lymph node status of N3.

53.   The method as described in any one of embodiments 1 to 52, wherein the breast cancer comprises one or more cells having a histological grade selected from G1, G2 or G3.

54. The method of embodiment 53, wherein the breast cancer comprises one or more cells with G1 histological grade.

55.   The method as described in embodiment 53, wherein the breast cancer comprises one or more cells with G2 histological grade.

56. The method of embodiment 53, wherein the breast cancer comprises one or more cells having a G3 histological grade.

57. A method as described in any one of embodiments 1 to 56, wherein the breast cancer comprises tumors of T0, T1, T2, T3 or T4 classification.

58. The method as described in embodiment 57, wherein the breast cancer comprises tumors of T1, T2 or T3 classification.

59. The method as described in embodiment 57, wherein the breast cancer comprises a tumor of T0 category.

60. The method of embodiment 57 or 58, wherein the breast cancer comprises a T1 classification tumor.

61. The method of embodiment 57 or 58, wherein the breast cancer comprises a T2 tumor.

62. The method of embodiment 57 or 58, wherein the breast cancer comprises a T3 tumor.

63. The method as described in embodiment 57, wherein the breast cancer comprises a T4 class tumor.

64.   The method of any one of embodiments 1 to 63, wherein the breast cancer has a Ki67 status of 20 or less.

65.   The method of any one of embodiments 1 to 63, wherein the breast cancer has a Ki67 status greater than 20.

66. The method of any one of embodiments 1 to 65, wherein prior to administration, the patient has received a loading dose of (i) riboxil and/or (ii) endocrine therapy.

67.   The method of any of embodiments 1 to 18 and 20 to 66, wherein the patient has received at least one prior treatment for cancer.

68. The method of implementation 19 or 67, wherein the previous treatment is an adjunct to another previous treatment.

69. The method as described in embodiment 67 or 68, wherein the previous treatment is surgery.

70. The method as described in embodiment 69, wherein the surgery comprises complete surgical resection of the cancer.

71. The method as described in embodiment 69 or 70, wherein the surgery is a mastectomy.

72. The method of embodiment 67 or 68, wherein the previous treatment is chemotherapy.

73. The method of embodiment 72, wherein the previous treatment is adjuvant chemotherapy.

74. The method of implementation method 72, wherein the previous treatment is neoadjuvant chemotherapy.

75.   The method as described in embodiment 67 or 68, wherein the previous treatment is endocrine therapy.

76. The method of implementation method 67 or 68, wherein the previous treatment is radiation therapy.

77.   The method as described in any of embodiments 19 and 67 to 76, wherein the patient has not responded to previous treatment.

78.   The method of any one of embodiments 1 to 77, wherein the patient is located in a geographic region selected from North America, Western Europe, or Oceania.

79.   The method as described in any one of embodiments 1 to 78, wherein the patient is Asian.

80.   The method as described in any one of embodiments 1 to 79, wherein the patient is aged between 18 and 45 years old.

81.   The method as described in any of embodiments 1 to 79, wherein the patient is 45 to 54 years old.

82.   The method as described in any one of embodiments 1 to 79, wherein the patient is 54 to 64 years old.

83.   The method as described in any of embodiments 1 to 79, wherein the patient is older than 64 years old.

84.   The method of any of embodiments 1 to 83, wherein the patient has a BMI of 25 or greater.

85.   The method of any one of embodiments 1 to 83, wherein the patient has a BMI of less than 25.

86. A method as described in any of embodiments 1 to 85, wherein the treatment improves the patient's condition compared to patients not receiving the treatment and/or compared to the patient's condition before treatment.

87. The method of any of embodiments 1 to 86, wherein the treatment reduces the risk of invasive disease.

88. The method of embodiment 87, wherein the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than 1 when the risk is calculated relative to patients not receiving the treatment.

89. The method of embodiment 88, wherein the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than or equal to 0.78 when the risk is calculated relative to patients not receiving the treatment.

90.   The method of any of embodiments 1 to 26 and 28 to 89, wherein the patient is a premenopausal female or male and the treatment reduces the risk of invasive disease, corresponding to a hazard ratio of less than or equal to 0.72 when the risk is calculated relative to patients not receiving the treatment.

91.   The method of any of embodiments 87 to 89, wherein the cancer is HR+/HER2- stage III early breast cancer and the treatment reduces the risk of invasive disease, corresponding to a hazard ratio of less than or equal to 0.74 when the risk is calculated relative to patients not receiving the treatment.

92. The method of any of embodiments 87 to 89, wherein the cancer is HR+/HER2- stage II early breast cancer and the treatment reduces the risk of invasive disease, corresponding to a hazard ratio of less than or equal to 0.76 when the risk is calculated relative to patients not receiving the treatment.

93. The method of any of embodiments 87 to 89, wherein the cancer is HR+/HER2- stage III early breast cancer and the treatment reduces the risk of invasive disease by at least 25%, corresponding to a hazard ratio of 0.75 when the risk is calculated relative to patients not receiving the treatment.

94. A method as described in any of embodiments 1 to 93, wherein the treatment reduces the risk of invasive disease to similar levels in patient subgroups including patients with stage II early breast cancer, patients with stage III early breast cancer, premenopausal female or male patients, and postmenopausal female patients.

95. A method as described in any of embodiments 1 to 94, wherein the treatment does not result in a shortening of overall survival, corresponding to a hazard ratio of 0.76 when the risk is calculated relative to patients not receiving the treatment.

96. The method of any one of embodiments 1 to 95, wherein the treatment reduces and/or prevents one or more of the risk of cancer recurrence, cancer spread, the development and/or growth of additional cancers, and death from cancer.

97. The method of embodiment 96, wherein the treatment reduces cancer recurrence, wherein the recurrence is one or more of invasive ipsilateral breast tumor (IBTR) recurrence, loco-regional invasive recurrence, and distant recurrence.

98. The method of embodiment 96, wherein the treatment reduces cancer spread, wherein the cancer spread is invasive contralateral breast cancer or another primary invasive cancer.

99. The method of any one of embodiments 1 to 98, wherein the treatment prevents death from cancer. XI. Definitions

Except in the examples or where otherwise indicated, all numbers used herein expressing amounts of ingredients, dosages, or reaction conditions are to be understood in all cases as modified by the term "about", as interpreted by those skilled in the relevant art. Unless otherwise indicated, the term "about" as used herein is equivalent to ± 10% of the given numerical value.

"Adjuvant therapy" (or adjuvant therapy) refers to therapy given after initial treatment, e.g., to reduce the risk of disease recurrence. In cancer, adjuvant therapy may be administered, in particular, to reduce the risk of cancer recurrence, e.g., by destroying cancer cells remaining after initial treatment. For example, a therapy comprising a dose of riboxil in combination with an aromatase inhibitor may be administered as an adjuvant therapy after initial treatment (e.g., including surgery, radiation therapy, and/or chemotherapy).

"Neoadjuvant therapy" (or neoadjuvant therapy) refers to treatment delivered before primary treatment. In cancer, neoadjuvant therapy can specifically shrink the size of a tumor or kill cancer cells that have spread.

"Co-administer" or "co-administration" or "combination administration" and the like are intended to cover the administration of selected therapeutic agents to a single patient and to cover treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.

"Combination" refers to a fixed combination of two or more agents (also referred to as co-agents or combination partners), for example, in one dosage unit form, or a non-fixed combination (or kit of parts) for combined administration, wherein a first agent (also referred to as a first therapeutic agent) and a second agent (also referred to as a second therapeutic agent) can be administered independently at the same time or administered separately within time intervals, for example, wherein the time intervals allow the combination partners to provide a synergistic (e.g., synergistic) effect. As used herein, the term "combination administration" and the like are intended to encompass administration of the selected combination partners to a single subject (e.g., a patient) in need thereof, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time. The term "fixed combination" means that the active ingredients (e.g., combination partners) are both administered to a patient simultaneously in the form of a single dosage. The term "non-fixed combination" or "kit of parts" means that the active ingredients (e.g., combination partners) are provided separately (e.g., within a kit) and/or are administered to a patient concurrently or sequentially (without specific time limits) as separate dosage forms, wherein such administration provides therapeutically effective levels of the two compounds in the patient.

A "dosage range" refers to the upper and lower limits of acceptable variation in the amount of a given therapeutic agent. Typically, any amount of the agent within the given range can be administered to a patient being treated.

A "loading dose" can be an initial dose of a drug that can be given at the beginning of or before the start of a course of treatment and then stepped down to a different, typically lower dose (e.g., a therapeutic or maintenance dose). A loading dose can be a single dose or a short-term regimen of a compound administered to a subject to rapidly increase the blood concentration level of a drug. Suitably, the short-term regimen used herein will be: 1 to 14 days; e.g., 1 to 7 days; e.g., 1 to 3 days; e.g., three days; e.g., two days; e.g., one day. In some embodiments, a "loading dose" can increase the blood concentration of a drug to a therapeutically effective level. In some embodiments, a "loading dose" can be combined with a therapeutic dose of a drug to increase the blood concentration of a drug to a therapeutically effective level. A "loading dose" can be administered once a day, or more than once a day (e.g., up to 4 times a day). In some embodiments, a loading dose can be used for drug molecules that have a long half-life or slow elimination in the body.

"Pharmaceutical preparation" or "pharmaceutical composition" refers to a mixture or solution containing at least one therapeutic agent suitable for administration to warm-blooded animals (e.g., humans).

The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms which are suitable, within the scope of sound medical judgment, for use in contact with the tissues of mammals (especially humans) without causing excessive toxicity, irritation, allergic reaction and other problematic complications and which are commensurate with a reasonable benefit/risk ratio.

"Subject", "patient" or "warm-blooded animal" is intended to include animals. Examples of subjects include mammals, such as humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals. In certain embodiments, the subject is a human.

"Therapeutically effective" preferably refers to an amount of a therapeutic agent that is effective in providing a therapeutic response or preventing the progression of cancer in a subject. A therapeutically effective treatment or therapeutically effective amount of a treatment need not completely cure the subject, but may partially or completely delay, ameliorate, reverse or reduce at least one or more signs, symptoms or manifestations of the disease.

"Treatment" or "treating" may be preventive and/or therapeutic (including but not limited to palliative, symptom-relieving, symptom-reducing), as well as delaying the progression of a disease or condition (e.g., cancer). The term "preventive" means preventing or delaying the onset or recurrence of a disease (e.g., cancer). As used herein, the term "delaying progression" means administering the combination to a patient who is in the pre-stage or early stages of the cancer to be treated, a patient who has been diagnosed with a precancerous form of the corresponding cancer, and/or a patient who has been diagnosed as being at risk of developing a condition corresponding to the cancer.

A "tumor" is an abnormal mass of tissue. A tumor may contain cancer cells. If a tumor does not spread or invade nearby tissue or other parts of the body, it may be described as benign. If a tumor spreads to other tissues or parts of the body, it may be described as malignant. XII. Abbreviations AE Adverse Events AI Aromatase inhibitors AJCC American Cancer Society ALND Axillary lymph node dissection ALP Alkaline phosphatase ALT Alanine transaminase ANC Absolute neutrophil count aPTT Activated partial thromboplastin time AST Aspartate aminotransferase ATC Anatomical Therapeutic Chemistry AUC Area under the curve AV Chamber BC Breast cancer BCRP Breast cancer resistance protein BSEP Bile salt delivery pump CA Competent authority CBP Fertility CCND1 Cyclin D1 CDK Cyclic protein-dependent serine-threonine protein kinase CI Confidence interval CISH Chromogenic in situ hybridization Ctrough Valley concentration Cmax Maximum serum concentration CMO&PS Medical Office and Patient Safety Officer COSMIC Catalog of somatic mutations in cancer CRF Case Report Form; the term CRF can apply to EDC or paper CSR Clinical research reports CT Computed tomography CTCAE Common terminology standards for adverse events ctDNA Circulating tumor DNA ctRNA Circulating tumor RNA CV Coefficient of variation CYP Cytochrome P450 DCIS Duct carcinoma in situ DDFS Distant disease-free survival DDI Drug-drug interactions DHEA Dehydroepiandrosterone DILI Drug-induced liver injury DNA DNA DX Diagnosis EBC Early Breast Cancer EBCTCG EBC Clinical Trial Collaboration Group ECG Electrocardiogram ECHO Echocardiogram ECOG Eastern Cancer Collaborative EDC Electronic Data Acquisition eGFR Estimated glomerular filtration rate EORTC-QLQ European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire EOT Treatment completed EQ-SD-SL EuroQoL 5-level scale ER Estrogen receptor ET Endocrine therapy FAS Full analysis set FDA U.S. Food and Drug Administration FDG-PET Fluorodeoxyglucose positron emission tomography FISH Fluorescent in situ hybridization FSH Follicle-stimulating hormone G2-3 Organizational Science Level 2-3 GCP Drug Clinical Trial Management Standards GDPR General Data Protection Regulation (EU) 2016/679 GGT γ-Glutaryl transferase GI Gastrointestinal GnRH Gonadotropin-releasing hormone GWAS Genome-wide association studies HADS Hospital Anxiety and Depression Scale HBV Hepatitis B virus β-hCG β-human chorionic gonadotropin HCV Hepatitis C virus HER2 Human epidermal growth factor receptor 2 HIPAA Health Insurance Privacy and Accountability Act (USA) HIV Human immunodeficiency virus HLA Human leukocyte antigen HR Hormone receptors IB Researcher's Handbook IBTR Invasive ipsilateral breast tumor ICH International Coordination Council iDFS Invasive disease-free survival IDMC Independent Data Monitoring Committee IEC Independent Ethics Committee IHC Immunohistochemistry ILD Interstitial lung disease IMP Investigational Drugs IN Researcher Notification INR International normalized ratio IRB Institutional Review Board IRT Interactive Response Technology IUD Intrauterine device iv Intravenous LC-MS/MS Liquid chromatography-tandem mass spectrometry LDH Lactate dehydrogenase LFT Liver function tests LLOQ Lower limit of quantitation LPLV Last visit of the last patient LRRFS Locoregional relapse-free survival LVEF Left ventricular ejection fraction MATE1 Multidrug and toxin efflux protein-1 MDRD Kidney Disease Diet Modification MI Myocardial infarction MRI Magnetic resonance imaging msec millisecond MUGA Multi-gate acquisition NaF-PET Sodium fluoride positron emission tomography NCI National Cancer Institute NSAI Nonsteroidal aromatase inhibitors OCT2 Organic cation transporter 2 ORR Overall response rate OS Overall survival PAS Pharmacokinetic Analysis Set PFS Progression-free survival P-gp P-glycoprotein PgR or PR Progesterone receptor PICF Patient Informed Consent PK Pharmacokinetics PK-ANC PK-absolute neutrophil count PK-QTcF PK-QT interval in ECG corrected by Fridericia formula PPS Meet the protocol set PRO Patient-Reported Outcomes PT Prothrombin time QD Once a day QoL Quality of life QT QT interval in ECG QTc QT interval in ECG (corrected) QTCE QT interval in ECG (corrected according to Fridericia formula) R Retinoblastoma RFS Relapse-free survival RNA RNA RoW Rest of the World SAE Serious adverse events SAP Statistical Analysis Project SC Steering Committee SEER Surveillance, epidemiology, and end results SERM Selective estrogen receptor modulators SGOT Serum glutamine oxalyl acetate aminotransferase SGPT Serum glutamine pyruvate aminotransferase SISH Silver in situ hybridization SLN Sentinel lymph node STEEP Standardized Definition of Treatment Endpoints in Adjuvant Breast Cancer Trials SUSAR Suspected unexpected serious adverse reaction T _1/2 half life TBIL Total bilirubin TdP Torsades de pointes TEAE Adverse reactions during treatment TEN Toxic epidermal necrolysis _Tmax The time when the maximum observed concentration ( _max ) occurs TNM Tumor, Lymph Nodes, and Metastases ULN Upper limit of normal US Ultrasound TRIO Translational Oncology Research VAS Visual analog scale WBC leukocyte WHO World Health Organization XIII. References

All publications, patents, and patent applications mentioned herein are incorporated by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety. XIV. Examples

Hereinafter, the present invention will be described in more detail and with particular reference to examples, but such examples are not intended to limit the present invention. a.    Example 1. Overview of clinical trials

The Phase 3 trial with the protocol title “A Phase III, Multicenter, Randomized, Open-Label Trial Evaluating the Efficacy and Safety of Riboxil Plus Endocrine Therapy as Adjuvant Therapy in Patients with Hormone Receptor-Positive, HER2-Negative, Early-Stage Breast Cancer” is described on ClinicalTrials.gov, Identifier: NCT03701334 (the entire disclosure of that webpage is incorporated herein by reference). The trial has been and is being conducted according to the protocol described below.

Study Design: See Figure 1. Summary of the Clinical Protocol for the NATALEE Trial (A New Adjuvant Trial Using Riboxil [LEE011]) Project Title A phase III, multicenter, randomized, open-label trial evaluating the efficacy and safety of ribociclib plus endocrine therapy as an adjuvant in patients with hormone receptor-positive, HER2-negative, early-stage breast cancer (the New Adjuvant Trial with Riboxil [LEE011]: NATALEE). Test No. CLEE011O12301C (TRIO033) Trial Sponsor Novartis AG Participation Research Center About 425 research centers around the world will participate in the trial. Research Drugs Riboxili (LEE011) Indications Adjuvant treatment for hormone receptor (HR)-positive, HER2-negative, early breast cancer (EBC). Group Premenopausal and postmenopausal women and men with HR-positive, HER2-negative EBC who were appropriately surgically resected and eligible for adjuvant nonsteroidal aromatase inhibitors (NSAIs) for at least 5 years. Purpose / End Point Trial Design and Treatment This is a Phase III, multicenter, randomized, open-label trial evaluating the efficacy and safety of riboxilib plus ET as adjuvant therapy in women and men with HR-positive, HER2-negative EBC. iDFS is the primary endpoint of the trial, as defined according to the STEEP system. The trial will include pre- and postmenopausal women and men with EBC who are HR-positive, HER2-negative, and have anatomic stage groups of III, IIB, or a subset of stage IIA cases (as defined in inclusion criterion #8, see below), who have undergone appropriate surgical resection, radiation therapy (if indicated), adjuvant chemotherapy or neoadjuvant chemotherapy (if indicated), and are considered eligible for adjuvant ET of at least 60 months duration. See Figure 1. Approximately 5,000 patients will be randomized in a 1:1 ratio (using an interactive response technology system [IRT]) to two treatment groups: • Investigational Group: • Riboxil 400 mg, taken orally once daily on Days 1 to 21 of a 28-day cycle, for 36 months (approximately 39 cycles) from randomization. And • ET consisting of: • For postmenopausal women: letrozole 2.5 mg, taken orally once daily continuously or anastrozole 1 mg, taken orally once daily continuously. • For premenopausal women and men: letrozole 2.5 mg, taken orally once daily continuously or anastrozole 1 mg, taken orally once daily continuously, combined with goserelin 3.6 mg subcutaneously once every 4 weeks. The duration of ET in the trial is 60 months from the date of randomization. • Control arm: • ET: Same as study arm. In both arms, ET will be administered according to local clinical guidelines and current local prescribing information. Subsequent ET (or any other anticancer treatment) given after the protocol-required 60 months of ET (or after early discontinuation of ET in the trial) will be administered according to the investigator's clinical judgment and will not be considered trial treatment. Randomization will be stratified by: • Menopausal status: premenopausal women and men versus postmenopausal women • AJCC 8th edition anatomical stage group: anatomical stage II versus anatomical stage III • Prior neoadjuvant/adjuvant chemotherapy: yes versus no • Geographic region: North America/Western Europe/Australia versus rest of the world Enrollment will be capped at approximately 2,000 patients in the anatomical stage II group. The trial will include screening, treatment, and follow-up phases. The trial includes an exploratory component that will require tumor and blood sample collection (except for patients enrolled in China). Eligibility Criteria Eligibility criteria Patients must meet all of the following criteria to be eligible for this trial: 1. A signed and dated Patient Informed Consent Form (PICF) was obtained prior to any trial-specific screening procedures. 2. Patients were ≥ 18 years of age at the time of signing of the PICF. 3. Patients were females, or males, with known postmenopausal status at the time of randomization or initiation of adjuvant ET, whichever occurred first. Postmenopausal status is defined as: • Patients who have undergone bilateral oophorectomy, or • Age ≥ 60 years, or • Age < 60 years and amenorrhea for 12 months or more (in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression) with follicle-stimulating hormone (FSH) and plasma estradiol in the postmenopausal range based on local normal ranges. • If taking tamoxifen or toremifene and age < 60 years, FSH and plasma estradiol levels are in the postmenopausal range. NOTES • For women who are premenopausal at the start of adjuvant chemotherapy, amenorrhea is not a reliable indicator of menopausal status because ovarian function may remain intact or restored despite anovulation/amenorrhea. For these women with treatment-induced amenorrhea, serial measurements of FSH and/or estradiol are required according to local clinical guidelines to determine postmenopausal status. • For the purposes of this trial, all women who did not meet the criteria for postmenopausal status were considered premenopausal. 4. Patients have histologically confirmed unilateral primary invasive adenocarcinoma of the breast with an initial cytological or histological diagnosis (i.e., date of pathology report confirming the BC diagnosis) within 18 months before randomization. Patients with multicentric and/or multifocal tumors are eligible if all lesions examined by histopathology meet the pathological criteria in inclusion criteria 5 and 6. 5. The patient's breast cancer is ER and/or PgR positive as determined by the most recent tissue sample analyzed by a local laboratory. 6. The patient has HER2-negative breast cancer, defined as a negative in situ hybridization test or an immunohistochemistry (IHC) status of 0+ or 1+. If IHC is 2+, a negative in situ hybridization (FISH, CISH, or SISH) test is required to confirm HER2-negative status (based on the most recent tissue sample analyzed by a local laboratory test). 7. Patients (except those enrolled in China) have available archival tumor tissue from surgical specimens for submission to the central laboratory (Note: for patients receiving neoadjuvant systemic therapy and with pathological complete remission, archival tumor tissue at the time of initial diagnosis or before the administration of neoadjuvant therapy is mandatory). 8. Patients with completely removed tumor after surgical resection with microscopic margins free of tumor on the final surgical specimen and who fall into one of the following categories: • Anatomical stage group III, or • Anatomical stage group IIB, or • Anatomical stage group IIA with any of the following: • N1, or • N0 with: • Grade 3, or • Grade 2 and meet any of the following criteria: • Ki67 ≥ 20%, or • Oncotype DX Breast Recurrence Score ≥ 26, or • Prosigna/PAM50 classified as high risk, or • MammaPrint classified as high risk, or • EndoPredict EPclin Risk Score classified as high risk Notes: • For patients with anatomic stage IIA (N0) tumor: • If grade is 1 or unknown (Gx), the patient is ineligible. • If grade 2, gene expression test results (by Oncotype DX, Prosigna/PAM50, MammaPrint, or EndoPredict EPclin) or Ki67 levels should be used if obtained according to local practice (i.e., not mandatory for the purpose of the trial). Results must be available at screening. • Any preoperative staging/specimens and/or surgical specimens for patients receiving neoadjuvant therapy must meet the above criteria (for stage and, if stage IIA, N0, also for grade and Ki67 or gene expression testing). • Classification into the AJCC 8th edition anatomic stage groups requires determination of T, N, and M categories. ALND is the preferred method for axillary lymph node staging, but SLN dissection may be used to determine N category in the following situations: • No metastases in the SLN (patient is considered pN0). • Only micrometastases in the SLN (patient is considered pN1mi). • Patient has T1-2 with no clinically evident lymph nodes preoperatively, has not received neoadjuvant chemotherapy, has at least one macrometastasis in 1 or 2 SLNs, and no confluent lymph nodes or significant extranodal disease on SLN dissection (patient is considered pN1). In all other cases, ALND is required to determine N category. 9. Patient has completed adjuvant chemotherapy and/or neoadjuvant chemotherapy per institutional guidelines prior to screening, if indicated. 10. If indicated, the patient has completed adjuvant radiation therapy according to institutional guidelines before screening. 11. The patient has no contraindications to adjuvant ET on trial and plans to receive ET for 5 years (from the date of randomization) or longer. 12. The patient may have received any standard neo-adjuvant and/or adjuvant ET at the time of PICF sign-off, but randomization should be within 12 months of the initial start date of ET. Ovarian suppression or short-term ET for fertility preservation is not considered neo-adjuvant/adjuvant ET. If the patient is receiving tamoxifen or toremifene as adjuvant ET, a washout period of 5 half-lives (i.e., 35 days) is required before randomization (during which time the patient can take an AI). 13. The patient's Eastern Cooperative Oncology Group (ECOG) performance status is 0 or 1. 14. Patients have adequate bone marrow and organ function as defined by the following local laboratory values: • Absolute neutrophil count (ANC) ≥ 1.5 × 10 ⁹ /L • Platelets ≥ 100 × 10 ⁹ /L • Hemoglobin ≥ 9.0 g/dL • Estimated glomerular filtration rate (eGFR) according to the Modification of Diet in Nephropathy (MDRD) formula ≥ 30 mL/min/1.73m ² • Alanine transaminase (ALT) < 2.5 × upper limit of normal (ULN) • Aspartate transaminase (AST) < 2.5 × ULN • Serum total bilirubin <ULN; or total bilirubin ≤ 3.0 × ULN or direct bilirubin ≤ 1.5 × ULN in patients with well-documented Geppel syndrome • International Normalized Ratio (INR) ≤ 1.5 (unless the patient is receiving an anticoagulant and the INR was within the therapeutic range for the intended use of the anticoagulant for 7 days prior to randomization) • The patient must have the following laboratory values within normal limits or corrected to normal limits with supplementation before randomization (corrected local laboratory values should be documented within normal limits): • Potassium • Magnesium • Total calcium (corrected for serum albumin) 15. Standard 12-lead ECG values assessed by a central laboratory, such as: • Screening QTcF interval (using Fridericia-corrected QT interval) < 450 milliseconds (msec) • Resting heart rate 50-90 beats/min (determined by ECG) 16. Patients must be willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other trial procedures. 17. Females of childbearing potential (CBP), defined as all females physiologically capable of pregnancy (see Inclusion Criteria #18 for additional information), must have a confirmed negative serum pregnancy test (for beta-hCG) within 14 days prior to randomization. 18. Females with CBP must be willing to use highly effective contraception. Contraception must be continued during trial treatment and for 21 days after stopping treatment. Highly effective methods of contraception include: • Complete abstinence (when this is consistent with the patient’s preferred and usual lifestyle). Cyclic abstinence (e.g., calendar, ovulation-based, temperature-based, postovulation methods) and external ejaculation are not acceptable methods of contraception. • Female sterility (surgical bilateral oophorectomy, with or without hysterectomy), total hysterectomy or tubal ligation at least 6 weeks prior to the start of the trial treatment. In the case of oophorectomy alone, only if the female reproductive status has been confirmed by subsequent hormonal level assessment. • Male partner sterility (at least 6 months before randomization). For female patients in the trial, the vasectomized male partner should be the patient's only partner. If vasectomy in the male partner is the highly effective contraceptive method of choice, the success of the vasectomy should be medically confirmed according to local practice. • Insertion of an intrauterine device (IUD). Clarification: • Oral (estrogen and progestin), transdermal, injectable, implantable, hormone-containing intrauterine systems, or any other hormonal contraceptive methods were not permitted in this trial. • Women were considered to have CBP unless: they had ≥ 12 months of natural (spontaneous) amenorrhea and had an appropriate clinical profile (i.e., age appropriate, history of vasomotor symptoms) or had undergone surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks before randomization. In the case of oophorectomy alone, a woman was considered not to have CBP only if her reproductive status had been confirmed by follow-up hormone level assessments. • After completion of trial treatment, patients should use effective contraception according to local guidelines. Exclusion Criteria Patients eligible for this trial must not meet any of the following criteria: 2. Patients have received any CDK4/6 inhibitors. 3. Patients have received prior treatment with tamoxifen, raloxifene, or AIs to reduce breast cancer risk (“chemoprevention”) and/or to treat osteoporosis within the past 2 years before randomization. Patients are using concomitant hormone replacement therapy. 4. Patients have received prior treatment with anthracyclines with a cumulative dose of 450 mg/m ² or more for doxorubicin and 900 mg/m ² or more for epirubicin. 5. Patients have known hypersensitivity reactions to Riboxil and/or any formulation of ET (e.g., rare genetic problems such as galactose intolerance, Lapp lactase deficiency, glucose-galactose malabsorption, and soy allergy). 6. Patients have distant metastasis of breast cancer beyond regional lymph nodes (stage IV according to the 8th edition of the AJCC) and/or evidence of recurrence after curative surgery. 7. Patients are concurrently using other anti-neoplastic therapies other than adjuvant ET (see Inclusion Criteria #12). 8. Patients have undergone major surgery, chemotherapy, or radiotherapy within 14 days before randomization. 9. Patients have not recovered from clinical and laboratory acute toxicity related to previous anticancer therapy to NCI CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) version 4.03 ≤ Grade 1 on the day of randomization. Exceptions to this criterion: patients with any grade of alopecia, amenorrhea, grade 2 neuropathy are allowed to enter the trial, or patients with other toxicities that do not pose a safety risk to the patient (at the discretion of the investigator) are allowed to enter the trial. 10. Patients have concurrent aggressive malignancies or previous aggressive malignancies that have completed treatment within 2 years before randomization. NOTE: Patients with appropriately treated basal cell or squamous cell skin cancer or curatively resected cervical carcinoma in situ are eligible. 11. Patients with a known history of human immunodeficiency virus (HIV) infection (testing is not mandatory unless required by local regulations). 12. Patients with known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (testing is not mandatory unless required by local regulations). 13. Clinically significant, uncontrolled cardiac disease and/or cardiac complex abnormalities, including any of the following: • Documented history of myocardial infarction (MI), angina, symptomatic pericarditis, or coronary artery bypass graft within 6 months prior to trial entry. • Documented cardiomyopathy. • Left ventricular ejection fraction (LVEF) < 50% as determined by a multiple gate acquisition (MUGA) scan or echocardiogram (ECHO) (optional test) • QT syndrome or family history of idiopathic sudden death or congenital QT syndrome, or any of the following: • Risk factors for torsade de pointes (TdP), including uncorrected hypocalcemia, hypokalemia, or hypomagnesemia, history of heart failure, or history of clinically significant/symptomatic bradycardia. • One or more concomitant medications with a known risk of prolonging the QT interval and/or known to cause TdP that cannot be discontinued or replaced by a safe alternative (e.g., within 5 half-lives or 7 days prior to starting trial treatment). • Unable to determine the QTcF interval. • Clinically significant arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade atrioventricular (AV) block (e.g., bifascicular block, Mobitz type II, and third-degree AV block). • Uncontrolled arterial hypertension, systolic pressure > 160 mmHg. 14. Patients are currently receiving any of the following medications within 7 days prior to randomization: • Concomitant medications, herbal supplements, and/or fruits (e.g., grapefruit, pomelo, starfruit, lime) and their juices known to be strong inhibitors or inducers of CYP3A4/5 • Drugs with a narrow therapeutic window and primarily metabolized by CYP3A4/5 15. Patients are currently receiving or have received systemic corticosteroids ≤ 2 weeks prior to starting trial treatment, or have not fully recovered from the side effects of such treatment. NOTE: The following corticosteroids are permitted: short-term (< 5 days) systemic corticosteroids; any duration of topical application (e.g., for rash), inhalation spray (e.g., for obstructive airway disease), eye drops, or local injection (e.g., intra-articular). 16. Patients with compromised gastrointestinal (GI) function or GI disease that may significantly alter absorption of the oral trial therapy (e.g., uncontrolled ulcerative disease, uncontrolled nausea, vomiting, or diarrhea, malabsorption syndrome, or small bowel resection). 17. Patients have any other concurrent severe and/or uncontrolled medical conditions that, according to the investigator's judgment, will lead to unacceptable safety risks, prohibit patients from participating in clinical trials or affect protocol compliance (such as chronic pancreatitis, chronic active hepatitis, cirrhosis or any other major liver disease, untreated or uncontrolled active fungal, bacterial or viral infections, active infections requiring systemic antibacterial therapy, etc.) or limit expected life expectancy to ≤ 5 years. 18. Participated in other studies involving one or more investigational drugs within 30 days before randomization or within 5 half-lives of one or more investigational drugs (whichever is longer), or participated in any other type of medical research that is judged to be scientifically or medically incompatible with this trial. If the patient is enrolled or plans to be enrolled in another study not involving the study drug, the consent of the Medical Monitor is required to determine eligibility. 19. Women who are pregnant or breastfeeding (lactating) or who plan to become pregnant or breastfeed during the trial. evaluate Trial visits will be conducted at screening, randomization, during treatment, approximately 30 days after discontinuation of ribociclib (study arm only), end of treatment (EOT), approximately 30 days after discontinuation of all trial treatments, and during follow-up. Efficacy Assessments Efficacy assessments of the primary endpoint iDFS will include detection of locoregional recurrence, distant recurrence, ipsilateral and contralateral invasive BC, second primary invasive non-BC, and death. Clinical assessments of recurrence events will be performed every 12 weeks (± 2 weeks) for the first 24 months from randomization and every 24 weeks (± 3 weeks) thereafter. Mammograms will be performed annually. Clinically suspected recurrences will be confirmed by additional imaging, and every effort will be made to confirm by histology/cytology (unless unsafe at the discretion of the investigator). Survival will be assessed for 60 months after the last patient is randomized until death, withdrawal of consent, loss to follow-up, or end of trial, whichever occurs first. Survival information may be obtained by clinical visit, telephone call, or other means. Safety Assessments Safety assessments will be performed on each patient, including routine safety monitoring (AE collection, hematology laboratory tests, serum chemistry, vital signs measurements, performance status, physical examination, and ECG). QoL and healthcare utilization assessments QoL will be assessed at screening and during treatment and follow-up by periodic questionnaires (i.e., EORTC QLQ-C30, EORTC QLQ-BR23, EQ-5D-5L, and HADS). Use of subsequent anticancer therapy, time to first subsequent anticancer therapy, and healthcare utilization will be assessed in each group. PK assessments Approximately 130 patients from the study groups will be part of the PK subset. Plasma samples will be obtained pre- and post-dose on C1D15 for determination of ribociclib. Statistical methods The primary efficacy analysis will compare the distribution of iDFS between the two treatment groups using a hierarchical log-rank test at a one-sided 2.5% significance level, using stratification information at the time of randomization. The distribution of iDFS will be estimated using the Kaplan-Meyer method. iDFS at the end of each year in each of the two treatment groups will be presented with 95% confidence intervals. Hazard ratios and 95% confidence intervals for iDFS will be estimated using hierarchical Cox regression using stratification information according to IRT at the time of randomization. Results Summary of Results The interim analysis of the NATALEE trial showed:

In the adjuvant setting, Kisqali plus standard endocrine therapy (ET) significantly reduced the risk of disease relapse compared to standard ET alone.

NATALEE is the first and only active Phase III study of a CDK4/6 inhibitor and showed consistent benefit across a broad population of patients with Stage II and III HR+/HER2- early breast cancer (EBC) at risk of relapse, including those without lymph node involvement.

The primary endpoint of invasive disease-free survival (iDFS) was met. Kisqali plus ET significantly reduced the risk of disease recurrence compared with standard adjuvant ET alone, with consistent benefits in patients with stage II and stage III EBC, regardless of lymph node involvement. •   The study met the primary endpoint of iDFS at interim analysis 3 (426/500 events) •     The one-sided p-value of 0.0014 met the early response stopping margin (p < 0.0128) •     The iDFS risk was reduced by approximately 25% (HR: 0.748, 95% CI (0.619-0.906)) •     3-year iDFS rate: RIB+ET: 90.4% vs. ET alone: 87.1%; Δ: 3.3% •   Overall consistent iDFS effect in key subgroups •     Stage III - HR: 0.74 (0.59-0.92); Stage II - HR: 0.76 (0.52-1.1) •     Premenopausal and male - HR 0.72 (0.53-0.98); postmenopausal - HR: 0.78 (0.613-0.997) •   Positive trends were observed for all 2-year efficacy endpoints: RFS, DDFS, and OS •     Any shortening of overall survival (OS) could be excluded: HR 0.76 (0.54-1.07), p-value: 0.0559

In terms of safety, the trial confirmed a well-tolerated safety profile. In addition, the 400 mg ribociclib dose showed an improved profile with low overall toxicity, especially dose-dependent adverse events (cardiac QT interval and neutropenia). There were no new safety findings compared to the known and established safety profile of ribociclib therapy. The discontinuation rate due to adverse events in patients with early breast cancer within 3 years was similar to that in patients with metastatic breast cancer. Compared with the earlier "monarch-E" trial, diarrhea was not a common (> 5%) grade 3 or 4 adverse reaction, and no patient stopped or reduced their ribociclib dose because of this.

In summary, patients in the RIB+ET group had significantly longer iDFS than those in the ET alone group (HR 0.748, p = 0.0014), and the 3-year iDFS rate increased to 90.4% (vs. 87.1%). The iDFS benefit was consistent across different stratification factors and other subgroups. The secondary endpoints of overall survival, relapse-free survival, and distant disease-free survival were consistently in favor of the RIB+ET group. In addition, the addition of RIB had a favorable safety profile with no new signals. Overall, the addition of RIB to standard of care ET showed a statistically significant and clinically meaningful improvement in iDFS, as well as a well-tolerated safety profile. Therefore, the combination therapy can be considered suitable for a broad population of patients with stage II or III HR+/HRE2- early breast cancer, including N0 patients whose cancer has not spread to nearby lymph nodes. This was unexpected based on the results of other parallel studies. Assessment of health-related quality of life (HRQOL) in NATALEE

QoL was analyzed after a median follow-up of 34 months. Approximately 20% of patients completed 3 years of ribociclib plus endocrine therapy.

The prespecified analyses of HRQOL were based on patient-reported outcomes based on a number of survey scales: EORTC QLQ-C30 (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire), for function (physical, social, and emotional) and general health; EORTC QLQ-BR23, for breast cancer symptoms; EQ-VAS (Euro-QoL Visual Analogue Scale) of EQ-5D-5L; and Hamilton Anxiety and Depression Scale (see also Figures 5-8 for exemplary questionnaires). HRQOL was maintained in patients with HR+/HER2- EBC when reboxilide was added to standard of care adjunct to NSAI compared with NSAI alone.

Physical function and global health scores were maintained over time in both the Riboxil + NSAI and NSAI alone groups. XV. Example 2. Trial Protocol

The NATALEE trial has been and is being conducted according to the protocol described in Appendix A. XVI. Example 3. First Interpretable Results and Updated Analysis

The first decipherable results are described in Appendix B.

After 5.6 months of additional follow-up (median follow-up duration was 33.3 months) and with 78.3% of patients completing study treatment with Kisqali® (riboxili), the updated analysis showed a sustained iDFS benefit and that secondary endpoints, including overall survival (OS), remained stable.

The iDFS benefit was consistent across key patient subgroups; in patients with stage II and stage III tumors, Kisqali reduced the risk by 30% and 24.5%, respectively.

The results consolidated the benefit seen at an earlier interim analysis, with adjuvant Kisqali plus a nonsteroidal aromatase inhibitor as standard endocrine therapy (ET) reducing the risk of disease recurrence by 25.1% compared with ET alone in patients with stage II and III hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) early breast cancer (EBC) (HR = 0.749; 95% CI: 0.628, 0.892; p = 0.0006).

Kisqali iDFS showed benefit in pre-specified subgroups:

Kisqali data were also consistent across all secondary efficacy endpoints, including distant disease-free survival (DDFS) (25.1% risk reduction) and relapse-free survival (RFS) (27.3% risk reduction). Overall survival (OS) results will continue to evolve in the long term, as events were less than 4% in both treatment arms (3.3% in the Kisqali-ET arm and 3.4% in the ET-only arm).

Aside from the laboratory abnormalities, the safety profile of Kisqali at the 400 mg dose was consistent with previously reported adverse events (AEs), which were generally low grade. AEs of particular concern (Grade 3 or higher) were neutropenia (44.3%), liver-related AEs (e.g., elevated transaminases) (8.6%), and QT interval prolongation (1.0%)1,2. No new safety signals were identified. XVII. APPENDIX A - CLINICAL TRIAL PROTOCOL

Approximately 425 research centers around the world will participate in the trial. A list of participating investigators will be maintained by Translational Research in Oncology (TRIO). AE Adverse Events AI Aromatase inhibitors AJCC American Cancer Society ALND Axillary lymph node dissection ALP Alkaline phosphatase ALT Alanine transaminase ANC Absolute neutrophil count aPTT Activated partial thromboplastin time AST Aspartate aminotransferase ATC Anatomical Therapeutic Chemistry AUC Area under the curve AV Chamber BC Breast cancer BCRP Breast cancer resistance protein BSEP Bile salt delivery pump CA Competent authority CBP Fertility CCND1 Cyclin D1 CDK Cyclic protein-dependent serine-threonine protein kinase CI Confidence interval CISH Chromogenic in situ hybridization Ctrough Valley concentration Cmax Maximum serum concentration CMO&PS Medical Office and Patient Safety Officer COSMIC Catalog of somatic mutations in cancer CRF Case Report Form; the term CRF can apply to EDC or paper CSR Clinical research reports CT Computed tomography CTCAE Common terminology standards for adverse events ctDNA Circulating tumor DNA ctRNA Circulating tumor RNA CV Coefficient of variation CYP Cytochrome P450 DDFS Distant disease-free survival DDI Drug-drug interactions DHEA Dehydroepiandrosterone DILI Drug-induced liver injury DNA DNA EBC Early Breast Cancer EBCTCG EBC Clinical Trial Collaboration Group ECG Electrocardiogram ECHO Echocardiogram ECOG Eastern Cancer Collaborative EDC Electronic Data Acquisition eGFR Estimated glomerular filtration rate EORTC-QLQ European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire EOT Treatment completed EQ-SD-SL EuroQoL 5-level scale ER Estrogen receptor ET Endocrine therapy FAS Full analysis set FDA U.S. Food and Drug Administration FDG-PET Fluorodeoxyglucose positron emission tomography FISH Fluorescent in situ hybridization FSH Follicle-stimulating hormone G2-3 Organizational Science Level 2-3 GCP Drug Clinical Trial Management Standards GDPR General Data Protection Regulation (EU) 2016/679 GGT γ-Glutathione transferase GI Gastrointestinal GnRH Gonadotropin-releasing hormone GWAS Genome-wide association studies HADS Hospital Anxiety and Depression Scale HBV Hepatitis B virus β-hCG β-human chorionic gonadotropin HCV Hepatitis C virus HER2 Human epidermal growth factor receptor 2 HIPAA Health Insurance Privacy and Accountability Act (USA) HIV Human immunodeficiency virus HLA Human leukocyte antigen HR Hormone receptors IB Researcher's Handbook ICH International Coordination Council iDFS Invasive disease-free survival IDMC Independent Data Monitoring Committee IEC Independent Ethics Committee IHC Immunohistochemistry ILD Interstitial lung disease IMP Investigational Drugs IN Researcher Notification INR International normalized ratio IRB Institutional Review Board IRT Interactive Response Technology IUD Intrauterine device iv Intravenous LC-MS/MS Liquid chromatography-tandem mass spectrometry LDH Lactate dehydrogenase LFT Liver function tests LLOQ Lower limit of quantitation LPLV Last visit of the last patient LRRFS Locoregional relapse-free survival LVEF Left ventricular ejection fraction MATE1 Multidrug and toxin efflux protein-1 MDRD Kidney Disease Diet Modification MI Myocardial infarction MRI Magnetic resonance imaging msec millisecond MUGA Multi-gate acquisition NaF-PET Sodium fluoride positron emission tomography NCI National Cancer Institute NSAI Nonsteroidal aromatase inhibitors OCT2 Organic cation transporter 2 ORR Overall response rate OS Overall survival PAS Pharmacokinetic Analysis Set PFS Progression-free survival P-gp P-glycoprotein PcqI Progesterone receptor PICF Patient Informed Consent PK Pharmacokinetics PK-ANC PK-absolute neutrophil count PK-QTcF PK-QT interval in ECG corrected by Fridericia formula PPS Meet the protocol set PRO Patient-Reported Outcomes PT Prothrombin time QD Once a day QoL Quality of life QT QT interval in ECG QTc QT interval in ECG (corrected) QTCE QT interval in ECG (corrected according to Fridericia formula) RFS Relapse-free survival RNA RNA RoW Rest of the World SAE Serious adverse events SAP Statistical Analysis Project SC Steering Committee SEER Surveillance, epidemiology, and end results SGOT Serum glutamine oxalyl acetate aminotransferase SGPT Serum glutamine pyruvate aminotransferase SISH Silver in situ hybridization SLN Sentinel lymph node STEEP Standardized Definition of Treatment Endpoints in Adjuvant Breast Cancer Trials SUSAR Suspected unexpected serious adverse reaction T _1/2 half life TBIL Total bilirubin TdP Torsades de pointes TEN Toxic epidermal necrolysis _Tmax The time when the maximum observed concentration ( _max ) occurs TNM Tumor, Lymph Nodes, and Metastases ULN Upper limit of normal US Ultrasound TRIO Translational Oncology Research VAS Visual analog scale WBC leukocyte WHO World Health Organization Program Overview Project Title A phase III, multicenter, randomized, open-label trial evaluating the efficacy and safety of ribociclib plus endocrine therapy as an adjuvant in patients with hormone receptor-positive, HER2-negative, early-stage breast cancer (the New Adjuvant Trial with Riboxil [LEE011]: NATALEE). Test No. CLEE011O12301C (TRIO033) Trial Sponsor Novartis AG Participation Research Center About 425 research centers around the world will participate in the trial. Research Drugs Riboxili (LEE011) Indications Adjuvant treatment for hormone receptor (HR)-positive, HER2-negative, early breast cancer (EBC). Group Premenopausal and postmenopausal women and men with HR-positive, HER2-negative EBC who were appropriately surgically resected and eligible for adjuvant nonsteroidal aromatase inhibitors (NSAIs) for at least 5 years. Background and Rationale EBC and Adjuvant Therapy for HR- Positive, HER2- Negative EBC Breast cancer (BC) is the most commonly diagnosed cancer worldwide. In 2012, there were an estimated 1.7 million new cases of BC and 522,000 deaths attributable to BC worldwide. In the United States, BC is expected to be the most common cancer diagnosed in 2018, with an estimated 268,670 new cases and 41,400 deaths. Based on Surveillance, Epidemiology, and End Results (SEER) data collected between 1975 and 2012, 93% of diagnosed BC cases are EBC, of which 62% are confined to the breast tissue and 31% are located in the breast tissue and regional lymph nodes. Although many EBC patients can achieve disease-free status with local therapy, distant recurrence due to micrometastatic disease is common and is the leading cause of death in EBC patients. An estimated 75% of BC express steroid hormone receptors (estrogen receptor [ER] and/or progesterone receptor [PgR]) and may therefore benefit from adjuvant endocrine therapy (ET) with tamoxifen or aromatase inhibitors (AIs) (letrozole, anastrozole, or exemestane). Unlike chemotherapy, ET reduces the risk of recurrence and BC death in HR-positive EBC. Current clinical guidelines for adjuvant ET for HR-positive EBC recommend that premenopausal women receive (a) 5-10 years of tamoxifen with or without ovarian suppression (ovarian suppression is recommended for women at high risk of recurrence after adjuvant chemotherapy), or (b) 5 years of AI with ovarian suppression. Clinical guidelines and expert opinion recommend that postmenopausal women: (a) initially receive AI for 5 years (or up to 10 years), or (b) initially receive tamoxifen for 2-3 years followed by AI for a total of up to 5 years, or AI for up to 5 years, or (c) receive tamoxifen for approximately 5 years followed by AI for 5 years, or (d) receive tamoxifen for up to 10 years. Limited data on EBC in men suggest that tamoxifen or a combination of an AI and a gonadotropin-releasing hormone (GnRH) agonist should be used as adjunctive ET as a first choice. Despite extensive research on EBC and recent advances in multimodal management, relapses remain common, especially in patients with adverse clinical, pathological, and genomic features. Among patients with HR-positive, HER2-negative EBC who have multiple (≥ 4) regional lymph node metastases (roughly corresponding to anatomic stage group III in the AJCC 8th edition breast cancer staging system), approximately 25%-30% of patients will relapse within 5 years regardless of treatment; despite ET for 5 years, only 48% of these patients will be free of distant relapse within 20 years, and almost half of patients will die from BC within 20 years. Although patients with 1-3 regional lymph node metastases (generally corresponding to anatomic stage II group in the 8th edition of the AJCC breast cancer staging system) may have a lower risk of recurrence than patients in anatomic stage III group, 31% of these patients will experience distant recurrence despite ET, and 28% of patients will die from BC within 20 years. Therefore, new treatment strategies are needed to improve the clinical outcomes of patients with HR-positive, HER2-negative EBC. Clinical experience with riboxil in advanced BC Riboxil is an orally bioavailable and highly selective small molecule inhibitor with highly specific nanomolar inhibitory activity against the CDK4/cyclin-D1 and CDK6/cyclin-D3 enzyme complexes. Reboxil directly acts on the cyclin D-CDK4/6-p16-Rb pathway, blocking the progression of the cell cycle and causing cell cycle arrest. Reboxil has been approved by multiple regulatory agencies, including the U.S. Food and Drug Administration (FDA) and the European Commission. The FDA has approved it in combination with the following drugs: (1) AI for the treatment of pre-/perimenopausal or postmenopausal women with HR-positive, HER2-negative advanced or metastatic BC as initial endocrine-based therapy; or (2) fulvestrant for the treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic BC as initial endocrine-based therapy or after disease progression during ET. In Europe, ribociclib is indicated for the treatment of women with HR-positive, HER2-negative locally advanced or metastatic BC in combination with an AI or fulvestrant as initial endocrine-based therapy or in women who have previously received ET. For premenopausal or perimenopausal women, ET should be combined with a luteinizing hormone-releasing hormone agonist. Rationale for Trial Conduct and Trial Design Although adjuvant ET for HR-positive EBC is effective in reducing the risk of relapse and improving survival, relapses remain common, especially in patients with features suggestive of an intermediate or high risk of relapse, such as those in the II and III anatomic stage groups. The addition of the CDK4/6 inhibitor ribociclib to ET has been shown to be clinically effective and have a tolerable toxicity profile for HR-positive, HER2-negative advanced BC; therefore, the addition of ribociclib in the adjuvant setting may prolong invasive disease-free survival (iDFS) in HR-positive, HER2-negative EBC patients at intermediate and high risk of relapse by improving major endocrine responsiveness and preventing or delaying the development of acquired resistance to ET. Therefore, the aim of this randomized, open-label trial was to evaluate the effect of adding ribociclib to standard adjuvant ET on iDFS in HR-positive, HER2-negative EBC patients with anatomic stage group III, IIB, or IIA subsets (as defined by inclusion criterion #8). In this trial, riboxil will be administered at a dose of 400 mg once daily for 3 weeks on/1 week off. The 400 mg riboxil dose has consistent efficacy (based on a post hoc exploratory analysis) and a potentially improved safety profile in terms of QTc interval prolongation and hematologic toxicity compared to the standard 600 mg dose, and is therefore expected to be well tolerated over the recommended 3-year treatment duration. Purpose / End Point Trial Design and Treatment This is a Phase III, multicenter, randomized, open-label trial evaluating the efficacy and safety of riboxilib plus ET as adjuvant therapy in women and men with HR-positive, HER2-negative EBC. iDFS is the primary endpoint of the trial, as defined according to the STEEP system. The trial will include pre- and postmenopausal women and men with HR-positive, HER2-negative EBC with anatomic stage groups of III, IIB, or IIA case subsets (as defined by inclusion criterion #8) who have undergone appropriate surgical resection, radiation therapy (if indicated), adjuvant chemotherapy or neoadjuvant chemotherapy (if indicated), and are considered eligible for adjuvant ET of at least 60 months duration. See Figure 1. Approximately 5,000 patients will be randomized 1:1 (using an interactive response technology system [IRT]) to two treatment groups: • Investigational Group: • Riboxil 400 mg, taken orally once daily on Days 1 to 21 of a 28-day cycle, for 36 months (approximately 39 cycles) from randomization. AND • ET consisting of: • For postmenopausal women: letrozole 2.5 mg, taken orally once daily continuously or anastrozole 1 mg, taken orally once daily continuously. • For premenopausal women and men: letrozole 2.5 mg, taken orally once daily continuously or anastrozole 1 mg, taken orally once daily continuously, combined with goserelin 3.6 mg subcutaneously once every 4 weeks. The duration of ET in the trial is 60 months from the date of randomization. • Control arm: • ET: Same as study arm. In both arms, ET will be administered according to local clinical guidelines and current local prescribing information. Subsequent ET (or any other anticancer treatment) given after the protocol-required 60 months of ET (or after early discontinuation of ET in the trial) will be administered according to the investigator's clinical judgment and will not be considered trial treatment. Randomization will be stratified by: • Menopausal status: premenopausal women and men versus postmenopausal women • AJCC 8th edition anatomical stage group: anatomical stage II versus anatomical stage III • Prior neoadjuvant/adjuvant chemotherapy: yes versus no • Geographic region: North America/Western Europe/Australia versus rest of the world Enrollment will be capped at approximately 2,000 patients in the anatomical stage II group. The trial will include screening, treatment, and follow-up phases. The trial includes an exploratory component that will require tumor and blood sample collection (except for patients enrolled in China). Eligibility Criteria Eligibility criteria Patients must meet all of the following criteria to be eligible for this trial: 1. A signed and dated Patient Informed Consent Form (PICF) was obtained prior to any trial-specific screening procedures. 2. Patients were ≥ 18 years of age at the time of signing of the PICF. 3. Patients were females, or males, with known postmenopausal status at the time of randomization or initiation of adjuvant ET, whichever occurred first. Postmenopausal status is defined as: • Patients who have undergone bilateral oophorectomy, or • Age ≥ 60 years, or • Age < 60 years and amenorrhea for 12 months or more (in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression) with follicle-stimulating hormone (FSH) and plasma estradiol in the postmenopausal range based on local normal ranges. • If taking tamoxifen or toremifene and age < 60 years, FSH and plasma estradiol levels are in the postmenopausal range. NOTES • For women who are premenopausal at the start of adjuvant chemotherapy, amenorrhea is not a reliable indicator of menopausal status because ovarian function may remain intact or restored despite anovulation/amenorrhea. For these women with treatment-induced amenorrhea, serial measurements of FSH and/or estradiol are required according to local clinical guidelines to determine postmenopausal status. • For the purposes of this trial, all women who did not meet the criteria for postmenopausal status were considered premenopausal. 4. Patients have histologically confirmed unilateral primary invasive adenocarcinoma of the breast with an initial cytological or histological diagnosis (i.e., date of pathology report confirming the BC diagnosis) within 18 months before randomization. Patients with multicentric and/or multifocal tumors are eligible if all lesions examined by histopathology meet the pathology criteria in inclusion criteria 0 and 0. 5. The patient's breast cancer is ER and/or PgR positive as determined by the most recent tissue sample analyzed by the local laboratory. 6. The patient has HER2-negative breast cancer, defined as a negative in situ hybridization test or an immunohistochemistry (IHC) status of 0+ or 1+. If IHC is 2+, a negative in situ hybridization (FISH, CISH, or SISH) test is required to confirm the HER2-negative status (based on the most recent tissue sample analyzed by the local laboratory). 7. Patients (except those enrolled in China) have available archival tumor tissue from surgical specimens for submission to the central laboratory (Note: for patients receiving neoadjuvant systemic therapy and with pathological complete remission, archival tumor tissue at the time of initial diagnosis or before the administration of neoadjuvant therapy is mandatory). 8. Patients with completely removed tumor after surgical resection with microscopic margins free of tumor on the final surgical specimen and who fall into one of the following categories: • Anatomical stage group III, or • Anatomical stage group IIB, or • Anatomical stage group IIA with any of the following: • N1, or • N0 with: • Grade 3, or • Grade 2 and meet any of the following criteria: • Ki67 ≥ 20%, or • Oncotype DX Breast Recurrence Score ≥ 26, or • Prosigna/PAM50 classified as high risk, or • MammaPrint classified as high risk, or • EndoPredict EPclin Risk Score classified as high risk Notes: • For patients with anatomic stage IIA (N0) tumor: • If grade is 1 or unknown (Gx), the patient is ineligible. • If grade 2, gene expression test results (by Oncotype DX, Prosigna/PAM50, MammaPrint, or EndoPredict EPclin) or Ki67 levels should be used if obtained according to local practice (i.e., not mandatory for the purpose of the trial). Results must be available at screening. • Any preoperative staging/specimens and/or surgical specimens for patients receiving neoadjuvant therapy must meet the above criteria (for stage and, if stage IIA, N0, also for grade and Ki67 or gene expression testing). • Classification into the AJCC 8th edition anatomic stage groups requires determination of T, N, and M categories. ALND is the preferred method for axillary lymph node staging, but SLN dissection may be used to determine N category in the following situations: • No metastases in the SLN (patient is considered pN0). • Only micrometastases in the SLN (patient is considered pN1mi). • Patient has T1-2 with no clinically evident lymph nodes preoperatively, has not received neoadjuvant chemotherapy, has at least one macrometastasis in 1 or 2 SLNs, and no confluent lymph nodes or significant extranodal disease on SLN dissection (patient is considered pN1). In all other cases, ALND is required to determine N category. 9. Patient has completed adjuvant chemotherapy and/or neoadjuvant chemotherapy per institutional guidelines prior to screening, if indicated. 10. If indicated, the patient has completed adjuvant radiation therapy according to institutional guidelines before screening. 11. The patient has no contraindications to adjuvant ET on trial and plans to receive ET for 5 years (from the date of randomization) or longer. 12. The patient may have received any standard neo-adjuvant and/or adjuvant ET at the time of PICF sign-off, but randomization should be within 12 months of the initial start date of ET. Ovarian suppression or short-term ET for fertility preservation is not considered neo-adjuvant/adjuvant ET. If the patient is receiving tamoxifen or toremifene as adjuvant ET, a washout period of 5 half-lives (i.e., 35 days) is required before randomization (during which time the patient can take an AI). 13. The patient's Eastern Cooperative Oncology Group (ECOG) performance status is 0 or 1. 14. Patients have adequate bone marrow and organ function as defined by the following local laboratory values: • Absolute neutrophil count (ANC) ≥ 1.5 × 10 ⁹ /L • Platelets ≥ 100 × 10 ⁹ /L • Hemoglobin ≥ 9.0 g/dL • Estimated glomerular filtration rate (eGFR) according to the Modification of Diet in Nephropathy (MDRD) formula ≥ 30 mL/min/1.73m ² • Alanine transaminase (ALT) < 2.5 × upper limit of normal (ULN) • Aspartate transaminase (AST) < 2.5 × ULN • Serum total bilirubin <ULN; or total bilirubin ≤ 3.0 × ULN or direct bilirubin ≤ 1.5 × ULN in patients with well-documented Geppel syndrome • International Normalized Ratio (INR) ≤ 1.5 (unless the patient is receiving an anticoagulant and the INR was within the therapeutic range for the intended use of the anticoagulant for 7 days prior to randomization) • The patient must have the following laboratory values within normal limits or corrected to normal limits with supplementation before randomization (corrected local laboratory values should be documented within normal limits): • Potassium • Magnesium • Total calcium (corrected for serum albumin) 15. Standard 12-lead ECG values assessed by a central laboratory, such as: • Screening QTcF interval (using Fridericia-corrected QT interval) < 450 milliseconds (msec) • Resting heart rate 50-90 beats/min (determined by ECG) 16. Patients must be willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other trial procedures. 17. Females of childbearing potential (CBP), defined as all females physiologically capable of pregnancy (see Inclusion Criteria #18 for additional information), must have a confirmed negative serum pregnancy test (for beta-hCG) within 14 days prior to randomization. 18. Females with CBP must be willing to use highly effective contraception. Contraception must be continued during trial treatment and for 21 days after stopping treatment. Highly effective methods of contraception include: • Complete abstinence (when this is consistent with the patient’s preferred and usual lifestyle). Cyclic abstinence (e.g., calendar, ovulation-based, temperature-based, postovulation methods) and external ejaculation are not acceptable methods of contraception. • Female sterility (surgical bilateral oophorectomy, with or without hysterectomy), total hysterectomy or tubal ligation at least 6 weeks prior to the start of the trial treatment. In the case of oophorectomy alone, only if the female reproductive status has been confirmed by subsequent hormonal level assessment. • Male partner sterility (at least 6 months before randomization). For female patients in the trial, the vasectomized male partner should be the patient's only partner. If vasectomy in the male partner is the highly effective contraceptive method of choice, the success of the vasectomy should be medically confirmed according to local practice. • Insertion of an intrauterine device (IUD). Clarification: • Oral (estrogen and progestin), transdermal, injectable, implantable, hormone-containing intrauterine systems, or any other hormonal contraceptive methods were not permitted in this trial. • Women were considered to have CBP unless: they had ≥ 12 months of natural (spontaneous) amenorrhea and had an appropriate clinical profile (i.e., age appropriate, history of vasomotor symptoms) or had undergone surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks before randomization. In the case of oophorectomy alone, a woman was considered not to have CBP only if her reproductive status had been confirmed by follow-up hormone level assessments. • After completion of trial treatment, patients should use effective contraception according to local guidelines. Exclusion Criteria Patients eligible for this trial must not meet any of the following criteria: 1. Patients have received any CDK4/6 inhibitors. 2. Patients have received prior treatment with tamoxifen, raloxifene, or AIs to reduce breast cancer risk (“chemoprevention”) and/or treat osteoporosis within the past 2 years before randomization. Patients are concurrently using hormone replacement therapy. 3. Patients have received prior treatment with anthracyclines with a cumulative dose of 450 mg/m ² or more for doxorubicin and 900 mg/m ² or more for epirubicin. 4. Patients have known hypersensitivity reactions to Riboxil and/or any formulation of ET (e.g., rare genetic problems such as galactose intolerance, Lapp lactase deficiency, glucose-galactose malabsorption, and soy allergy). 5. Patients have distant metastasis of breast cancer beyond regional lymph nodes (stage IV according to the 8th edition of the AJCC) and/or evidence of recurrence after curative surgery. 6. Patients are concurrently using other anti-neoplastic therapies other than adjuvant ET (see Inclusion Criteria #0). 7. Patients have undergone major surgery, chemotherapy, or radiotherapy within 14 days before randomization. 8. Patients have not recovered from clinical and laboratory acute toxicity related to previous anticancer therapy to NCI CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) version 4.03 ≤ Grade 1 on the day of randomization. Exceptions to this criterion: patients with any grade of alopecia, amenorrhea, grade 2 neuropathy are allowed to enter the trial, or patients with other toxicities that do not pose a safety risk to the patient (at the discretion of the investigator) are allowed to enter the trial. 9. Patients have concurrent aggressive malignant tumors or previous aggressive malignant tumors that have completed treatment within 2 years before randomization. NOTE: Patients with appropriately treated basal cell or squamous cell skin cancer or curatively resected cervical carcinoma in situ are eligible. 10. Patients with a known history of human immunodeficiency virus (HIV) infection (testing is not mandatory unless required by local regulations). 11. Patients with known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (testing is not mandatory unless required by local regulations). 12. Clinically significant, uncontrolled cardiac disease and/or cardiac complex abnormalities, including any of the following: • Documented history of myocardial infarction (MI), angina, symptomatic pericarditis, or coronary artery bypass grafting within 6 months prior to trial entry. • Documented cardiomyopathy. • Left ventricular ejection fraction (LVEF) < 50% as determined by a multiple gate acquisition (MUGA) scan or echocardiogram (ECHO) (optional test) • QT syndrome or family history of idiopathic sudden death or congenital QT syndrome, or any of the following: • Risk factors for torsade de pointes (TdP), including uncorrected hypocalcemia, hypokalemia, or hypomagnesemia, history of heart failure, or history of clinically significant/symptomatic bradycardia. • One or more concomitant medications with a known risk of prolonging the QT interval and/or known to cause TdP that cannot be discontinued or replaced by a safe alternative (e.g., within 5 half-lives or 7 days prior to starting trial treatment). • Unable to determine the QTcF interval. • Clinically significant arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade atrioventricular (AV) block (e.g., bifascicular block, Mobitz type II, and third-degree AV block). • Uncontrolled arterial hypertension, systolic pressure > 160 mmHg. 13. Patients are currently receiving any of the following medications within 7 days prior to randomization: • Concomitant medications, herbal supplements, and/or fruits (e.g., grapefruit, pomelo, starfruit, lime) and their juices known to be strong inhibitors or inducers of CYP3A4/5 • Drugs with a narrow therapeutic window and primarily metabolized by CYP3A4/5 14. Patients are currently receiving or have received systemic corticosteroids ≤ 2 weeks prior to starting trial treatment, or have not fully recovered from the side effects of such treatment. NOTE: The following corticosteroids are permitted: short-term (< 5 days) systemic corticosteroids; any duration of topical application (e.g., for rash), inhalation spray (e.g., for obstructive airway disease), eye drops, or local injection (e.g., intra-articular). 15. Patients with compromised gastrointestinal (GI) function or GI disease that may significantly alter absorption of the oral trial therapy (e.g., uncontrolled ulcerative disease, uncontrolled nausea, vomiting, or diarrhea, malabsorption syndrome, or small bowel resection). 16. Patients have any other concurrent severe and/or uncontrolled medical conditions that, according to the investigator's judgment, will lead to unacceptable safety risks, prohibit patients from participating in clinical trials or affect protocol compliance (such as chronic pancreatitis, chronic active hepatitis, cirrhosis or any other major liver disease, untreated or uncontrolled active fungal, bacterial or viral infections, active infections requiring systemic antibacterial therapy, etc.) or limit expected life expectancy to ≤ 5 years. 17. Participating in other studies involving one or more investigational drugs within 30 days before randomization or within 5 half-lives of one or more investigational drugs (whichever is longer), or participating in any other type of medical research that is judged to be scientifically or medically incompatible with this trial. If the patient is enrolled or plans to be enrolled in another study not involving the study drug, the consent of the Medical Monitor is required to determine eligibility. 18. Women who are pregnant or breastfeeding (lactating) or who plan to become pregnant or breastfeed during the trial. evaluate Trial visits will be conducted at screening, randomization, during treatment, approximately 30 days after discontinuation of ribociclib (study arm only), end of treatment (EOT), approximately 30 days after discontinuation of all trial treatments, and during follow-up. Efficacy Assessments Efficacy assessments of the primary endpoint iDFS will include detection of locoregional recurrence, distant recurrence, ipsilateral and contralateral invasive BC, second primary invasive non-BC, and death. Clinical assessments of recurrence events will be performed every 12 weeks (± 2 weeks) for the first 24 months from randomization and every 24 weeks (± 3 weeks) thereafter. Mammograms will be performed annually. Clinically suspected recurrences will be confirmed by additional imaging, and every effort will be made to confirm by histology/cytology (unless unsafe at the discretion of the investigator). Survival will be assessed for 60 months after the last patient is randomized until death, withdrawal of consent, loss to follow-up, or end of trial, whichever occurs first. Survival information may be obtained by clinical visit, telephone call, or other means. Safety Assessments Safety assessments will be performed on each patient, including routine safety monitoring (AE collection, hematology laboratory tests, serum chemistry, vital signs measurements, performance status, physical examination, and ECG). QoL and healthcare utilization assessments QoL will be assessed at screening and during treatment and follow-up by periodic questionnaires (i.e., EORTC QLQ-C30, EORTC QLQ-BR23, EQ-5D-5L, and HADS). Use of subsequent anticancer therapy, time to first subsequent anticancer therapy, and healthcare utilization will be assessed in each group. PK assessments Approximately 130 patients from the study groups will be part of the PK subset. Plasma samples will be obtained pre- and post-dose on C1D15 for determination of ribociclib. Tumor tissue samples will be collected for exploratory biomarker assessments (except for patients enrolled in China) to identify biomarkers that predict benefit from ribociclib and to assess molecular alterations in genes associated with HR-positive BC and cell cycle progression. All patients (except for those enrolled in China) will be required to provide mandatory archival paraffin tumor tissue from a self-healing surgical specimen. If available, additional tumor tissue samples will be collected from tumor biopsies at initial diagnosis or before initiation of neoadjuvant chemotherapy (if administered). Additional tumor biopsies will be mandatory at relapse (unless unsafe for the patient at the investigator's discretion) to identify potential biomarkers and explore potential mechanisms of disease relapse (except for patients enrolled in China). Mandatory blood samples will be collected for ctDNA/ctRNA at baseline, periodically (until distant relapse), and at relapse (except for patients enrolled in China). In patients who consent for this assessment (except for patients enrolled in China), optional blood samples will be collected for pharmacogenomic analysis. In addition, optional additional biomarker analysis is planned for consenting patients if permitted by local regulations. Statistical methods The primary efficacy analysis will compare the distribution of iDFS between the two treatment groups using a stratified log-rank test at a one-sided 2.5% significance level, using stratified information at the time of randomization. The distribution of iDFS will be estimated using the Kaplan-Meyer method. iDFS at the end of each year in each of the two treatment groups will be presented with 95% confidence intervals. Hazard ratios and 95% confidence intervals for iDFS will be estimated using stratified Cox regression using stratified information according to IRT at the time of randomization. Three interim efficacy analyses are planned. The first interim analysis is planned to be performed after approximately 40% of iDFS events have been recorded (approximately 200 events), allowing the trial to be stopped for futility (non-binding). The first interim analysis will not declare efficacy. The second and third interim analyses will be conducted after all patients have been randomized and approximately 70% and 85% of iDFS events have been recorded (approximately 350 and 425 events), respectively, allowing for stopping the trial due to superior efficacy. If the trial is not stopped at the interim analysis, the final iDFS analysis will be conducted after approximately 500 iDFS events have been recorded. Sample size calculations are based on the primary variable, iDFS. It is assumed that the 5-year iDFS rate for patients with anatomic stage II (excluding low-risk patients) is approximately 79% (based on data from a retrospective study evaluating the prognostic impact of Ki67 and other disease characteristics in HR-positive, HER2-negative EBC) and 72% for patients with anatomic stage III (based on data from patients with ≥ 4 lymph nodes treated with AIs in the EBC Clinical Trials Consortium meta-analysis). Based on these assumptions and the expected distribution of patients by anatomic stage, the overall 5-year iDFS in the control group is expected to be approximately 74.8%. The addition of riboxil to standard ET is expected to reduce the risk of iDFS by 27%, or an expected hazard ratio of 0.73. With an overall hazard ratio of 0.73 and 0.76, respectively, 500 iDFS events would provide approximately 93% and 85% power. Assuming a 15% dropout rate at the time of the final iDFS analysis (i.e., a dropout risk of 0.00629 per month), a total of 5,000 patients would need to be randomized, including approximately 3,000 patients with anatomic stage III. 1. Background and rationale 1.1. Disease overview 1.1.1. Epidemiology

Breast cancer (BC) is the most commonly diagnosed cancer worldwide. In 2012, an estimated 1.7 million new cases of BC and 522,000 deaths were attributed to the disease worldwide. ¹ The incidence of BC varies across ethnic groups and geographic locations around the world, ranging from 27 per 100,000 in Central Africa and East Asia to 92 per 100,000 in North America. ² In the United States, BC is expected to be the most common cancer diagnosed in 2018, with an estimated 268,670 new cases and 41,400 deaths. ³ The incidence of BC in European countries was estimated to be 458,337 in 2012. ⁴ BC is uncommon in men, reportedly accounting for approximately 1% of all BC, but its incidence is increasing. ⁵

The vast majority of newly diagnosed BC cases are early breast cancer (EBC), which is confined to the breast tissue and regional lymphatics and may be treated with locoregional treatments such as surgery and radiation therapy. Based on Surveillance, Epidemiology, and End Results (SEER) program data collected between 1975 and 2012, 93% of diagnosed cases were EBC, of which 62% were confined to the breast tissue and 31% were confined to the breast tissue and regional lymph nodes. ⁶ 1.1.2. Treatment of EBC

In addition to primary surgical therapy, treatment of EBC usually includes other anti-tumor therapies such as radiation therapy and adjuvant or neoadjuvant systemic therapy. Although many EBC patients can achieve disease-free status through surgical resection and radiation therapy, distant recurrence caused by micrometastatic disease is more common and is also the main cause of death in EBC patients. ⁷ According to a meta-analysis of nearly 150,000 women in 200 randomized clinical trials conducted by the EBC Clinical Trials Collaboration Group (EBCTCG), among EBC patients who did not receive any adjuvant systemic therapy, approximately 36% and 20% of patients will experience recurrence and die from BC during the 5-year follow-up period, respectively. ⁸ Furthermore, patients with hormone receptor (HR)-positive EBC continue to experience recurrence and BC-related mortality 5 years after surgery, with only 45% of patients reported to be recurrence-free at 15-year follow-up.

Adjuvant systemic therapy, including cytotoxic, biologic, and endocrine therapies, can reduce locoregional and distant recurrences, reduce BC-related mortality, and improve overall survival (OS) in patients with EBC. ⁸ The need for and selection of adjuvant systemic therapy is based on the individual risk of recurrence and is guided by a variety of clinical, pathologic, and genomic predictive and prognostic factors of the tumor and the patient, such as tumor stage, histopathologic grade, tumor HR status, human epidermal growth factor receptor-2 (HER2) status, multigene test recurrence scores, proliferation markers such as Ki67, menopausal status, patient comorbidities, and age. Using these factors, the risk of recurrence after EBC surgery can be classified as low, moderate/intermediate, or high. ⁷ Although there is no consensus on the definition of these risk groups, in general, patients with smaller tumors, no regional lymph node metastases, low tumor grade, HR-positive and HER2-negative status, and a low relapse gene panel score have a lower risk of relapse (i.e., 5-year relapse rate of 5%-10%). These patients are often considered for adjuvant endocrine therapy (ET) rather than chemotherapy because the clinical benefit of the latter is relatively low. On the other hand, patients with multiple regional lymph node metastases, high tumor grade, HER2-positive status, or a high relapse gene panel score have a higher risk of relapse. Such patients are usually considered for adjuvant chemotherapy (and HER2-targeted agents for HER2-positive BC) and, if the tumor exhibits HR, adjuvant ET (usually given after completion of chemotherapy).

An estimated 75% of BC express steroid hormone receptors (estrogen receptor [ER] and/or progesterone receptor [PgR]), and therefore these patients may benefit from adjuvant ET with tamoxifen or an aromatase inhibitor (AI) (letrozole, anastrozole, or exemestane). ⁹ ET, unlike chemotherapy, reduces the risk of recurrence and BC death in HR-positive EBC. ⁸

Current clinical guidelines recommend adjuvant ET for HR-positive EBC: ^{10, 11} • For premenopausal women: • 5–10 years of tamoxifen with or without ovarian suppression, or • 5 years of AI therapy with ovarian suppression. ¹² • For postmenopausal women: • 5 years of initial AI therapy (or up to 10 years based on results from the MA.17R ^trial13 ), or • 2–3 years of initial tamoxifen therapy followed by AI therapy (up to 5 years total, or up to 5 years on AI therapy), or • approximately 5 years of tamoxifen therapy followed by 5 years of AI therapy, or • up to 10 years of tamoxifen therapy. ^{10, 11} • For men: Limited data suggest that tamoxifen or a combination of an AI and a gonadotropin-releasing hormone (GnRH) agonist should be considered as the first-line ET for HR-positive, HER2-negative EBC. ¹⁴

Despite extensive research and recent advances in multimodal management of EBC, relapses remain common, especially in patients with adverse clinical, pathologic, and genomic features. Approximately 25%-30% of patients with HR-positive, HER2-negative EBC who have multiple (≥ 4) regional lymph node metastases (roughly corresponding to anatomic stage III in the 8th edition of the AJCC breast cancer staging system) will relapse within 5 years of ET (including AI). ⁸ Despite ET lasting 5 years, only 48% of these patients remain free of distant relapse within 20 years, and almost half of patients will die from BC within 20 years. ¹⁵ Although patients with 1–3 regional lymph node metastases (generally corresponding to anatomic stage II in the AJCC 8th edition breast cancer staging system) may have a lower risk of recurrence than patients in anatomic stage III, 31% of these patients will experience distant recurrence despite ET, and 28% will die from BC within 20 years. ¹⁵

Therefore, new treatment strategies are needed to improve the clinical outcomes of patients with HR-positive, HER2-negative EBC. 1.1.3.    Role of the CDK4/6 pathway in BC

Dysregulation of the CDK4/6-Rb-E2F pathway is an important contributor to ET resistance in BC. Luminal A and B subtypes of BC (85% of which are ER-positive and HER2-negative) have higher rates of cyclin D/CDK activation; amplification of cyclin D1 (CCND1) was observed in 29% and 58% of luminal A and B tumors, respectively, and CDK4 was observed in 14% and 25% of tumors. ^{16, 17} Luminal A subtype tumors also have a loss of CDKN2A, which encodes the CDK inhibitor ^p16INK4A . ¹⁸ The luminal subtype also maintains Rb expression, which is key to benefit from treatment with CDK4/6 inhibitors. ¹⁹

Dysregulation of cell cycle checkpoints may have clinical and therapeutic implications. For example, HR-positive BC patients who display a genetic expression signature of Rb loss have a shorter relapse-free survival (RFS) after adjuvant tamoxifen therapy. ²⁰ An oncogene expression signature of E2F activation has also been associated with higher proliferation of residual tumor cells after neoadjuvant AI therapy. Thus, activation of the CDK4/6-Rb-E2F pathway promotes endocrine resistance, and treatment with CDK4/6 inhibitors or knockdown of CDK4 expression results in reactivation of Rb, rebinding of E2F, and subsequent cell cycle arrest, thereby terminating the proliferation of endocrine-resistant cells.

Selective inhibitors of CDK4/6, such as palbociclib, abemaciclib, and ribociclib, have demonstrated synergistic effects with ET in preclinical studies, have shown efficacy in clinical studies, and have been approved for the initial treatment of patients with HR-positive, HER2-negative advanced BC (in combination with an AI) or after disease progression after prior ET (in combination with fulvestrant) ^21-26 (For more information on the efficacy of ribociclib, please refer to the latest ribociclib Investigator Brochure (IB)).

Considering the efficacy of CDK4/6 inhibitors in HR-positive, HER2-negative advanced BC, co-targeting the CDK4/6-Rb-E2F pathway with CDK4/6 inhibitors may be a feasible strategy to enhance endocrine responsiveness and prevent or delay the development of acquired resistance and should be explored in the adjuvant setting.

Emerging data from ongoing trials (PALLAS and monarchE) investigating other CDK4/6 inhibitors in HR-positive, HER2-negative EBC suggest that patients with anatomic stage III disease may have increased benefit from treatment in the adjuvant setting compared with patients with anatomic stage II disease. ^{27, 28} The PALLAS trial, which is investigating palbociclib in both stage II (including a subset of lower-risk stage IIA patients) and stage III EBC, recently reported a negative outcome, whereas the monarchE trial, which is investigating abemaciclib and appears to include stage III patients, reported a positive outcome. Although there are differences in the design of these two studies and in the biochemical properties of the two CDK4/6 inhibitors studied, early indications that CDK4/6 inhibition may produce a greater therapeutic effect in high-risk stage III EBC cannot be ignored. 1.2. Overview of study treatments and other investigational treatments

This trial included treatment with ribociclib (LEE011) and ET treatment with a nonsteroidal aromatase inhibitor (NSAI; anastrozole or letrozole) +/- goserelin. 1.2.1.    Overview of ribociclib

Reboxil is an orally bioavailable and highly selective small molecule inhibitor with highly specific nanomolar inhibitory activity against the CDK4/cyclin-D1 and CDK6/cyclin-D3 enzyme complexes. As of the date of this document, Reboxil has been approved by multiple regulatory agencies, including the U.S. Food and Drug Administration (FDA) and the European Commission. The FDA has approved it in combination with: (1) an AI for the treatment of pre-/perimenopausal or postmenopausal women with HR-positive, HER2-negative advanced or metastatic BC as initial endocrine-based therapy; or (2) fulvestrant for the treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic BC as initial endocrine-based therapy or after disease progression during ET. In Europe, reboxil is indicated for the treatment of women with HR-positive, HER2-negative locally advanced or metastatic BC in combination with an AI or fulvestrant as initial endocrine-based therapy or in women who have previously received ET. For pre- or perimenopausal women, ET should be combined with a luteinizing hormone-releasing hormone agonist. 1.2.1.1. Non-clinical data

For more details, please refer to the latest Riboxil IB. 1.2.1.2. Clinical Experience

Reboxil is being studied in multiple clinical trials at various stages of development in patients with BC and other solid tumors. For details on the clinical trials, please refer to the latest Reboxil IB. 1.2.1.2.1.     Clinical Safety of Reboxil

The clinical safety of ribociclib has been evaluated in several combination trials with endocrine agents such as letrozole, tamoxifen, exemestane, fulvestrant, and goserelin. The safety profile of ribociclib in combination with a NSAI (+/- goserelin) was investigated in two phase III trials in advanced BC (MONALEESA-2 and MONALEESA-7). ^{24, 29}

Based on the results of the MONALEESA-7 trial, the combination of ribotoxib and tamoxifen is not recommended due to an increased risk of QT prolongation. ²⁹

For a comprehensive review of the safety profile of ribociclib in combination with endocrine agents, please refer to the latest ribociclib IB. 1.2.1.2.2.     Clinical efficacy of ribociclib

Three phase III combination trials have been published in patients with advanced BC evaluating the efficacy of ribociclib and endocrine agents, two of which evaluated ribociclib in combination with a NSAI (+/- goserelin). ^{24, 29}

For more detailed information on the efficacy profile of Reboxil, please refer to the latest Reboxil IB. 1.2.1.2.3.     Clinical Pharmacokinetics of Reboxil

The clinical pharmacokinetics (PK) of riboxil were evaluated in a Phase I study (Study CLEE011X2101) in patients with advanced solid tumors or lymphomas. After a single oral dose of 400 mg capsule formulation, riboxil was absorbed with a median T _max of 4.00 h (range: 0.58 to 4.20 h). After repeated daily oral administration, riboxil reached steady state around day 8. At steady state, the geometric mean of riboxil plasma C _max was 1040 ng/mL (geometric coefficient of variation [CV] 49.3%), and AUC _0-24h was 11400 ng*h/mL (geometric CV 57.8%). The geometric mean effective T _1/2 of Riboxil is 31.6 h (geometric CV 33.2%), and the accumulation ratio is 2.46 (geometric CV 24.6%). LEQ803 is the active metabolite of Riboxil and has similar PK properties to the parent drug. After repeated daily administration, Riboxil and LEQ803 will not accumulate in large quantities.

Based on in vitro and in vivo studies, reboxil undergoes extensive hepatic metabolism in humans via CYP3A. In humans, reboxil is eliminated primarily via hepatic clearance, with a lesser role for renal clearance. Most of the administered dose is excreted via feces (69.1%), with a small amount excreted via urine (22.6%). Reboxil accounts for approximately 23% of the total radioactivity in plasma (CLEE011A2102). The most predominant metabolites in plasma are CCI284 (N-hydroxylated), LEQ803 (N-demethylated), and M1 (di-glucuronide), each accounting for < 10% of the total radioactivity. The clinical activity (pharmacology and safety) of ribociclib after treatment was primarily due to the parent drug, with negligible contribution from circulating metabolites.

Concomitant use of ribociclib with strong CYP3A4 inhibitors or strong CYP3A4 inducers should be avoided as ribociclib exposure may be significantly affected. After a single oral dose of 400 mg ribociclib, co-administration of a strong CYP3A4 inhibitor (ritonavir) increased the AUC _inf of ribociclib by 3.2-fold (CLEE011A2101). After a single oral dose of 600 mg ribociclib, co-administration of a strong CYP3A4 inducer (rifampicin) decreased the AUC _inf of ribociclib by 89% (CLEE011A2101).

Reboxil is a moderate to potent inhibitor of CYP3A4 but has no substantial effects on CYP1A2 substrates in humans (CLEE011A2106). Coadministration of midazolam (CYP3A4 substrate) with multiple doses of reboxil (400 mg) increased midazolam exposure by 3.8-fold. Coadministration of caffeine (CYP1A2 substrate) with multiple doses of reboxil (400 mg) increased caffeine exposure by 20% (1.2-fold). Concomitant use of sensitive CYP3A4 substrates with a narrow therapeutic index should be avoided. Concomitant use of CYP1A2 substrates is not expected to result in clinically important drug-drug interactions (DDIs).

Food does not affect the PK of reboxil administered as capsule or tablet formulations; therefore, reboxil capsules or tablets can be taken without regard for meals (CLEE011A2111, CLEE011A2103).

Based on PK data from the MONALEESA-2 and MONALEESA-7 trials, no significant DDI was observed between ribociclib and the combination partners letrozole or anastrozole. Based on population PK analysis, concomitant use of letrozole or anastrozole had no effect on ribociclib exposure.

For more details, please refer to the latest Riboxil IB. 1.2.2.    Overview of adjuvant endocrine therapy

Tamoxifen, NSAIs (ie, letrozole, anastrozole), and steroidal AIs (ie, exemestane) are used for adjunctive ET in women with HR-positive EBC. AIs can be used either as pre-emptive therapy or after 2-3 or 5 years of previous tamoxifen therapy (see Section 0). The long-term efficacy of these two AI administration methods is similar. ³⁰ Clinical treatment guidelines recommend that there is no convincing evidence of meaningful clinical efficacy or toxicity differences between letrozole, anastrozole, and exemestane, and that similar precautions and monitoring activities should be undertaken regardless of the type of AI administered. ¹¹ GnRH agonists are used to achieve gonadal suppression in premenopausal women or men.

The following sections provide general information about NSAIs and goserelin. For comprehensive safety and efficacy information and guidance for each medication, refer to current local prescribing information and local clinical guidelines. 1.2.2.1. Letrozole Overview

Letrozole is a nonsteroidal competitive inhibitor of the aromatase system. Letrozole works by highly selectively inhibiting the conversion of androgens (which are primarily derived from the adrenal glands and are the major source of estrogen in postmenopausal women) to estrogens. Two weeks of treatment with letrozole at a daily dose of 0.1 to 5 mg induces a 75% to 95% decrease in estrogen levels without significant clinical or laboratory toxicity or changes in levels of other endocrine hormones. ^{31, 32}

Letrozole is administered orally once daily in a dose of 2.5 mg. It is rapidly and completely absorbed from the gastrointestinal (GI) tract. Concomitant intake of food has no effect on the extent of letrozole absorption. Letrozole is metabolized by CYP3A4 to a pharmacologically inactive metabolite, and renal excretion of the glucuronide conjugate of this metabolite is the major route of letrozole elimination.

In a Phase Ib/II dose-escalation/expansion study (CLEE011X2107), letrozole (2.5 mg/day) and riboxil (600 mg/day, 3 weeks on/1 week off) did not affect each other's metabolism.

The most commonly reported adverse events (AEs) with letrozole in the adjuvant and extended-adjuvant clinical trials were hot flashes, arthralgia/arthritis, and myalgia. In general, the intensity of the adverse reactions observed was mild to moderate. Adjuvant use of letrozole (or anastrozole) is associated with decreased bone mass density, which may lead to osteoporosis and related fractures. Monitoring of bone mass density should be considered.

Due to their mechanism of action, letrozole and other AIs should not be used for the above indications in women with intact ovarian function or in men who are not castrated.

For more information about letrozole, see current local prescribing information. 1.2.2.2. Anastrozole Overview

Anastrozole, like letrozole, is a selective NSAI. It significantly reduces serum estradiol concentrations with no detectable effect on adrenal cortical steroid or aldosterone formation. Anastrozole is administered orally once daily at a dose of 1 mg with or without food. Anastrozole is metabolized by N-dealkylation, hydroxylation, and glucuronidation. Hepatic metabolism accounts for approximately 85% of anastrozole elimination. Renal elimination accounts for approximately 10% of total clearance. The major circulating metabolite of anastrozole lacks pharmacological activity. Based on in vitro data, anastrozole metabolism occurs primarily via CYP3A4 and UGT1A4. ³³ Therefore, anastrozole metabolism may be affected by coadministration with riboxil. However, doses of anastrozole up to 10 mg/day (10 times the daily dose) have been studied and all doses evaluated were well tolerated with no serious acute toxicity attributed to anastrozole. ³⁴

For more information about anastrozole, refer to current local prescribing information. 1.2.2.3. Overview of GnRH agonists

GnRH agonists are synthetic analogs of gonadotropin-releasing hormone that desensitize the pituitary gland to GnRH by persistently stimulating GnRH receptors. GnRH agonists differ from naturally occurring GnRH in that the decapeptide structure has been modified (usually by substitution of amino acids at position 6, but also at positions 9 and 10) to reduce degradation of the molecule.

Goserelin was the GnRH agonist used in this trial. The most common AEs occurring in women treated with goserelin included hot flashes, headache, sweating, acne, emotional burden, depression, decreased libido, vaginitis, breast atrophy, seborrhea, and peripheral edema. In men, goserelin may be associated with hot flashes, sexual dysfunction, decreased erections, and lower urinary tract symptoms.

For more information about goserelin, please refer to current local prescribing information and/or clinical guidelines. 1.3. Rationale 1.3.1.    Rationale for conducting the trial

Although adjuvant ET for HR-positive EBC is effective in reducing the risk of relapse and improving survival, relapses are still common, especially in patients with features suggesting an intermediate or high risk of relapse, such as those with II and III anatomic stage groups. Most of these relapses are in the form of distant metastases, are usually incurable, and ultimately lead to death from BC. ¹⁵

The addition of riboxil to ET has been shown to have clinical efficacy and a tolerable toxicity profile for HR-positive, HER2-negative advanced BC; therefore, the addition of riboxil in the adjuvant setting may prolong invasive disease-free survival (iDFS) in patients with HR-positive, HER2-negative EBC at intermediate or high risk of relapse by improving primary endocrine responsiveness and preventing or delaying the development of acquired resistance to ET.

The purpose of this randomized, open-label trial was to evaluate the effect of adding ribociclib to standard adjuvant ET on iDFS in a subset of patients with HR-positive, HER2-negative EBC who were classified as stage III, IIB, or IIA in the anatomical stage group (as defined in inclusion criterion #8). 1.3.2.    Rationale for the trial design

This is a phase III, multicenter, randomized, open-label trial evaluating the addition of ribociclib to standard adjuvant ET in women and men with HR-positive, HER2-negative EBC. Adjuvant ET in postmenopausal women will be with NSAIs (letrozole, anastrozole), and adjuvant ET in premenopausal women and men will be with a NSAI in combination with goserelin.

The randomized, stratified, multicenter design of this trial balanced known and unknown prognostic factors in assigning treatment and minimized allocation bias.

In this open-label trial, appropriate adjudication of outcomes, especially the primary endpoint, is critical to the validity of the trial results. To reduce bias, the primary endpoint chosen is objective (iDFS) and will use a standardized definition (based on the STEEP system of standardized definitions of efficacy endpoints in adjuvant breast cancer trials). ³⁵ In addition, iDFS events are not only based on clinical or radiological assessment but also confirmed by histology or cytology (unless the procedure would impose an unacceptable risk to the patient), so objective confirmation is required for recurrence to be considered an iDFS event. In addition, if a patient discontinues trial treatment for reasons other than distant recurrence, recurrence assessment should continue according to the STEEP criteria until distant recurrence. All of these elements support the validity and objectivity of the primary recurrence assessment for the iDFS endpoint and ensure that the trial results were not influenced by the open-label design. Furthermore, because ribociclib is associated with a neutropenia rate of approximately 75%, ³⁶ concealing treatment assignment may not be effective.

The trial will include pre- and postmenopausal women and men with HR-positive, HER2-negative EBC in the anatomical stage groups (according to the 8th edition of the AJCC) of stage III, IIB, or a subset of IIA cases (as defined in inclusion criterion #8). These anatomical stage groups include (mostly) tumors with regional lymph node metastases and/or large primary lesions, which are at high risk of recurrence despite ET and may benefit from the addition of ribociclib.

Ki67 or gene expression testing, if available, will be used to identify patients with node-negative anatomical stage IIA and grade 2 histologic grade who are considered to be at high risk. Despite poor reproducibility, the Ki67 index is commonly used worldwide to estimate prognosis and guide adjuvant therapy selection decisions in ER-positive, HER2-negative EBC. Although the cutoff values used to define a high Ki67 index lack standardization and are variable, their prognostic or predictive value has been demonstrated in multiple studies. ³⁷ A cutoff value of 20% is considered appropriate to stratify patients with ER-positive, HER2-negative EBC at high risk. ^{38, 39} Gene expression tests that assess genomic risk categories of BC provide clinicians with prognostic information that can help personalize treatment and have been widely adopted, particularly for identifying those patients with a favorable prognosis who do not require adjuvant chemotherapy. ^{10, 11, 40, 41} Given that some patients with anatomic stage IIA have a favorable prognosis compared with those with anatomic stage IIB or III, only patients with node-negative stage IIA tumors who were grade 3 or 2 and had a high Ki67 index (≥ 20%) or were considered high risk by validated gene expression testing (as defined in inclusion criterion #8) were included.

Emerging data based on other CDK4/6 inhibitor EBC trials suggest an increased benefit in the anatomic stage III group, with the number of patients with stage II disease capped at approximately 2,000 in the total study population of approximately 5,000 patients.

Both premenopausal and postmenopausal women will be included, as the efficacy and safety of ribociclib are not expected to differ in this population. Stratification by menopausal status will be used to reduce potential differences in clinical outcomes between premenopausal and postmenopausal women.

Classification into the AJCC 8th edition anatomic staging groups requires determination of T, N, and M categories. Axillary lymph node dissection (ALND) is the preferred method for axillary lymph node staging; however, sentinel lymph node (SLN) dissection may be used to determine N-category in selected patients (see Inclusion Criteria #0).

Based on the results of the ACOSOG Z0011 clinical trial, in which patients with metastatic SLNs were randomly assigned to undergo ALND or no additional surgery, SLN clearance without subsequent ALND in the setting of a positive SLN became an acceptable practice for selected patients. The trial showed that the 5-year disease-free survival (83.9% with SLN clearance alone and 82.2% with SLN clearance alone followed by ALND) and OS (92.5% vs. 91.8%, respectively) were comparable between the two groups, and that surgical complications were fewer with SLN clearance alone. ⁴²

Although this approach has been recommended by some clinical guidelines and consensus and is listed as an option for surgical management of the axillary fossa in eligible patients, ^10,11,43,44 the omission of ALND makes accurate staging of BC more challenging. Because approximately 85% of patients in the ALND arm of Z0011 had N1 disease, patients who met the trial eligibility criteria (T1-T2, <3 metastatic SLNs, no clinically significant nodal disease before surgery, no significant extranodal tumor invasion, no neoadjuvant systemic therapy, and prior lumpectomy and adjuvant radiation) were considered to be N-category N1.

Randomisation will be stratified by menopausal status, anatomical stage group, use of previous neoadjuvant/adjuvant chemotherapy, and geographic region (see Section 0). Menopausal status was chosen as a stratification factor because it may reflect different treatment options and prognosis. Premenopausal women were grouped in the same stratum as male patients, as recurrence rates may be higher in men and premenopausal women than in postmenopausal women, and the number of men was expected to be too small to make this a separate stratum. Finally, because neoadjuvant or adjuvant chemotherapy reduces relapse in HR-positive EBC (no significant difference in relapse-free survival between adjuvant and neoadjuvant chemotherapy), randomization will also be stratified according to whether patients have received any previous neoadjuvant/adjuvant chemotherapy.

The primary efficacy of the investigational intervention will be assessed by its effect on iDFS as defined in the STEEP (Standardized Definitions of Effective Endpoints) system. ³⁵ The definition of iDFS in the STEEP system is broad, clinically relevant, and includes the most commonly accepted DFS events in published EBC trials. 1.3.3. Rationale for regimen and dose selection

In clinical trials in patients with advanced BC, ribociclib was shown to be tolerable and effective at a dose of 600 mg/day on days 1 to 21 of a 28-day cycle when combined with ET (see section 0).

Because relapses in HR-positive, HER2-negative EBC occur late, with most relapses observed beginning one year after surgery and continuing for at least 15 years after diagnosis, a short duration of adjuvant ribotoxib therapy may not be sufficient to detect a meaningful effect on relapse rate. ⁴⁵ Therefore, to provide adequate ribotoxib exposure in this trial while balancing the potential toxicity of prolonged therapy, ribotoxib (in combination with ET) will be administered for 36 months at a dose of 400 mg/day on days 1–21 of a 28-day cycle. This schedule and duration of ribotoxib therapy should be sufficient to detect a meaningful effect on relapse rate.

PK-QTcF (PK-ECG QT interval corrected by Fridericia's formula) and PK-ANC (PK-absolute neutrophil count) modeling showed that QTcF prolongation and neutropenia were related to ribociclib concentrations. Post hoc exploratory analyses showed that patients who started with 600 mg ribociclib and subsequently had dose reductions to 400 mg and 200 mg had sustained benefits in terms of efficacy (progression-free survival [PFS] and overall response rate [ORR]). To reduce the incidence of QTc interval prolongation, neutropenia and other AEs, this trial will explore a lower dose of riboxil in patients with HR-positive, HER2-negative EBC, namely 400 mg once daily, with 3 weeks on/1 week off in a 28-day cycle.

Regarding the risk of QTcF prolongation, mean ∆QTcF values were consistent across the MONALEESA-2, MONALEESA-3, and MONALEESA-7 trials. ∆QTcF prolongation at 2 hours post-dose on Cycle 1 Day 15 (C1D15) relative to baseline was 19.6 milliseconds (msec), 20.6 msec, and 18.6 msec, respectively, in the MONALEESA-2, MONALEESA-3, and MONALEESA-7 (NSAI subgroups). Based on the highest ECG value in any assessment, a new post-baseline QTcF > 480 msec was observed in 23 (6.9%) patients in the ribociclib group in MONALEESA 2, 27 (5.6%) in MONALEESA-3, and 13 (5.3%) in MONALEESA-7 (NSAI subgroup). Although clinical sequelae are uncommon, there is an opportunity to reduce the risk of this event, as clinical trials have shown that ribociclib-induced QTcF prolongation is concentration-dependent (Riboxil IB 2017). Based on PK-QTcF modeling, a lower daily ribociclib dose is estimated to result in a lower mean ∆QTcF (Table A1). [ Table A1 ]: Changes from baseline in estimated _Cmax and mean QTcF for different ribociclib dosing regimens . Riboxil dosing schedule Estimated geometric mean C _max ( ng/mL ) Estimated mean ΔQTcF ( msec ) ( 90% CI ) for Riboxil + NSAI ^a 600 mg QD, 3 weeks on/1 week off (approved dosing regimen) 1870 22.6 (21.06, 24.06) 400 mg QD, 3 weeks on/1 week off 1080 18.9 (17.65, 20.11) ^a C _max,ss predicted based on the pop-PK model estimated by the PK-QT model. Both models were developed based on data from studies CLEE011X2101, CLEE011X1101, CLEE011X2107, CLEE011A2301, CLEE011E2301, and CLEE011F2301. Abbreviations: CI - confidence interval; C _max - maximum serum concentration of ribociclib; NSAI - nonsteroidal aromatase inhibitor; QD - once daily; ΔQTcF - change in ECG QT interval from baseline (corrected according to Fridericia's formula)

As a class effect of CDK4/6 inhibitors, another identified risk of ribociclib is neutropenia. ANC curve simulation showed that the decrease in ANC caused by ribociclib 400 mg once daily was less than that caused by ribociclib 600 mg once daily, and the lowest ANC value was close to or higher than the clinically significant ANC 1.5 x 10 ⁹ /L (see Figure 2).

Therefore, the 400 mg dose of ribociclib is expected to result in a less severe degree of neutropenia associated with its use.

Post hoc exploratory analyses of MONALEESA-2, MONALEESA-3, and MONALEESA-7 also showed that patients who started on 600 mg riboxil but whose dose was reduced (e.g., due to AEs or any other reason) to 400 mg and 200 mg continued to experience a treatment benefit in terms of PFS (Table A2) and ORR (Table A3). [ Table A2 ] : Median PFS by Dose Reduction of Riboxil and Placebo Trial Riboxil 600 mg Riboxil 600 mg to 400 mg Riboxil 600 mg to 400 mg to 200 mg Placebo MONALEESA-2 27.7 months 24.9 months 27.6 months 16.0 months MONALEESA-3 18.8 months 22.1 months NE* 12.8 months MONALEESA-7 22.1 months 24.7 months 27.5 months 13.0 months *NE: Not estimable [ Table A3 ]: ORR by ribociclib dose reduction and placebo Trial Riboxil 600 mg Riboxil 600 mg to 400 mg Riboxil 600 mg to 400 mg to 200 mg Placebo MONALEESA-2 35.1 (27.9, 42.3) 44.0 (34.3, 53.7) 60.3 (48.2, 72.4) 28.7 (23.9, 33.6) MONALEESA-3 29.8 (24.7, 35.0) 33.6 (25.7, 41.5) 41.9 (24.6, 59.3) 21.5 (16.3, 26.7) MONALEESA-7 40.6 (34.0, 47.1) 40.9 (30.6, 51.2) 52 (32.4, 71.6) 29.7 (24.8, 34.6) ¹ ORR (95% CI) according to local investigator assessment in MONALEESA-2 (CLEE011A2301), MONALEESA-3 (CLEE011F2301), and MONALEESA-7 (CLEE011E2301).

Although these PFS and ORR results should be interpreted with caution as the starting dose of 600 mg daily may have confounded these efficacy outcomes, these results do provide insight into the potential efficacy of lower ribociclib dose regimens. Notably, more than 20% of the ribociclib dose reduction occurred within the first 3 months of treatment.

In summary, based on PK-QTcF modeling, post hoc exploratory PFS analysis by dose reduction, and PK-ANC modeling, the 400 mg dose of riboxil may be less toxic than the 600 mg dose (e.g., lower ΔQTcF, lower incidence of neutropenia, and possibly other adverse events), while potentially providing efficacy (in terms of PFS and ORR). Therefore, in this trial, the 400 mg daily dose of riboxil (400 mg once daily, 3 weeks of dosing/1 week of rest) will be studied as the starting dose, and the dose can be reduced to 200 mg if necessary based on the severity of toxicity. 1.3.4.    Rationale for the selection of combination drugs

Riboxil will be used in combination with standard ET approved for adjuvant treatment of EBC and will include the NSAI letrozole or anastrozole. In premenopausal women and men, ET will include gonadal suppression with goserelin, administered subcutaneously every 4 weeks.

Preclinical and clinical data of ET co-administered with riboxil showed that the combination with ET was effective for HR-positive, HER2-negative advanced BC with reversible and manageable toxicity (see Section 0). 1.3.5.    Rationale for the selection of comparator drugs

The ET used in this trial is standard ET for patients with ER-positive EBC. Patients in the control group will receive standard NSAI (letrozole or anastrozole) for 60 months from the date of randomization, according to local clinical guidelines and current prescribing information. In premenopausal women and men, ET will include gonadal suppression with a GnRH agonist (goserelin), which is recommended for patients with intact ovarian or testicular function. Goserelin is administered subcutaneously every 4 weeks. In this trial, a one-month depot formulation of goserelin must be used to suppress gonadal function (for both women and men) because a 3-month depot formulation does not reliably suppress estrogen levels in all female patients. ¹¹ 1.3.6. Risks and Benefits

Based on preclinical and clinical data, treatment with riboxil plus ET is expected to be tolerable, and toxicity is expected to be manageable and reversible by interrupting treatment, reducing the riboxil dose, or discontinuing the drug.

Patients in this trial will be carefully monitored for key toxicities observed with RIBOXILB (see latest RIBOXILB IB) or ET (see section 0). Risks will be further minimized by adherence to inclusion/exclusion criteria (see section 0), avoidance of contraindicated medications (see section 0), close safety monitoring (see section 0), and guidelines for dosing adjustments (see section 0).

An Independent Data Monitoring Committee (IDMC) (see Section 0) will be established to monitor safety and efficacy. A Steering Committee (SC) (see Section 0) will be established, including investigators participating in the trial, Novartis AG, and Translational Research in Oncology (TRIO) personnel, to ensure transparent management of the trial according to the protocol. TRIO and Novartis AG teams will continuously evaluate trial data to detect safety signals. In addition, the Novartis AG safety management team will review and evaluate all emerging data from the entire RIBO program in a timely manner for potential safety signal assessments. 2. Objectives and Endpoints

The objectives and relevant endpoints are described in Table A4 below. [ Table A4 ] : Objectives and relevant endpoints Purpose End analyze main See Section 0 Comparison of iDFS of Riboxil + ET vs ET in HR-positive, HER2-negative EBC patients iDFS ³⁵ assessed by investigators using STEEP criteria secondary See Section 0 1. To evaluate the relapse-free survival (RFS) of the two treatment groups RFS ³⁵ using the STEEP standard 2. To evaluate the distant disease-free survival (DDFS) of the two treatment groups DDFS ³⁵ using the STEEP standard 3. Evaluation of OS in the two treatment groups OS was defined as the time from the randomization date to the date of death from any cause. 4. Patient-reported outcomes (PROs) evaluating health-related quality of life (QoL) in both treatment groups Changes from baseline in the physical function subscale scores and the global health status/QoL scale scores assessed by the EORTC QLQ-C30 5. Evaluate the safety and tolerability of treatment options Frequency and severity of AEs, laboratory, and electrocardiographic (ECG) abnormalities 6. Characterization of the PK of Riboxil when given in combination with NSAIs (and goserelin, if applicable) PK parameters of Riboxil (e.g. C _trough ) and other applicable parameters Exploratory See Section 0 1. To explore the locoregional relapse-free survival (LRRFS) of the two treatment groups LRRFS was defined as the time from the randomization date to the date of the first event of locally invasive breast recurrence, regional invasive recurrence, or death from any cause. 2. Explore the use of follow-up anti-cancer therapy Incidence of subsequent anticancer therapy and time to first subsequent anticancer therapy 3. Explore the utilization of medical and health resources Number of hospital admissions, total hospital stays, length of stay, emergency room visits, and other patient visits 4. Explore prognostic and predictive biomarkers for treatment with Riboxil and ET Assess baseline tumor and circulating tumor (ct) DNA and ctRNA samples for expression and alterations of genes related to, but not limited to, the CDK and ER pathways and their correlation with therapeutic endpoints. Expression of markers such as Ki67 can be assessed by immunochemistry 5. Explore the potential molecular mechanisms of resistance to Riboxil and ET Assess gene expression and alterations in tumor biopsies and ctDNA/ctRNA collected at baseline and at relapse 6. Explore the role of ctDNA/ctRNA in monitoring and predicting disease recurrence Assess gene expression and changes in ctDNA/ctRNA collected serially at baseline, during treatment, after treatment, and at relapse 3. Experimental design 3.1. Overall experimental design

This is a Phase III, multicenter, randomized, open-label trial evaluating the efficacy and safety of riboxil plus ET as adjuvant therapy in women and men with HR-positive, HER2-negative EBC. iDFS was the primary endpoint of the trial, as defined according to the STEEP system. ³⁵

The trial will include pre- and postmenopausal women and men with HR-positive, HER2-negative EBC with AJCC 8th edition anatomic stage group III, IIB, or a subset of IIA cases (as defined in inclusion criterion #8) who have undergone appropriate surgical resection, radiation therapy (if indicated), adjuvant chemotherapy or neoadjuvant chemotherapy (if indicated), and are considered eligible for adjuvant ET for at least 60 months from the date of randomization. Patients who have previously started any standard neoadjuvant/adjuvant ET are eligible for inclusion in the trial, provided that ET was started within 12 months prior to randomization.

The trial will include the following phases: •   Screening phase •   Treatment phase •   Follow-up phase

See 1 for a schematic diagram of the test design and Section 0 for a detailed description of the test phases.

Approximately 5,000 patients will be randomly assigned (by interactive response technology [IRT]) in a 1:1 ratio using the following stratification factors: •   Menopausal status: premenopausal women and men vs. postmenopausal women •   AJCC 8th edition anatomical stage group: anatomical stage II vs. anatomical stage III •   Previous neoadjuvant/adjuvant chemotherapy: yes vs. no •   Geographic region: North America/Western Europe/Australia vs. rest of the world (RoW) Enrollment is capped at approximately 2,000 patients in the anatomical stage II group.

Starting on Cycle 1 Day 1 (C1D1), randomized patients will receive either: •   Study arm: • Riboxil 400 mg orally once daily on Days 1 to 21 of 28-day cycles for 36 months (approximately 39 cycles) from the date of randomization. and • ET consisting of: •      For postmenopausal women: letrozole 2.5 mg orally once daily or anastrozole 1 mg orally once daily. •      For premenopausal women and men: letrozole 2.5 mg orally once daily or anastrozole 1 mg orally once daily in combination with goserelin 3.6 mg subcutaneously every 4 weeks.

The duration of ET in the trial was 60 months from the date of randomization. •   Control group: • ET: Same as the study group.

In both groups, ET will be administered according to local clinical guidelines and current local prescribing information. Subsequent ET (or any other anticancer treatment) given after the protocol-required 60 months of ET (or after early discontinuation of ET in the trial) will be administered according to the investigator's clinical judgment and will not be considered trial treatment.

Safety assessments will be performed for each patient (see Sections 0 and 0) and will include routine safety monitoring. For recurrence events (see Appendix 3: Recurrence Detection Guidelines), assessments will be performed every 12 weeks during the first 24 months after randomization and every 24 weeks thereafter until confirmed remote recurrence, death, withdrawal of consent, loss to follow-up, or closure of the trial, whichever occurs first (see Table A12).

Patients who discontinue all trial treatment will enter a follow-up period during which relapse and survival will be recorded. Survival will be assessed 60 months after the last patient is randomized until death, withdrawal of consent, loss to follow-up, or end of the trial (whichever occurs first).

Three interim iDFS analyses and one final analysis are planned (see Section 0). See Figure 1 for the trial design. 3.2. Number of patients and sites

Approximately 5,000 patients from approximately 425 research centers around the world will be randomly assigned to the trial. 3.3. End of the trial

If the primary endpoint of iDFS is statistically significant at the second, third interim analysis, or final analysis, data collection will continue and the trial will be declared closed at 60 months + 30 days from the date the last patient was randomized.

If the primary endpoint of iDFS is not valid at the first interim analysis, or if iDFS is not statistically significant at the final iDFS analysis, the trial will be declared closed after all patients have discontinued trial treatment and completed the 30-day safety follow-up visit. For details on the interim and final iDFS analyses, see Section 0.

A given patient's participation in a trial ends when the following occurs first: •   End of the trial •   The patient withdraws consent •   The patient is lost to follow-up •   Death •   Early termination of the trial at the country/region or site level (see Section 0) •   Early termination of the trial by Novartis AG (see Section 0). 3.3.1.    Early Termination of the Trial

Novartis AG may terminate a trial at any time for any reason. If such a decision is made, the investigator will be informed of the procedures to be followed. In accordance with applicable regulations, the Institutional Review Board/Independent Ethics Committee (IRB/IEC) and the Competent Authority (CA) will be notified of the premature termination of the trial.

In addition , a CA decision may prematurely terminate a trial within a country, or a change in IRB/IEC opinion may lead to the termination of a trial at the local level.

This trial can achieve its objectives only if appropriate patients are enrolled. Patients who do not meet all inclusion criteria or who meet at least one of the exclusion criteria will not be randomized in the trial. No waiver of eligibility will be granted by Novartis AG or TRIO.

For additional information on patient selection and randomization, see Section 0. 4.1. Inclusion Criteria

Patients eligible for inclusion in this trial must meet all of the following criteria: 1. A signed and dated Patient Informed Consent Form (PICF) is obtained prior to any trial-specific screening procedures. 2. Patients are ≥ 18 years of age at the time of signing of the PICF. 3. Patients are females, or males, with known postmenopausal status at the time of randomization or initiation of adjuvant ET, whichever occurs first.

Postmenopausal status is defined as: • Patients who have undergone bilateral oophorectomy, or • Age ≥ 60 years, or • Age < 60 years and amenorrhea for 12 months or more (in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression) with follicle-stimulating hormone (FSH) and plasma estradiol in the postmenopausal range based on local normal ranges. • If taking tamoxifen or toremifene and age < 60 years, FSH and plasma estradiol levels are in the postmenopausal range. Clarification: • For women who are premenopausal at the start of adjuvant chemotherapy, amenorrhea is not a reliable indicator of menopausal status because ovarian function may remain intact or restored despite anovulation/amenorrhea. For these women with treatment-induced amenorrhea, serial measurements of FSH and/or estradiol are required according to local clinical guidelines to determine postmenopausal status. • For the purposes of this trial, all women who did not meet the criteria for postmenopausal status were considered premenopausal. 4. Patients have histologically confirmed unilateral primary invasive adenocarcinoma of the breast with an initial cytological or histological diagnosis (i.e., date of pathology report confirming the BC diagnosis) within 18 months before randomization. Patients with multicentric and/or multifocal tumors are eligible if all lesions examined by histopathology meet the pathology criteria in inclusion criteria 0 and 0. 5. Patients have breast cancer that is ER and/or PgR positive as determined by the most recent tissue sample analyzed by a local laboratory. 6. Patients have HER2-negative breast cancer, defined as a negative in situ hybridization test or an immunohistochemistry (IHC) status of 0+ or 1+. If IHC is 2+, a negative in situ hybridization (FISH, CISH, or SISH) test is required to confirm HER2-negative status (based on the most recent tissue sample analyzed by a local laboratory test). 7. Patients (except those enrolled in China) have available archival tumor tissue from surgical specimens for submission to the central laboratory (Note: for patients receiving neoadjuvant systemic therapy and with pathological complete remission, archival tumor tissue at the time of initial diagnosis or before the administration of neoadjuvant therapy is mandatory). 8. The patient has had a completely removed tumor after surgical resection with no tumor on the final surgical specimen microscopic margins and falls into one of the following categories (see Figure 3): • Anatomical stage group III, or • Anatomical stage group IIB, or • Anatomical stage group IIA with any of the following: • N1, or • N0 with: • Grade 3, or • Grade 2 and meets any of the following criteria: • Ki67 ≥ 20%, or • Oncotype DX Breast Recurrence Score ≥ 26, or • Prosigna/PAM50 classified as high risk, or • MammaPrint classified as high risk, or • EndoPredict EPclin risk score classified as high risk. Clarification: • For patients with anatomic stage IIA tumors (N0): • If grade is 1 or unknown (Gx), the patient is ineligible. • If grade is 2, gene expression test results (Oncotype DX, Prosigna/PAM50, MammaPrint, or EndoPredict EPclin) or Ki67 levels should be used, provided that they are obtained according to local practice (i.e., not mandatory for the purpose of the trial). Results must be provided at the time of screening. • Any preoperative staging/specimens and/or surgical specimens for patients receiving neoadjuvant therapy must meet the above criteria (for stage, and if stage IIA, N0, also for grade and Ki67 or gene expression testing). • Classification into the AJCC 8th edition anatomic staging groups (see Appendix 1: Anatomical Staging Group Guidelines for Breast Cancer Staging) requires determination of T, N, and M categories. ALND is the preferred method for axillary lymph node staging, but SLN dissection may be used to determine N category in the following circumstances: • No metastases in the SLNs (patients are considered pN0). • Only micrometastases in the SLNs (patients are considered pN1mi). • Patients have T1-2 with no clinically evident lymph nodes preoperatively, have not received neoadjuvant chemotherapy, have at least one macrometastasis in 1 or 2 SLNs, and no confluent lymph nodes or significant extranodal disease on SLN dissection (patients are considered pN1). In all other cases, ALND is required to determine N category. 9. Patients have completed adjuvant chemotherapy and/or neoadjuvant chemotherapy according to institutional guidelines prior to screening, if indicated. 10. Patients have completed adjuvant radiation therapy according to institutional guidelines prior to screening, if indicated. 11. Patients have no contraindications to adjuvant ET on trial and plan to receive ET for 5 years (from the date of randomization) or longer. 12. Patients may have received any standard neoadjuvant and/or adjuvant ET at the time of PICF sign-off, but randomization should be within 12 months of the initial start date of ET. Ovarian suppression or short-term ET for fertility preservation is not considered neoadjuvant/adjuvant ET. If the patient is receiving tamoxifen or toremifene as adjunctive ET, a 5 half-life (i.e., 35 days) washout period is required before randomization (during which time the patient can take the AI). 13. The patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 14. The patient has adequate bone marrow and organ function as defined by the following local laboratory values: • Absolute neutrophil count (ANC) ≥ 1.5 × 10 ⁹ /L. • Platelets ≥ 100 × 10 ⁹ /L. • Hemoglobin ≥ 9.0 g/dL. • Estimated glomerular filtration rate (eGFR) according to the Modification of Diet in Nephropathy (MDRD) formula ≥ 30 mL/min/1.73 m ² . • Alanine transaminase (ALT) < 2.5 × upper limit of normal (ULN). • Aspartate transaminase (AST) < 2.5 × ULN. • Serum total bilirubin <ULN; or total bilirubin ≤ 3.0 × ULN or direct bilirubin ≤ 1.5 × ULN in patients with well-documented Geppel syndrome. • International normalized ratio (INR) ≤ 1.5 (unless the patient is receiving an anticoagulant and the INR was within the therapeutic range for the intended use of the anticoagulant within 7 days prior to randomization). • Prior to randomization, the patient must have the following laboratory values within normal limits or corrected to normal limits with supplementation (corrected local laboratory values should be documented within normal limits): • Potassium • Magnesium • Total calcium (corrected for serum albumin) 15. Standard 12-lead ECG values assessed by the central laboratory, such as: • Screening QTcF interval (using Fridericia-corrected QT interval) < 450 msec. • Resting heart rate 50-90 beats/min (determined by ECG). 16. The patient must be willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures. 17. Women of childbearing potential (CBP), defined as all women physiologically capable of becoming pregnant (see Inclusion Criteria #0 for additional information), must have a confirmed negative serum pregnancy test (for beta-hCG) within 14 days prior to randomization. 18. Women with CBP must be willing to use highly effective contraception. Contraception must be continued during trial treatment and for 21 days after stopping treatment. Highly effective contraceptive methods include: • Complete abstinence (when this is consistent with the patient’s preferred and usual lifestyle). Cyclic abstinence (e.g., calendar, ovulation-based, temperature-based, post-ovulation methods) and ejaculation outside the body are not acceptable methods of contraception. • Female sterility (surgical bilateral oophorectomy, with or without hysterectomy), total hysterectomy or tubal ligation at least 6 weeks prior to the start of the trial treatment. In the case of oophorectomy alone, only if the female reproductive status has been confirmed by subsequent hormonal level assessment. • Male partner sterility (at least 6 months before randomization). For female patients in the trial, the vasectomized male partner should be the patient's only partner. If vasectomy in the male partner is the highly effective contraceptive method of choice, the success of the vasectomy should be medically confirmed according to local practice. • Insertion of an intrauterine device (IUD). Clarification: • Oral (estrogen and progestin), transdermal, injectable, implantable, hormone-containing intrauterine systems, or any other hormonal contraceptive methods were not permitted in this trial. • Women were considered to have CBP unless: they had ≥ 12 months of natural (spontaneous) amenorrhea and had an appropriate clinical profile (i.e., age appropriate, history of vasomotor symptoms) or had undergone surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks before randomization. In the case of oophorectomy alone, a woman was considered not to have CBP only if her reproductive status had been confirmed by follow-up hormone level assessments. • After completion of trial treatment, patients should use effective contraception according to local guidelines. See Figure 3, which provides a schematic diagram of inclusion according to anatomical stage groups. 4.2. Exclusion criteria

Patients eligible for this trial must not meet any of the following criteria: 1. Patients have received any CDK4/6 inhibitors. 2. Patients have received prior treatment with tamoxifen, raloxifene, or an AI in the past 2 years before randomization to reduce breast cancer risk (“chemoprevention”) and/or to treat osteoporosis. Patients are concurrently using hormone replacement therapy. 3. Patients have received prior treatment with anthracyclines with a cumulative dose of 450 mg/ ^m2 or more of doxorubicin and 900 mg/ ^m2 or more of epirubicin. 4. Patients have known hypersensitivity reactions to Riboxil and/or any formulation of ET (e.g., rare genetic problems such as galactose intolerance, Lapp lactase deficiency, glucose-galactose malabsorption, and soy allergy). 5. Patients have distant metastasis of breast cancer beyond regional lymph nodes (stage IV according to the 8th edition of the AJCC) and/or evidence of recurrence after curative surgery. 6. Patients are concurrently using other anti-neoplastic therapies other than adjuvant ET (see Inclusion Criteria #0). 7. Patients have undergone major surgery, chemotherapy, or radiotherapy within 14 days before randomization. 8. Patients have not recovered from clinical and laboratory acute toxicity related to previous anticancer therapy to NCI CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) version 4.03 ≤ Grade 1 on the day of randomization. Exceptions to this criterion: Patients with any grade of alopecia, amenorrhea, grade 2 neuropathy, or other toxicities that do not pose a safety risk to the patient at the discretion of the investigator are allowed to enter the trial. 9. Patients have concurrent invasive malignant tumors or previous invasive malignant tumors that have completed treatment within 2 years before randomization. Note: Patients with appropriately treated basal cell or squamous cell skin carcinoma or curatively resected cervical carcinoma in situ are eligible. 10. Patients with a known history of human immunodeficiency virus (HIV) infection (testing is not mandatory unless required by local regulations). 11. Patients with known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (testing is not mandatory unless required by local regulations). 12. Clinically significant, uncontrolled cardiac disease and/or cardiac complex abnormalities, including any of the following: • Documented history of myocardial infarction (MI), angina, symptomatic pericarditis, or coronary artery bypass grafting within 6 months prior to trial entry. • Documented cardiomyopathy. • Left ventricular ejection fraction (LVEF) < 50% as determined by multi-gated acquisition (MUGA) scan or echocardiogram (ECHO) (optional testing). • Prolonged QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome, or any of the following: • Risk factors for torsade de pointes (TdP), including uncorrected hypocalcemia, hypokalemia, or hypomagnesemia, history of heart failure, or history of clinically significant/symptomatic bradycardia. • One or more concomitant medications with a known risk for prolonging the QT interval and/or known to cause TdP that cannot be discontinued or replaced by a safe alternative (e.g., within 5 half-lives or 7 days prior to starting trial treatment). • QTcF interval cannot be determined. • Clinically significant arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade atrioventricular (AV) conduction block (e.g., bifascicular block, Mobitz type II, and third-degree AV block). • Uncontrolled arterial hypertension with systolic blood pressure > 160 mmHg. 13. Patients currently receiving any of the following medications within 7 days prior to randomization: • Concomitant medications, herbal supplements, and/or fruits (e.g., grapefruit, pomelo, star fruit, lime) and their juices known to be strong inhibitors or inducers of CYP3A4/5. • Drugs with a narrow therapeutic window and that are primarily metabolized by CYP3A4/5. 14. Patients are currently receiving or have received systemic corticosteroids within ≤ 2 weeks prior to starting trial therapy, or have not fully recovered from the side effects of such therapy. NOTE: The following corticosteroids are permitted: short-term (< 5 days) systemic corticosteroids; any duration of topical application (e.g., for rash), inhalation spray (e.g., for obstructive airway disease), eye drops, or local injection (e.g., intra-articular). 15. Patients have compromised GI function or GI disease that may significantly alter the absorption of oral trial therapy (e.g., uncontrolled ulcerative disease, uncontrolled nausea, vomiting, or diarrhea, malabsorption syndrome, or small bowel resection). 16. Patients have any other concurrent severe and/or uncontrolled medical conditions that, according to the investigator's judgment, will result in unacceptable safety risks, prohibit patients from participating in clinical trials or affect protocol compliance (e.g., chronic pancreatitis, chronic active hepatitis, cirrhosis or any other major liver disease, untreated or uncontrolled active fungal, bacterial or viral infections, active infections requiring systemic antimicrobial therapy, etc.) or limit expected life expectancy to ≤ 5 years. 17. Participating in other studies involving one or more investigational drugs within 30 days before randomization or within 5 half-lives of one or more investigational drugs (whichever is longer), or participating in any other type of medical research that is judged to be scientifically or medically incompatible with this trial. If the patient is enrolled or plans to be enrolled in another study not involving the study drug, the consent of the Medical Supervisor is required to determine eligibility. 18. Pregnant or lactating (lactating) women or women who plan to become pregnant or breastfeed during the trial. 5. Treatment 5.1. Trial Treatment

For this trial, the term “investigational drug” refers to Novartis’ drug riboxil (LEE011); riboxil is considered an investigational medicinal product (IMP) and will be provided by Novartis.

Other drugs used in this trial are NSAI and goserelin. Whether these ETs are considered IMPs or non-IMPs is determined at the regional or national/regional level. In such cases, the trial will be conducted in accordance with local laws. ETs will be purchased locally in accordance with local practices and regulations or provided by Novartis AG (or its designee). ETs will be administered in accordance with current local prescribing information and clinical guidelines.

“Trial treatment” refers to the combination of ET and riboxil in the study group, or ET alone in the control group (given for 60 months from randomization), or ET given after discontinuation of riboxil in the study group (given for 60 months from randomization).

Subsequent ET (or any other anticancer treatment) given after the protocol-required 60-month duration (or after early discontinuation of ET on trial) will be administered at the investigator's clinical judgment and will not be considered trial treatment.

The reference safety information for Reboxil is included in the "Reference Safety Information" section of the Reboxil IB. 5.1.1.    Schedule and Administration

Starting on C1D1, randomized patients will receive one of the following treatments: •   Study arm: •   Riboxil 400 mg (2 x 200 mg tablets, orally) daily on days 1 to 21 of a 28-day cycle, followed by a 7-day sabbatical (days 22 to 28). and •   ET consisting of: •   For postmenopausal women: •   Letrozole 2.5 mg orally daily or anastrozole 1 mg orally daily. •   For premenopausal women and men: •   Letrozole 2.5 mg orally daily or anastrozole 1 mg orally daily in combination with: •   Goserelin 3.6 mg subcutaneously every 4 weeks. •   Control group: • ET (same as study group) consisting of: • For postmenopausal women: •      Letrozole 2.5 mg orally daily or anastrozole 1 mg orally daily. • For premenopausal women and men: •      Letrozole 2.5 mg orally daily or anastrozole 1 mg orally daily in combination with: •      Goserelin 3.6 mg subcutaneously once every 4 weeks.

The investigational treatment should be administered as described in this section and in Section 0.

Randomization and C1D1 should ideally occur on the same day. A window period of up to 7 days between randomization and C1D1 was allowed.

C1D1 was defined as the date on which the patient received the first dose of trial treatment after randomization (Note: for patients who received ET before randomization, C1D1 was considered the date on which they received the first dose of ribociclib [study group] or the first dose of ET [control group] after randomization).

A full cycle of treatment is defined as 28 days. Cycles must be scheduled based on C1D1 as the starting point. Trial assessments allow for a ± 3-day flexibility window (except when an ECG is required on C1D1) to accommodate any scheduling issues, but the treatment schedule remains fixed based on C1D1 as the starting point. Because the cycles are fixed, if for any reason ribociclib is started later than D1 of a cycle, however, it should still be stopped on D21 and the patient should then continue the 7-day drug-free period.

If ribociclib administration is interrupted for > 28 days due to ribociclib-related toxicity, it must be permanently discontinued. Detailed information and examples are provided in the CRF filling guide. [ Table A5 ] : Dosage and treatment schedule Experimental treatment Drug forms and routes of administration Dosage Frequency and / or schedule Riboxil (LEE011 200 mg) Oral tablets 400 mg Once daily on days 1 to 21 of each 28-day cycle Letrozole 2.5 mg Oral tablets 2.5 mg Give continuously once a day Anastrozole 1 mg Oral tablets 1 mg Give continuously once a day Goserelin 3.6 mg Implants, in prefilled syringes and for subcutaneous use 3.6 mg Days 1 ± 3 of each 28-day cycle

Reboxil will be administered as a steady, fixed dose, not by weight or body surface area. 5.1.1.1. Guidelines for discontinuing treatment

In the study arm, treatment with riboxil will continue until (whichever comes first): •   Completion of 36 months of treatment from the date of randomization (approximately cycle 39), regardless of any interruption in treatment. •   First relapse (any or combination of local, regional, or distant relapse, or contralateral invasive BC, or second primary non-breast invasive cancer). •   Modification of trial treatment due to toxicity leading to treatment discontinuation (see section 0). •   Interruption of riboxil dosing for > 28 days due to riboxil-related toxicity. •   Patient withdraws consent. •   Patient is lost to follow-up. •   Death. •   Discontinuation of trial treatment for any other reason. •   Novartis AG terminates the trial.

In both arms, ET will be given as trial treatment until (whichever comes first): •   Completion of 60 months from the date of randomization. •   Local, regional, and/or distant recurrence (duration of ET after contralateral invasive BC or second primary non-breast invasive cancer is based on the best clinical judgment of the investigator). •   Intolerable toxicity. •   Patient withdraws consent. •   Patient is lost to follow-up. •   Death. •   Discontinuation of trial treatment for any other reason. •   Termination of the trial by Novartis AG.

Patients may voluntarily stop the trial treatment at any time for any reason. If a patient decides to stop the trial treatment, the investigator must make reasonable efforts (e.g., phone, email, letter) to understand the main reason for the decision and record this information on the patient chart and the appropriate pages of the case report form (CRF). If they state their intention to withdraw their consent to participate in the trial, they will be considered to have withdrawn.

The investigator should discontinue trial treatment for a given patient if he or she believes that continued treatment would be detrimental to the patient's health. Trial treatment must be discontinued in the following circumstances: •   Pregnancy. •   Breastfeeding. •   Any protocol deviation that, in the judgment of the sponsor, creates a significant risk to patient safety.

If any trial treatment is permanently discontinued, the following guidelines should be followed (see also sections 0 and 0): •   Within the study arm: •   Patients who permanently discontinue riboxili for any reason will continue to have the 30-day post-riboxili safety follow-up visit and will continue to receive ET during the treatment period of the trial. Once all trial treatments are discontinued, patients will continue to have the end-of-treatment (EOT) and 30-day safety follow-up visits and will continue to participate in the trial during the follow-up period. •   Patients who permanently discontinue ET while receiving riboxili must also discontinue riboxili and will continue to have the EOT and 30-day safety follow-up visits (see sections 0 and 0). They will continue to participate in the trial during the follow-up period. •   In the control arm: •   Patients who permanently discontinue ET for any reason will continue to have EOT and 30-day safety follow-up visits and will continue to participate in the trial during the follow-up period. 5.1.2.    General Dosing Guidelines 5.1.2.1. Riboxil

Reboxil should be taken as follows: •   Administer Reboxil on the first 21 days of a 28-day cycle. Patients should not restart a new Reboxil cycle until they have completed the 7-day drug-free period. •   Patients must take Reboxil (and ET) in the clinic under the supervision of the investigator or designee when they have a visit on scheduled D1 of a cycle (or within the allowed + 3-day window). On all other days, patients may take Reboxil (and ET) at home. •   Patients should be instructed to take Reboxil and ET at the same time each day with a large glass of water (approximately 250 mL or approximately 8 oz.). Patients can determine if they prefer morning or early afternoon dosing, but they should maintain consistency in their schedule. Evening dosing is strongly discouraged.

NOTE: For the first cycle, patients in the PK subgroup (see section 0) must take reboxil and ET in the morning due to the PK evaluation of C1D15. Patients can then determine if they prefer morning or early afternoon dosing, but consistency of timing should be maintained. •   With or without food. •   Patients should be instructed to swallow tablets whole, without chewing or crushing them. •   If vomiting occurs during treatment, patients should not be allowed to re-dose until the next scheduled dose. The occurrence and frequency of any vomiting during the treatment cycle must be recorded in the AE section of the CRF. See section 0 for use of antiemetic medications. •   Any missed dose (not taken within 6 hours of the expected time) should be skipped and should not be replaced or made up the next day. •   Per exclusion criterion #14, patients must avoid consuming grapefruit, grapefruit hybrids, pomelo, starfruit, lime, or products containing various fruit juices during treatment with reboxilb and prior to the first dose. These foods are known to be CYP3A4 inhibitors and may increase reboxilb exposure (Note: oranges and orange juice are permitted). •   Herbal or dietary supplements known to be strong CYP3A4/5 inhibitors or inducers or with a known risk of QT prolongation are not permitted (see section 0). Multiple vitamins are permitted. •   Patients should be instructed not to take any medications reported as contraindicated in Section 0 (see also Appendix 4: Concomitant Medications). 5.1.2.1.1.     Additional Medication Administration Guidelines for Pharmacokinetic Sampling and ECG Acquisition

On C1D15 (for patients in the PK subgroup only; see Section 0) and/or ECG collection days (for all patients), the following additional guidelines should be followed: •   Predose PK samples should be collected before trial treatment administration. •   Postdose PK samples should be collected after trial treatment administration. •   If predose ECG measurements should be collected, the ECG measurements should be obtained before trial treatment administration. •   If predose PK samples should also be obtained on the day of the ECG, the samples should be collected after the ECG and before trial treatment administration (see Section 0 for additional details). •   The following will be recorded in the CRF: the exact time of reboxil administration on the PK collection day, the actual PK blood sampling time, and the date and time of reboxil administration on the day before the PK assessment. Any sampling problems (e.g., patient took trial medication before blood sampling, missed scheduled sampling time, sample not collected according to schedule) should be noted as a note on the CRF. 5.1.2.2. Endocrine Therapy

ET (in both groups) will be administered as permitted by the protocol according to local clinical guidelines and current local prescribing information.

Patients must take ET (and ribociclib in the study arm) in the clinic on the scheduled visit day under the supervision of the investigator or designee. If pre-drug ECG measurements are to be collected, ECG measurements should be obtained before the administration of trial treatment (including ET).

Goserelin was administered subcutaneously on D1 ± 3 of each 28-day cycle according to current local prescribing information (Note: the 3-month depot formulation of goserelin was not permitted in the trial). In patients who were receiving monthly goserelin (or other monthly GnRH agonists) prior to randomization, their treatment regimen could be continued unchanged (i.e., not synchronized with the trial cycles) or goserelin administration could be synchronized with the cycles. Patients who were receiving goserelin every 3 months prior to randomization must switch to the monthly formulation. It is recommended that women receiving goserelin be monitored regularly according to local institutional clinical guidelines to confirm postmenopausal values of gonadotropins and sex hormones by local laboratories.

In the study arm, during treatment with Riboxil, the investigator is not allowed to change the NSAI unless intolerable toxicity, patient request, or any other important medical event that requires a change in the NSAI occurs (the investigator should clearly record the reason for the ET change during Riboxil treatment in the CRF). After the end of Riboxil treatment, the investigator will be allowed to change the NSAI according to clinical guidelines and local prescription information (the investigator must record the reason for the ET change in the CRF).

ETs other than NSAIs and goserelin were not permitted during the trial treatment period. 5.2. Dose Adjustments and Adverse Event Management 5.2.1.    Riboxil 5.2.1.1. Dose Levels

For patients who are intolerant of the protocol-specified dosing regimen, a single dose adjustment is permitted to allow the patient to continue taking reboxil (see Table A6). Such changes must be documented on the CRF. If a second dose reduction is required to manage a reboxil-related AE, reboxil must be discontinued. No further dose increases are permitted. [ Table A6 ] : Dose Adjustment Guidelines Riboxili Dosage Tablet quantity and strength Starting dose 400 mg 2 x 200 mg tablets Dose Level -1 200 mg 1 x 200 mg tablet 5.2.1.2. Riboxil dosage adjustment

Recommendations for dose interruptions and reductions of ribociclib for the management of ribociclib-related AEs are summarized in Tables A7, A8, A9, A10, and A11.

The treating investigator's clinical judgment should guide each patient's management plan based on an individual benefit/risk assessment.

Unplanned laboratory evaluations may be performed if recording of (potential) AEs is medically indicated to facilitate decision making (e.g., dose adjustment).

Reboxil must be discontinued in the following circumstances: • Events requiring discontinuation as described in Table A7, Table A8, Table A9, Table A10, and Table A11. • Interruption of dosing for > 28 days due to reboxil-related toxicity. 5.2.1.2.1. Dose Modifications for Hematologic and Hepatotoxicity [ Table A7 ] : Reboxil Dose Modifications, Management Recommendations, and Mandatory Discontinuations for Hematologic Adverse Reactions ( CTCAE v4.03 ) Toxicity / Grade Dosage Adjustments and Administration Recommendations Thrombocytopenia Grade 1 (≥ 75 x 10 ⁹ /L) No dosage adjustment required. Grade 2 (≥ 50 x 10 ⁹ /L - < 75 x 10 ⁹ /L) Interrupt dosing until recovery to ≤ Grade 1. Restart ribociclib at the same dose level. Grade 3 (≥ 25 x 10 ⁹ /L - < 50 x 10 ⁹ /L) Interrupt dosing until recovery to ≤ Grade 1. Restart sreboxil at same dose level. If Grade 3 toxicity recurs: Temporarily interrupt dosing until recovery to ≤ Grade 1 and reduce sreboxil to next lower dose level. Level 4 (< 25 x 10 ⁹ /L) Interrupt dosing until recovery to ≤ Grade 1. Restart sreboxil at the next lower dose level. If Grade 4 toxicity recurs: Withhold sreboxil (mandatory). Decreased absolute neutrophil count ( ANC ) Grade 1 (≥ 1.5 x 10 ⁹ /L) No dosage adjustment required. Grade 2 (≥ 1.0 - < 1.5 x 10 ⁹ /L) No dosage adjustment required. Grade 3 (≥ 0.5 - ＜ 1.0 x 10 ⁹ /L) Interrupt dosing until recovery to ≥ 1.0 x 10 ⁹ /L. Restart sribociclib at same dose level. If Grade 3 toxicity recurs: Temporarily interrupt dosing until recovery to ≥ 1.0 x 10 ⁹ /L. • If resolved in ≤ 7 days, restart at same dose level. • If resolved in > 7 days, restart sribociclib at next lower dose level. Level 4 (＜ 0.5 x 10 ⁹ /L) Interrupt dosing until recovery to ≥ 1.0 x 10 ⁹ /L. Restart ribociclib at the next lower dose level. Febrile neutropenia Grade 3 ANC < 1.0 x 10 ⁹ /L and single temperature > 38.3°C (101°F) or sustained temperature ≥ 38°C (100.4°F) for more than 1 hour Interrupt dosing until ANC ≥ 1.0 x 10 ⁹ /L and afebrile. Restart at next lower dose level. If febrile neutropenia recurs, discontinue ribociclib (mandatory). Grade 4 Life-threatening consequences; urgent intervention required Discontinue Riboxil (mandatory). Anemia (hemoglobin) Grade 1 (≥ 10.0 g/dL) No dosage adjustment required. Level 2 (≥ 8.0 g/dL - < 10.0 g/dL) No dosage adjustment required. Grade 3 (< 8.0 g/dL, requiring transfusion) Interrupt dosing until recovery to ≤ Grade 2. Restart ribociclib at the same dose level. Grade 4 Life-threatening consequences; urgent intervention required Discontinue Riboxil (mandatory). [ Table A8 ]: Riboxil dose adjustments, management recommendations, and mandatory discontinuations for hepatotoxicity ( CTCAE v4.03 ) Hepatotoxicity (bilirubin, SGPT/ALT , SGOT/AST ) Total bilirubin (without ALT/AST ) increases above baseline Grade 1 (＞ULN - 1.5 x ULN) (confirmed after 48 h-72 h) Keep monitoring dose levels and LFTs every two weeks. Grade 2 (>1.5 - 3.0 x ULN) Interrupt ribociclib dosing. If resolved to ≤ Grade 1 in ≤ 21 days, restart at same dose level. If resolved to ≤ Grade 1 in > 21-28 days or toxicity recurs, restart at next lower dose level. Repeat liver enzyme bilirubin testing twice weekly for 2 weeks after dosing resumption. If toxicity recurs after dose reduction or recovers to ≤ Grade 1 for > 28 days, withhold ribociclib (mandatory). Grade 3 (>3.0 - 10.0 x ULN) Interrupt ribociclib until resolved to ≤ Grade 1, then restart at next lower dose level. Repeat liver enzyme bilirubin testing twice weekly for 2 weeks after dosing is resumed. Withhold ribociclib if resolved to ≤ Grade 1 in > 28 days or toxicity recurs (mandatory). Level 4 (＞10.0 x ULN) Discontinue Riboxil (mandatory). Confounding factors and/or alternative causes of elevated total bilirubin should be excluded prior to dosing interruption/dose reduction. They include, but are not limited to: evidence of liver metastases, evidence of obstruction (e.g., elevated ALP and GGT typical of gallbladder or duct disease), hyperbilirubinemia due to a single indirect component (i.e., direct bilirubin component ≤ 1 x ULN) due to hemolysis or Gilbert's syndrome, other medications, viral hepatitis, alcoholic or autoimmune hepatitis, other hepatotoxic drugs. For patients with Gilbert's syndrome, these dose adjustments apply only to changes in direct bilirubin. If bilirubin is elevated, it will be broken down. Elevated AST or ALT AST or ALT (without bilirubin) elevated > 2 x ULN Same as baseline level or increased from baseline level 0 to level 1 (confirmed after 48 h-72 h) No dose adjustment is required, monitor liver function tests (LFTs) per protocol if same as baseline grade, or every two weeks if increased from baseline Grade 0 to Grade 1. Grade 2 (> 3.0 - 5.0 x ULN) Interrupt ribociclib dosing. If resolved to ≤ baseline grade in ≤ 21 days, restart at same dose level. If resolved to ≤ baseline grade in > 21 days or toxicity recurs, restart at next lower dose level. Repeat liver enzyme bilirubin testing twice weekly for 2 weeks after dosing resumption. If toxicity recurs after dose reduction or recovery to ≤ baseline grade > 28 days, withhold ribociclib (mandatory). Grade 3 (>5.0 - 20.0 x ULN) Interrupt sirolimus dosing until resolved to ≤ baseline level, restart at next lower dose level. Repeat liver enzyme bilirubin testing twice weekly for 2 weeks after dosing is resumed. If recovery to ≤ baseline level > 28 days, discontinue sirolimus (mandatory). If toxicity recurs, discontinue sirolimus (mandatory). Level 4 (＞20.0 x ULN) Stop taking Riboxil (mandatory) AST or ALT and concurrent bilirubin For patients with normal ALT, AST, and total bilirubin at baseline: AST or ALT > 3.0 x ULN combined with total bilirubin > 2 x ULN, no evidence of cholestasis or For patients with elevated AST or ALT or total bilirubin at baseline: [AST or ALT > 2 x baseline and > 3.0 x ULN] or [AST or ALT > 8.0 x ULN] - whichever is lower - combined with [total bilirubin > 2 x baseline and > 2.0 x ULN] Stop taking Riboxil (mandatory) Confounding factors and/or alternative causes of elevated transaminases should be excluded prior to dose interruption/dose reduction. They include, but are not limited to: concomitant medications, herbal preparations or dietary supplements, infection, hepatobiliary disease or obstruction, liver metastases, and alcohol consumption.

For additional follow-up of potential cases of drug-induced liver injury (DILI), see Section 0. 5.2.1.2.2.     Dose Adjustments for QTcF Prolongation

For guidance on how to collect and interpret ECGs, see Section 0. Table A9 : Ribociclib dose adjustments, management recommendations, and mandatory discontinuations for QTcF prolongation ( CTCAE v4.03 ) Level Dosage Adjustments and Administration Recommendations For all levels 1. Check the quality of the ECG and QT values and repeat if necessary. 2. Perform serum electrolyte analysis (potassium, calcium, and magnesium). If outside the normal range, interrupt ribociclib administration, correct with supplements or appropriate therapy as soon as possible, and repeat electrolytes until normal is recorded. 3. Review concomitant medications for possible inhibition of CYP3A4 and/or prolongation of the QT interval. 4. Verify correct dosing and compliance with ribociclib administration. 1* QTcF 450-480 msec Follow steps 1-4 as directed in “For All Grades.” No dosage adjustments are necessary. 2* QTcF 481-500 msec Interrupt sreboxili. Follow steps 1-4 as indicated in “For All Grades.” Repeat ECG within 1 hour of first QTcF ≥ 481 msec. Repeat ECG as clinically indicated until QTcF recovers to < 481 msec. Restart at same dose level. No dose adjustment is necessary for first occurrence. If QTcF ≥ 481 msec recurs, reduce sreboxili by 1 dose level for second occurrence. If QTcF ≥ 481 msec recurs (third occurrence), sreboxili must be permanently discontinued. For any patient who interrupts treatment due to a QTcF ≥ 481 msec, repeat the ECG 7 and 14 days after resuming dosing (and then as clinically indicated). 3* At least two separate ECGs showing QTcF ≥ 501 msec Interrupt sreboxil. Perform steps 1-4 as directed in “For All Grades”. Repeat ECG within 1 hour of first QTcF ≥ 501 msec. If QTcF remains ≥ 501 msec, consult a cardiologist (or qualified specialist) and repeat cardiac monitoring if indicated until QTcF recovers to < 481 msec. • If QTcF recovers to < 481 msec, restart at the next lower dose level. • If QTcF remains ≥ 481 msec after performing steps 1-4 as directed in “For All Grades”, discontinue sreboxil (mandatory). If QTcF ≥ 501 msec recurs, discontinue sreboxil (mandatory). For any patient who interrupts treatment due to QTcF ≥ 501 msec, repeat ECG at 7 and 14 days after resuming dosing (and then as clinically indicated). 4 [QT/QTcF change from baseline ≥ 501 msec or > 60 msec] AND [TdP or polymorphic ventricular tachycardia, or signs/symptoms of serious arrhythmia] Discontinue riboxil (mandatory). Perform steps 1-4 as directed in “For All Levels”. Consult a cardiologist (or qualified specialist) and repeat cardiac monitoring if indicated until QTcF returns to < 481 msec. *All values refer to single measurement results. 5.2.1.2.3. Dosage Modifications for Interstitial Lung Disease/Pneumonitis [ Table A10 ] : Riboxil Dosage Modifications, Management Recommendations, and Mandatory Discontinuations for Interstitial Lung Disease ( ILD ) / Pneumonitis ( CTCAE v4.03 ) Level Dosage Adjustments and Administration Recommendations 1 Asymptomatic No dosage adjustment is necessary. Initiate appropriate medication and monitoring as clinically indicated. 2 With symptoms Interrupt sribociclib until recovery to ≤ Grade 1, then restart sribociclib at the next lower dose level*. 3 and 4 Severe Discontinue Riboxil (mandatory). *An individualized benefit-risk assessment should be performed before restarting Riboxil. 5.2.1.2.4. All other adverse reactions guidance

The investigator must use his/her clinical judgment to determine whether serum electrolyte (particularly potassium, calcium, and magnesium) assessments are necessary for all other adverse reactions.

In any case of potassium, calcium, or magnesium outside the normal range, reboxil must be interrupted and the electrolyte/electrolyte corrected with appropriate therapy. Documentation of recovery of the electrolyte/electrolyte abnormality must be provided before re-starting reboxil.

Patients who develop Grade 2 or higher renal impairment during treatment (not due to other contributing factors) must discontinue riboxili treatment.

For all other riboxil-related AEs, including toxic epidermal necrolysis (TEN) (grade 4 events according to CTCAE), follow the recommendations in Table A11 (see Tables A7, A8, A9, and A10 for dose modification guidance for hematologic, hepatic, QTcF, and ILD/pneumonitis, respectively). [ Table A11 ] : Riboxil dose modifications, management recommendations, and mandatory discontinuations for all other adverse reactions Level Dosage Adjustments and Administration Recommendations 1 No dosage adjustment is recommended. Initiate appropriate medical therapy and monitoring. 2 Interrupt dosing until recovery to ≤ Grade 1. Initiate appropriate medical therapy and monitoring. Restart sreboxil at same dose level. If same toxicity recurs at Grade 2, interrupt sreboxil until recovery to ≤ Grade 1. Restart sreboxil at next lower dose level. 3 Interrupt dosing until recovery to ≤ Grade 1. Initiate appropriate medical therapy and monitoring. Restart sreboxil at the next lower dose level. If toxicity recurs as Grade 2 or 3, withhold sreboxil (mandatory). 4 Discontinue riboxil (mandatory) and treat with appropriate medical therapy. 5.2.1.3. Toxicity tracking

AEs or abnormal laboratory values that persist when ribociclib is discontinued must be followed until they resolve to baseline or the event stabilizes. The recommended frequency of this follow-up is weekly for 4 weeks and then every 4 weeks thereafter (until resolved or stabilized). See Section 0 for information on the observation period for AEs and serious adverse events (SAEs). 5.2.1.4. Management of Potential Cases of Drug-Induced Liver Injury (DILI)

Elevated transaminases combined with elevated total bilirubin (TBIL) may indicate DILI and should be considered a clinically significant event.

The threshold for potential DILI may depend on the patient's baseline AST/ALT and TBIL values; patients who meet any of the following criteria will require further follow-up as described below: •   For patients with normal ALT, AST, and TBIL values at baseline: AST or ALT > 3.0 x ULN combined with TBIL > 2.0 x ULN •   For patients with elevated AST or ALT or TBIL values at baseline: (AST or ALT > 2 x baseline and > 3.0 x ULN) or (AST or ALT > 8.0 x ULN) (whichever is lower) combined with (TBIL > 2 x baseline and > 2.0 x ULN)

Medical evaluation is required to ensure that the liver test elevations are not due to cholestasis, which is defined as an alkaline phosphatase (ALP) elevation > 2.0 x ULN in patients without bone metastases, an R value < 2, or an elevated ALP liver fraction in patients with bone metastases. (Note: The R value is calculated by dividing ALT by ALP, and both values use multiples of the ULN. It indicates the relative pattern of ALT and/or ALP elevations due to cholestasis or hepatocellular liver damage or a mixed pattern of damage).

In the absence of cholestasis, these patients must discontinue ribociclib immediately and repeat LFTs as soon as possible, preferably within 48 hours of abnormal result detection. Evaluation should include laboratory testing, a detailed medical history, physical assessment, and the possibility of liver metastases or new liver lesions, obstruction/compression, etc.

Hepatotoxicity monitoring includes the following LFTs: albumin, ALT, AST, total, direct and indirect bilirubin, ALP (resolved if ALP is grade 2 or higher), creatine kinase, prothrombin time (PT)/INR, and GGT. For patients with Geppel syndrome: Total and direct bilirubin must be monitored, with intensive monitoring only for changes in direct bilirubin.

If elevations in AST, ALT, and/or bilirubin require interruption of medication, close observation is recommended and involves: •   Repeat liver enzyme and serum bilirubin testing two or three times weekly. If abnormalities stabilize or return to normal values, retesting can be reduced to weekly or less frequently. •   Obtain a more detailed history of presenting symptoms. •   Obtain a more detailed history of past illness and/or complications, including any history of preexisting liver disease or risk factors. •   Obtain a history of concomitant medications (including over-the-counter, herbal, and dietary supplements), alcohol, recreational drug use, and special diets. •   Rule out liver metastases. •   Rule out acute viral hepatitis types A, B, C, D, and E; hepatotropic virus infection (cytomegalovirus, Epstein-Barr, herpes simplex); autoimmune or alcoholic hepatitis; nonalcoholic steatohepatitis; anoxic/ischemic liver disease; and biliary disease. •   Obtain history of exposure to environmental chemical agents. •   Perform additional testing to evaluate liver function as appropriate (eg, INR, direct bilirubin). •   Consider gastroenterology or hepatobiliary consultation. •   Evaluate for cardiovascular dysfunction or impaired liver oxygenation, including hypotension or right-sided heart failure, which may be a cause of liver dysfunction. •   Consider liver biopsy when clinically indicated to assess pathology and extent of potential liver damage.

All cases of DILI that meet the above laboratory criteria and that do not reveal an alternative cause for abnormal LFTs on repeat testing should be considered “medically significant” and therefore meet the SAE definition (Section 0) and must be reported as an SAE using the term “potential drug-induced liver injury.” All events must be followed up and the outcome clearly documented. Test results and other clinically significant information will be documented in the CRF. 5.2.2.    Endocrine Therapy

ET-related AEs will be managed according to local clinical guidelines and investigator judgment. If ET needs to be interrupted for more than 4 weeks due to ET-related AEs, the medical monitor should be contacted to discuss whether to continue the trial treatment. 5.3. Trial Treatment Management

See Section 0 for details on the schedule and administration of investigational treatments. 5.3.1.    Packaging and Labeling

Reboxil (and ET, if supplied by Novartis AG) will be supplied as open-label patient-specific supplies. Drug labels will comply with the legal requirements of each country and be printed in the local language. They will include storage conditions for the drug but will not provide information for patients. 5.3.2.    Supply and Storage

Reboxil (and ET, if provided by Novartis AG) must be received by designated personnel at the trial site, handled and stored safely and appropriately, and kept in a secure location accessible only to the investigator and designated site personnel. Upon receipt, trial treatments should be stored according to the instructions specified on the drug label, Reboxil IB, or local product information. 5.3.3.    Compliance and Inventory

The investigator or site staff should instruct patients to take the trial treatments according to the protocol (to promote compliance). Site staff must ensure that patients clearly understand the instructions and fully follow the schedule. Site staff will ensure that the appropriate dose of each trial treatment is provided during each cycle.

During treatment, the investigator and/or designated site personnel will assess compliance at each patient visit, and information provided by the patient and/or caregiver will be recorded in the original documentation.

Administration of trial treatment will be recorded in the appropriate section of the CRF. In addition, patients will fill out a diary to record their daily intake. They will be instructed to return all unused Reboxil (and ET, if provided by Novartis AG) (partially used containers and empty containers) with their diary at each visit during treatment. Site staff will inventory returned medications and assess trial treatment compliance.

For Reboxil (and ET, if provided by Novartis AG), the Investigator or designee must maintain accurate records of trial treatment receipt and dispensing in a drug inventory log. Drug inventories will be reviewed by the Trial Monitor during site visits and upon completion of the trial. 5.3.4.    Disposal and Destruction

Destruction of Reboxil (and ET, if provided by Novartis AG) may be carried out at a local Novartis AG facility, the drug supply group, or a third party, as applicable. Destruction of investigational treatments provided by Novartis AG at a site is permitted only if authorized by Novartis AG or a designee and permitted by local regulations. 5.4. Concomitant medications and treatments 5.4.1.    General considerations

The patient must be instructed to inform the study center of any new medications she/he takes after signing the PICF.

All concomitant medications and significant non-pharmacological therapies (including physical therapy, vitamins, herbal/natural medicines, and blood transfusions) administered from 30 days before randomization until 36 months after the randomization date (until the 30-day post-reboxil safety follow-up visit for the study arm) must be listed in the CRF (unless EOT occurs before completion of 36 months of treatment; in this case, collection will cease at the 30-day safety follow-up visit).

For patients who experience a distant disease recurrence, if collection of concomitant medications and nonpharmacological therapies was previously discontinued as per the above paragraph, every effort should be made to restart collection of medications used to treat pain, depression, and anxiety at the time of recurrence and within 12 months of the distant recurrence, following the same schedule as for PRO collection after recurrence (see Table A20).

Patients taking concomitant medications chronically should maintain the same dose and dosing schedule throughout the trial, whenever medically feasible and indicated.

Bone-modifying agents (e.g., bisphosphonates, denosumab) are permitted for the treatment of osteoporosis and may be used as adjunctive therapy to reduce bone recurrence and improve BC outcomes when administered according to the Ontario Cancer Treatment Centre/American Society of Clinical Oncology guidelines or corresponding local guidelines. ⁴⁶ When so indicated, initiation of bone-modifying agents prior to randomization is strongly recommended.

Patients were not allowed to participate in any other parallel investigational drug or device studies.

Participation in other studies involving one or more investigational drugs within 30 days prior to randomization or within 5 half-lives of one or more investigational drugs, whichever is longer, or participation in any other type of medical research judged to be scientifically or medically incompatible with this trial is prohibited. If a patient is enrolled or planned to be enrolled in another study not involving an investigational drug, the consent of the Medical Monitor is required to determine eligibility.

While patients are receiving the trial treatment, they are not allowed to: • Take any other research or anticancer treatment. • Take hormonal contraception (including use of the intrauterine system) or hormonal medications (used as hormone replacement therapy to treat menopausal symptoms), phytoestrogens (as these may reduce the effectiveness of ET). 5.4.2. Concomitant medications and treatments with ET

Consult local clinical guidelines and current local prescribing information for medications and treatments that are permitted or contraindicated for concomitant use with ET.

Appropriate preventive or therapeutic measures should be taken for osteopenia, osteoporosis, elevated blood cholesterol, or any other ET-related AEs based on the investigator's judgment and local clinical guidelines. 5.4.3.    Concomitant medications and treatments with Riboxil

The following sections provide guidance regarding concomitant medications and therapies with ribociclib. 5.4.3.1. Contraindicated Concomitant Therapies

The following drugs are contraindicated during treatment with ribociclib: •   Potent inhibitors or inducers of CYP3A4/5 (may significantly increase or decrease ribociclib exposure, respectively). •   CYP3A4/5 substrates with a narrow therapeutic index (ribociclib may increase exposure of these drugs, leading to toxicity of these drugs). •   Drugs with a known risk of QT prolongation and/or TdP (combination use with ribociclib may result in QT prolongation and TdP). •   Concomitant use of tamoxifen or toremifene.

Herbal drugs/preparations or dietary supplements that are strong CYP3A4/5 inhibitors or inducers or have a known risk of QT prolongation. These include, but are not limited to: St. John's wort, kava, ephedra, Gingko biloba, dehydroepiandrosterone (DHEA), yohimbe bark, saw palmetto, black cohosh, and ginseng. Patients should stop taking these preparations/drugs at least 7 days prior to randomization. The potential for DDIs must be considered when using concomitant medications associated with hot flashes and other anticipated symptoms associated with this indication/ET use.

See Appendix 4: Concomitant Medications for a detailed list of prohibited medications. This list is not comprehensive and is provided for reference only. If you have any questions, please contact the TRIO Medical Supervisor. 5.4.3.2. Concomitant Therapies That Require Caution

Drugs that should be used with caution during treatment with ribociclib are listed below: •   Drugs with a possible risk of QT prolongation and/or TdP (may cause QT prolongation and TdP). •   Moderate inhibitors or inducers of CYP3A4/5 (may increase or decrease ribociclib exposure, respectively). •   Sensitive substrates of CYP3A4/5 that do not have a narrow therapeutic index (ribociclib may increase exposure to these drugs). •   Based on in vitro data (see the latest Reboxil IB for details), co-administration of Reboxil with potent inhibitors of the bile salt export pump (BSEP) may result in intrahepatic cholestasis, and co-administration of Reboxil with sensitive substrates of the renal transporters MATE1 and OCT2 (may increase exposure to substrates of these transporters, but no animal or clinical data are available to support these claims). •   Sensitive substrates of the breast cancer resistance protein (BCRP) transporter (may increase exposure to substrates of these transporters, but no animal or clinical data are available to support these claims).

Please see Appendix 4: Concomitant Medications for a detailed list of medications that should be used with caution. This list is not comprehensive and is provided for reference only. Please contact the TRIO Medical Monitor with any questions. These medications should be excluded if possible. If these medications must be given at the discretion of the Investigator, they should be used with caution and if the concomitant medication is only needed for a short period of time, consider interrupting ribociclib. 5.4.3.3. Drugs that cause QT prolongation

Whenever possible, avoid coadministration of the drug with any other drug that has a known, possible, or conditional risk of TdP or that may increase the risk of drug-related QT prolongation (e.g., by increasing exposure to riboxil or exposure to QT-prolonging drugs via a potential DDI).

Drugs with a known risk of QT prolongation are contraindicated during treatment with riboxil. If concomitant administration of a drug with a known risk of TdP is necessary and cannot be avoided, riboxil administration must be interrupted.

If concomitant administration of a drug with a "possible" or "conditional" risk of TdP is required during the trial, riboxil administration may be restarted under close clinical and ECG monitoring to ensure patient safety, based on the investigator's assessment and clinical needs.

A list of drugs associated with QT prolongation and/or TdP is available online (www.qtdrgs.org). Refer to the current riboxil IB and other drug labels and Appendix 4: Concomitant Medications for information on possible interactions with other drugs. 5.4.3.4. Permitted Concomitant Therapies

Medications required for the treatment of AEs, management of cancer symptoms, intercurrent illnesses, and supportive care medications such as analgesics, antiemetics, and antidiarrheals are permitted, except as described in Section 0 and Appendix 4: Concomitant Medications. Potential drug interactions between Riboxil and concomitant medications should always be considered. 5.4.3.5. Considerations for other concomitant therapies 5.4.3.5.1.     Corticosteroids

Chronic administration of corticosteroids (e.g., dexamethasone and prednisone) is known to induce CYP3A enzymes, potentially reducing reboxilb exposure to subtherapeutic levels. Systemic corticosteroids should not be administered during reboxilb treatment, except for the following: •   Topical application (e.g., for rash), inhaled spray (e.g., for obstructive airway disease), eye drops, or local injection (e.g., intra-articular injection); •   Short-term (< 5 days) systemic corticosteroids, ≤ 4 mg dexamethasone for anti-inflammatory efficacy (e.g., for chronic obstructive pulmonary disease or as an antiemetic). 5.4.3.5.2.     Hematopoietic Growth Factors

The use of white blood cell (WBC) growth factors and ribociclib for primary prophylaxis is not recommended. Their use is permitted when administered according to the American Society of Clinical Oncology clinical practice guidelines or equivalent local guidelines. ⁴⁷ 5.4.3.5.3. Use of antiemetic drugs

Based on the definition of emetogenicity for antineoplastic agents, ribociclib has very low to low emetogenic potential. ⁴⁶

According to clinical guidelines for anticancer drugs, antiemetic therapies with low to very low emetogenic potential can be used to treat and/or prevent treatment-induced nausea and vomiting. ^{49, 50}

Potential drug interactions between ribociclib and antiemetic medications should always be considered. An example of a contraindicated antiemetic medication is ondansetron, which may cause TdP when used in combination with ribociclib.

See Section 0, Section 0, and Appendix 4: Concomitant Medication for a list of medications that are permitted (with caution) or contraindicated for use with Reboxil. 5.4.3.5.4.     Concomitant Surgery

For patients in the study arms who require surgery during trial treatment, the following are recommended: • Relevant laboratory results (e.g., hematology) should be reviewed prior to surgery. • Schedule surgery within one week of not having received sirolimus treatment to allow for hematologic recovery. • Review concomitant medication regimen guidelines to ensure that patients do not receive contraindicated therapies pre/postoperatively. • After surgery, the decision to restart sirolimus treatment should be made based on a clinical assessment of satisfactory recovery, at the investigator’s discretion. 6. Trial Visits and Assessments 6.1. Screening and Randomization 6.1.1. Screening

Once the patient signs the Master PICF, she/he must be recorded in the IRT (same day) and this is considered the start of the Screening Period (see Section 0).

At this point, a unique patient number (Patient ID) is assigned. This number remains as the primary identifier for the patient throughout their participation in the trial, even if the patient is rescreened. The Patient ID consists of the study site number (Site ID) suffixed with a sequential patient number to uniquely identify each patient across the database. 6.1.2.    Randomization

Patients will be assigned to one of two treatment groups in a 1:1 ratio. Randomization will be stratified according to the factors reported in Section 0.

Once all screening assessments have been conducted (within the appropriate time window) and the investigator has confirmed eligibility status, randomization can proceed. Randomization will be performed in the IRT according to the instructions provided in the applicable user manual. 6.1.3.   Screening Failure

Patients who have signed a PICF but are not randomized for any reason will be considered screen failures and will be recorded as such in the IRT. Limited data on screen failure patients will be entered in the CRF according to the CRF completion guidelines. 6.1.4.    Rescreening

Only one rescreening is permitted per patient if the patient has not been randomized previously (i.e., IRT randomization). In this case, the patient number originally assigned will be used and will be used to identify the patient throughout their participation in the trial. If the investigator chooses to rescreen a patient after a screening failure, a new PICF must be signed.

If rescreening is performed, all re-evaluated evaluation results must meet the eligibility criteria. When determining eligibility, the laboratory examination performed closest to the randomization date will be considered and the results must meet the eligibility criteria.

For rescreened patients, there is no need to resample ctDNA/ctRNA unless the patient is receiving any ongoing anticancer treatment at the time of sampling. 6.2. Visit and Assessment Schedule

Table A12 lists all protocol-required assessments, with mandatory visits indicated by an "X". All data obtained from these assessments must be supported by the patient's original documentation.

The permitted visit windows are as follows (unless otherwise stated): • Randomization must occur within 42 days of the PICF signature date (Note: for patients receiving tamoxifen at the time of PICF signature, a washout period prior to randomization is considered per inclusion criterion #12). • All screening assessments must occur within 28 days prior to randomization. • Randomization and C1D1 should ideally occur on the same day. A window of up to 7 days is permitted between randomization and the C1D1 visit. • For all visits, a window of ± 3 days is permitted for applicable assessments (except for the ECG required for C1D1) to allow for scheduling considerations. • Assessments that may result in dose adjustments of trial treatment (e.g., dosing interruptions, dose reductions, discontinuation of treatment) should be reviewed by the investigator prior to initiation of treatment. [ Table A12 ] : Schedule of Visits and Assessments Evaluation ↓ Program Chapter ↓ Screening period Treatment period Follow-up period Visit → Filter Cycle 1 ​ Cycle 2 ​ Cycles 3 to 6 (per cycle ) Cycle 7 until 36 months after randomization ( every 3 cycles from C7D1 ) Safety follow-up after 30 days of Riboxil (study group only) From 36 months after randomization to EOT EOT 30- day security tracking Tracking Day → All assessments were completed within 28 days of randomization (unless otherwise stated) 1 15 1 15 1 1 30 days after last dose of Riboxil ( ±3 ) See Section 0 Within 15 days after the last dose of any study treatment 30 days after the last dose of all study treatments ( ±3 ) See Section 0 , Section 0 PICF and IRT Master PICF Signature 0;0 X (within 42 days before randomization) IRT Records 0; 0; 0 X (PICF and randomization) X X IRT drug distribution (for remdesivir and sponsor-provided ET) NA X X X X X (once every 12 weeks) Patient and BC history Demographics, medical history, BC history 0 X ER/PgR/HER2 status known 0 X Menopausal status 0;0 X When clinically indicated Inclusion/Exclusion Criteria 0 X Physical examination Physical examination 0 X X* X X X X ECOG performance status 0 X X* X X X X Vital signs, weight 0;0 X X* X X X X X X height 0 X Laboratory evaluation Hematology 0 X X* X X X X X X Biochemistry 0 X X* X X X X X X Blood clotting 0 X When clinically indicated Serum pregnancy test (for women with CBP) 0 X (within 14 days before randomization) Serum or urine pregnancy test (for women with CBP) 0 X* X X X (see Section 0) X Relapse Assessment Clinical evaluation (STEEP) 0 X X (every 12 weeks [± 2 weeks] for the first 24 months, then every 24 weeks [± 3 weeks] until remote recurrence is confirmed) Mammogram (unless bilateral mastectomy is done) 0 X (unless within 12 months of screening) X (every 12 months [± 4 weeks] and as clinically indicated until confirmed distant recurrence) Additional imaging (CT, MRI, US, PET, bone scan, X-ray, mammography) 0 X (as clinically indicated) X (within 4 weeks of clinically suspected local, regional, or distant recurrence or contralateral invasive BC or second primary non-breast invasive cancer according to Appendix 3: Recurrence Detection Guidelines) Histological (or cytological) confirmation of recurrence 0 X (as clinically indicated) X (within 4 weeks of clinically suspected local, regional, or distant recurrence or contralateral invasive BC or second primary non-breast invasive cancer according to Appendix 3: Recurrence Detection Guidelines) Survival status assessment Living Status 0 X Cardiac Assessment Single 12-lead ECG 0 X X X X X X (C3 and C6 only) X (if QTcF ≥ 481 msec at any time before cycle 7) X Adverse events, concomitant medications, and subsequent medications AE (non-serious) 0;0 X (only if relevant to trial participation) X (Continued up to 36 months from randomization [in the study arm, until the 30-day post-ribociclib safety follow-up visit]. See Table A21 for details) SAE 0;0 X (continuous) X (if related to experimental treatment) Concomitant medications and procedures 0 X (continuous, from 30 days before randomization until 36 months after randomization [in the study group, until the 30-day post-ribociclib safety follow-up visit]) If a distant relapse occurs, every effort should be made to collect medications used to treat pain, depression, and anxiety at the time of relapse and up to 12 months after confirmation of relapse (same timeline as PRO collection after relapse) Subsequent anti-cancer therapy 0; 0; 0 X X X Pharmacokinetics PK samples (PK subset only) 0 X Biomarkers ** Tumor tissue (archive): confirmed to be usable for testing 0 X Tumor tissue at relapse 0 X (from local, regional, and distant recurrences - unless unsafe for the patient at the discretion of the investigator -) Blood for ctDNA/ctRNA 0 X (until C1D1, before medication) X (C4D1, C13D1, C25D1, then every 48 weeks [± 3 weeks] after C25D1 and when local, regional, and distant recurrences occur) Blood for drug genetics analysis (optional) 0 X (C1D1, or within the first 12 weeks after randomization) Patient-Reported Outcomes EORTC QLQ-C30 0 X X (Every 12 weeks [± 2 weeks] during the first 24 months and every 24 weeks [± 3 weeks] thereafter until distant recurrence. At EOT. At confirmation of first recurrence and at confirmation of distant recurrence [if first recurrence is not distant recurrence], and within the first 12 months after confirmation of distant recurrence. After confirmation of distant recurrence, within 12 months: every 12 weeks [± 2 weeks] if distant recurrence is confirmed within the first 24 months after randomization date; or every 24 weeks [± 3 weeks] if distant recurrence is confirmed after the first 24 months after randomization date) EORTC QLQ-BR23 (women only) 0 X EQ-5D-5L 0 X HADS 0 X Resource Utilization Hospitalization, emergency room visit, other related clinic visit 0 X (Continuous during treatment and follow-up. If a distant relapse occurs, up to 12 months after confirmation of relapse - same schedule as PRO collection after relapse -) Trial treatment administration Riboxil (research group only) 0 Once daily on days 1 to 21 of each 28-day cycle for 36 months from randomization NSAI 0 Once daily, continuous dosing, for 60 months from randomization Goserelin (if applicable) 0 Days 1 ± 3 of each 28-day cycle, continuing for 60 months from randomization *Procedures marked with an "X*" (i.e., an X with an asterisk in the superscript) are only required if not performed within 14 days prior to C1D1. **Biomactor samples were collected from all patients (except those enrolled in China). 6.3. Trial Phase and Interviews 6.3.1. Screening Period

The screening period begins when the patient signs the master PICF and ends when she/he is randomized or fails screening. No trial-specific procedures may be performed before the master PICF is signed (Note: randomization must occur within 42 days of the PICF signing date).

During the screening period, the investigator must: •   Perform all screening procedures within 28 days before randomization (see Table A12 for a list of assessments to be performed). •   Assess the inclusion and exclusion criteria detailed in Section 0.

The following information will be collected at Screening: • Patient demographics and other baseline characteristics: • Menopausal status • Medical history and ongoing medical conditions • BC history: including (but may not be limited to) initial diagnosis, stage, ER, PgR, HER2 status, histopathological grade according to the Breast Cancer Histological Grading ^System51 , Ki67 (if available), any gene expression test results (if available), previous anti-tumor therapy. • Collection of SAEs and non-serious AEs (only if related to trial participation). • Collection of medications and relevant non-medical therapies within 30 days prior to randomization. • Confirmation of availability of required archival paraffin tumor tissue (see Section 0). • Blood for ctDNA/ctRNA (may be collected prior to C1D1 administration). • PRO Questionnaire (see Section 0).

In addition, the following evaluations will be performed at screening: •   Physical examination, vital signs, height, weight. •   ECOG performance status. •   Laboratory evaluations (hematology, biochemistry, coagulation, serum pregnancy test for women with CBP). •   Single ECG. •   Clinical evaluation for recurrence, mammography (unless performed within 12 months prior to start of screening), and radiographic and/or histologic/cytologic evaluations (as clinically indicated). See Section 0, Appendix 2: Standardized Definitions of Treatment Endpoints in Adjuvant Breast Cancer Trials (Based on STEEP) Guidelines and Appendix 3: Guidelines for Detection of Recurrence. 6.3.2.    Treatment Period

The treatment period begins when the patient starts receiving trial treatment (C1D1) and ends at the 30-day safety follow-up visit. 6.3.2.1. Trial treatment

After randomization, trial treatment should be started as soon as possible and no later than 7 days after randomization. Trial treatment will continue until the criteria in Section 0 are met.

During trial treatment, visits are required according to the following schedule: •   Until completion of 36 months of trial treatment, from the date of randomization: according to the schedule specified in Table A12 (i.e., every 28 ± 3 days from C1 to C6; thereafter every three cycles from C7D1). •   After completion of 36 months of trial treatment, from the date of randomization: according to Section 0, patients should have outpatient visits at the frequency determined in that section to assess for relapses. Other visits and assessments may be performed according to local clinical guidelines.

See Table A12 and Section 0 for details on the assessments performed at each visit during treatment. 6.3.2.2. Safety Follow-up Visit after 30 Days of Riboxil

Patients in the study arm must undergo a safety evaluation 30 days after the last dose of ribociclib. A 30-day post-ribociclib safety follow-up visit will be conducted 30 days (± 3 days) after the last dose of ribociclib. AEs, concomitant medications/related non-drug therapies, and healthcare resource utilization data (if any) will be collected at this visit. No other tests or assessments are required.

For patients who permanently discontinue riboxili concurrently with ET, a 30-day safety follow-up visit will be conducted 30 days (± 3 days) after the last dose of all trial treatments, which will serve as the 30-day post-riboxili safety follow-up.

Discontinuation of Riboxil will be documented in the IRT. 6.3.2.3. End of Treatment Visit

Patients who discontinue all trial treatments should have an EOT visit within 15 days of the last dose of all trial treatments (i.e., last dose of on-trial ET in the control arm; last dose of sribociclib and ET or last dose of ET alone [if sribociclib was previously discontinued] in the study arm).

The following assessments will be performed at this visit: •   Physical examination, vital signs, weight. •   ECOG performance status. •   Laboratory assessments (hematology, biochemistry, serum or urine pregnancy test for women with CBP) •   Single ECG collection. •   Collect: •   Non-serious AEs and/or SAEs (as applicable, per Section 0) •   Concomitant medications/related non-medical therapies (as applicable, per Section 0) •   Healthcare resource utilization data. •   Relapse clinical assessments (as applicable, per Section 0). •   PRO questionnaire (see Section 0). •   Collect subsequent antineoplastic therapy (i.e., surgery, radiation, local and systemic antineoplastic medications, if any).

The reason for EOT will be recorded in the IRT.

If the decision is made to discontinue a patient at a regularly scheduled visit, that visit can be used as an EOT visit rather than having the patient return for another visit.

If a patient fails to return for an EOT visit assessment for unknown reasons, every effort should be made to contact them (e.g., phone, email, letter) as specified in Section 0.

After EOT, patients will undergo a 30-day safety follow-up visit as described in the following chapters and then enter the follow-up period. 6.3.2.4. 30-Day Safety Follow-up Visit

All patients must undergo a 30-day safety evaluation after the last dose of all trial treatments. The 30-day safety follow-up visit will be conducted 30 days (± 3 days) after the last dose of all trial treatments.

SAEs (and non-serious AEs, as applicable, per Section 0), subsequent antineoplastic therapy, and healthcare resource utilization data, if any, will be collected at this visit. No other testing or assessments are required.

If a patient refuses to return for the 30-day safety follow-up visit or is unable to return for the 30-day safety follow-up visit, every effort should be made to contact them by telephone to determine if any AEs have occurred. Attempts to contact the patient should be documented in the original documentation (e.g., date of telephone call, registered mail, etc.). 6.3.3.   Follow-up Period

The follow-up period will begin after the 30-day safety follow-up visit and will continue until death, withdrawal of consent, loss to follow-up, or closure of the trial, whichever occurs first.

Patients will be assessed for recurrence and survival according to Section 0 and Section 10. For patients who discontinue trial treatment for reasons other than remote recurrence (or death, loss to follow-up, or withdrawal of consent), recurrence assessments will be performed during the follow-up period (according to Section 0) until documentation of remote disease recurrence, death, withdrawal of consent, loss to follow-up, or end of the trial.

Prior to a distant recurrence, follow-up visits will be performed at the time of clinical evaluation of recurrence according to the schedule in Section 0 (i.e., every 12 weeks [± 2 weeks] after randomization during the first 24 months and every 24 weeks [± 3 weeks] thereafter). After a distant recurrence is documented, survival information will be obtained according to the schedule in Section 0 (i.e., every 12 weeks [± 2 weeks] after randomization during the first 24 months and every 24 weeks [± 3 weeks] thereafter).

Implementation of selected PROs under Section 0 and collection of health care utilization data under Section 0 must continue during this phase.

During the follow-up period, the use of any subsequent antineoplastic therapy initiated after cessation of trial treatment will be recorded.

SAEs that the investigator believes are related to the trial treatment will continue to be reported. 6.3.4.    Withdrawal of Consent

Patients may voluntarily withdraw their consent to participate in a trial at any time and for any reason. Consent is withdrawn only if the patient: •   no longer wishes to participate in the trial, and •   does not wish to allow further collection of personal data

In such cases, the investigator should make reasonable efforts (e.g., telephone, email, letter) to understand the patient's primary reason for deciding to withdraw his/her consent and record this information.

The trial treatment must be discontinued, no further assessments will be performed, and data that would have been collected at subsequent visits will be considered missing.

No further attempts to contact the patient were permitted unless safety findings required notification or follow-up.

Every effort should be made to complete the assessment prior to withdrawal. The final assessment should be performed at the time of patient withdrawal and considered the EOT visit (for patients who withdraw before completing trial treatment).

Novartis AG will continue to retain and use the collected trial information (including any data obtained from analysis of patient samples until their withdrawal) in accordance with applicable law.

All biological samples that have not been analyzed at the time of withdrawal will not be used unless permitted by applicable law. They will be stored in accordance with applicable legal requirements. 6.3.5.    Lost Visits

For patients whose status is unclear due to failure to attend a trial visit without stating an intent to withdraw consent, the investigator should show a "due diligence" by contacting the patient, family, or primary care physician and documenting in the original documentation the steps taken to contact the patient, such as date of telephone call, registered mail, etc. Patients should not be considered lost until due diligence is completed. 6.4. Description of Trial Assessments 6.4.1.    Efficacy Assessments

Evaluation of efficacy for the primary endpoint of iDFS (as well as secondary and exploratory efficacy endpoints) will include locoregional recurrence, distant recurrence, ipsilateral and contralateral invasive BC, and second primary non-breast invasive cancers (see Appendix 2: Standardized Definitions of Efficacy Endpoints in Adjuvant Breast Cancer Trials (Based on STEEP) Guidelines and Appendix 3: Recurrence Detection Guidelines).

The outcome evaluation also includes a vital status evaluation under Section 0.

Evaluations of efficacy were determined calendar-wise, using the randomization date (not the date of the previous evaluation) as reference, regardless of treatment interruptions.

If a patient discontinues trial treatment for reasons other than distant disease recurrence (or death, loss to follow-up, or withdrawal of consent), recurrence assessments should continue according to the schedules in Tables A12 and A13 until distant disease recurrence, patient withdrawal of consent, patient loss to follow-up, death, or end of trial. Recurrence follow-up will not be discontinued at the occurrence of local or regional recurrence, contralateral invasive BC events, or second primary non-breast invasive cancers. 6.4.1.1. Recurrence Assessments

Recurrences (according to the STEEP system) will be reported as local, regional, distant, contralaterally invasive BC, and second primary non-breast invasive cancers (excluding basal cell carcinoma or squamous cell carcinoma of the skin) (see Appendix 2: Standardized Definitions of Efficacy Endpoints in Adjuvant Breast Cancer Trials [Based on STEEP] for guidance).

Imaging assessments described in Sections 0 and 10 are consistent with standard of care imaging assessments performed in patients with EBC. No additional radiographic studies are required as part of this protocol. 6.4.1.1.1.     Clinical Evaluation and Mammography

Recurrence testing will be done by clinical evaluation including history and physical examination. Clinical evaluation for recurrence will be performed as follows: •   At screening within 28 days before randomization. •   Then every 12 weeks (± 2 weeks) after randomization (using the date of randomization rather than the date of the previous evaluation as the reference date) for the first 24 months and every 24 weeks (± 3 weeks) thereafter.

NOTE: The 12-week (or 24-week) interval should be observed regardless of suspension of trial treatment or unplanned assessments. A ± 2 or 3-week window is allowed for scheduling considerations (as described above).

Planned mammograms (unless bilateral mastectomy is done): •   At screening (unless done within 12 months before screening). •   Then every 12 months (± 4 weeks) after randomization (if mammogram was done at screening) or every 12 months (± 4 weeks) from the date of the last mammogram done before screening, as appropriate. Mammograms should also be performed as clinically indicated.

The interval between mammography procedures should not exceed 12 months (+ 4 weeks).

If recurrence is suspected during clinical evaluation or planned mammography, evaluation according to Section 0 is necessary.

Clinical evaluation and mammography for recurrence should continue until documented recurrence of distant disease, death, withdrawal of consent, loss to follow-up, or end of trial. Patients who develop local and/or regional recurrence in the absence of distant disease should continue to be followed for recurrence per this section. 6.4.1.1.2.     Additional Imaging Evaluation and Confirmation of Recurrence

Recurrences suspected during the clinical evaluation or planned mammography must be evaluated by additional medical imaging as clinically indicated. In addition, every effort should be made to confirm recurrence by histology (or by cytology, as applicable) as defined in this section and Appendix 3: Guidelines for Recurrence Detection, unless testing would pose an unacceptable risk to the patient.

Relapses that are only clinically suspected but not confirmed as described in Appendix 3: Per the STEEP system, relapse detection guidelines will not be reported in the CRF as confirmed relapses and will not be considered iDFS events.

Imaging evaluations (excluding planned mammograms, although mammograms may be used to evaluate suspected recurrence during the clinical evaluation) will be performed after the clinical evaluation and within 4 weeks of a clinically suspected recurrence. The findings of the radiologic evaluation (evaluation of suspected recurrence or unconfirmed findings) will be documented on the CRF.

After a recurrence is clinically suspected, evaluation may be performed using any of the following radiologic evaluations: • Computed tomography (CT) or magnetic resonance imaging (MRI) of the chest, abdomen, or pelvis • Brain CT or MRI • Whole-body bone scan (bone scintigraphy) • Regional bone CT, MRI, or X-ray for any lesions identified on the whole-body bone scan that are not visible on CT or MRI of the chest, abdomen, and pelvis • CT or MRI of other sites (e.g., neck, extremities) • Ultrasound (US) • Fluorodeoxyglucose ( ¹⁸ F) positron emission tomography (FDG-PET), PET-CT • Mammography (for evaluation of suspected recurrence during clinical evaluation)

CT with intravenous (i.v.) contrast is the preferred imaging modality after a suspected recurrence. However, if the patient is known to have a contraindication to i.v. contrast or a contraindication develops during the trial, a helical CT of the chest without contrast (MRI is not recommended due to respiratory artifacts) and contrast-enhanced MRI of the abdomen and pelvis (if possible) should be performed.

A whole-body bone scan (e.g., Tc-99m bone scan, sodium fluoride PET [NaF-PET] bone scan) may be performed to identify the location of recurrence in bone tissue. If bone metastases are identified by bone scan, they must be confirmed by histology (preferably) or radiographic imaging (by X-ray, CT, MRI, or FDG-PET-CT) if biopsy confirmation is unsafe (at the discretion of the investigator).

If histologic confirmation (or cytology, as appropriate) poses an unacceptable risk to the patient, imaging may be used alone to confirm distal recurrence in bone tissue (CT, MRI, or FDG-PET-CT) and the central nervous system (CT or MRI, both with i.v. contrast).

If there are cutaneous, subcutaneous, or other superficial lesions for which imaging may not be informative, in the judgment of the investigator, it is acceptable not to perform imaging procedures to evaluate such lesions. In such cases, histologic or cytologic confirmation is necessary and sufficient. [ Table A13 ] : Imaging Acquisition Plan program Screening period Treatment and follow-up period Any of the following: CT or MRI (with contrast unless contraindicated), bone scan, US, PET, plain radiograph, mammography Not mandatory Within 4 weeks of clinical suspicion of recurrence* (including local, regional, distant) or contralateral invasive BC or second primary non-BC. Note: If there are cutaneous, subcutaneous, or other superficial lesions for which imaging may not be informative, it is acceptable not to perform imaging procedures to evaluate such lesions. Mammogram (unless bilateral mastectomy is done) Mandatory unless completed within 12 months before screening begins Every 12 months (± 4 weeks) after randomization (if mammography was performed at screening) or every 12 months (± 4 weeks) from the date of the last mammogram before screening, as applicable. Mammograms should also be performed as clinically indicated. The interval between mammographic procedures should not exceed 12 months (+ 4 weeks). Mammography should continue until documented recurrence of remote disease, death, withdrawal of consent, loss to follow-up, or end of the trial. *Clinical Assessment of Relapse: Assessed by planned clinical assessment every 12 weeks (± 2 weeks) for the first 24 months, then every 24 weeks (± 3 weeks) thereafter, or at any time when relapse is suspected. Note: Imaging data will be collected and stored according to local regulations. The local investigator's assessment will be used for primary/secondary endpoint analysis and treatment decisions. In the future, a retrospective central review of imaging data from locally stored images may be performed if deemed necessary by the sponsor.

If relapse is suspected clinically and/or by imaging, every effort should be made to confirm the relapse by histology (or cytology, as applicable) as defined in Table A14 and Appendix 3: Guidelines for Relapse Detection, unless the procedure poses an unacceptable risk to the patient. Histology/cytology confirmation of relapse should be performed within 4 weeks of clinical suspicion of relapse. All findings and results should be recorded in the appropriate CRF. If biopsy is not possible, the reason should be recorded in the CRF. [ Table A14 ] : Histology / Cytology Collection Plan program Screening period Treatment period and post-treatment follow-up period Histological or cytological evaluation of relapse Not mandatory Within 4 weeks of clinically suspected recurrence* (including local, regional, distant), contralateral invasive BC, or second primary non-BC. Clinical evaluation of recurrence with or without radiographic and/or histological/cytological confirmation should continue until documented distant disease recurrence, death, withdrawal of consent, loss to follow-up, or end of trial. *Clinical evaluation of relapse: assessed by planned clinical evaluation every 12 weeks (± 2 weeks) during the first 24 months, then every 24 weeks (± 3 weeks) thereafter or at any time when relapse is suspected. 6.4.1.2. Survival status assessment

Survival information during the follow-up period may be obtained by clinical visits, telephone calls, or other means according to the schedule in Table A12.

For patients who remain on follow-up for recurrence under Section 0, no specific additional visits/calls are required to assess survival.

Survival will be assessed according to the following schedule: •   If 30-day safety follow-up was performed within the first 24 months after randomization: every 12 weeks (± 2 weeks) until 24 months after the randomization date, and every 24 weeks (± 3 weeks) thereafter. •   If 30-day safety follow-up was performed after the first 24 months after the randomization date: every 24 weeks (± 3 weeks).

Survival assessments will continue until death, withdrawal of consent, loss to follow-up, or end of the trial (whichever occurs first). 6.4.2.    Safety Assessments

Patient safety will be monitored by assessing physical examination, ECOG performance status, height, weight, vital signs, ECG, laboratory evaluations (including hematology, biochemistry, and coagulation), and collection of AEs at each applicable visit. See Section 0 for details on AE collection and reporting. 6.4.2.1. Physical Examination

The physical examination should be performed according to the visit schedule outlined in Table A12.

At screening, the physical examination consists of a full-body examination, which should include: general appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, vascular, and nervous system examination. If indicated, a rectal, genital, breast, and pelvic examination will be performed. Information regarding the physical examination must be present in the original documentation from the study center.

Significant findings that occurred before the signing of the Master PICF consent form must be included in the History page of the patient’s CRF. Significant new findings that began or worsened after informed consent must be recorded in the AE page of the patient’s CRF.

After screening, a symptom/sign-driven physical examination is acceptable, except for testing for recurrence (see Section 0). 6.4.2.2. Vital Signs

Vital signs (temperature, pulse rate, blood pressure) will be monitored according to the visiting schedule (see Table A12). Blood pressure (systolic and diastolic) and pulse should be measured after the patient has been sitting quietly for approximately five minutes. 6.4.2.3. Height and weight

Height will be measured only at Screening. Weight will be measured at Screening and at subsequent times as specified in Table A12. 6.4.2.4. Physical Status

Performance status will be assessed using the ECOG Performance Status Scale ⁵² as specified in Table A15 according to the schedule given in Table A12. [ Table A15 ] : ECOG Performance Status Score describe 0 Fully active, able to perform all pre-disease behaviors without restriction 1 Limited physically demanding activities, but ambulatory and able to perform light or sedentary work, such as light housework, office work 2 Ambulatory and able to perform all self-care but unable to perform any work activities. More than 50% of waking time 3 Able to perform limited self-care and confined to bed or chair for more than 50% of waking time 4 Totally disabled. Unable to perform any self-care. Totally confined to bed or chair 5 die 6.4.2.5. Laboratory evaluation

Clinical laboratory analyses (hematology, biochemistry, coagulation, and other tests as required) are performed by local laboratories (see Table A16). The only exception is home pregnancy testing, which may be performed under Section 0 of C7.

The investigators were responsible for reviewing all laboratory reports from patients in the trial and for evaluating the clinical significance of any abnormalities.

A copy of the laboratory's certification and a table of normal ranges and units for each parameter collected in the CRF must be provided to TRIO. In addition, if at any time the patient's laboratory parameters are obtained from another (outside) laboratory, a copy of that laboratory's certification and a table of normal ranges and units must be provided to TRIO.

Unplanned local laboratory evaluations may be performed if recording of (potential) AEs is medically indicated to facilitate decision making (e.g., dose adjustment).

Abnormal laboratory parameters that are clinically significant, suggestive, require therapeutic intervention (e.g., hematologic abnormalities requiring transfusion), or require a change in trial therapy will be recorded on the AE CRF page according to Section 0, as applicable. The severity of laboratory data will be graded using the CTCAE version 4.03. Additional analyses will be performed at the discretion of the investigator. [ Table A16 ] : Clinical Laboratory Parameter Collection Plan Test Category Test Name Hematology WBC count and differential (neutrophils, lymphocytes, monocytes, eosinophils, and basophils), other differential counts (if available), hemoglobin, and platelet counts. Biochemistry Sodium, potassium, uric acid, urea or blood urea nitrogen, creatinine, eGFR*, fasting glucose, corrected calcium**, magnesium, phosphorus, and albumin. AST (SGOT), ALT (SGPT), TBIL, direct bilirubin, GGT and ALP, amylase, lipase, and lactate dehydrogenase (LDH). Blood clotting aPTT、INR Other tests (if applicable) Serum and urine pregnancy tests. FSH, estradiol, to confirm menopausal status (pre/post). Note: FSH and estradiol are not recorded on the CRF but are used to confirm menopausal status * eGFR is only required at screening and will be calculated using the 4-variable MDRD formula: eGFR in mL/min/1.73 ^m2 = 175 x Serum Cr ^-1.154 x Age ^-0.203 x 1.212 (if patient is black) x 0.742 (if female). ** If corrected calcium is not available from the local laboratory, the recommended formula is: Corrected Calcium = (0.8 x [Normal Albumin - Patient Albumin]) + Serum Calcium. 6.4.2.5.1. Hematology

Hematology testing should be performed according to the schedule outlined in Table A12. See Table A16 for details of the full hematology panel. 6.4.2.5.2.     Biochemistry

Biochemical tests should be performed according to the schedule in Table A12. For details on the full biochemical panel, see Table A16. 6.4.2.5.3.     Coagulation

INR and aPTT should be performed according to the schedule outlined in Table A12. 6.4.2.5.4.     Pregnancy Testing and Assessment of Menopausal Status/Fertility

When applicable, FSH and estradiol should be performed according to Table A12 and Table A16. When applicable, FSH and estradiol will be performed at screening to confirm eligibility and to confirm menopausal status (see Inclusion Criteria #0).

A serum pregnancy test must be performed at screening for all women with CBP. During the treatment period, pregnancy testing will be performed as follows: •   Each cycle from C1 to C6: urine or serum pregnancy test according to Table A12. •   From C7 until 36 months after randomization: o   In the study group: urine or serum pregnancy test will be performed monthly. It is acceptable for the patient to perform the urine test at home and promptly inform the investigator or designee (e.g., by telephone) of the results. Pregnancy testing may be performed at the study center during the month of the scheduled trial visit according to Table A12. o   In the control group: urine or serum pregnancy test every 3 cycles. •   EOT visit: urine or serum pregnancy test. 6.4.2.6. Electrocardiogram

At each time point indicated in Table A17, a standard 12-lead ECG assessment (supine position) will be performed after the patient has rested for approximately 10 minutes.

All ECGs collected during the trial (including unplanned ECGs with clinically relevant findings) will be transmitted to the central laboratory and will be centrally reviewed by an independent reviewer. For each ECG transmitted, an ECG report will be sent from the central laboratory to the study site.

At screening, the central laboratory ECG evaluation will be used to determine patient eligibility per inclusion criteria #15. NOTE: It is recommended that an ECG be obtained at least 3 business days prior to the scheduled randomization date to ensure that the site receives the ECG evaluation from the central laboratory for eligibility assessment.

After randomization, the investigator (or a qualified physician at another study site) will assess the ECG and will determine the duration of the QTcF and any potential reboxil dose adjustments (see Section 0). If the ECG report from the central laboratory shows a QTcF ≥ 481 msec, reboxil dosing should be interrupted (if not previously done) and the patient should be managed according to Section 0. The interpretation of the follow-up must be performed by a qualified physician at the study site and documented in the CRF. ECG assessments by local cardiologists may be performed at any time during the trial at the discretion of the investigator.

When a predrug ECG is to be collected, the ECG measurement must be performed before administration of the test treatment.

If a predose PK sample is to be obtained on the day of the ECG, the sample should be collected after the ECG and before the administration of the trial treatment. For additional guidance on the timing of the ECG related to the administration of ribociclib and PK sampling on C1D15, see Error! Reference source not found. and Section 0. [ Table A17 ] : ECG Collection Schedule Cycle patient sky time ECG Type Filter all -28 to -1 Any time Single 12-lead 1 all Day 1 Before medication ¹ Single 12-lead all Day 15 ^{Part 2} Before medication ¹ Single 12-lead all 2 h after drug administration (± 15 min) Single 12-lead all 4 h after drug administration (± 15 min) Single 12-lead 2 all Day 1 Before medication ¹ Single 12-lead all Day 15 Before medication ¹ Single 12-lead 2 h after drug administration (± 15 min) Single 12-lead 3 all Day 1 Before medication ¹ Single 12-lead 6 all Day 1 Before medication ¹ Single 12-lead 7 and every 3 periods thereafter (i.e. 7, 10, 13, etc.) until ³⁶ months after randomization3 Patients with QTcF ≥ 481 msec at any time before cycle 7 Day 1 Before medication Single 12-lead EOT Any time Single 12-lead Unplanned ECG Any time Single 12-lead ¹ The exact date and time of dosing must be recorded on the appropriate CRF. ² ECG assessments should be performed prior to PK sampling. ³ Or until RIBOXIL discontinuation (in the study arm) or ET discontinuation (in the control arm), if treatment is stopped prior to completion of 36 months.

QTcF values using Fridericia correction (formula see below) will be centrally reviewed.

If any ECG reading after randomization includes new clinically relevant abnormal ECG findings or a QTcF value ≥ 481 msec, riboxil must be interrupted, the ECG must be repeated, and the management guidelines detailed in Table A9 must be followed.

Unscheduled ECG examinations may be repeated at any time during the trial at the discretion of the Investigator and as clinically indicated.

Each ECG tracing should be labeled with the trial number, patient number, date, and maintained in the original file at the trial site. Clinically significant ECG abnormalities present at screening should be reported on the medical history CRF page when the patient signs the PICF. New or worsening clinically significant findings that occur after informed consent must be recorded on the AE CRF page. 6.4.3.    Pharmacokinetic Assessment

Approximately 130 patients from the study group will be considered the PK subset. Plasma samples for ribociclib assays will be obtained from these patients at the time points indicated in Table A18. [ Table A18 ] : PK blood sampling schedule for patients in the PK subset Cycle sky Relative to the planned time of medication administration (sampling window) Blood volume ( mL ) 1 15 Before administration (0 h) ^a 2 1 15 2 h after drug administration (± 15 min) 2 1 15 4 h after drug administration (± 30 min) 2 ^aPK samples were collected immediately before drug administration.

See Sections 0 and 0 for additional guidance regarding the timing of PK sample collection related to riboxili dosing and ECG on C1D15.

Every effort will be made to obtain PK samples at nominal times relative to the planned dosing schedule. However, samples obtained within the sampling window at the planned times will be considered per protocol.

See Section 0 for guidance on the data that should be collected in the CRF on the PK sampling day. If vomiting occurs during treatment, the patient should not be allowed to restart the medication and should be restarted the next day. The occurrence and frequency of any vomiting must be recorded in the AE section of the CRF. In addition, the date and exact time of vomiting should only be recorded if it occurs within 4 hours of dosing on the day of PK sampling.

If a pre- or post-dose sample was not collected on C1D15, every effort should be made to collect a supplemental sample between Days 16 and 21 of C1, following the same rules as above.

PK samples will be analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) with a lower limit of quantitation (LLOQ) of approximately 1.00 ng/mL. Any results below the LLOQ and any missing samples will be recorded accordingly. Residual plasma from the analysis may be used for exploratory metabolite assessments or other bioanalytical purposes (e.g., cross-checking between different study centers, stability assessment).

Instructions for collection, preparation, and transport are provided in the applicable laboratory manual. 6.4.4.    Biomarkers

Genetic variants leading to upregulation of CDK signaling are frequently observed in BC. Therefore, studying aberrations in genes associated with the CDK pathway in patients enrolled in this trial will allow the assessment of potential predictive and/or prognostic biomarkers in patients with EBC. Biomarkers suggestive of mechanisms of treatment resistance and underlying disease relapse will also be studied. Although the goal of biomarker analysis is to provide supportive data for clinical trials, there may be circumstances in which a decision is made to cease collection or not to perform or discontinue analysis for practical or strategic reasons. For example, there may be insufficient sample numbers, issues related to sample quality, or issues related to the assay that preclude analysis. Alternatively, the power may be insufficient to perform relevant analyses due to limited sample numbers. Therefore, depending on the results obtained during the trial, the collection and/or analysis of some samples may be omitted at the discretion of Novartis AG.

Tumor and blood samples will be collected from all patients (except those enrolled in China) according to Table A19. Biomarker sample collection is calendar-based, regardless of any treatment interruption.

All evaluations will be performed by a laboratory designated by Novartis AG. Instructions for collection, preparation, and transport are provided in the applicable laboratory manual. [ Form A19 ] : Biomarker Sample Collection Plan Sample Type Require Visit Time point Volume Tumor samples (from all patients except those enrolled in China) Archival paraffin tumor tissue from surgical specimens (or, in patients receiving neoadjuvant therapy and with a pathologic complete response, at initial diagnosis or before initiation of neoadjuvant therapy) (tumor block [preferable] or 20 unstained slides [15 for patients receiving neoadjuvant therapy]). Mandatory During screening: Samples are submitted to the central laboratory for availability confirmation NA N/A Archival paraffin tissue from the breast tumor at the time of initial diagnosis (tumor block [preferably] or 20 unstained slides) If you can Recurrent paraffin tumor tissue (tumor mass [preferably] or 20 unstained slides) Mandatory (unless unsafe for the patient) In local, regional, and distant recurrences until distant recurrence is confirmed Within 4 weeks of local, regional, or distant recurrence and before starting new treatment N/A Blood samples (from all patients except those enrolled in China) Blood for ctDNA/ctRNA Mandatory Screening (until C1D1, before dosing), C4D1, C13D1, and C25D1 Before medication 4 x 10 mL Every 48 weeks (± 3 weeks) after C25D1 until distant recurrence Before medication 4 x 10 mL In local, regional, and distant recurrences Within 4 weeks of confirmation of local, regional, or distant recurrence and before starting new anticancer therapy 4 x 10 mL Blood for drug genetics analysis As needed. Patient consent required C1D1 or next available visit within the first 12 weeks of randomization Any time 6 mL 6.4.4.1. Pathway Inhibition and Biomarker Assessment of Efficacy 6.4.4.1.1. Tumor Tissue Assessment (Mandatory)

Tumor tissue samples will be collected to identify biomarkers that predict benefit from ribociclib and explore mechanisms underlying disease relapse. Tumor tissue will be used to evaluate molecular alterations in several genes associated with HR-positive BC and cell cycle, such as but not limited to CDK4, CDK6, CCND1, CCNE1, p53, PIK3CA, RB1. ¹⁷ Protein (e.g., Ki67, pRb by IHC) and/or gene expression will also be assessed in tumor material. Broad panel testing or whole exome sequencing may be used to detect any additional mutations and assess their potential impact on clinical outcomes.

The tumor samples required are (see also Table A19): •   Mandatory archival paraffin tumor tissue from the healing surgical specimen (see inclusion criteria #0): this may be a tumor block (preferable) or 20 unstained slides (15 for patients receiving neoadjuvant therapy). As archival samples may not be at the institution providing the diagnosis, the site will be responsible for locating them and preparing the tumor block or unstained slides (or having them prepared) if necessary. •   If possible, obtain a tumor tissue sample from the tumor biopsy specimen at the time of initial diagnosis or before initiation of neoadjuvant therapy. This sample is mandatory for patients who receive neoadjuvant therapy and have a pathological complete response (see Inclusion Criteria #0). •   Mandatory tumor biopsy at relapse and before starting new anti-tumor therapy (unless it is unsafe for the patient at the discretion of the investigator). For patients with synchronous local/regional and distant relapse, samples from local/regional relapse and distant sites are required if feasible and safe for the patient.

The tumor biopsy will be sent to a designated laboratory, which will review the biopsy to ensure quality and sufficient tumor tissue quantity before starting a new anticancer therapy. If the quality or quantity of the biopsy does not meet the requirements, the investigator will be notified and another biopsy attempt will be performed before starting a new anticancer therapy (if safe for the patient). 6.4.4.1.2.     Blood Assessment (Mandatory)

Mandatory blood samples (4 x 10 mL) for plasma ctDNA/ctRNA will be collected according to Table A19.

ctDNA/ctRNA plasma samples will be used to evaluate mutations, copy number variations, and gene expression associated with HR-positive BC (e.g., PIK3CA, ESR1) and the CDK4/6 pathway and/or cancer using the most sensitive and advanced technologies available at the time of testing. The use of ctDNA/ctRNA in plasma samples provides a unique opportunity to monitor mutations and gene expression in a non-invasive manner during treatment, allowing for the detection of changes in tumor burden and monitoring response to treatment and disease relapse. ^53-56 Mutation evaluation at relapse may provide information on potential mechanisms of resistance to hormonal and/or CDK4/6 targeted therapies. 6.4.4.2. Additional Biomarker Assessment (As Needed)

The trial includes an optional biomarker component, which is assumed to be generated (i.e., a discovery-based study) and/or supported by exploratory objectives.

When additional samples (tumor, blood, DNA, RNA) of sufficient quantity and quality are available, and if permitted by local regulations, samples may be stored for up to 15 years after the end of the trial and further analyzed to address scientific questions related to Reboxil or cancer, including studies to aid in the development of cancer detection, monitoring, or treatment methods. The decision to conduct such exploratory biomarker studies will be based on the final data from this trial or from new scientific discoveries related to the drug class or disease, as well as reagent and assay availability.

Such studies will be conducted only in patients who have provided consent for this optional portion of the trial. 6.4.4.3. Pharmacogenetic Assessment (Optional)

Whole blood will be collected for genomic DNA extraction to conduct genome-wide association studies (GWAS), such as human leukocyte antigen (HLA) and CYP3A4 genotyping, to explore genetic factors (such as CYP3A4 polymorphisms) that may affect response to treatment (adverse reactions [such as neutropenia] and treatment efficacy). The patient data of this trial can be combined with other trials to increase statistical power.

The sample will be obtained only from patients who have provided consent for this optional portion of the trial. 6.4.5.    Resource Utilization Assessment

Healthcare resource utilization will be evaluated as an exploratory endpoint in this trial to characterize the impact of the investigational treatment on this aspect of healthcare. Additionally, these data may be used to support evaluations to characterize the economic impact of the investigational treatment regimen.

Health care resource utilization data should be collected throughout the treatment and follow-up period, as described in Table A12.

Every effort should be made to collect data on health care utilization after a relapse. Such data will be collected within 12 months of a remote relapse and should follow the same timeline as the collection of PROs after a relapse (see Table A20).

Hospitalization data of interest will focus on those hospitalizations reported as SAEs as required in Section 0. Hospitalizations due to the following reasons will not be reported: •   Routine treatment or monitoring of the indication under investigation, not related to any worsening of the condition. •   Elective or pre-planned treatment for a pre-existing condition that is unrelated to the indication under investigation and has not been aggravated since informed consent was given. •   Social reasons and temporary care in the absence of any worsening of the patient’s general condition.

Information related to length of stay (e.g., admission, discharge date), hospital unit facility used (e.g., emergency department, intensive care unit, general ward, etc.), reason for hospitalization related to investigational treatment regimens, illness and/or disease progression, or any other reason will be of interest; discharge information will also be evaluated.

In addition, the following data will be collected: •   Emergency room visits that did not result in subsequent hospitalization, and reason/etiology for the visit. •   Additional visits (not protocol required) to the treating investigator due to BC-related reasons or treatment-related AEs. 6.4.6.    Patient-reported outcomes

At the visits indicated in Tables A12 and A20, the following questionnaires will be administered to patients: •   European Organisation for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire (EORTC QLQ-C30, version 3.0) •   EORTC BC-Specific Quality of Life Questionnaire (EORTC QLQ-BR23, version 1.0) •   Generic Health Utility Index EuroQoL 5-Level Scale (EQ-5D-5L) •   Hospital Anxiety and Depression Scale (HADS) Questionnaire

Unless otherwise stated, all PRO measures were collected with a ± 3-day window and were collected on a calendar-determined basis, using the randomization date (not the date of the previous assessment) as reference, regardless of treatment interruption.

The EORTC QLQ-C30 (version 3.0), EORTC QLQ-BR23 (version 1.0), and EQ-5D-5L will be used to assess PRO indicators for health-related QOL, function, disease symptoms, and treatment-related side effects. The EORTC QLQ-C30, EORTC QLQ-BR23, and EQ-5D-5L are recognized as reliable and valid indicators and are commonly used in clinical trials for BC patients. ^57-59 In addition, the HADS questionnaire will be used to determine the level of anxiety and depression experienced by the patients. ⁶⁰

All paper questionnaires should be administered according to the following guidelines: •   Questionnaires will be in the patient’s local language. •   They will be administered to patients at the start of the applicable visit and prior to any interaction with the investigator, including any testing, treatment, or receipt of results of any tests, to avoid biasing the patient’s perspective. •   Patients should be given adequate space and time to complete all questionnaires, and all administered questionnaires should be reviewed for completeness. If missing responses are found, patients should be encouraged to complete any missing responses. •   If a patient is unable to complete the questionnaire in person, a designated study coordinator may obtain the patient’s responses by reading each question aloud, followed by the corresponding response category, and typing the patient’s response. No assistance should be provided to the patient by anyone other than the designated study coordinator. The coordinator should not influence the patient’s responses. Study coordinators cannot restate questions or translate questions into simpler language; the question must be read verbatim. •   An attempt should be made to collect responses to all questionnaires from all patients, including those who discontinue before the trial is completed. If a patient refuses to complete the questionnaire, or if a patient is unable to complete the questionnaire in the local language, this should be documented in the source record. A patient's refusal or inability to complete the questionnaire in the local language is not a protocol deviation. •   Investigators should not encourage patients to change responses reported in the questionnaire.

The Investigator should review and evaluate the completed questionnaires, including responses to the questions and any unsolicited notes written by the patient, prior to or during the visit to identify responses that may indicate a potential AE or SAE. If an AE or SAE is confirmed, the physician should record the event as directed in Section 0 of this protocol.

After completion at each applicable time point, the questionnaires will be entered into the CRF by study site staff.

See Appendix 5 for sample patient-reported outcomes for each questionnaire and more information about them. [ Table A20 ] : Patient-Reported Outcome ( PRO ) Collection Plan Questionnaire Visit sky time EORTC QLQ-C30 EORTC QLQ-BR23 EQ-5D-5L HADS Filter Day -28 to Day -1 For pre-relapse assessments, the questionnaire should be administered before any clinical assessment, medication administration, or diagnostic testing; for relapse assessments, the questionnaire should be administered within 30 days of clinical suspicion of relapse. Treatment period and follow-up period (including EOT) • After randomisation, every 12 weeks (± 2 weeks) for the first 24 months and every 24 weeks (± 3 weeks) thereafter until distant recurrence. • At EOT. • At first confirmed recurrence. • At confirmed distant recurrence (if first recurrence was not a distant recurrence). • Within the first 12 months after confirmed distant recurrence: • Every 12 weeks (± 2 weeks) if distant recurrence was confirmed within the first 24 months after randomisation, or • Every 24 weeks (± 3 weeks) if distant recurrence was confirmed after the first 24 months after randomisation. 7. Safety Monitoring and Reporting 7.1. Observation Period

For observation periods for AEs (non-serious) and SAEs, please refer to Table A21. [ Table A21 ] : Reporting Periods for AEs and SAEs Period AE (non-serious) SAE Start: Primary PICF Signature End: C1D1 (before medication) Only when relevant to trial participation All (regardless of relationship) Start: C1D1 (during/after dosing) End: 36 ^months after randomizationa All (regardless of relationship) All (regardless of relationship) Start: 36 months after randomization End: 30-day safety follow-up visit Not reportable All (regardless of relationship) Start: 30-day safety follow-up visit End: End of trial Not reportable Only when associated with an experimental treatment ^aIn the study arm, collection according to row 2 of the table should continue until the 30-day post-reboxil safety follow-up visit. If this visit occurs before completion of 36 months of reboxil treatment due to premature discontinuation of reboxil, collection will be extended to 36 months after randomization. If ET (control arm) or reboxil + ET (study arm) is discontinued before completion of 36 months of treatment, collection of all AEs (regardless of relationship) will cease at the 30-day safety follow-up visit. 7.2. Adverse events 7.2.1. Definition and reporting

An AE is defined as the occurrence of an undesirable sign or signs, symptoms or medical conditions (or an exacerbation of any pre-existing condition).

Whenever possible, AEs (including laboratory abnormalities that constitute the AE) should be described using a diagnosis rather than individual underlying signs and symptoms. When a clear diagnosis cannot be determined, each sign or symptom should be reported as a separate AE.

The occurrence of AEs should be sought through non-indicated questioning of the patient. AEs may also be detected when provided voluntarily by the patient during the screening process or between visits or through physical examination, laboratory testing, or other evaluations.

Each AE should be evaluated, to the extent possible, to determine: •   Severity level (per NCI CTCAE v4.03. See Table A22 for severity levels for events not listed in NCI CTCAE v4.03) •   Duration (start and end dates) •   Relationship to trial treatment •   Actions taken in response to trial treatment •   Other actions taken (e.g., concomitant medications or non-pharmacological therapies given) •   Whether it was severe, as defined for SAEs as described in Section 0, and what severity criteria were met •   Outcome.

Adverse reactions are defined as all untoward and unexpected reactions to an IMP associated with any dose administered. “Reaction to an IMP” means that a causal relationship between the drug and the adverse event is at least reasonably possible, i.e., such a relationship cannot be ruled out. For the assessment of the causality of an AE, the investigator should use his or her knowledge of the patient, detailed information about the AE, the circumstances surrounding the event, and an evaluation of any potential alternative causes to determine whether the AE is considered related to the trial treatment. [ Table A22 ] : Adverse Event Severity Rating Scale for Events Not Listed in NCI CTCAE v4.03 Level describe 1 Mild; no symptoms or mild symptoms; clinical or diagnostic observation only; no intervention required. 2 Moderate; minimal, local, or noninvasive intervention required; limits age-appropriate instrumental activities of daily living (ADL)*. 3 Severe or medically significant but not immediately life-threatening; requiring hospitalization or prolonged hospitalization; disabling; limiting self-care ADL**. 4 Life-threatening consequences; urgent intervention required. 5 Deaths related to AEs. *Instrumental ADLs are things like preparing meals, shopping for groceries or clothing, using the phone, managing money, etc. **Self-care ADLs are things like bathing, dressing and undressing, feeding oneself, going to the toilet, taking medications, and staying in bed.

AEs should be followed until they resolve, until they are judged permanent, the patient is lost to follow-up, or the patient withdraws consent. They should be assessed at each visit (or more frequently, if necessary) for any changes in: •   Severity •   Suspected relationship to the trial treatment •   Actions taken in response to the trial treatment •   Interventions required for treatment •   Outcome 7.2.2.    Aggravation of pre-existing conditions

Exacerbations of pre-existing conditions after PICF signing should be recorded in the AE CRF. Conditions that were present at the time of informed consent should be recorded in the patient's medical history page of the CRF. 7.2.3.    Laboratory Test Abnormalities

Laboratory test abnormalities that constitute AEs in their own right (i.e., those that are considered clinically significant, suggestive of signs or symptoms, requiring therapeutic intervention [e.g., hematologic abnormalities requiring transfusion], or requiring a change in trial therapy) should be recorded on the AE CRF page. Laboratory abnormalities that do not meet the definition of an AE should not be reported as AEs. Grade 3 or 4 events per CTCAE do not automatically indicate an SAE unless they meet the definition of severity as defined below and/or at the discretion of the investigator. The protocol may require that drug administration be withheld for a laboratory test abnormality, in which case the abnormality is still an AE by definition and must be reported as such.

The same observation period applies to laboratory test abnormalities identified as AEs/SAEs as other non-serious AEs or SAEs (see Table A21: Reporting Periods for AEs and SAEs).

Whenever possible, a diagnosis rather than symptoms should be provided (e.g., anemia rather than low hemoglobin). Laboratory abnormalities that meet AE criteria should be followed until they normalize or an adequate explanation for the abnormality is found. When the abnormal laboratory or test result corresponds to a sign/symptom of a reported AE, it is not necessary to record the laboratory/test result separately as an additional event. 7.2.4. Recurrent Adverse Events

Recurrent AEs are defined as AEs that resolve between patient evaluation time points and subsequently recur. Each AE recurrence should be recorded separately in the AE CRF. 7.2.5.    Death

Death should be considered an outcome, not an independent event. Events or conditions leading to or contributing to a fatal outcome should be recorded as a single medical concept in the AE CRF.

Information on any deaths (AE-related or not) will also be collected via the Death CRF. 7.2.6.    Recurrence of Breast Cancer

If BC recurrence (including recurrence resulting in fatal outcome) is recorded using appropriate methods (e.g., recurrence confirmed according to STEEP criteria), it should not be reported as an AE, including an SAE. The progression of malignancy should not be reported as an AE, including an SAE.

AEs separate from progression of malignancies (e.g., deep vein thrombosis with progression or hemoptysis with detection of disease progression, etc.) will be reported according to conventional guidance regarding the proper attribution of such events to the drug. 7.2.7.    Second primary malignancies

Any second primary malignancy must be reported as an AE; if the event meets at least one severity criterion, it must be reported as an SAE. 7.3. Serious Adverse Events 7.3.1.    Definitions

An SAE is defined as any adverse event that meets at least one of the following criteria: •   Is fatal •   Is life-threatening (i.e., the investigator believes that the adverse event puts the patient at immediate risk of death at the time of its occurrence) •   Requires hospitalization or prolongation of an existing hospitalization •   Resulting in permanent or significant disability/disability •   Constitutes a congenital anomaly/birth defect •   Is medically significant, defined as an event that endangers the patient or may require medical or surgical intervention to prevent one of the outcomes listed above Please note that hospitalizations due to the following reasons should not be reported as SAEs: •   Routine treatment or monitoring of study indications not related to worsening of any medical condition. •   Elective or pre-planned treatment for pre-existing conditions that are unrelated to the indication under investigation and have not been aggravated since informed consent was given. •   Social reasons and temporary care in the absence of any deterioration in the patient's general condition. •   Treatment on an emergency outpatient basis, which is an event leading to hospital admission and involving an event that does not meet any of the definitions of the above SAEs.

All confirmed cases of DILI (see Section 0) must be reported as SAEs, regardless of severity. 7.3.2.    Reporting

To ensure patient safety, every SAE (regardless of suspected causality) occurring after the patient has provided informed consent and until at least the 30-day safety follow-up visit (see Table A20) must be reported to Novartis AG without undue delay and in any case within 24 hours of becoming aware of its occurrence.

Any additional information on the SAE, including complications, progression of the initial SAE, and recurrent episodes, must be reported immediately as follow-up to the original event within 24 hours of receipt of the follow-up information by the Investigator. SAEs that occur at a different time interval or are considered completely unrelated to a previously reported SAE should be reported separately as new events.

Any SAE occurring after the 30-day safety follow-up visit should be promptly reported to Novartis AG within 24 hours of being notified of its occurrence if the investigator suspects a causal relationship to the trial treatment.

Information about all SAEs is collected and recorded on the Serious Adverse Event Reporting Form; all applicable sections of the form must be completed to provide a clinically comprehensive report. The investigator must evaluate and document the relationship of each SAE to each specific trial treatment (if there is more than one), complete the English-language SAE Reporting Form, and submit the completed form to Novartis AG within 24 hours of being notified of the occurrence. Detailed instructions regarding the SAE submission process and signature requirements will be found in the Investigator Folder provided to each site.

Follow-up information is submitted in the same manner as the original SAE report. Each reoccurrence, complication, or progression of the original event should be reported as a subsequent report of that event, regardless of when it occurred. Follow-up information should describe whether the event resolved or persisted, and if so, how it was treated, and whether the patient continued or discontinued the trial treatment or participation.

If the SAE is considered to be related to riboxil and has not been previously documented in the IB or package insert (new occurrence), the Assistant Head of Medical Office and Patient Safety (CMO&PS) at Novartis AG may require additional information from the investigator for reporting to the health authorities. Novartis AG may need to issue an Investigator Notification (IN) to notify all investigators participating in any trial of the same medicinal product that the SAE has been reported. Suspected and Unexpected Serious Adverse Reactions (SUSAR) will be collected and reported to the CA and IEC/IRB in accordance with Directive 2001/20/EC or as required by national regulatory requirements in participating countries. 7.4. Pregnancy

To ensure patient safety, every pregnancy that occurs while a patient is receiving trial treatment must be reported to Novartis AG without undue delay and in any case within 24 hours of becoming aware of its occurrence.

Pregnancy follow-up should be performed to determine outcomes including spontaneous or voluntary termination, birth details, and the presence or absence of any birth defects, congenital anomalies, or maternal and/or neonatal complications. Pregnancy follow-up should be documented in the same format and should include an assessment of possible relationship to the outcome of any pregnancy studied.

Any SAE occurring during pregnancy (e.g., fetal events, maternal events during or after pregnancy, or congenital anomalies/birth defects in the child) must be reported separately as an SAE. 7.5. Warnings and Precautions

At the time of approval of this clinical trial protocol, no evidence was available to indicate that special warnings or precautions were appropriate, other than those indicated in the provided Riboxil IB. Additional safety information collected between IB updates will be communicated in the IN. This information will be included in the PICF and should be discussed with patients during the trial as needed. 7.6. Independent Data Monitoring Committee

The trial will have an IDMC that is independent of all other individuals associated with the conduct of the clinical trial, including the site investigators participating in the trial. The IDMC will be established before the first patient is randomized.

The IDMC will be responsible for reviewing safety results and will regularly monitor the accumulating safety data in the trial approximately every six months, provided that sufficient patients have been randomized. In addition, the IDMC will conduct a safety review after the first patient completes 12 months of trial treatment. In addition, an additional safety review may be conducted if requested by the IDMC Chair. The IDMC will also review efficacy data at planned interim analyses.

It is expected that the IDMC will consist of at least two physicians with appropriate disease area qualifications, a patient advocate, and a statistician. Before the IDMC charter and interim analysis plan are finalized, a meeting will be held with the IDMC to describe its roles and responsibilities and to discuss potential data format and process issues. 8. Statistical Methods and Data Analysis

It is planned to combine data from all participating sites so that sufficient numbers of patients are available for analysis. Interim and final analyses will be performed by designated providers.

Any data analysis performed independently by any investigator should be submitted to Novartis AG prior to publication or presentation. 8.1. Analysis Set 8.1.1.    Complete Analysis Set

The full analysis set (FAS) includes all patients who were randomly assigned to a trial treatment. Patients will be analyzed according to the intention-to-treat principle according to the treatment group to which they were randomized and the stratum to which they were assigned during the randomization procedure. 8.1.2.    Safety set

The safety analysis set includes all randomized patients who received any trial treatment (i.e., at least one dose of ribociclib or ET). Patients will be analyzed according to the trial treatment they actually received.

The actual treatment received corresponds to: •   Riboxil + ET, if the patient took at least one dose of Riboxil •   ET, if the patient never received Riboxil 8.1.3.   Per-protocol set

The per-protocol set (PPS) consists of the subset of patients in the FAS who meet protocol requirements. All protocol deviations or conditions that lead to exclusion from the PPS will be detailed in one or more trial-specific documents. If the FAS and PPS are different and the primary analysis is significant, a sensitivity analysis of the iDFS primary endpoint may be performed using data from the PPS. 8.1.4.    Pharmacokinetic Analysis Set

The pharmacokinetic analysis set (PAS) included all patients who received at least one dose of ribociclib and had at least one evaluable post-dose concentration measurement. 8.2. Patient Demographics/Other Baseline Characteristics

Demographics and other baseline data (including disease characteristics/prognostic data) will be presented by treatment group for the FAS set and summarized descriptively.

Categorical data are presented as frequencies and percentages. For continuous data, mean, standard deviation, median, minimum, and maximum are presented.

Relevant medical history and current medical conditions at baseline will be summarized by system organ class, preferred term, and treatment group. 8.3. Treatment (investigational treatments, concomitant therapies, compliance)

The safety analysis set will be used for the analysis in this section. Categorical data will be summarized as frequencies and percentages. For continuous data, the mean, standard deviation, median, minimum, and maximum values will be presented.

The duration of exposure to reboxil and ET (in months) and the dose intensity (calculated as the ratio of the actual cumulative dose received to the actual duration of exposure) and relative dose intensity (calculated as the ratio of dose intensity to planned dose intensity) will be summarized by descriptive statistics. The cumulative dose and mean daily dose of reboxil and ET for each patient will be summarized using descriptive statistics (e.g., mean, standard deviation, and median).

The number of patients with dose modifications (reduction, interruption, or permanent discontinuation) and the reasons will be summarized by treatment group, and all dosing data will be listed.

Concomitant medications and important non-pharmacological therapies before and after the start of the trial treatment will be listed and summarized by treatment group according to the Anatomical Therapeutic Chemical (ATC) classification system. 8.4. Primary Objectives

The primary objective of this trial was to compare iDFS (according to the STEEP system) between riboxil and ET and ET in premenopausal and postmenopausal women and men with HR-positive, HER2-negative EBC ³⁵ . 8.4.1. Variables

The primary efficacy variable of the trial is iDFS, which is defined as the time from the date of randomization to the first event of locally invasive breast recurrence, regional invasive recurrence, distant recurrence, death (any cause), contralateral invasive BC, or second primary non-breast invasive cancer (excluding basal cell carcinoma and squamous cell carcinoma of the skin). iDFS events will be assessed locally. See Section 0 below for attrition. 8.4.2.    Statistical assumptions, models, and analytical methods

Assuming a proportional hazard ratio for iDFS, the following statistical hypotheses will be tested to determine the primary efficacy objective: in This is the iDFS hazard ratio (Riboxil + ET vs ET).

The primary efficacy analysis testing this hypothesis and comparing the two treatment groups will include an overall unilateral stratified log-rank test at a 2.5% significance level based on the randomized stratified factors: •   Menopausal status: premenopausal women and men versus postmenopausal women •   AJCC 8th edition anatomical stage group: anatomical stage II versus anatomical stage III •   Previous neoadjuvant/adjuvant chemotherapy: yes versus no •   Geographic region: North America/Western Europe/Australia versus rest of the world

The primary efficacy variable, iDFS, will be analyzed using the Lan-DeMets (O’Brien-Fleming) alpha spending function and the unconstrained Lan-DeMets (O’Brien-Fleming) beta spending function at three interim analyses (the first interim analysis may allow the trial to be stopped for futility, and the second and third interim analyses may allow the trial to be declared superior efficacy) and the final analysis for a group sequential design. Analyses will be performed based on the FAS population according to treatment group and stratification assigned at randomization. The iDFS distribution will be estimated using the Kaplan-Meyer method, and Kaplan-Meyer curves will be presented for each treatment group. iDFS at the end of each year for each of the two treatment groups will be presented with 95% confidence intervals (CIs). Hazard ratios for iDFS and their 95% CIs will be calculated from stratified Cox models using the same stratification factors as for the log-rank test.

If the primary efficacy analysis is statistically significant, additional descriptive analyses of iDFS will be performed approximately two years after the primary iDFS analysis and at the end of the trial. 8.4.3.    Handling Missing Values/Deletions/Discontinuations

If no iDFS events are observed by the analysis cutoff date, the iDFS will be deleted. The deletion date will be the date of the last recurrence assessment on or before the data cutoff date. 8.4.4.    Supportive Analyses

As a sensitivity analysis performed in FAS, hazard ratios and 95% CIs for iDFS will be obtained from: •   Unstratified and unadjusted Cox models for covariates. •   Stratified and adjusted Cox models for covariates. Covariates to be included will be detailed in SAP.

If the FAS and PPS were different and the primary analysis was significant, an iDFS analysis was also performed based on the PPS using the same analysis convention as the primary efficacy analysis.

If the primary analysis is statistically significant, subgroup analyses will be performed to assess the homogeneity of treatment effects across demographics and baseline disease characteristics (e.g., stage, menopausal status, previous anticancer treatment, etc.). Subgroups to be considered in the SAP will be defined.

Descriptive statistics (number of patients missing and reasons for missing) will be used to examine patterns of missing data by treatment group. 8.5. Secondary objectives 8.5.1.    Secondary efficacy objectives

Analyses will be performed at the primary analysis of iDFS (or at the 2nd or 3rd interim analysis if the efficacy margin is exceeded, or at the final iDFS analysis otherwise) and at the end of the trial for all secondary efficacy objectives (see Section 0). Each secondary efficacy endpoint will be analyzed in the FAS population according to randomized treatment group and stratum assigned at randomization.

The distribution of each efficacy endpoint will be estimated using the Kaplan-Meier method and compared between the two treatment groups using the strata assigned at randomization using a one-sided 2.5% significance level stratified log-rank test. Hazard ratios and their 95% CIs will be calculated using a stratified Cox model based on the strata assigned at randomization. Secondary endpoints will not be adjusted for multiple comparisons. 8.5.1.1. Relapse-free survival

RFS is defined as the time from the randomization date to the first event of local invasive breast recurrence, regional invasive recurrence, distant recurrence, or death (from any cause). Patients without RFS events will be censored at the time of the last recurrence assessment on or before the data cutoff date. 8.5.1.2. Distant Disease-Free Survival

DDFS is defined as the time from the date of randomization to the date of the first event of distant recurrence, death (any cause), or second primary non-breast invasive cancer (excluding basal cell carcinoma and squamous cell carcinoma of the skin). Patients without DDFS events will be censored at the time of the last recurrence assessment on or before the data cutoff date. 8.5.1.3. Overall Survival

OS was defined as the time from the date of randomization to the date of death from any cause. If a patient was not known to have died, OS was censored at the most recent date the patient was known to be alive (on or before the data cutoff date).

OS will be analyzed at the primary analysis of iDFS (2nd or 3rd interim analysis if efficacy margin exceeded, otherwise final iDFS analysis), approximately two years after the primary iDFS analysis, and at the end of the trial (see Section 0). Assuming a 5-year OS rate of 87% in the control group and a hazard ratio of 0.85 between the two groups, and assuming that approximately 10% of patients will be lost to follow-up at the final iDFS analysis for OS (i.e., hazard ratio for loss = 0.004/month), the expected number of OS events at the 2nd and 3rd interim analyses, the final iDFS analysis, two years thereafter, and at the end of the trial are approximately 187, 225, 271, 474, and 641, respectively. 8.5.2.    Patient-Reported Outcomes

The physical function subscale score of the EORTC QLQ-C30 will be the primary PRO variable of interest. The global health status/QoL scale score of the EORTC QLQ-C30, the emotional function and social function subscale scores of the EORTC QLQ-C30, the BC symptom scale score of the EORTC QLQ-BR23, the VAS of the EQ-5D-5L, and the anxiety domain and depression domain scores of the HADS will be secondary PRO variables of interest. The FAS will be used to analyze the PRO data.

Descriptive statistics will be used to summarize the absolute changes in PRO scores and scale scores at each program assessment relative to baseline rating scales.

As the primary analysis of PROs, to best exploit repeated PRO assessments, PRO scores in all subscales obtained from the EORTC QLQ-C30, breast symptom scores from the QLQ-BR23, VAS from the EQ-5D-5L, and anxiety and depression domain scores from the HADS will be analyzed using a repeated measures model for longitudinal data to assess treatment effects over time. The least squares mean differences between the treatment and control groups at the selected time points will be presented with the corresponding two-sided 95% CIs. 8.5.2.1. Handling missing values/deletions/discontinuations

Missing item data in the scale will be handled according to the instrument manual. If the total score or subscale score is missing at the visit, no interpolation will be applied.

For repeated measures analyses, patients with baseline and at least one non-missing post-baseline assessment will be included. All available data will be used in a repeated measures model appropriate for longitudinal data, assuming that missing scores at any time point are missing at random. If deemed appropriate, additional sensitivity analyses may be performed to assess possible violations of the missing at random assumption for the missing data mechanism. Details will be specified in SAP. 8.5.3.    Safety Objectives 8.5.3.1. Analysis Sets and Analysis Groups

For all safety analyses, the Safety Analysis Set will be used. All lists and tables will be presented by treatment group.

The entire observation period will be divided into three mutually exclusive parts: 1. Pre-treatment phase: from the day the patient signs the informed consent form to the day before the first dose of trial treatment (any Riboxil or ET dose on or after the randomization day) 2. Treatment phase: from the day of the first dose of trial treatment to 30 days after the last dose of trial treatment 3. Post-treatment phase: 31 days after the last dose of trial treatment 8.5.3.2. Adverse events

The summary tabulation of AEs will include only AEs that initiated or worsened during the treatment period, i.e., treatment-emergent AEs.

The incidence of treatment-emergent AEs (new or increased relative to baseline) will be summarized by system organ class and/or preferred terminology, severity (based on CTCAE grade v4.03), type of AE, and relationship to trial treatment.

SAEs and non-serious AEs will be tabulated during the treatment period. All deaths (on-treatment and post-treatment) will be summarized.

All AEs, deaths, and SAEs (including those from both the pre- and post-treatment periods) will be listed, and those collected during the pre- and post-treatment periods will be labeled. 8.5.3.3. Laboratory Abnormalities

Laboratory values will be assigned a grade programmatically according to the NCI CTCAE version 4.03 . The CTCAE grade is calculated based solely on observed laboratory values and does not take into account clinical assessments.

All nonmissing values that are not graded 1 or higher are assigned a CTCAE grade of 0. Grade 5 will not be used. Missing values will not be graded.

For laboratory tests that have not been graded by CTCAE, results will be categorized as low/normal/high based on the laboratory's normal range.

The following summaries are generated separately for hematology and biochemistry tests: •   Listing of all laboratory data with values labeled to show the corresponding CTCAE v4.03 grade (if applicable), categorized relative to the laboratory normal range For laboratory tests with grades defined by CTCAE •   Worst post-baseline CTCAE grade (regardless of baseline status). Only the worst grade observed after baseline will be counted once per patient. •   Baseline to worst on-treatment values will be compared using a toggle table for CTCAE grades For laboratory tests not graded by CTCAE, •   Baseline to worst on-treatment values will be compared using a toggle table categorized as “low”/“normal”/“high”/“low and high”.

In addition to the tables and lists above, other exploratory analyses may be specified in SAP, such as plots or box plots of the original time course or changes in laboratory tests over time. 8.5.3.4. Other safety data 8.5.3.4.1.     ECG

Categorical analyses of QT/QTc interval data based on the number of patients who met or exceeded pre-specified limits for absolute QT/QTc interval or change from baseline will be presented. In addition, a list of these patients by treatment group will be generated. 8.5.3.4.2.     Vital Signs

Vital sign data will be tabulated and presented, and significant values will be marked. 8.5.3.5. Supportive Analyses for Secondary Objectives

The primary safety analysis will be repeated in subgroups of patients by treatment group. Subgroups to be considered in the SAP will be defined. 8.5.3.6. Tolerability

Tolerability will be studied in terms of dose reductions and medication interruptions due to AEs. Reasons for dose reductions and interruptions will be listed and summarized by treatment group. Tolerability of ET during the on-treatment phase and post-treatment phase will be summarized (Section 0). 8.5.4.    Pharmacokinetic Purpose

PK analyses will be performed using the PAS. PK concentrations of riboxil will be summarized by visit and planned time point using descriptive statistics. All PK concentration data will be presented if applicable.

All concentrations below the LLOQ will appear as zero in the listing, be marked as such, and be treated as zero in any calculation of summary statistics, but will be treated as missing in the calculation of geometric means and their CVs.

Model-based approaches can be used to explore potential relationships between efficacy or safety endpoints and ribotox concentrations. Exploratory PK analyses can be performed. 8.6. Exploratory Objectives

Exploratory endpoints will not be adjusted for multiple comparisons and details may be recorded in a separate SAP. 8.6.1.    Loco-regional recurrence-free survival

LRRFS was defined as the time from the randomization date to the first event of local (ipsilateral) invasive breast recurrence, regional invasive recurrence, or death from any cause. Patients without LRRFS events were censored at the time of the last recurrence on or before the data cutoff date.

If there are sufficient numbers of events, LRRFS will be analyzed at the primary analysis of iDFS (2nd or 3rd interim analysis if efficacy margin exceeded, otherwise final iDFS analysis) and at the end of the trial (see Section 0). LRRFS data will be presented and summarized by treatment group. 8.6.2.    Resource Utilization

Data related to resource utilization (as described in Section 0) will be used to support health economic evaluations.

Trial-specific analyses will focus on descriptive statistics of hospitalizations and hospital facility visits that occurred during the treatment and follow-up periods and will be summarized by treatment group. Summary statistics for hospitalizations will include the number of patients hospitalized, total and average number of hospitalizations and duration of hospitalization, reason for hospitalization, type of hospital facility (e.g., emergency department, intensive care unit, general ward, etc.), and discharge summary.

Details of data analysis will be specified in SAP (if applicable). 8.6.3.    Use of subsequent anti-neoplastic therapy

Subsequent anticancer therapy use will be characterized by the incidence of subsequent anticancer therapy, time to first anticancer therapy, and time to first systemic anticancer therapy. These data will be presented and summarized by treatment group. If there are sufficient numbers of events, the duration of first systemic anticancer therapy can be explored in both treatment groups. 8.6.4.    Biomarkers

As a project standard, Novartis AG will analyze only biomarkers collected in trial databases. For exploratory markers, since the study was not powered enough to assess hypotheses related to specific biomarkers, the goal of these exploratory statistical analyses should be considered to generate new scientific hypotheses. These hypotheses can be compared with results found in the literature and confirmed by data derived from subsequent clinical trials. No adjustment for multiple comparisons of exploratory analyses is planned. In addition, additional post hoc exploratory assessments are expected and may be performed.

In some cases, a decision may be made to stop sample collection, or not perform or stop analysis of blood/archival tumor samples/fresh tumor biopsies/fine needle aspirates for practical or strategic reasons (e.g., issues related to sample quality and/or quantity or assay-related issues). In such cases, the sample quantity may not be sufficient for a rigorous data analysis, and the available data are presented and may be summarized. 8.6.4.1. Overview of Data Analysis

Additional analyses that may be performed after the completion of the end-of-trial clinical study report (CSR) will be documented in a separate report. Such analyses may include, but are not limited to, pooled analyses of data from this trial combined with data from other trials or analyses of biomarkers generated from samples collected during the trial but analyzed after database lock and completion of the CSR. Data analyses will be described in the SAP Supplement or in a separate analysis plan document, as applicable. 8.6.4.2. Data Analysis Principles 8.6.4.2.1.     Analysis Sets

The FAS will be used for all biomarker analyses. Unless otherwise specified, all statistical analyses of biomarker data will be performed on patients for whom biomarker data are available. 8.6.4.2.2.     Basic Tables, Figures, and Lists

IHC marker data (e.g., Ki67) will be listed by marker and treatment group and summarized using summary statistics (mean, standard deviation, median, minimum, maximum).

Gene expression data and next generation sequencing data (also called deep sequencing data) will be generated on a panel of tumor specific genes. Because these data are extensive and complex, only those genes and key pathways of interest that are relevant to BC will be displayed. To understand the relationship to the response Kaplan-Meier curve, the median iDFS and 95% CI for the genes of most interest will be generated using altered status versus unaltered status. All of these analyses will be detailed in SAP or in separate biomarker analysis plans.

Blood samples will be collected to assess gene expression and alterations in ctDNA/ctRNA. Data will be generated from samples at baseline, during treatment, after treatment, and at relapse. Gene expression and alterations in genes associated with the CDK pathway and BC (e.g., ESR1, PIK3CA) will be assessed if feasible using ctDNA/ctRNA technology available at the time of assessment.

Known mutations and amplifications in the displayed genes, as defined by the COSMIC (Catalogue of Somatic Mutations in Cancer) database, are listed and summarized by treatment group and overall using counts and percentages.

Genes whose alteration status is assessed in tumor tissue and ctDNA will be compared using a 2 x 2 concordance table to assess their concordance.

Finally, the change data collected at the recurrence is listed alongside the baseline sample data of the same type. Only where there are inconsistencies between the two sources are shown.

Any additional exploratory analyses of biomarkers will be detailed in the SAP or in a separate biomarker analysis plan. 8.6.4.2.3.     Advanced Analytical Methods

Advanced analytical methods may be performed to explore relationships between biomarkers and trial endpoints and identify patterns in the data. More details will be provided in SAP or in separate biomarker analysis plans. 8.7. Interim and Final iDFS Analyses

Three interim analyses are planned after approximately 200, 350, and 425 of the approximately 500 target iDFS events have been recorded (i.e., at information scores of approximately 40%, 70%, and 85%, respectively). These interim analyses are expected to occur approximately 27 months, 35 months, and 39 months after the date of randomization of the first patient in the trial. The primary objective of the first interim analysis is to stop early due to lack of efficacy (futility). The analysis was not intended to declare a superior efficacy at the first interim analysis. The second and third interim analyses will allow the trial to declare a superior efficacy. The second interim analysis will be conducted only after all patients have been randomized and (if not withdrawn early) have undergone at least one post-baseline recurrence assessment according to Section 0.

The efficacy stopping boundaries will be constructed using an alpha spending function based on a three-stage (Lan-DeMets) group-consistent design and an (O'Brien-Fleming) type stopping boundary (as implemented in East 6.4). ⁶¹

A Lan-DeMets (O’Brien-Fleming) type stopping boundary as implemented in East 6.4 is used as the beta spending function to determine the non-binding ineffective boundary. The choice of the non-binding nature of the ineffective stopping boundary ensures that the effective stopping boundary is not affected.

Based on the choice of beta-spending function above, if the first interim analysis is performed at exactly 200 iDFS events, the futility margin expressed on a p-value scale (or Z-statistic scale) in the first interim period is calculated to be p = 0.6752 (or Z = 0.4544). The observed (i.e., nominal) p-value must be greater than the p-value scale efficacy margin = 0.6752 (or the observed Z-statistic must be > Z-statistic scale margin = 0.4544) to conclude that there is no efficacy. If the second interim analysis is performed at exactly 350 iDFS events, the efficacy margin expressed on a p-value scale (or Z-statistic scale) in the efficacy period is calculated to be p = 0.0074 (or Z = -2.438). The observed (i.e., nominal) p-value must be less than 0.0074 to conclude that there is superior efficacy at the second interim analysis. Similarly, if the third interim analysis is performed at exactly 425 iDFS events, the efficacy margin expressed on the p-value scale (or Z-statistic scale) in the efficacy period is calculated to be p = 0.0129 (or Z = -2.2296). The observed p-value must be less than 0.0129 to conclude that there is superior efficacy at the third interim analysis.

Because the number of events observed at the interim analysis may not be exactly equal to the planned 200, 350, and 425 iDFS events, it is necessary to recalculate the efficacy and futility margins based on the actual number of events observed at the interim and the target total number of events using the pre-specified α and β spending functions and to calculate accurate information scores. The p-value (or Z-test statistic) observed at the interim analysis is then compared to the recalculated efficacy (or futility) margin.

If the trial continues to the final iDFS analysis, the final iDFS analysis will be performed when approximately 500 iDFS events have been recorded. If 200, 350, and 425 events are observed at the interim analysis, the trial continues, and 500 events are obtained at the final analysis, the observed p-value must be less than 0.0202 (or the observed Z-statistic must be < -2.0503) to declare statistical significance. In practice, the final analysis will be based on the actual number of iDFS events recorded at the final iDFS analysis cutoff date and the alpha consumed at the interim analysis. The margins for the final analysis will be derived based on a pre-specified alpha-consuming function so that the overall significance level for all analyses remains at 0.025.

The statistical properties of the group sequential design are summarized in Table A23 below. [ Table A23 ] : Simulation Probability of Stopping for Efficacy or Inefficacy at Interim or Final iDFS Analysis Scene Stage # iDFS Events Simulation cumulative probability ( % ) Simulation increment probability ( % ) Stopped due to treatment failure Stopped due to ineffectiveness Stopped due to treatment failure Stopped due to ineffectiveness Under H ₀ (HR = 1) Midterm 1 200 32.7 32.7 Midterm 2 350 0.8 0.8 Midterm 3 425 1.5 - 0.7 Final 500 2.3 0.8 Under _Ha (HR = 0.73) Midterm 1 200 0.4 0.4 Midterm 2 350 68.4 68.4 Midterm 3 425 84.8 16.3 Final 500 93.1 8.3 Under other _Ha (HR = 0.76) Midterm 1 200 0.8 0.8 Midterm 2 350 54.0 54.0 Midterm 3 425 73.3 19.3 Final 500 85.2 12.0 At other H _a (HR = 0.80) Midterm 1 200 2.1 2.1 Midterm 2 350 35.3 35.3 Midterm 3 425 53.5 18.2 Final 500 67.9 14.4 Note: Simulations were performed in East 6.4, number of simulations = 10,000, and randomization seed = 123

Interim analysis results will be provided to the IDMC by an independent statistician who is not a member of the trial management staff.

The estimated timing of the iDFS interim and final analyses is summarized in Table A24.

At the time of the interim analysis of iDFS, the IDMC will determine if (i) the iDFS analysis has exceeded the pre-specified limit of efficacy, or (ii) the trial needs to be terminated for any reason, including futility or safety. Further details will be described in the IDMC charter. [ Table A24 ] : Estimated Timing of Interim and Final Analysis Months since first patient randomized (approximately) # iDFS Events Cumulative confidence relative to a hazard ratio of 0.73 27 200 (40%) 0 35 350 (70%) 68.4% 39 425 (85%) 84.8% 44 500 93.1% Calculated using East 6.4 8.8. Sample size calculation

The sample size calculation was based on the primary variable iDFS. Details of the hypothesis to be tested and the testing strategy are described in Sections 0 and 10. In the trial, the enrollment rate of patients with anatomic stage II was expected to be approximately 40%, and the enrollment rate of patients with anatomic stage III was approximately 60%. The 5-year iDFS rate was assumed to be approximately 79% for patients with anatomic stage II (excluding low-risk patients) (based on data from a retrospective study that evaluated the prognostic effect of Ki67 and other disease characteristics in HR-positive, HER2-negative EBC62) and approximately ⁷² % for patients with anatomic stage III (based on data from patients with ≥ 4 lymph nodes treated with AI in the EBCTCG meta- ^analysis30 ). Based on these assumptions and the expected distribution of patients by anatomical stage, the overall 5-year iDFS in the control group is expected to be approximately 74.8%. The addition of riboxil treatment to standard ET is expected to reduce the risk of iDFS by 27%, with an expected hazard ratio of 0.73. When the overall hazard ratio is 0.73 and 0.76, respectively, 500 iDFS events will provide approximately 93% and 85% power. The calculation hypothesis was analyzed by a one-sided log-rank test at an overall significance level of 2.5%. Patients were randomized to the two treatment groups in a 1:1 ratio. A 4-stage group sequential design with Lan-DeMets (O'Brien-Fleming) alpha spending function and Lan-DeMets (O'Brien-Fleming) beta spending function was used to define an unconstrained futility rule at the interim analysis, using an information score of 40% (futility only) for the first interim analysis and 70% and 85% (effect only) for the second and third interim analyses, respectively. The final analysis will be performed after approximately 500 iDFS events have been recorded.

Assuming an enrollment rate of approximately 170 patients per month starting in Q3-2020 and a dropout rate of 15% at the final iDFS analysis (i.e., dropout hazard rate = 0.00629 per month), a total of 5,000 patients will need to be randomized to observe the target 500 iDFS events approximately 44 months after the first patient randomization date. These calculations were performed using the East 6.4 software package. Sample size for PK collection is based on

It is planned that approximately 100 evaluable patients will be included in this trial for PK characterization. Assuming that approximately 20% of patients are not PK evaluable due to issues such as sample collection and handling, it is planned to collect PK samples of reboxil from approximately 130 patients in the study group. The sample size and sampling time points are selected based on historical data and the PK characteristics of reboxil. No formal statistical inference is planned. 9. Administrative, ethical and regulatory standards 9.1. Quality control and assurance

Before the start of the trial, at the site activation visit, or at an investigator meeting, the authorized representative of the sponsor will review the protocol and CRF with the investigator and his/her staff. During the trial, the sponsor representative will visit the site for ongoing data verification to confirm that the data entered into the CRF by authorized site personnel is accurate, complete, and can be confirmed from the original documents; the safety and rights of participants are being protected; and the trial is being conducted in accordance with the current approved protocol, other trial protocols, the International Council for Harmonization of Good Clinical Practice (ICH-GCP), and applicable regulatory requirements.

The investigator must allow the monitor access to all relevant original documents to confirm their consistency with the CRF entries. Novartis monitoring standards require full confirmation of the existence of informed consent, compliance with inclusion/exclusion criteria, and the existence of SAE documentation. The monitor takes additional steps based on the trial-specific monitoring plan to ensure that the trial is properly conducted and documented.

During or after the trial, the Investigator/Institution may also be subject to an audit by Novartis AG or a designee or an inspection by the CA. The auditor/inspector will review the documents at the site to ensure that the trial is conducted in accordance with the protocol, GCP and one or more applicable regulatory requirements, and that data are generated, documented/recorded and reported. During these activities, the Investigator/Institution will allow authorized representatives of the Sponsor and CA to inspect (and copy, if required by applicable law) clinical records.

During monitoring visits, audits and regulatory reviews, the investigator and related personnel should be present when necessary. 9.2. Ethical considerations 9.2.1. Ethical conduct of the trial

This clinical trial was designed, conducted and reported in accordance with the ethical principles set forth in ICH-GCP, applicable local regulations (including EU Directives 2001/20/EC and 2005/28/EC and Title 21 of the U.S. Code of Federal Regulations), and the Declaration of Helsinki. This trial will be conducted in accordance with ethical, scientific, and medical standards that protect the rights and welfare of participants. 9.2.2.    Responsibilities of Investigators and IRB/IEC

The protocol, proposed PICF, other relevant documents, and any information given to patients must be reviewed and approved by an appropriately constituted IRB/IEC before use at the site. An affirmative decision must be obtained from the IRB/IEC that the clinical trial has been reviewed and may be conducted at the institution/site within the limitations set by the IRB, the institution, GCP, and applicable regulatory requirements. This decision will be made in writing to the investigator, and a copy of the decision will be provided to the sponsor.

Before starting the trial at the site, the investigator must sign the protocol signature page, confirming that he/she agrees to conduct the trial in accordance with these documents and all instructions and procedures in this protocol.

The investigator will agree to submit required progress reports to the IRB/IEC and report any SAEs, life-threatening problems, or deaths (if applicable) in accordance with local regulations. The investigator or sponsor will inform the IRB/IEC of SUSARs in other clinical trials conducted with the investigational drug in accordance with local regulations. The investigator must inform the IRB/IEC of trial terminations. 9.2.3.    Informed Consent Procedures

Eligible patients may be included in a trial only after they have been given relevant information about the intended purpose of the trial, the trial treatments, procedures, and the benefits and risks to which the patient may be exposed, and after they have provided written (witnessed by an impartial witness, where required by law or regulation), IRB/IEC-approved informed consent, or, if this is not possible, by a legally acceptable representative of the patient, where permitted by local regulations. A legally acceptable representative is an individual or other agency authorized under applicable law to consent on behalf of a potential patient to the patient's participation in a trial. If a patient's representative gives consent, the patient should be informed of the trial to the extent possible to the extent that he/she understands it. If the patient is capable of doing so, he/she should personally sign and date the written informed consent or a separate consent form to indicate his/her consent.

The approved PICF will be read by the patient or his/her legal representative and an impartial witness (when required by law) and the Investigator, then dated and signed. The Investigator will retain the original PICF at the study site and provide the patient with a copy of the original (or photocopy) of the signed PICF. Informed consent must be obtained before any trial-specific procedures are performed, for example, before any clinical treatment is performed solely for the purpose of determining eligibility. Procedures that should be performed as part of the practice of medicine and would be completed regardless of whether entry into the trial is considered, such as the diagnosis or treatment of a disease or medical condition, may be performed and the results subsequently used to determine trial eligibility without obtaining prior consent. The process of obtaining informed consent should be documented in the patient's original file. The date the patient's informed consent was actually obtained will be recorded in the CRF.

Novartis AG (or authorized representative) will provide the Investigator in a separate document with a proposed PICF that is deemed appropriate for this trial and complies with ICH-GCP guidelines and regulatory requirements.

The PICF will include a statement by which the patient gives duly authorized personnel and representatives of the sponsor, the IRB/IEC, and the CA direct access to their data, which will be processed in accordance with applicable regulations, such as the Health Insurance Privacy and Accountability Act (HIPAA) and the General Data Protection Regulation (GDPR).

Any changes proposed by the Investigator to this PICF must be approved by Novartis AG (or authorized representative) prior to submission to the IRB/IEC, and a copy of the approved version must be provided to the Inspector upon approval by the IRB/IEC.

Women with CBP should be informed that taking the trial drug may pose unknown risks to the fetus if they become pregnant during the trial, and women with CBP should agree that in order to participate in the trial, they will comply with contraceptive requirements for the duration of the trial. If there is any concern that the patient cannot reliably comply with this requirement, they should not enter the trial.

If significant new information becomes available that may be relevant to the patient’s consent and willingness to continue participating in the trial, the PICF will be revised and submitted to the IRB/IEC and CA (if applicable) for approval/affirmative opinion. The new information will then be discussed promptly with the patient, and if she/he agrees to continue participating in the trial, the revised PICF will be signed and dated, and the patient will receive a copy.

Patients may withdraw from the trial at any time without affecting future treatment. In any case, withdrawal should be recorded in the patient's clinical record. 9.2.3.1. Additional consent form

There are two optional consent forms from the patient: one for additional biomarker assessments if residual samples are left (see Section 0) and one for collection of additional blood samples for pharmacogenetic assessments (see Section 0).

In order to participate in such sub-studies, the patient must give his/her explicit consent. If a patient chooses not to participate in the as-needed assessment, this will not affect the patient's ability to participate in the main study trial. 9.2.4.    Protocol Adherence

The investigators state that they will conduct due diligence to avoid protocol deviations. Under no circumstances may the investigators contact Novartis AG, TRIO, or their agents to request approval for protocol deviations, as no authorized deviations will be permitted.

If the investigator believes that a deviation from the protocol would improve the conduct of the trial, a protocol amendment must be considered, but it cannot be implemented unless such an amendment is agreed to by Novartis AG and approved by the IRB/IEC and CA.

Although approval of a formal protocol amendment is required, the Investigator is expected to take any necessary immediate action for the safety of any patient included in the trial, even if that action represents a departure from the protocol. In such cases, the TRIO must be notified of the action and the site's IRB/IEC must be notified within 10 working days, depending on local regulations (e.g., the UK requires notification of urgent safety measures within 3 days).

All significant deviations from the plan will be recorded and reported in the CSR. 9.2.5.    Plan Amendments

Any changes or additions to the protocol may only be made in a written protocol amendment, which must be approved by Novartis AG, the CA (if required), and the IRB/IEC. Prior to IRB/IEC approval, only amendments necessary to eliminate immediate risks to patients and to ensure patient safety may be implemented. 9.3. Trial Stoppage

Novartis AG reserves the right to stop the study under certain conditions. 9.4. Data Processing and Record Keeping 9.4.1.    Study Documents, Record Keeping and Document Retention

Each participating site will maintain appropriate medical and research records for this trial in accordance with ICH E6 GCP Section 4.9 and regulatory and institutional requirements to protect subject confidentiality.

Primary documents are original records of all information, clinical findings, observations, or other activities in a clinical trial that are necessary to reconstruct and evaluate the trial. Examples of such primary documents and data records include, but are not limited to, hospital records, clinical and office charts, laboratory notes, memos, patient diaries or evaluation checklists, pharmacy dispensing records, data recorded by automated instruments, certified copies or transcripts after confirmation of accuracy and completeness, microfilms, negatives, microfilm or magnetic media, X-rays, and patient files and records maintained in pharmacies, laboratories, and medical and technical departments involved in the clinical trial. Changes to primary documents must be traceable, should not obscure the original entry, and should be explained if necessary (e.g., by audit trails).

The investigator/institution must maintain study documents as specified in ICH E6 GCP Section 8 and in accordance with applicable regulations and/or guidelines. The investigator/institution must take steps to prevent the accidental or premature destruction of such documents.

Essential documents (both paper and electronic) must be retained for at least fifteen (15) years after the completion of the trial, unless Novartis AG provides written permission to dispose of the documents or unless applicable laws, regulations and/or guidelines require that the documents be retained for an additional period of time. 9.4.2.    Data Collection

The trial electronic CRF is the primary data collection tool for the trial. Data reported in the CRF from the original document should agree with the original document, or differences should be explained. All data required in the CRF must be recorded. Any missing data must be explained. The system will maintain an audit trail.

Designated site staff will enter protocol-required data into the CRF within 7 calendar days of availability. The CRF has been constructed using fully validated, secure network-enabled software that complies with the requirements of 21 CFR Part 11. Site staff will not be given access to the Electronic Data Capture (EDC) system until they have been trained. An automated validation program checks for data discrepancies in the CRF, allowing investigators to modify or confirm entered data.

The principal investigator is responsible for ensuring that data entered into the CRF and all other required reports are complete, accurate, and entered and updated in a timely manner.

PRO data will be recorded by the patient on paper forms and entered into the CRF by site staff.

Blood samples for laboratory data will be collected and processed locally. ECG data will be sent to a central laboratory for processing and results will be sent electronically to the site and Novartis AG (or authorized representative).

Biomarker blood samples and tumor samples will be collected by the research center and sent to a central laboratory designated by Novartis AG for processing, and the results will be sent electronically to Novartis AG (or authorized representative). 9.4.3.    Database Management

Novartis AG (or authorized representative) will review the completeness and accuracy of data entered by study staff. This is an open-label trial. Investigators, patients, TRIO, and the sponsor will be fully informed of treatment assignments. To minimize the potential impact of knowledge of trial treatment, no meta-statistical analyses (of efficacy or safety across the trial) will be performed by treatment group (except for those specified in the protocol) until the final iDFS analysis.

An electronic data query describing the nature of the problem and requesting clarification for discrepancies and missing values will be created and sent to the site via the EDC system. Designated site staff will be required to respond to the query within a specified timeline and make any necessary changes to the data.

Concomitant treatments, previous medications, and systemic anticancer therapies entered into the database will be coded using the World Health Organization (WHO) Drug Reference List using the Anatomical Therapeutic Chemical Classification system. Historical/current medical conditions and AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) terminology.

Randomization codes and data regarding all trial treatments assigned to patients and all IRT assigned dose changes will be tracked in a system provided by one or more vendors (who will also manage the IRT database). The data will be sent electronically to Novartis AG personnel (or authorized representative).

After the data are verified to be complete and accurate, a database lock will be declared. Authorization is required prior to making any database changes to locked data via a joint written agreement between TRIO and the Global Head of Biostatistics and Data Management and the Global Head of Clinical Development at Novartis AG.

Once the database is locked, the researcher will receive an electronic or paper copy of the patient data for archiving at the research center. 9.4.4.    Data Protection

Patients’ Personal Data and Investigators’ Personal Data will be used in the conduct of this trial and should be treated in accordance with all applicable laws and regulations (e.g., HIPAA and GDPR).

When processing or archiving personal data related to researchers and/or patients, TRIO, Novartis AG and their representatives shall take all appropriate measures to protect and prevent any unauthorized third party access to this data. 9.4.5.    Data Confidentiality

The investigator must ensure patient confidentiality; no patient may be identified in any documents submitted to TRIO or Novartis AG (or its representatives), for example, signed PICFs and patient enrollment logs containing the patient's name must be kept strictly confidential. Such documents must be kept at the site to allow for patient identification.

The data collection system for this trial uses built-in security features to encrypt all data for two-way transmission, preventing unauthorized access to confidential participant information. Access to the system will be controlled by a series of individually assigned user identification codes and passwords, which can only be used by authorized personnel who have completed prerequisite training.

Prior to entering key sensitive personally identifiable information (patient initials and exact date of birth), the site will be prompted to confirm that collection of this data is permitted. If the site indicates that national regulations or ethics committee standards do not permit collection of these items, the system will not solicit patient initials. Year of birth will be solicited (in lieu of exact date of birth) to confirm that the patient meets protocol age requirements and to enable the use of appropriate age-related normal ranges when evaluating laboratory test results.

All information concerning the trial and any previously unpublished information is considered confidential and proprietary. This confidential information remains the exclusive property of Novartis AG and may not be disclosed to others without the prior written consent of Novartis AG. The information may not be used except in connection with the conduct of the trial. 9.5. Steering Committee

The SC will consist of investigators with extensive experience in BC treatment who are participating in the trial (but not members of the IDMC), patient advocates, and representatives from Novartis AG and TRIO from the clinical trial team.

The SC will recommend and approve amendments as necessary to ensure that the trial is transparently managed in accordance with the protocol. The SC will review the clinical trial protocol and any amendments, if applicable. The SC will also work with the clinical trial team to develop recommendations for publication of trial results, including rules for authorship. Details of the SC's role will be defined in the SC Charter. 9.6. Financial Disclosures

Financial disclosures should be provided by trial personnel directly involved in the treatment or evaluation of patients at the study site before the start of the trial. 9.7. Liability Insurance

If requested, the investigator may forward to the IRB/IEC a copy of the insurance document provided by the sponsor to cover his/her responsibilities and those of any other participating parties. 9.8. Use of Information and Publications

Novartis AG is committed to high ethical standards for reporting results from trials of its innovative medicines, including timely communication and publication of clinical trial results, regardless of their outcome. Novartis AG ensures that key design elements of the protocol will be published on publicly accessible databases, such as www.clinicaltrials.gov, before the start of the trial. In addition, results from interventional clinical trials in adult patients will be published on www.novartisclinicaltrials.com, a publicly accessible database of clinical trial results (i.e., last patient visit [LPLV]), within 1 year of trial completion.

This study may not be published, reproduced, or presented without the approval of Novartis AG and SC, as applicable.

Novartis AG follows the International Committee of Medical Journal Editors' guidelines for authorship (www.icmje.org) and other specific guidelines of the journals or conferences to which the publications will be submitted.

Authors will not receive compensation for publications written by Novartis AG directly or through professional medical writing agencies. One or more authors may be asked to present academic posters or oral presentations at scientific meetings; however, no compensation will be provided for such presentations.

As part of Novartis AG's commitment to full transparency in publications, Novartis AG supports full disclosure of all sources of funding for trials and publications, as well as any actual and potential conflicts of interest of a financial and non-financial nature for all authors, including medical writing/editorial support, where applicable.

For Novartis guidance on the publication of results of Novartis sponsored studies, see www.novartis.com. 10. References 1. Torre LA, Bray F, Siegel RL, et al.: Global cancer statistics, 2012. CA Cancer J Clin 65:87-108, 2015 2. GLOBOCAN: Estimated Cancer Incidence, Mortality and Prevalence Worldwide 2012 [Internet] [cited June 26, 2018] Retrieved from: http://globocan.iarc.fr/old/bar_sex_site.asp?selection=3152&title=Breast&statistic=2&populations=6&window=1&grid=1&color1=5&color1e=&color2=4&color2e=&submit=%C2%A0Execute%C2%A0 3 . Siegel RL, Miller KD, Jemal A: Cancer statistics, 2018.CA Cancer J Clin 68:7-30, 2018 4 . Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, et al: Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012.Eur J Cancer [European Journal of Cancer] Oxford 1990 49:1374-1403, 2013 5. Eggemann H, Ignatov A, Smith BJ, et al: Adjuvant therapy with tamoxifen compared to aromatase inhibitors for 257 male breast cancer patients. Breast Cancer Res Treat 137:465-470, 2013 6. SEER Cancer Statistics Review, 1975-2015 [Internet]. National Cancer Institute, Bethesda, MD, 2018 Retrieved from: https://seer.cancer.gov/csr/1975_2015/ 7 . Anampa J, Makower D, Sparano JA: Progress in adjuvant chemotherapy for breast cancer: an overview. BMC Med 13:195, 2015 8 . Early Breast Cancer Trialists' Collaborative Group (EBCTCG): Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365:1687-1717, 2005 9 . Hammond J MEH, Hayes DF, Dowsett M, et al: American Society of Clinical Oncology/College Of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol Off J Am Soc Clin Oncol 28:2784-2795, 2010 10 . Senkus E, Kyriakides S, Ohno S, et al.: Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol Off J Eur Soc Med Oncol 26 Suppl 5:v8-30, 2015 11 . National Cancer Information Network. Breast cancer (2019, 1st edition) [Internet]. NCCN, 2019 [cited May 6, 2019] Retrieved from: https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf 12. Francis PA, Pagani O, Fleming GF, et al: Tailoring Adjuvant Endocrine Therapy for Premenopausal Breast Cancer. N Engl J Med 379:122-137, 2018 13. Goss PE, Ingle JN, Pritchard KI, et al: Extending Aromatase-Inhibitor Adjuvant Therapy to 10 Years. N Engl J Med 14 . Zagouri F, Sergentanis TN, Azim HA, et al.: Aromatase inhibitors in male breast cancer: a pooled analysis. Breast Cancer Res Treat 151:141-147, 2015 15 . Pan H, Gray R, Braybrooke J, et al.: 20-Year Risks of Breast-Cancer Recurrence after Stopping Endocrine Therapy at 5 Years. N Engl J Med 377:1836-1846, 2017 16 . Holm K, Staaf J , Jönsson G, et al.: Characterisation 17 . Cancer Genome Atlas Network: Comprehensive molecular portraits of human breast tumours. Nature 490:61-70, 2012 18 . Beroukhim R, Mermel CH , Porter D, et al.: The landscape of somatic copy-number alteration across human cancers. Nature 463:899-905, 2010 19 . Thangavel C, Dean JL, Ertel A, et al.: Therapeutically activating RB: reestablishing cell cycle control in endocrine therapy-resistant breast cancer. Endocr Relat Cancer 18:333-345, 2011 20 . Bosco EE, Wang Y, Xu H, et al.: The retinoblastoma tumor suppressor modifies the therapeutic response of breast cancer. J. Clin. Invest. 117:218-228, 2007 21 . Turner NC, Ro J, André F, et al.: Palbociclib in Hormone-Receptor-Positive Advanced Breast Cancer. N Engl J Med 373:209-219, 2015 22. Loibl S, Turner NC, Ro J, et al.: Palbociclib (PAL) in combination with fulvestrant (F) in pre-/peri-menopausal (PreM) women with metastatic breast cancer (MBC) and prior progression on endocrine therapy - results from Paloma-3. J Clin Oncol J Clin Oncol 34:524-524, 2016 23 . Goetz MP, Toi M, Campone M, et al: MONARCH 3: Abemaciclib As Initial Therapy for Advanced Breast Cancer. J Clin Oncol Off J Am Soc Clin Oncol 35:3638-3646, 2017 24 . Hortobagyi GN, Stemmer SM, Burris HA, et al: Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer. N Engl J Med 25 . Slamon DJ, Neven P, Chia S, et al.: Phase III Randomized Study of Ribociclib and Fulvestrant in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: MONALEESA-3. J Clin Oncol Off J Am Soc Clin Oncol JCO2018789909, 2018 26 . Finn RS, Martin M, Rugo HS, et al.: Phase III Randomized Study of Ribociclib and Fulvestrant in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: MONALEESA- 3 . J Clin Oncol Off J Am Soc Clin Oncol JCO2018789909, 2018 Palbociclib and Letrozole in Advanced Breast Cancer. N Engl J Med 375:1925-1936, 2016 27 . Verzenio® (abemaciclib) Significantly Reduced the Risk of Cancer Returning in People with High Risk HR+, HER2- Early Breast Cancer [Internet]. Eli Lilly Co. [cited on August 4, 2020] Retrieved from: https://investor.lilly.com/news-releases/news-release-details/verzenior-abemaciclib-significantly-reduced-risk-cancer 28 . Pfizer Tripathy D, Im SA, Colleoni M, et al: Ribociclib plus endocrine therapy for premenopausal women with hormone -receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial [Ribocillin plus endocrine therapy for premenopausal women with hormone receptor-positive, advanced breast cancer (MONALEESA-7): a randomized phase III trial] [Internet]. Lancet Oncol 0, 2018 [cited 29 June 2018] Retrieved from: https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30292-4/abstract 30. Early Breast Cancer Trialists' Collaborative Group (EBCTCG): Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet London, England 386:1341-1352, 2015 31. Lipton A, Demers LM, Harvey HA, et al: Letrozole (CGS 20267). A phase I study of a new potent oral aromatase inhibitor of breast cancer [Letrozole (CGS 20267). 32 . Trunet PF, Bhatnagar AS, Chaudri HA, et al: Letrozole (CGS 20267), a new oral aromatase inhibitor for the treatment of advanced breast cancer in postmenopausal patients. Acta Oncol. Stockholm, Sweden, 35 Suppl. 5:15-18, 1996. 33 . Edavana VK, Dhakal IB, Williams S, et al: Potential role of UGT1A4 promoter SNPs in anastrozole pharmacogenomics [Potential role of UGT1A4 promoter SNP in the pharmacogenomics of anastrozole]. Drug Metab Dispos Biol Fate Chem 41:870-877, 2013 34 . Plourde PV, Dyroff M, Dowsett M, et al: ARIMIDEX: a new oral, once-a-day aromatase inhibitor. J Steroid Biochem Mol Biol 53:175-179, 1995 35 . Hudis CA, Barlow WE, Costantino JP, et al: Proposal for standardized definitions for efficacy end points in adjuvant breast cancer trials: the STEEP system 36 . Riboxil Investigator's Manual 37 . Dowsett M, Nielsen TO, A'Hern R, et al: Assessment of Ki67 in breast cancer: recommendations from the International Ki67 in Breast Cancer working group. J Natl Cancer Inst 103:1656-1664, 2011 38 . Bustreo S, Osella-Abate S, et al: Assessment of Ki67 in breast cancer: recommendations from the International Ki67 in Breast Cancer working group. J Natl Cancer Inst 103:1656-1664, 2011 Cassoni P, et al: Optimal Ki67 cut-off for luminal breast cancer prognostic evaluation: a large case series study with a long-term follow-up. Breast Cancer Res Treat 157:363-371, 2016 39. Tashima R, Nishimura R, Osako T, et al: Evaluation of an Optimal Cut-Off Point for the Ki-67 Index as a Prognostic Factor in Primary Breast Cancer: A Retrospective Study [Internet]. PLoS ONE 10, 2015. [cited 13 Aug 2018] Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4503758/ 40. Krop I, Ismaila N, Andre F, et al: Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women With Early-Stage Invasive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline Focused Update. J Clin Oncol 35:2838-2847, 2017 41. Overview | Tumour profiling tests to guide adjuvant chemotherapy decisions in early breast Cancer [Detection of tumour features to guide decisions about adjuvant chemotherapy in early-stage breast cancer] | Guidelines | NICE [Internet] [cited 6 May 2019] Retrieved from: https://www.nice.org.uk/guidance/dg34 42. Giuliano AE, Ballman KV, McCall L, et al: Effect of Axillary Dissection vs No Axillary Dissection on 10-Year Overall Survival Among Women With Invasive Breast Cancer and Sentinel Node Metastasis: The ACOSOG Z0011 (Alliance) Randomized Clinical Trial. Z0011 (Alliance) randomized clinical trial]. JAMA 318:918-926, 2017 43 . Lyman GH, Somerfield MR, Bosserman LD, et al: Sentinel Lymph Node Biopsy for Patients With Early-Stage Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update [Sentinel Lymph Node Biopsy for Patients With Early-Stage Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update] J Clin Oncol 35:561-564, 2016 44 . Curigliano G, Burstein HJ, P Winer E, et al: De-escalating and escalating treatments for early-stage breast cancer: the St. Gallen International Expert Consensus Conference on the Primary Therapy of Early Breast Cancer 2017 [Dose-escalation and dose-escalation therapy in early breast cancer: international consensus meeting on initial treatment of early breast cancer, St. Gallen 2017]. Ann Oncol Off J Eur Soc Med Oncol 28:1700-1712, 2017 45. Early Breast Cancer Trialists' Collaborative Group (EBCTCG): Long-term outcomes for neoadjuvant versus adjuvant chemotherapy in early breast cancer: meta-analysis of individual patient data from ten randomised trials. Lancet Oncol. 19:27-39, 2018 46 . Dhesy-Thind S, Fletcher GG, Blanchette PS, et al: Use of Adjuvant Bisphosphonates and Other Bone-Modifying Agents in Breast Cancer: A Cancer Care Ontario and American Society of Clinical Oncology Clinical Practice Guideline [Internet]. J Clin Oncol, 2017 [cited 19 Dec 2018] Retrieved from: http://ascopubs.org/doi/abs/10.1200/JCO.2016.70.7257 47 . Smith TJ, Bohlke K, Lyman GH, 48 . Grunberg SM, Warr D, Gralla RJ, et al.: Evaluation of new antiemetic agents and definition of antineoplastic agent emetogenicity--state of the art. Support Care Cancer 19 Suppl 1:S43-47, 2011 49 . F, Molassiotis A, Herrstedt J, et al: 2016 MASCC and ESMO guideline update for the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting and of nausea and vomiting in advanced cancer patients. Ann Oncol Off J Eur Soc Med Oncol 27:v119-v133, 2016 50. National Cancer Information Network. Antiemesis (version 3.2018) [Internet]. NCCN, 2018 [cited 12 July 2018] Retrieved from: https://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf 51. Elston CW, Ellis IO: Pathological prognostic factors in breast cancer.I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. I. The value of histologic grade in breast cancer: experience with large studies and long-term follow-up. Histopathology 41:154-161, 2002 52 . Oken MM, Creech RH, Tormey DC, et al: Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982 53 . Dawson SJ, Rosenfeld N, Caldas C: Circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med 369:93-94, 2013 54. Esposito A, Bardelli A, Criscitiello C, et al.: Monitoring tumor-derived cell-free DNA in patients with solid tumors: clinical perspectives and research opportunities. Cancer Treat Rev 40:648-655, 2014 55. Hurvitz S, Abad MF, Rostorfer R, et al.: Interim results from neoMONARCH: A neoadjuvant phase II study of abemaciclib in postmenopausal women with HR+/HER2- breast cancer (BC) [Internet]. Ann Oncol. Annals of Oncology 27, 2016 [cited June 26, 2018] Retrieved from: https://academic.oup.com/annonc/article/27/suppl_6/LBA13/2800510 56 . Murtaza M, Dawson SJ, Pogrebniak K, et al: Multifocal clonal evolution characterized using circulating tumour DNA in a case of metastatic breast cancer. Nat Commun 6:8760, 2015 57 . Aaronson NK, Ahmedzai S, Bergman B, et al: The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology 58 . Sprangers MA, Groenvold M, Arraras JI, et al.: The European Organization for Research and Treatment of Cancer breast cancer-specific quality-of-life questionnaire module: first results from a three-country field study. J Clin Oncol Off J Am Soc Clin Oncol 14:2756-2768, 1996 59 . Rabin R, 60 . Zigmond AS, Snaith RP: The hospital anxiety and depression scale. Acta Psychiatr Scand 67:361-370, 1983 61 . Lan KKG, DeMets DL: Discrete Sequential Boundaries for Clinical Trials. Biometrika 70:659-663, 1983 62 . Fasching PA, Gass P , Häberle L, et al.: Prognostic effect of Ki-67 in 63. Amin MB, Edge S, Greene F, et al. (eds): AJCC Cancer Staging Manual (8th ed.). Springer International Publishing, 2017. [cited 29 June 2018] Retrieved from: https://doi.org/10.1007/s10549-019-05198-9 64. Amin MB, Edge S, Greene F, et al. (eds): AJCC Cancer Staging Manual (8th ed.). Springer International Publishing, 2017. [cited 29 June 2018] Retrieved from: //www.springer.com/la/book/9783319406176 11. Appendix Appendix 1: Breast Cancer Staging Anatomical Staging Group Guidelines

The guidelines for anatomical staging groups according to the 8th edition of the AJCC that apply to this trial are presented below (modified from ⁶³ ). [ Table A25 ] : AJCC 8th edition anatomical staging groups (excluding stage IV groups) Anatomical staging group T- Class N- Category 0 Tis N0 I A T1 N0 IB T0-1 N1mi IIA T0-1 N1 T2 N0 IIB T2 N1 T3 N0 IIIA T0-3 N2 T3 N1 IIIB T4 N0-2 IIIC Any T N3 Note: T2, T3, and T4 tumors with lymph node micrometastasis (N1mi) are staged using the N1 category. Appendix 2: Guidelines for Standardized Definitions of Response Endpoints in Adjuvant Breast Cancer Trials (Based on STEEP)

The iDFS endpoint definitions applicable to this study are presented in Table A26 below. [ Table A26 ] : Proposed standardized definitions of endpoints in clinical trials of breast cancer in adjuvant therapy End Invasive ipsilateral breast tumor recurrence Local / regional invasive recurrence Remote recurrence * Deaths due to BC Death due to non- BC causes Unexplained death Invasive contralateral BC** Ipsilateral DCIS Contralateral DCIS Second primary invasive cancer (non-breast) *** OS X X X iDFS X X X X X X X X DDFS X X X X X RFS X X X X X X LRRFS X X X X X Modified from Table 2 in ³⁵ Note: Lobular carcinoma in situ is not included as an event in these definitions because it is not generally considered a direct precursor to breast cancer. Abbreviations: BC, breast cancer; DCIS, ductal carcinoma in situ; OS, overall survival; iDFS, invasive disease-free survival; DDFS, distant disease-free survival; DRFS, distant recurrence-free survival; LRRFS: locoregional recurrence-free survival; RFS, recurrence-free survival. *The site of first metastasis should also be reported using the appropriate common data element terminology. **The term "contralateral invasive breast cancer" is preferred over "second primary breast cancer" because it is less ambiguous. Ipsilateral invasive breast cancer is presumed to be a recurrence. ***Second primary non-breast cancers should not include squamous or basal cell skin cancer, or new carcinoma in situ of any site. Appendix 3: Recurrence Detection Guidelines

Relapse will be detected by planned or unplanned clinical evaluation. Suspected relapse will be evaluated by medical imaging and confirmed by histology (or cytology, as appropriate), unless the patient is at unacceptable risk or otherwise specified under Section 0.

Recurrence will be classified as local, regional, or distant recurrence, or as contralateral invasive breast cancer or a second primary non-breast invasive cancer, based on the following guidelines: • Locally invasive breast cancer recurrence or ipsilateral invasive breast tumor recurrence: Invasive breast cancer involves the same breast as the primary tumor. Ductal and lobular carcinoma in situ and tumors in the contralateral breast and/or contralateral lymph nodes are not considered locally invasive recurrences.

Local recurrence must be confirmed by histology. The histologic type of locally invasive breast cancer recurrence should be documented in the CRF. • Regional breast cancer recurrence: Invasive breast cancer in the ipsilateral axilla, regional lymph nodes (all grades), chest wall, or skin of the ipsilateral breast. Tumors in the contralateral breast are not considered regional recurrences.

Local recurrence must be confirmed by histology (preferably) or cytology. The specific site of regional recurrence should be recorded in the CRF. • Distant recurrence: Distant metastasis of breast cancer (bone, distant lymph nodes, internal organs, CNS, bone marrow, etc.) or any non-local or regional invasive site of breast cancer recurrence.

Distant recurrence must be confirmed by histology (preferably) or cytology unless such a procedure would impose an unacceptable risk to the patient.

If bone metastases are identified by bone scanning, they must be confirmed by histology (preferably) or radiologic imaging (CT, MRI, or FDG-PET-CT) if they cannot be confirmed biopsy-based.

If biopsy is unavailable, central nervous system metastases must be confirmed by histology (preferably), cytology, or radiologic imaging (CT or MRI, both with intravenous (IV) contrast).

All other sites of metastasis must be confirmed by histology (preferably) or cytology unless such a procedure would present an unacceptable risk to the patient.

The top three locations of distant metastases should be reported on the CRF, with priority given to visceral (including brain) metastases rather than bone metastases, distant lymph nodes, or skin metastases. • Contralateral invasive breast cancer: Any invasive breast cancer in the contralateral breast, with or without contralateral lymph node involvement. Contralateral invasive breast cancer must be confirmed by histology. In situ/noninvasive contralateral breast cancer is not included in contralateral invasive breast cancer. The histologic type and specific site of contralateral invasive breast cancer should be recorded on the CRF. • Second primary non-breast invasive cancer: Any second primary non-breast invasive cancer. Second primary non-breast invasive cancer must be confirmed by histology. Carcinoma in situ/noninvasive and basal cell or squamous cell carcinomas of the skin are not considered second primary non-breast invasive cancers. The histologic type and location of second primary non-breast invasive cancers should be documented on the CRF. Appendix 4: Concomitant Medications

In general, any concomitant medications required for patient care are permitted in this study unless specifically prohibited by the following instructions. Administration of study drugs in combination may result in drug-drug interactions (DDIs), which may result in reduced activity or increased toxicity of concomitant medications and/or ribociclib.

The following list is based on the Novartis Pharma PK Scientific Memorandum, Drug-Drug Interactions (DDIs) and Coadministration Precautions from Novartis Pharma Clinical Trials (published January 2018), which was compiled from the Indiana University School of Medicine P450 Drug Interaction Table (https://drug-interactions.medicine.iu.edu/Main-Table.aspx) and supplemented by the FDA Draft Guidance for Industry Drug Interaction Studies - Study Design, Data Analysis, and Implications for Dosing and Labeling (February 2012) (fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm292362.pdf) and the University of Washington Drug Interaction Database (www.druginteractioninfo.org).

For a current list of medications that may cause QT prolongation and/or TdP, please refer to the CredibleMeds® website (https://crediblemeds.org/).

These lists are not comprehensive and are provided for informational purposes only. If you have any questions, please contact the TRIO Medical Supervisor. Please note that these lists may include medications that are considered prohibited under Section 0; their inclusion in the following list should not be construed as permission for their use. [ Table A27 ] : List of prohibited medications during treatment with Riboxil Category Drug Name Strong CYP3A4/5 inhibitors atazanavir/ritonavir, boceprevir, clarithromycin, cobicistat, conivaptan, danoprevir/ritonavir, darunavir/ritonavir, elvivir/ritonavir, grapefruit juice, idelalis, indinavir, indinavir/ritonavir, itraconazole, ketoconazole, lopinavir/ritonavir, miracil, nefazodone, nelfinavir, omiprevir/paliprevir/dasabuvir/ritonavir (VIEKIRA PAK), posaconazole, ritonavir, saquinavir/ritonavir, telaprevir, telithromycin, pranavir/ritonavir, troleandomycin, voriconazole Strong CYP3A4/5 inducers Apalutamide, carbamazepine ³ , enzalutamide, lumacaftor, mitotane, phenobarbital, phenytoin ³ , rifabutin, rifampicin ³ , St. John's wort (Hypericum perforatum) ^2,3 CYP3A4/5 substrates with NTI ¹ Alfentanil, astemizole, cisapride, cyclosporine, diergotamine (dihydroergotamine), ergotamine, fentanyl, lomitapide ⁵ , lovastatin, nicardipine, nisoldipine, pimozide, quinidine, simvastatin, sirolimus, tacrolimus ^Drugs with known risk of QT prolongation4 Amiodarone, anagrelide, arsenic trioxide, astemizole, azithromycin, bepridil chloroquine, cocaine chlorpromazine, cilostazol, ciprofloxacin, cisapride, citalopram, clarithromycin, disopyramide, dofetilide, domperidone, donepezil, dronedarone, droperidol, erythromycin, escitalopram, flecainide, fluconazole, gatifloxacin, grepafloxacin, halofantrine, haloperidol, ibutilide, levofloxacin, levomethasone Levomepromazine, Levosulpride, Levomethadyl, Mesoridazine, Methadone, Moxifloxacin, Ondansetron, Oxaliplatin, Popoline hydrochloride (intracoronary), Pentamidine, Pimozide, Probucol, Procainamide, Propofol, Quinidine, Roxithromycin, Sevoflurane, Sotalol, Sparfloxacin, Sulpiride, Sultopride, Terlipressin, Trodiline, Terfenadine, Methiothionine, Vandetanib Herbal preparations/drugs or dietary supplements The use of herbal preparations/drugs or dietary supplements known as strong inducers or inhibitors of CYP3A4/5 or with a known risk of QT prolongation was prohibited throughout the study. These include, but are not limited to: St. John's wort, kava, ephedra, ginkgo, dehydroepiandrosterone (DHEA), yohimbe bark, saw palmetto, black cohosh, and ginseng. Patients should stop using these herbal preparations/drugs or dietary supplements 7 days prior to the first dose of study medication. Other Research and Anti-Cancer Therapies Patients may not receive other study treatments during the study. Patients may not be given anticancer treatments other than the trial treatment (chemotherapy, hormonal therapy, including but not limited to all SERMS (including raloxifene), biological or radiation therapy, and surgery) while they are receiving study drug. If a patient requires such medication, the patient must stop the study drug. ¹ NTI = narrow therapeutic index drug for which exposure-response patterns indicate that increased exposure with concomitant use of a potent inhibitor could result in serious safety concerns (e.g., TdP) or for which the difference between the minimum toxic and minimum effective blood concentrations is < 2-fold. ² Herbal products ³ P-gp inducers ⁴ List provided as of December 2019. Check https www.crediblemeds.org/healthcare-providers/drug-list for updated lists. ⁵ Drug with hepatotoxicity risk warning. Whenever possible, avoid coadministration of QT prolonging drugs or any other drug that could increase the risk of drug-related QT prolongation (e.g., by increasing exposure to risboxil or exposure to QT prolonging drugs via a potential DDI). A definitive list of drugs with a known risk, possible risk, or conditional risk of QT prolongation and/or TdP is available online at qtdrugs.org. Source: Novartis Pharma PK Science Memo: Drug-Drug Interactions (DDIs) and Coadministration Precautions from Novartis Pharma Clinical Trials (January 2018), which is compiled from the Indiana University "Clinically Relevant" Flockhart Table™, the University of Washington Drug Interaction Database, and the FDA Drug Development and Drug Interactions: Substrates, Inhibitors, and Inducers. [ Table A28 ] : List of drugs that should be used with caution during treatment with Riboxil Category Drug Name Moderate CYP3A4/5 inhibitors Aprepitant, amprenavir, asafoetida resin (Ferula asafoetida), cimetidine, crizotinib, diltiazem, faldaprevir, imatinib, isavuconazole, netupitant, nilotinib, tofisopam, Schisandra sphenanthera, verapamil Intermediate CYP3A4/5 inducers Bosentan, dabrafenib, efavirenz, etravirine, genistein, lopinavir ⁵ , modafinil, nafcillin, telotristat Sensitive CYP3A4/5 substrate ¹ α-Dihydroergocritin, apixaban, aprepitant, atorvastatin, avanafil, bosutinib, brotizolam, budesonide, buspirone, cannabinoids ⁶ , cannabidiol ⁶ , cobimetinib, darifenacin, dasatinib, ebastine, eletriptan, eplerenone, everolimus, felodipine, fluticasone, grazosperm, ibrutinib, isavuconazole, ivabradine, ivacaftor, lumefantrine, lurasidone, maraviroc, midazolam, midostaurin, naloxegol, neratinib, perospirone, quetiapine, ridaforolimus, rivaroxaban, sildenafil, simiprevir, ticagrelor, tilidine, tolvaptan, triazolam, ulipristal, vardenafil, venetoclax, vicriviroc, cyclosporine BSEP Inhibitor Alectinib, atorvastatin, bromocriptine, candesartan, clobetasol, clofazimine, dabigatran, dipyridamole, glyburide, grazolidinone, ledipasvir, mifepristone, pioglitazone, reserpine, rifamycin, cimiprevir, telmisartan, tincodar, troglitazone, velpatasvir ^Drugs with a possible risk of QT prolongation2 Alfuzol, apomorphine, aripiprazole, artemisinin + piperaquine, asenapine, atazanavir, atomoxetine, bedaquiline, bendamustine, bortezomib, bosutinib, buprenorphine, cabozantinib, capecitabine, ceritinib, clomipramine, crizotinib, clozapine, cyanometab (cyanometab sulfaquinone), dabrafenib, dasatinib, degarelix, delamanid, desipramine, dexmedetomidine, dolasetron, edema Favirenz, ergamine, epirubicin, eribulin mesylate, ezogabine (retigabine), famotidine, felamidate, fingolimod, flupenthixol, gemifloxacin, granisetron, hydrocodone-ER, iloperidone, imipramine (melipramine), isradipine, ketaserin, rapa tinib, lenvatinib, leuprolide, loperamide, lithium, meperidone, midostaurin, mifepristone, mirabegron, mirtazapine, moexipril/HCTZ, necitumumab, nilotinib, norfloxacin, nortriptyline, nosinasan, ofloxacin, olanzapine, osimertinib, oxytocin, paliperidone, palonosetron, panobinostat, pasireotide, pazopanib, perfluoropropane lipids Microspheres, fenazolidinone, pilsicainide, pimavanserin, pipampirone, isoprenaline, prothiophene, quetiapine, ranolol, rilpivirine, risperidone, romidepsin, sertindole, sorafenib, sunitinib, tamoxifen, telavancin, tetrabenazine, tipiracil/trifluridine, tizanidine, tolterodine, toremifene, trimipridine, tropasetron, vardenafil, vemurafenib, venlafaxine, vorinostat, ziprasidone MATE1/2 substrate ³ Acyclovir, ceftriaxone, cimetidine, fexofenadine, ganciclovir, glycopyrrolate, metformin, pindolol, pilsicainide, ranitidine, topotecan, varenicline OCT1/2 substrate ⁴ Amantadine, carboplatin, cisplatin, ceftriaxone, cefuroxime, ipratropium bromide, lamivudine, linagliptin, metformin, oxaliplatin, oxybutynin, phenformin, pyrrolidone, pilsicainide, pindolol, ranitidine, sorafenib, tropazepam, trospium, umeclidinium, and zidovudine BCRP substrate Daunorubicin, dotirapir, doxorubicin, hematoporphyrin, imatinib, methotrexate, mitoxantrone, pitavastatin, rosuvastatin, irinotecan, ethinyl estradiol, sulfasalazine, sofosbuvir, tenofovir, topotecan, venetoclax ^1Sensitive substrates include drugs for which plasma AUC values have been demonstrated to increase 5-fold or greater when co-administered with a potent inhibitor. ^2List provided is as of January 2018. Check https www crediblemeds.org/healthcare-providers/drug-list for updated lists. ^3MATE1 and MATE2 share considerable substrate specificity. ^4OCT1 and OCT2 share considerable substrate specificity. ^5Lopinavir and atazanavir are contraindicated in combination with ritonavir. ⁶ Based on data showing an approximately 2- to 3-fold increase in exposure to cannabidiol (CBD), tetrahydrocannabinol (THC), and 11-hydroxyTHC when co-administered with ketoconazole (CYP3A4 inhibitor); Stott et al., Springerplus. 2013; 2: 236 Source: Novartis AG PK Science Memo: Drug-Drug Interactions (DDIs) and Co-Medication Precautions from Clinical Trials, Novartis AG (January 2018), which is compiled from the Indiana University “Clinically Relevant” Flockhart Table™, the University of Washington Drug Interaction Database, and the FDA Drug Development and Drug Interactions: Substrates, Inhibitors, and Inducers. Appendix 5. Patient-reported outcomes EORTC QLQ-C30 and EORTC QLQ-BR23

The EORTC QLQ-C30 contains 30 items, consisting of multiple scales and single-item scales. These include 5 functional scales (physical, role, emotional, cognitive, and social functioning), 3 symptom scales (fatigue, nausea/vomiting, and pain), 6 single items (dyspnea, insomnia, loss of appetite, constipation, diarrhea, and financial impact), and a global health status/QoL scale. ⁵⁷

The EORTC QLQ-BR23 is used only in conjunction with the EORTC QLQ-C30 for women and provides information on an additional 23 items specifically related to breast cancer. It contains 5 multi-item scales to assess systemic therapy side effects, arm symptoms, breast symptoms, body image, and sexual function. In addition, individual items assess sexual enjoyment, hair loss, and future outlook.

All scales and individual items will be scored on a scale ranging from 0 to 100. Higher scale scores represent higher levels of response. Thus, a high score on the functioning scale represents a higher level of functioning/attained health; a high score on the global health status/QoL represents a higher level of QoL, but a high score on the symptom scale/item represents a higher level of symptoms/problems. All scoring will follow the scoring procedures defined in the EORTC scoring manual.

Examples of these two questionnaires are shown in Figures 5 and 6. The questionnaires provided in this article are examples for reference only. The questionnaires completed by patients in the trial will be provided by TRIO to be used as original documents. EQ-5D-5L

The EQ-5D-5L is a standardized measure of health utility that provides a single index value for an individual’s health status. The EQ-5D-5L is often used in the economic evaluation of health care and has been shown to be a valid and reliable scale. ⁵⁹ The EQ-5D-5L contains one item for each of the five dimensions of health-related QOL (HRQOL, i.e., mobility, self-care, usual activities, pain or discomfort, and anxiety or depression). The response options for each item vary from no problem (e.g., “…no problem getting around”), moderate problem (e.g., “…some problem getting around”), or extreme problem (e.g., “…cannot get around”). Patient responses on the five dimensions of HRQOL reflect a specific health state that is mapped to a population preference weight for that state on a continuous scale ranging from 0 (death) to 1 (perfect health). A visual analogue scale (VAS) ranging from 0 to 100 is also included to record patients’ ratings of their overall health state. Higher EQ-5D-5L scores represent better health. Scoring and processing of all data will follow the user guidelines defined by the EuroQoL group. ⁵⁹

An example of the questionnaire is shown in Figure 7. The questionnaire provided in this article is an example for reference only. The questionnaires completed by the patients in the trial will be provided by TRIO to be used as original documents. HADS

The HADS is a 14-item self-completed questionnaire designed to screen for depression and anxiety in both in-hospital and community settings. The HADS takes approximately 10 minutes to complete and has been widely used to measure depression and anxiety in adults. Although the term "hospital" refers to the setting in which the scale was first developed, many studies conducted around the world have demonstrated that the scale is also valid when used in community settings and primary care medical practice.

Even-numbered questions are related to depression, and odd-numbered questions are related to anxiety. All items are scored on a scale of 3 to 0, with a maximum score of 21 for each subscale. Scores of 11 or higher indicate a probable emotional disorder, and scores of 8 to 10 suggest a disorder. For ease of interpretation, depression and anxiety are separate indicators that can be mapped onto four ranges: normal (0-7), mild (8-10), moderate (11-15), and severe (16-21). For missing data, scores for individual items can be inferred using the average of the remaining six items. However, if more than one item is missing, the questionnaire should not be scored.

An example of the questionnaire is shown in Figure 8. The questionnaires provided in this article are examples for reference only. The questionnaires completed by the patients in the trial will be provided by TRIO to be used as original documents. VIII - Appendix B - First Interpretable Results 1. Executive Summary (a) Table B0-1 Summary of Results Key parameters Definition Ending Main destination Comparison of invasive disease-free survival (iDFS) between Riboxil + ET and ET alone Crossing the efficacy boundary in IA-3 Source: Table B4.1-1, Table B4.1-2 Secondary End Point OS, RFS, DDFS Source: Table B4.2-1, Table B4.2-2, Table B4.2-3 Security TEAE Frequency of TEAEs Source: Table B5.1-1 Security Serious TEAE, death Frequency of severe TEAEs Source: Table B5.1-2, Table B5.1-7, Table B5.1-8 • Study CLEE011O12301C is a Phase III, multicenter, randomized, open-label trial evaluating the efficacy and safety of a 3-year regimen of ribociclib (RIB) (400 mg dose, 3 weeks on/1 week off) in combination with a 5-year regimen of endocrine therapy (letrozole/anastrozole) (ET) and goserelin (for premenopausal women) as adjuvant treatment in patients with hormone receptor-positive, HER2-negative, early breast cancer. • From January 10, 2019 to April 20, 2021, a total of 5101 patients were randomized in a 1:1 ratio to the RIB + ET group (n = 2549) or the ET group only (n = 2552). Randomization was stratified by: • AJCC anatomical stage: II [2154 (42.2%)] vs III [2947 (57.8%)] • Menopausal status: premenopausal/male [2253 (44.2%)] vs postmenopausal [2848 (55.8%)] • Prior chemotherapy: yes [4432 (86.9%)] vs no [669 (13.1%)] • Region: North America/Western Europe/Australia [3128 (61.3%)] vs rest of the world [1973 (39.7%)] • The efficacy margin was achieved at the protocol-prespecified third interim analysis (IA3) review of the data by the IDMC on March 21, 2023. Therefore, the committee recommends stopping the study to achieve early efficacy and therefore this interim efficacy analysis is now considered the final analysis of the study to demonstrate superiority of RIB + ET compared to ET with regard to iDFS. However, efficacy data will continue to be collected until approximately 5 years after the last patient was randomized. This document describes the first interpretable results (FIR) of IA3 performed on the database locked on February 22, 2023. • This FIR provides the key efficacy and safety results of Study IA3 and does not include any clinical interpretation. • The IA3 cutoff date (January 11, 2023) was planned based on a projection of approximately 425 iDFS events (approximately 85% of the total 500 events). At the time of database lock, 426 iDFS events (85.2% of the total 500 events) were recorded as of the cutoff date. The median follow-up duration was 34 months (from randomization to data cutoff date). The minimum follow-up duration was 21 months. The median iDFS follow-up duration was 27.7 months in both groups. • Treatment groups were balanced with respect to demographics and baseline characteristics • 2549 patients were randomized to the RIB + ET group, of whom 2526 (99.1%) received treatment. 2552 patients were randomized to the ET only group, of whom 2442 (95.7%) received treatment. • 23 (0.9%) patients in the RIB + ET group and 110 (4.3%) patients in the ET-only group discontinued treatment before receiving any treatment. • 1984 (77.8%) patients in the RIB + ET group and 1826 (71.6%) patients in the ET-only group are still receiving treatment. • 515 (20.2%) patients in the RIB + ET group completed the 3-year RIB treatment regimen. • The most common reason for RIB discontinuation was adverse events, reported in 477 patients (18.7%). • Discontinuation of the primary efficacy endpoint due to patient decision, withdrawal of consent, or loss to follow-up was reported in 239 (10.2%) patients in the RIB + ET group and 282 (11.1%) patients in the ET-only group. • The study met its primary objective . There were 426 iDFS events in the study (189 [7.4%] in the RIB group and 237 [9.3%] in the ET group), with a relative reduction in the risk of iDFS events of approximately 25.2% (HR 0.748, 95% CI: (0.618, 0.906); one-sided stratified log-rank test p-value = 0.0014). The results exceeded the prespecified Lan-DeMets (O'Brien-Fleming) stopping boundary (p-value less than 0.0128 to declare superior efficacy). • The 3-year iDFS rate was 90.4% with 95% CI (88.6%, 91.9%) in the RIB + ET group and 87.1% with 95% CI (85.3%, 88.8%) in the ET group alone. • In the subgroup of patients with anatomical stage II EBC, there were 49/1011 (4.8%) iDFS events in the RIB + ET group and 65/1034 (6.3%) in the ET group alone, with an iDFS hazard ratio of 0.761, 95% CI: (0.525, 1.103). • The 3-year iDFS rate was 94.2% in the RIB + ET group, with a 95% CI of (92.1%, 95.7%), and the corresponding value for the ET group alone was 91.2%, with a 95% CI of (88.5%, 93.3%). • In the subgroup of patients with anatomical stage III EBC, there were 140/1528 (9.2%) iDFS events in the RIB + ET group and 172/1512 (11.4%) in the ET group alone, with an iDFS hazard ratio of 0.74, 95% CI: (0.592, 0.925). • The 3-year iDFS rate was 87.3% in the RIB + ET group, with a 95% CI of (84.3%, 89.8%), and the corresponding value for the ET group alone was 84.1%, with a 95% CI of (81.4%, 86.4%). • Overall, the improvement in iDFS was generally consistent across all pre-specified subgroups, including menopausal status and nodal status • N0: HR 0.630, 95% CI (0.341, 1.165) for RIB + ET vs. ET alone • N1-N3: HR 0.771, 95% CI (0.630, 0.944) for RIB + ET vs. ET alone • Premenopausal and males: HR 0.722, 95% CI (0.530, 0.983) for RIB + ET vs. ET alone • Postmenopausal: HR 0.781, 95% CI (0.613, 0.997) for RIB + ET vs. ET alone Per the study protocol, the iDFS secondary efficacy endpoint was formally tested in the overall study population only. • Relapse-free survival (RFS): 159/2549 (6.2%) and 207/2552 (8.1%) RFS events were reported in the RIB + ET group and the ET group, respectively. The RFS HR for RIB + ET compared to ET alone was 0.719, with a 95% CI of (0.584, 0.884). The one-sided nominal p-value was 0.0008. • Distant disease-free survival (DDFS): 167/2549 (6.6%) and 212/2552 (8.3%) DDFS events were reported in the RIB + ET group and the ET group, respectively. The DDFS HR for RIB + ET vs. ET alone was 0.739, with a 95% CI of (0.603, 0.905). The one-sided nominal p-value was 0.0017. • Overall survival (OS): 61/2549 (2.4%) and 73/2552 (2.9%) OS events were reported in the RIB + ET group and the ET alone group, respectively. The OS HR for RIB + ET vs. ET alone was 0.759, with a 95% CI of (0.539, 1.068). The one-sided nominal p-value was 0.0563. • p-values for secondary efficacy endpoints are nominal and not adjusted for multiplicity Safety and tolerability • Median duration of study treatment exposure was 30.1 months in the RIB + ET group and 30.0 months in the ET only group (from start of treatment to last treatment (based on data cutoff date)) • 515 (20.2%) patients completed the 3-year RIB regimen and 1450 (56.9%) patients achieved 2 years or more of treatment. • 1071 (42.4%) patients reduced their RIB dose. 566 (22.4%) patients required RIB dose reduction due to AEs. • The following treatment-emergent adverse events (TEAEs) were reported in the RIB + ET group and the ET only group, respectively: • Any TEAE 97.9% vs 87.1% • ≥ Grade 3 TEAE 62.6% vs 17.8% • Severe TEAE 13.3% vs 9.9% • TEAE leading to treatment discontinuation 20.7% vs 5.3% • A total of 19 (0.8%) and 9 (0.4%) patients in the RIB + ET group and the ET only group, respectively, died during the treatment period (up to 30 days after the end of treatment). The main causes of treatment-period mortality in the RIB + ET group and the ET-only group were: • Adverse events 0.5% vs. 0.2% • Disease recurrence 0.3% vs. 0.2% • Others 0% vs. < 0.1% • Among the treatment-period deaths due to adverse events, 6 (0.2%) patients in the RIB + ET group and 1 (0.0%) patient in the ET-only group died from Covid-19. • The main causes of overall mortality during the study period (during and after treatment) in the RIB + ET group and the ET-only group were, respectively: • Disease relapse/progression 1.6% vs. 2.5% • Adverse events 0.5% vs. 0.2% • Others 0.2% vs. 0.4% • Grade 3/4 hematology laboratory abnormalities in the RIB + ET group and the ET-only group were, respectively: • Low neutrophils (10E9/L) 44.6% vs. 1.7% • Low white blood cells (10E9/L) 27.3% vs. 0.6% • Low lymphocytes (10E9/L) 19.4% vs. 7.0% • Grade 3/4 biochemistry laboratory abnormalities in the RIB + ET group and the ET-only group were, respectively: • Alanine aminotransferase (IU/L) elevated 7.9% vs. 1.0% • Aspartate aminotransferase (IU/L) elevated grade 5.1% vs. 1.1% • Gamma-glutamyl transferase (IU/K) elevated 3.7% vs. 3.6% • Significant ECG values determined based on central review • QTcF interval increase from baseline > 60 ms occurred in 0.8% vs. 0.1% of the RIB + ET and ET-only groups, respectively • QTcF > 480 ms occurred in 0.4% vs. 0.2% of the RIB + ET and ET-only groups, respectively • QTcF > 500 ms occurred in 0.1% vs. 0.0% of the RIB + ET and ET-only groups, respectively • (ALT or AST) > 3 × ULN and TBL > 2 × ULN and ALP < 2 × ULN: reported in a total of 8 patients (0.3%) in the RIB + ET group and 1 patient (0.0%) in the ET only group. 2 Additional information

without. 3 Patients studied3.1  Subject treatment (b) surface B0.1-1 Distribution of subjects (full analysis set) Riboxil + ET N = 2549 n ( % ) Only ET N = 2552 n ( % ) Untreated 23 (0.9) 110 (4.3) Treated 2526 (99.1) 2442 (95.7) Undergoing treatment 1984 (77.8) 1826 (71.6) Riboxili NSAI NSAI Number of patients who discontinued the component 1377 (54.0) 542 (21.3) 617 (24.2) Main reasons for deactivation Adverse Events 477 (18.7) 118 (4.6) 105 (4.1) Completed 515 (20.2) 0 0 die 3 (0.1) 5 (0.2) 3 (0.1) Relapse 109 (4.3) 142 (5.6) 186 (7.3) Missed 6 (0.2) 8 (0.3) 12 (0.5) other 14 (0.5) 8 (0.3) 8 (0.3) Patient decides to stop treatment 139 (5.5) 123 (4.8) 116 (4.5) Doctor's decision 24 (0.9) 25 (1.0) 26 (1.0) Deviation from the plan 7 (0.3) 5 (0.2) 7 (0.3) Subjects request to withdraw 80 (3.1) 108 (4.2) 154 (6.0) 3.2 Analysis set (c) surface B3.2-1 Analysis set sample size (full analysis set) Analysis Set ET + Riboxil N = 2549 n ( % ) Only ET N = 2552 n ( % ) Total N = 5101 n ( % ) Full analysis set 2549 (100) 2552 (100) 5101 (100) Security Analysis Set 2524 (99.0) 2442 (95.7) 4968 (97.4) Meet the protocol set 2496 (97.9) 2424 (95.0) 4920 (96.5) Note: The percentage denominator is based on the number of patients in the full analysis set. 3.3  Demographics and other baseline characteristics (d) surface B3.3-1 Demographics and Baseline Characteristics (Full Analysis Set) Features ET + Riboxil N = 2549 n ( % ) Only ET N = 2552 n ( % ) Total N = 5101 n ( % ) Age group ＜ 45 611 (24.0) 591 (23.2) 1202 (23.6) 45 to 54 849 (33.3) 895 (35.1) 1744 (34.2) 55 to 64 682 (26.8) 700 (27.4) 1382 (27.1) ≥ 65 407 (16.0) 366 (14.3) 773 (15.2) Lost 0 0 0 Age (years) n 2549 2552 5101 average value 52.9 52.7 52.8 SD 10.75 10.77 10.76 Minimum twenty four twenty four twenty four Median 52.0 52.0 52.0 Maximum 90 89 90 gender male 11 (0.4) 9 (0.4) 20 (0.4) female 2538 (99.6) 2543 (99.6) 5081 (99.6) unknown 0 0 0 Undifferentiated 0 0 0 Lost 0 0 0 Race White 1876 (73.6) 1868 (73.2) 3744 (73.4) Black or African American 42 (1.6) 47 (1.8) 89 (1.7) Asian 341 (13.4) 334 (13.1) 675 (13.2) Native Hawaiian or Other Pacific Islander 3 (0.1) 1 (0.0) 4 (0.1) American Indian or Alaska Native 4 (0.2) 3 (0.1) 7 (0.1) other 145 (5.7) 172 (6.7) 317 (6.2) Lost 138 (5.4) 127 (5.0) 265 (5.2) Ethnicity Hispanic or Latino 212 (8.3) 223 (8.7) 435 (8.5) Not Hispanic or Latino 2076 (81.4) 2054 (80.5) 4130 (81.0) unknown 172 (6.7) 201 (7.9) 373 (7.3) Lost 89 (3.5) 74 (2.9) 163 (3.2) district Asia 281 (11.0) 290 (11.4) 571 (11.2) Europe 1505 (59.0) 1506 (59.0) 3011 (59.0) North America/Australia 624 (24.5) 612 (24.0) 1236 (24.2) Latin America 139 (5.5) 144 (5.6) 283 (5.5) Lost 0 0 0 ECOG performance status 0 2106 (82.6) 2132 (83.5) 4238 (83.1) 1 440 (17.3) 418 (16.4) 858 (16.8) Lost 3 (0.1) 2 (0.1) 5 (0.1) Weight ( kg ) n 2534 2542 5076 average value 72.4 72.2 72.3 SD 16.20 15.53 15.86 Minimum 38 41 38 Median 70.0 70.0 70.0 Maximum 166 169 169 Height ( cm ) n 2523 2522 5045 average value 162.9 162.7 162.8 SD 6.78 6.85 6.81 Minimum 140 140 140 Median 163.0 163.0 163.0 Maximum 198 191 198 BMI ( kg/m² ) n 2518 2521 5039 average value 27.3 27.3 27.3 SD 5.81 5.70 5.76 Minimum 16 15 15 Median 26.3 26.5 26.4 Maximum 56 59 59 - Weight and height are the last nonmissing estimates on or before the randomization date. - BMI: Body mass index was calculated based on the raw data measurements. (e) surface B3.3-2 Cancer diagnosis and lesion spectrum (full analysis set) Features ET + Riboxil N = 2549 n ( % ) Only ET N = 2552 n ( % ) Total N = 5101 n ( % ) Tumor location Right side 1277 (50.1) 1258 (49.3) 2535 (49.7) Left side 1271 (49.9) 1287 (50.4) 2558 (50.1) Bilateral 1 (0.0) 7 (0.3) 8 (0.2) Lost 0 0 0 Histopathological grade at diagnosis - n ( % ) GX 30 (1.2) 32 (1.3) 62 (1.2) G1 218 (8.6) 240 (9.4) 458 (9.0) G2 1458 (57.2) 1451 (56.9) 2909 (57.0) G3 521 (20.4) 549 (21.5) 1070 (21.0) Not in progress 292 (11.5) 258 (10.1) 550 (10.8) Lost 30 (1.2) 22 (0.9) 52 (1.0) T stage at diagnosis - n ( % ) TX 175 (6.9) 173 (6.8) 348 (6.8) T0 4 (0.2) 7 (0.3) 11 (0.2) Tis 2 (0.1) 3 (0.1) 5 (0.1) T1 471 (18.5) 442 (17.3) 913 (17.9) T2 1181 (46.3) 1235 (48.4) 2416 (47.4) T3 471 (18.5) 472 (18.5) 943 (18.5) T4 200 (7.8) 184 (7.2) 384 (7.5) Lost 45 (1.8) 36 (1.4) 81 (1.6) N stage at diagnosis - n ( % ) NX 272 (10.7) 264 (10.3) 536 (10.5) N0 694 (27.2) 737 (28.9) 1431 (28.1) N1 1050 (41.2) 1049 (41.1) 2099 (41.1) N2 332 (13.0) 292 (11.4) 624 (12.2) N3 151 (5.9) 175 (6.9) 326 (6.4) Lost 50 (2.0) 35 (1.4) 85 (1.7) M stage at diagnosis - n ( % ) M0 2549 (100) 2552 (100) 5101 (100) M1 0 0 0 Lost 0 0 0 Ki67 score at initial diagnosis n 1861 1908 3769 average value 27.1 27.1 27.1 SD 19.88 19.50 19.69 Minimum 0 0 0 Median 20.0 20.5 20.0 Maximum 99 100 100 Ki67 Classification at Initial Diagnosis ≤ 14% 508 (19.9) 508 (19.9) 1016 (19.9) > 14% 1353 (53.1) 1400 (54.9) 2753 (54.0) ≤ 20% 938 (36.8) 954 (37.4) 1892 (37.1) > 20% 923 (36.2) 954 (37.4) 1877 (36.8) Lost 688 (27.0) 644 (25.2) 1332 (26.1) Histopathological grade of surgical specimens - n ( % ) GX 32 (1.3) 30 (1.2) 62 (1.2) G1 213 (8.4) 217 (8.5) 430 (8.4) G2 1460 (57.3) 1432 (56.1) 2892 (56.7) G3 684 (26.8) 702 (27.5) 1386 (27.2) Not in progress 159 (6.2) 168 (6.6) 327 (6.4) Lost 1 (0.0) 3 (0.1) 4 (0.1) T stage of surgical specimen - n ( % ) TX 20 (0.8) 9 (0.4) 29 (0.6) T0 56 (2.2) 52 (2.0) 108 (2.1) Tis 16 (0.6) 19 (0.7) 35 (0.7) T1 774 (30.4) 761 (29.8) 1535 (30.1) T2 1162 (45.6) 1198 (46.9) 2360 (46.3) T3 427 (16.8) 422 (16.5) 849 (16.6) T4 92 (3.6) 91 (3.6) 183 (3.6) Lost 2 (0.1) 0 2 (0.0) Surgical specimen N stage - n ( % ) NX 2 (0.1) 5 (0.2) 7 (0.1) N0 378 (14.8) 418 (16.4) 796 (15.6) N1 1062 (41.7) 1039 (40.7) 2101 (41.2) N2 733 (28.8) 690 (27.0) 1423 (27.9) N3 372 (14.6) 399 (15.6) 771 (15.1) Lost 2 (0.1) 1 (0.0) 3 (0.1) Ki67 score of surgical specimens n 1269 1332 2601 average value 20.6 20.9 20.7 SD 17.82 18.15 17.99 Minimum 0 0 0 Median 15.0 15.0 15.0 Maximum 99 98 99 Ki67 classification of surgical specimens ≤ 14% 541 (21.2) 577 (22.6) 1118 (21.9) > 14% 728 (28.6) 755 (29.6) 1483 (29.1) ≤ 20% 817 (32.1) 864 (33.9) 1681 (33.0) > 20% 452 (17.7) 468 (18.3) 920 (18.0) Lost 1280 (50.2) 1220 (47.8) 2500 (49.0) Time since initial diagnosis (months) n 2517 2528 5045 average value 11.8 11.8 11.8 SD 3.53 3.58 3.55 Minimum 1 1 1 Median 11.7 11.7 11.7 Maximum twenty three 27 27 Main histology - n ( % ) Invasive ductal carcinoma NOS 1857 (72.9) 1881 (73.7) 3738 (73.3) Invasive lobular carcinoma 455 (17.9) 450 (17.6) 905 (17.7) Medullary carcinoma 1 (0.0) 1 (0.0) 2 (0.0) Mucinous carcinoma 17 (0.7) 16 (0.6) 33 (0.6) Papillary carcinoma 18 (0.7) 12 (0.5) 30 (0.6) Tubular carcinoma 5 (0.2) 3 (0.1) 8 (0.2) Duct carcinoma in situ 1 (0.0) 0 1 (0.0) Lobular carcinoma in situ 0 0 0 other 194 (7.6) 189 (7.4) 383 (7.5) Lost 1 (0.0) 0 1 (0.0) Previous surgery - n ( % ) Mastectomy 1664 (65.3) 1691 (66.3) 3355 (65.8) Breast Conserving Surgery 978 (38.4) 963 (37.7) 1941 (38.1) Axillary lymph node dissection 2165 (84.9) 2149 (84.2) 4314 (84.6) Sentinel lymph node biopsy 926 (36.3) 920 (36.1) 1846 (36.2) other 143 (5.6) 162 (6.3) 305 (6.0) Lost 0 0 0 Preoperative HER2 ISH results (reported only when performed) - n ( % ) Expansion 4 (0.2) 7 (0.3) 11 (0.2) Non-expanding 612 (24.0) 653 (25.6) 1265 (24.8) Unclear 19 (0.7) 13 (0.5) 32 (0.6) unknown 6 (0.2) 11 (0.4) 17 (0.3) HER2 ISH results in surgical specimens (reported only when available) - n ( % ) Expansion 2 (0.1) 1 (0.0) 3 (0.1) Non-expanding 417 (16.4) 423 (16.6) 840 (16.5) Unclear 1 (0.0) 1 (0.0) 2 (0.0) unknown 2 (0.1) 2 (0.1) 4 (0.1) Preoperative HER2 IHC score (reported only if performed) - n ( % ) 0 856 (33.6) 881 (34.5) 1737 (34.1) 1+ 862 (33.8) 813 (31.9) 1675 (32.8) 2+ 464 (18.2) 480 (18.8) 944 (18.5) 3+ 5 (0.2) 5 (0.2) 10 (0.2) unknown 21 (0.8) 21 (0.8) 42 (0.8) HER2 IHC score of surgical specimens (reported only when available) - n ( % ) 0 625 (24.5) 610 (23.9) 1235 (24.2) 1+ 513 (20.1) 516 (20.2) 1029 (20.2) 2+ 235 (9.2) 262 (10.3) 497 (9.7) 3+ 1 (0.0) 3 (0.1) 4 (0.1) unknown 6 (0.2) 10 (0.4) 16 (0.3) Preoperative estrogen receptor ( ER ) IHC status (reported only if performed) - n ( % ) Positive 2342 (91.9) 2328 (91.2) 4670 (91.6) Negative 8 (0.3) 16 (0.6) 24 (0.5) unknown 0 1 (0.0) 1 (0.0) Estrogen receptor ( ER ) IHC status of surgical specimen (reported only when available) - n ( % ) Positive 1369 (53.7) 1403 (55.0) 2772 (54.3) Negative 2 (0.1) 5 (0.2) 7 (0.1) unknown 3 (0.1) 3 (0.1) 6 (0.1) Preoperative progesterone receptor ( PR ) IHC status (reported only if performed) - n ( % ) Positive 2051 (80.5) 2034 (79.7) 4085 (80.1) Negative 287 (11.3) 295 (11.6) 582 (11.4) unknown 12 (0.5) 16 (0.6) 28 (0.5) Progesterone receptor ( PR ) IHC status of surgical specimen (reported only when available) - n ( % ) Positive 1133 (44.4) 1149 (45.0) 2282 (44.7) Negative 236 (9.3) 255 (10.0) 491 (9.6) unknown 6 (0.2) 8 (0.3) 14 (0.3) ER/PR combination status - n ( % ) ER+/PR+ 2172 (85.2) 2132 (83.5) 4304 (84.4) ER+/PR- 359 (14.1) 392 (15.4) 751 (14.7) ER-/PR+ 3 (0.1) 12 (0.5) 15 (0.3) ER+/UNK 10 (0.4) 13 (0.5) 23 (0.5) UNK/PR+ 2 (0.1) 2 (0.1) 4 (0.1) UNK/PR- 1 (0.0) 1 (0.0) 2 (0.0) UNK/UNK 2 (0.1) 0 2 (0.0) AJCC 8th edition anatomical stage - n ( % ) 0th issue 0 0 0 Phase I 9 (0.4) 5 (0.2) 14 (0.3) Phase II 1011 (39.7) 1034 (40.5) 2045 (40.1) Stage III 1528 (59.9) 1512 (59.2) 3040 (59.6) Stage IV 0 0 0 Lost 1 (0.0) 1 (0.0) 2 (0.0) Genome testing Endopredict 23 (0.9) 28 (1.1) 51 (1.0) Mammaprint 46 (1.8) 51 (2.0) 97 (1.9) Oncotype DX 120 (4.7) 129 (5.1) 249 (4.9) Pam50 38 (1.5) 29 (1.1) 67 (1.3) other 109 (4.3) 103 (4.0) 212 (4.2) EndoPredict EPclin Risk Score High risk 19 (0.7) 21 (0.8) 40 (0.8) Low risk 4 (0.2) 7 (0.3) 11 (0.2) Lost 2526 (99.1) 2524 (98.9) 5050 (99.0) Mammaprint High risk 22 (0.9) 33 (1.3) 55 (1.1) Low risk 24 (0.9) 18 (0.7) 42 (0.8) Lost 2503 (98.2) 2501 (98.0) 5004 (98.1) Oncotype DX Breast Recurrence Score Relapse score ≥ 26 33 (1.3) 43 (1.7) 76 (1.5) Relapse score < 26 87 (3.4) 86 (3.4) 173 (3.4) Lost 2429 (95.3) 2423 (94.9) 4852 (95.1) Prosigna/PAM50 High risk 24 (0.9) 19 (0.7) 43 (0.8) Medium risk 10 (0.4) 7 (0.3) 17 (0.3) Low risk 4 (0.2) 3 (0.1) 7 (0.1) Lost 2511 (98.5) 2523 (98.9) 5034 (98.7) - Subjects may have had multiple prior surgeries, but each category was counted only once. - T stage T1 category collected T1mi, T1a, T1b, T1c. T4 category collected T4a, T4b, T4c, T4d. - N stage N0 category collected N0 and N0(i+). N1 category collected N1, N1a, N1c, N1mi. N2 category collected N2a, N2b, N2c. N3 category collected N3a, N3b, N3c. - AJCC 8th edition Stage 1 category collected IA and IB. Stage II category collected IIA and IIB. Stage III category collected IIIA, IIIB, and IIIC. For patients who have not received neo/adjuvant therapy, stage is based on post-surgery TNM, or for patients who have received neo/adjuvant therapy, stage is the worst stage using TNM at diagnosis and TNM after surgery. - Patients may have more than one genomic test type, but each type is counted only once. (f) surface B3.3-3 Anatomical stage group at randomization (full analysis set) Features ET + Riboxil N = 2549 n ( % ) Only ET N = 2552 n ( % ) Total N = 5101 n ( % ) Anatomical Stages 9 (0.4) 5 (0.2) 14 (0.3) Anatomical stage IIA 479 (18.8) 521 (20.4) 1000 (19.6) N1 267 (10.5) 280 (11.0) 547 (10.7) N0, where 212 (8.3) 241 (9.4) 453 (8.9) Level 3 104 (4.1) 109 (4.3) 213 (4.2) Level 2 and meets any of the following criteria 76 (3.0) 102 (4.0) 178 (3.5) Ki67 ≥ 20% 70 (2.7) 91 (3.6) 161 (3.2) Oncotype DX breast recurrence score ≥ 26 4 (0.2) 10 (0.4) 14 (0.3) Prosigna/PAM50 is high risk 6 (0.2) 3 (0.1) 9 (0.2) MammaPrint is high risk 2 (0.1) 4 (0.2) 6 (0.1) EndoPredict EPclin risk score is high risk 3 (0.1) 5 (0.2) 8 (0.2) Level 2, none of the above risk factors 28 (1.1) 26 (1.0) 54 (1.1) Anatomical stage IIB 532 (20.9) 513 (20.1) 1045 (20.5) III Anatomical staging 1528 (59.9) 1512 (59.2) 3040 (59.6) Missing stage 1 (0.0) 1 (0.0) 2 (0.0) - The AJCC 8th edition stage I category captures stages IA and IB. The stage III category captures stages IIIA, IIIB, and IIIC. For patients who have not received neo/adjuvant therapy, the stage is based on TNM after surgery, or for patients who have received neo/adjuvant therapy, the stage is the worst stage using TNM at diagnosis and TNM after surgery. - Ki67 is determined based on surgical specimen records. If surgical specimens for Ki67 are not available, the score at diagnosis is summarized. (g) surface B3.3-4 Previous anticancer treatment (full analysis set) Therapy ET + Riboxil N = 2549 n ( % ) Only ET N = 2552 n ( % ) Total N = 5101 n ( % ) Number of patients who received any prior anticancer drugs 2423 (95.1) 2439 (95.6) 4862 (95.3) Chemotherapy 2249 (88.2) 2245 (88.0) 4494 (88.1) Anthracyclines 2014 (79.0) 2037 (79.8) 4051 (79.4) Taxanes 2147 (84.2) 2132 (83.5) 4279 (83.9) other 2190 (85.9) 2189 (85.8) 4379 (85.8) Endocrine therapy 1824 (71.6) 1801 (70.6) 3625 (71.1) Aromatase inhibitors 1601 (62.8) 1592 (62.4) 3193 (62.6) Antiestrogens 344 (13.5) 341 (13.4) 685 (13.4) Gonadotropin-releasing hormone analogs 670 (26.3) 620 (24.3) 1290 (25.3) other 2 (0.1) 4 (0.2) 6 (0.1) Biological/targeted therapies 2 (0.1) 9 (0.4) 11 (0.2) other 9 (0.4) 6 (0.2) 15 (0.3) Treatment Background Assistance 2160 (84.7) 2150 (84.2) 4310 (84.5) Adjunctive chemotherapy 1223 (48.0) 1220 (47.8) 2443 (47.9) New Aids 1129 (44.3) 1148 (45.0) 2277 (44.6) New adjuvant chemotherapy 1085 (42.6) 1095 (42.9) 2180 (42.7) Minimum ATC Category Antineoplastic and Immunomodulatory Agents 2423 (95.1) 2439 (95.6) 4862 (95.3) Dermatology 0 1 (0.0) 1 (0.0) Musculoskeletal system 4 (0.2) 2 (0.1) 6 (0.1) Systemic hormonal preparations, excluding sex hormones and insulin 2 (0.1) 4 (0.2) 6 (0.1) Various 2 (0.1) 5 (0.2) 7 (0.1) Number of patients who received any previous anti-tumor radiotherapy 2292 (89.9) 2302 (90.2) 4594 (90.1) Time since the last radiotherapy (months) n 2292 2302 4594 average value 3.1 3.1 3.1 SD 2.48 2.50 2.49 Minimum 0 0 0 Median 2.3 2.3 2.3 Maximum 14 14 14 Location of last radiotherapy breast 1035 (40.6) 1004 (39.3) 2039 (40.0) Chest wall 1209 (47.4) 1210 (47.4) 2419 (47.4) Axillary lymph nodes 1010 (39.6) 973 (38.1) 1983 (38.9) Supraclavicular lymph nodes 1066 (41.8) 1079 (42.3) 2145 (42.1) Internal mammary lymph nodes 374 (14.7) 410 (16.1) 784 (15.4) other 287 (11.3) 310 (12.1) 597 (11.7) Duration of previous endocrine therapy (months) n 1818 1794 3612 average value 3.8 3.9 3.8 SD 2.78 2.77 2.77 Minimum 0 0 0 Median 3.1 3.2 3.2 Maximum 17 18 18 Number of patients who underwent any previous surgery 2548 (100) 2552 (100) 5100 (100) Time since the last surgery (months) n 2548 2552 5100 average value 7.9 7.9 7.9 SD 3.80 3.76 3.78 Minimum 0 0 0 Median 7.9 7.8 7.8 Maximum 18 twenty one twenty one Type of surgery Biopsy 679 (26.6) 673 (26.4) 1352 (26.5) Non-biological inspection 2542 (99.7) 2549 (99.9) 5091 (99.8) - Antineoplastic drugs are coded using the September 2022 WHO-DD version. - Subjects may have had multiple types of prior antineoplastic therapy, but each type of treatment or subtherapy is counted only once. - Subjects may have had multiple radiotherapy sites based on the last reported date, but each radiotherapy site is counted only once. - Subjects may have both adjuvant and neoadjuvant prior treatment backgrounds, but each treatment background is counted only once. - Time since the last radiotherapy ended = (randomization date - radiotherapy end date) (months). - Time since the last surgery ended = (randomization date - last surgery date) (months). 3.4 Subject exposure (h) surface B0.4-1 Exposure (Safety Analysis Set) Research treatment Riboxil N = 2524 n ( % ) ET + Riboxili N = 2524 ET N = 2444 Duration of exposure 0-3 months 304 (12.0) 122 (4.8) 168 (6.9) 3-6 months 164 (6.5) 84 (3.3) 79 (3.2) 6-9 months 91 (3.6) 58 (2.3) 50 (2.0) 9-12 months 51 (2.0) 48 (1.9) 55 (2.3) 12-15 months 51 (2.0) 40 (1.6) 45 (1.8) 15-18 months 52 (2.1) 34 (1.3) 43 (1.8) 18-21 months 90 (3.6) 57 (2.3) 65 (2.7) 21-24 months 272 (10.8) 318 (12.6) 281 (11.5) 24-27 months 110 (4.4) 103 (4.1) 92 (3.8) 27-30 months 324 (12.8) 381 (15.1) 349 (14.3) 30-33 months 337 (13.4) 188 (7.4) 189 (7.7) 33-36 months 665 (26.3) 491 (19.5) 460 (18.8) 36-39 months 13 (0.5) 364 (14.4) 338 (13.8) 39-42 months 0 193 (7.6) 179 (7.3) 42-45 months 0 34 (1.3) 42 (1.7) 45-48 months 0 9 (0.4) 9 (0.4) Duration of exposure (months) n 2524 2524 2444 average value 23.1 28.0 27.3 SD 12.23 10.82 11.48 Minimum 0 0 0 Median 27.4 30.1 30.0 Maximum 37 47 48 4 Efficacy Results4.1  Main efficacy results (i) Analysis of survival free from primary invasive disease - Kaplan - Mayer diagram (full analysis set), see Figure 9 (j) surface B4.1-1 iDFS Log-rank test results for (full analysis set) treatment n/N ( % ) compare Z statistic p -value * ET + Riboxili 189/2549 (7.4) Compared with ET only -2.9847 0.0014 ET only 237/2552 (9.3) - n = number of iDFS events. - N = total number of patients included in the analysis. - *One-sided p-values from the log-rank test, stratified by premenopausal women and men versus postmenopausal women, anatomic stage II versus anatomic stage III, prior neo/adjuvant chemotherapy (yes versus no), and North America/Western Europe/Australia versus rest of the world. (k) surface B4.1-2 iDFS of Cox Regression results (full analysis set) treatment n/N ( % ) compare Risk Ratio 95% CI ET + Riboxili 189/2549 (7.4) Compared with ET only 0.748 (0.618, 0.906) ET only 237/2552 (9.3) (l) surface B4.1-3 Kaplan-Meier-Strauss-Hofstra University , ADA - Mayer Estimates (Full Analysis Set) (m) surface B0.1-4 Invasive disease-free survival - First iDFS Type and location of events (full analysis set) ET + Riboxil N = 2549 n ( % ) Only ET N = 2552 n ( % ) Type of first iDFS event Invasive ipsilateral breast tumor recurrence 8 (0.3) 7 (0.3) Local/regional invasive recurrence 19 (0.7) 35 (1.4) Remote recurrence 120 (4.7) 170 (6.7) Invasive contralateral breast cancer 7 (0.3) 9 (0.4) die 13 (0.5) 7 (0.3) The main cause of death was adverse events 12 (0.5) 3 (0.1) The main cause of death was disease recurrence/progression 1 (0.0) 0 The main cause of death is other 0 4 (0.2) Second primary non-breast invasive cancer 30 (1.2) 28 (1.1) iDFS events recurring at one or more sites (excluding death and second primary non-breast invasive cancer) Ipsilateral breast 8 (0.3) 6 (0.2) Ipsilateral chest wall/skin 10 (0.4) 15 (0.6) Ipsilateral axillary fossa 4 (0.2) 7 (0.3) Regional lymph nodes 9 (0.4) 17 (0.7) Contralateral breast (with or without contralateral lymph nodes) 7 (0.3) 9 (0.4) bone 71 (2.8) 96 (3.8) Liver 34 (1.3) 53 (2.1) Lung/pleura 22 (0.9) 37 (1.4) Central nervous system 11 (0.4) 16 (0.6) Distant lymph nodes 17 (0.7) 23 (0.9) other 11 (0.4) 8 (0.3) - Patients may have multiple iDFS recurrence sites counted in the table, but each patient is counted only once. (n) surface B0.1-5 Analysis of primary invasive disease-free survival - Dropouts by treatment group (full analysis set) Number of patients N = 5101 n ( % ) ET + Riboxil ( N = 2549 ) Number of patients with iDFS events 189 (7.4) Number of patients lost 2360 (92.6) Lost reason No events 2134 (83.7) Withdrawal of consent 213 (8.4) Missed 13 (0.5) ET only ( N = 2552 ) Number of patients with iDFS events 237 (9.3) Number of patients lost 2315 (90.7) Lost reason No events 1972 (77.3) Withdrawal of consent 324 (12.7) Missed 19 (0.7) - The missing date is the last assessment before the earliest of the following dates: analysis deadline, withdrawal of consent, or last contact. - % is determined based on N in each group. (o) surface B4.1-6 iDFS Sensitivity analysis (full analysis set) Sensitivity analysis treatment n/N p- value Hazard ratio ( 95% CI ) Main analysis ET + Riboxili 189/2549 0.0014 0.748 (0.618, 0.906) ET only 237/2552 Primary analysis ( PPS ) ET + Riboxili 187/2496 0.0015 0.749 (0.618, 0.907) ET only 235/2424 Main analysis based on CRF ET + Riboxili 189/2549 0.0012 0.744 (0.614, 0.901) ET only 237/2552 Unstratified Log-Rank Checked Sum Cox Model ET + Riboxili 189/2549 0.0023 0.759 (0.627, 0.919) ET only 237/2552 Hierarchical Cox model adjusted for baseline covariates [a] ET + Riboxili 189/2549 0.0014 0.762 (0.628, 0.923) ET only 237/2552 Actual events [b] ET + Riboxili 186/2549 0.0019 0.752 (0.620, 0.912) ET only 232/2552 Backtrack [c] ET + Riboxili 189/2549 0.0014 0.748 (0.618, 0.906) ET only 237/2552 Deletion in response to anticancer therapy [d] ET + Riboxili 186/2549 0.0031 0.763 (0.629, 0.927) ET only 226/2552 Clinical relapse [e] ET + Riboxili 189/2549 0.0014 0.748 (0.618, 0.906) ET only 237/2552 Deleted covid deaths [f] ET + Riboxili 183/2549 0.0006 0.727 (0.600, 0.882) ET only 236/2552 -CI = confidence interval. [a] Baseline covariates included in the Cox proportional hazards model were age category (<45, 45-54, and 55-64 years vs. >64 years), ER/PR status (ER+/PR+ vs. other), and ET type (letrozole vs. anastrozole). [b] Analyses did not include events occurring after missing ≥ 2 tumor assessments. [c] For events occurring after missing ≥ 1 assessment, analyses used the date of the next planned assessment. [d] Analyses performed by dropping patients at the time of starting new anticancer therapy. [e] Analyses treating discontinuation of treatment due to disease relapse as an iDFS event with unconfirmed relapse. [f] Analyses performed by dropping patients who died due to COVID. - For [b], [c], and [d], the p-values are calculated based on the log-rank test. For [a], the value is calculated based on the Wald test statistic for HR. (p) surface B4.1-7 iDFS of Cox Return - Subgroup analysis (full analysis set) factor Subgroup treatment Number of patients Number of events Risk Ratio 95% CI Menopausal status* Premenopausal women and men ET + Riboxili 1126 71 0.722 (0.530, 0.983) ET only 1132 93 Postmenopausal women ET + Riboxili 1423 118 0.781 (0.613, 0.997) ET only 1420 144 AJCC Staging* AJCC Stage II ET + Riboxili 1011 49 0.761 (0.525, 1.103) ET only 1034 65 AJCC Stage III ET + Riboxili 1528 140 0.740 (0.592, 0.925) ET only 1512 172 Previous new/adjuvant chemotherapy* yes ET + Riboxili 2249 167 0.729 (0.596, 0.893) ET only 2245 215 no ET + Riboxili 300 twenty two 1.038 (0.575, 1.875) ET only 307 twenty two Region* NA/WE/O ET + Riboxili 1563 111 0.759 (0.591, 0.974) ET only 1565 139 ROW ET + Riboxili 986 78 0.757 (0.562, 1.019) ET only 987 98 Anatomical stage** IIA ET + Riboxili 479 13 0.500 (0.258, 0.968) ET only 521 27 IIB ET + Riboxili 532 36 0.930 (0.589, 1.467) ET only 513 38 IIIA ET + Riboxili 939 75 0.792 (0.580, 1.080) ET only 894 85 IIIB ET + Riboxili 168 18 0.678 (0.355, 1.295) ET only 149 20 IIIC ET + Riboxili 421 47 0.685 (0.472, 0.994) ET only 469 67 gender female ET + Riboxili 2538 188 0.758 (0.625, 0.918) ET only 2543 236 Previous adjuvant chemotherapy yes ET + Riboxili 1223 63 0.671 (0.486, 0.927) ET only 1220 89 no ET + Riboxili 1326 126 0.814 (0.642, 1.032) ET only 1332 148 Previous adjuvant chemotherapy yes ET + Riboxili 1085 111 0.785 (0.610, 1.011) ET only 1095 132 no ET + Riboxili 1464 78 0.717 (0.535, 0.961) ET only 1457 105 Previous radiation therapy yes ET + Riboxili 2292 170 0.739 (0.605, 0.903) ET only 2302 218 no ET + Riboxili 257 19 0.980 (0.519, 1.851) ET only 250 19 Previous endocrine therapy yes ET + Riboxili 1824 127 0.756 (0.598, 0.955) ET only 1801 157 no ET + Riboxili 725 62 0.774 (0.556, 1.079) ET only 751 80 Previous mastectomy yes ET + Riboxili 1664 147 0.853 (0.683, 1.066) ET only 1691 165 no ET + Riboxili 885 42 0.548 (0.375, 0.802) ET only 861 72 Race Asian ET + Riboxili 341 18 0.523 (0.290, 0.942) ET only 334 29 Non-Asian ET + Riboxili 2070 160 0.807 (0.654, 0.995) ET only 2091 192 district Europe ET + Riboxili 1505 122 0.875 (0.686, 1.116) ET only 1506 138 North America/Australia ET + Riboxili 624 47 0.697 (0.475, 1.025) ET only 612 58 Asia ET + Riboxili 281 9 0.338 (0.157, 0.728) ET only 290 twenty four Latin America ET + Riboxili 139 11 0.691 (0.323, 1.477) ET only 144 17 Age Category 1 ＜ 45 ET + Riboxili 611 39 0.683 (0.449, 1.038) ET only 591 50 45 to 54 ET + Riboxili 849 52 0.750 (0.524, 1.075) ET only 895 69 55 to 64 ET + Riboxili 682 64 0.839 (0.601, 1.170) ET only 700 76 ≥ 65 ET + Riboxili 407 34 0.723 (0.460, 1.137) ET only 366 42 Age Category 2 ＜Median ET + Riboxili 1216 71 0.727 (0.535, 0.989) ET only 1264 95 ≥ median ET + Riboxili 1333 118 0.775 (0.607, 0.990) ET only 1288 142 NSAI Type Letrozole ET + Riboxili 1729 127 0.790 (0.624, 0.999) ET only 1674 154 Anastrozole ET + Riboxili 797 62 0.702 (0.505, 0.976) ET only 768 83 Hormone receptor status ER+/PR+ ET + Riboxili 2172 140 0.726 (0.582, 0.906) ET only 2132 180 ER-/PR+ ET + Riboxili 3 1 506E6 (0.000, NE) ET only 12 0 ER+/PR- ET + Riboxili 359 48 0.908 (0.615, 1.339) ET only 392 54 Lymph node status N0 ET + Riboxili 285 16 0.630 (0.341, 1.165) ET only 328 28 N1-N3 ET + Riboxili 2261 173 0.771 (0.630, 0.944) ET only 2219 208 Tumor type T0 ET + Riboxili 8 1 324E5 (0.000, NE) ET only 6 0 T1-T3 ET + Riboxili 2345 164 0.742 (0.605, 0.910) ET only 2360 212 ＞ T3 ET + Riboxili 189 twenty two 0.827 (0.460, 1.486) ET only 181 twenty three Histological grade at the time of surgery Level 1 ET + Riboxili 213 9 0.778 (0.328, 1.846) ET only 217 12 Level 2 ET + Riboxili 1460 102 0.749 (0.577, 0.973) ET only 1432 125 Level 3 ET + Riboxili 684 61 0.776 (0.555, 1.085) ET only 702 78 Archive the Ki67 status of a tumor Ki67 ≤ 20 ET + Riboxili 1199 76 0.801 (0.593, 1.083) ET only 1236 95 Ki67 ＞ 20 ET + Riboxili 920 82 0.746 (0.559, 0.996) ET only 938 105 Histological subtype Catheter ET + Riboxili 1858 123 0.675 (0.536, 0.850) ET only 1881 174 Small Leaf ET + Riboxili 455 47 1.053 (0.696, 1.592) ET only 450 43 other ET + Riboxili 235 19 0.887 (0.473, 1.661) ET only 221 20 BMI at screening ≥ 25 ET + Riboxili 1505 124 0.848 (0.667, 1.079) ET only 1522 142 ＜ 25 ET + Riboxili 1013 64 0.635 (0.462, 0.873) ET only 999 93 *Randomization stratification factor from eCRF. **Subgroup AJCC stage from eCRF data (IIA vs. IIB vs. IIIA vs. IIIB vs. IIIC). -NE = not estimable. (q) About layered iDFS Forest plot of eCRF ) (full analysis set), see Figure 10

See Figure 11A-D for Forest Plots of iDFS - Subgroup Analyses (Full Analysis Set). Subgroups with unestimated HRs were removed from the forest plots. *-Hazard ratios for the ET + Riboxil group versus the ET-only group were calculated using a Cox proportional hazards model with treatment as a single covariate and premenopausal women and men versus postmenopausal women, anatomic stage II versus anatomic stage III, prior neo/adjuvant chemotherapy (yes versus no), and North America/Western Europe/Australia versus rest of the world as stratification factors. The ET-only group was the reference in the hazard ratio calculation.

Figures 12 and 13 are Kaplan-Meier survival curves of iDFS by anatomical stage II and III, respectively. 4.2 Secondary efficacy outcomes

For the Kaplan-Meyer curve of RFS (full analysis set), please refer to Figure 14 [ Table B4.2-1 ] Cox regression results of RFS (full analysis set) treatment n/N ( % ) compare Risk Ratio 95% CI ET + Riboxili 159/2549 (6.2) Compared with ET only 0.719 (0.584, 0.884) ET only 207/2552 (8.1) - n = number of RFS events. - N = total number of patients included in the analysis. - Hazard ratios for the ET + ribociclib group versus the ET-only group were calculated using a Cox proportional hazards model with treatment as a single covariate and premenopausal women and men versus postmenopausal women, anatomic stage II versus anatomic stage III, prior neo/adjuvant chemotherapy (yes versus no), and North America/Western Europe/Australia versus rest of the world as stratification factors. The ET-only group was the reference in the hazard ratio calculation. [Table B4.2-2] Log-rank results of DDFS (full analysis set) treatment n/N ( % ) compare Z statistic p -value * ET + Riboxili 159/2549 (6.2) Compared with ET only -3.144 0.0008 ET only 207/2552 (8.1) - n = number of OS events. - N = total number of patients included in the analysis. - *One-sided p-values from the log-rank test, stratified by premenopausal women and men versus postmenopausal women, anatomic stage II versus anatomic stage III, prior neo/adjuvant chemotherapy (yes versus no), and North America/Western Europe/Australia versus rest of the world. [ Table B4.2-3 ] Kaplan - Meier estimates of relapse-free survival (full analysis set)

For the Kaplan-Meyer curve of DDFS (full analysis set), please refer to Figure 15. Figure 4.2-2 Kaplan - Meyer curve of DDFS (full analysis set) [ Table B4.2-4 ] : Cox regression model results of DDFS (full analysis set) treatment n/N ( % ) compare Risk Ratio 95% CI ET + Riboxili 167/2549 (6.6) Compared with ET only 0.739 (0.603, 0.905) ET only 212/2552 (8.3) - n is the number of DDFS events. - N = total number of patients included in the analysis. - Hazards in the ET + ribociclib group were calculated versus those in the ET only group using a Cox proportional hazards model with treatment as a single covariate and premenopausal women and men versus postmenopausal women, anatomic stage II versus anatomic stage III, prior neo/adjuvant chemotherapy (yes versus no), and North America/Western Europe/Australia versus rest of the world as stratification factors. The ET only group was the reference in the hazard ratio calculation. [ Table B4.2-5 ] : Log-rank results of DDFS (full analysis set) treatment n/N ( % ) compare Z statistic p -value * ET + Riboxili 167/2549 (6.6) Compared with ET only -2.930 0.0017 ET only 212/2552 (8.3) - n is the number of DDFS events. - N = total number of patients included in the analysis. - *One-sided p-values from the log-rank test, stratified by premenopausal women and men versus postmenopausal women, anatomic stage II versus anatomic stage III, prior neo/adjuvant chemotherapy (yes versus no), and North America/Western Europe/Australia versus rest of the world. [ Table B4.2-6 ] Kaplan - Meyer estimates of distant disease-free survival (full analysis set)

For the Kaplan-Meier curve of OS (full analysis set), please see Figure 16. [ Table B4.2-7 ] Results of Cox regression model of OS (full analysis set) treatment n/N ( % ) compare Risk Ratio 95% CI ET + Riboxili 61/2549 (2.4) Compared with ET only 0.759 (0.539, 1.068) ET only 73/2552 (2.9) - n is the number of OS events. - N = total number of patients included in the analysis. - Hazard ratios for the ET + ribociclib group versus the ET-only group were calculated using a Cox proportional hazards model with treatment as a single covariate and premenopausal women and men versus postmenopausal women, anatomic stage II versus anatomic stage III, prior neo/adjuvant chemotherapy (yes versus no), and North America/Western Europe/Australia versus rest of the world as stratification factors. The ET-only group was the reference in the hazard ratio calculation. [ Table B4.2-8 ] : Log-rank results of OS (full analysis set) treatment n/N ( % ) compare Z statistic p -value * ET + Riboxili 61/2549 (2.4) Compared with ET only -1.5871 0.0563 ET only 73/2552 (2.9) - n = number of OS events. - N = total number of patients included in the analysis. - *One-sided p-values from the log-rank test, stratified by premenopausal women and men versus postmenopausal women, anatomic stage II versus anatomic stage III, prior neo/adjuvant chemotherapy (yes versus no), and North America/Western Europe/Australia versus rest of the world. [ Table B4.2-9 ] Kaplan - Meier estimates of overall survival (full analysis set) [ Table B4.2-10 ] OS sensitivity analysis: Cox regression model results of OS omitting COVID 19 deaths (full analysis set) treatment n/N ( % ) compare Risk Ratio 95% CI ET + Riboxili 55/2549 (2.4) Compared with ET only 0.691 (0.486, 0.984) ET only 72/2552 (2.9) - n is the number of OS events. - N = total number of patients included in the analysis. - Hazard ratios for the ET + ribociclib group versus the ET-only group were calculated using a Cox proportional hazards model with treatment as a single covariate and premenopausal women and men versus postmenopausal women, anatomic stage II versus anatomic stage III, prior neo/adjuvant chemotherapy (yes versus no), and North America/Western Europe/Australia versus rest of the world as stratification factors. The ET-only group was the reference in the hazard ratio calculation. [ Table B4.2-11 ] OS sensitivity analysis: Log-rank results of OS after missing COVID 19 deaths (full analysis set) treatment n/N ( % ) compare Z statistic p -value * ET + Riboxili 55/2549 (2.4) Compared with ET only -2.059 0.0197 ET only 72/2552 (2.9) - n is the number of OS events. - N = total number of patients included in the analysis. - *One-sided p-values from the log-rank test, stratified by premenopausal women and men versus postmenopausal women, anatomic stage II group versus anatomic stage III group, prior neo/adjuvant chemotherapy (yes versus no), and North America/Western Europe/Australia versus rest of the world. 5 Safety Results 5.1 Adverse Events [ Table B0.1-1 ] Summary of adverse events during treatment (Safety Analysis Set) Number of patients with at least one case ET + Riboxil N = 2524 n ( % ) Only ET N = 2444 n ( % ) Total N = 4968 n ( % ) TEAE 2470 (97.9) 2128 (87.1) 4598 (92.6) Serious TEAE 336 (13.3) 242 (9.9) 578 (11.6) TEAEs related to study treatment (Riboxil and / or ET ) 2362 (93.6) 1534 (62.8) 3896 (78.4) TEAEs related to Riboxil 2282 (90.4) 0 2282 (45.9) TEAEs related to ET 1609 (63.7) 1534 (62.8) 3143 (63.3) Serious TEAEs related to study treatment (Riboxil and / or ET ) 66 (2.6) 12 (0.5) 78 (1.6) Serious TEAEs related to Riboxil 57 (2.3) 0 57 (1.1) Serious TEAEs related to ET 29 (1.1) 12 (0.5) 41 (0.8) TEAEs leading to treatment discontinuation (Riboxil and / or ET ) 523 (20.7) 129 (5.3) 652 (13.1) TEAEs leading to discontinuation of ribociclib treatment 495 (19.6) 0 495 (10.0) TEAEs leading to discontinuation of ET treatment 147 (5.8) 129 (5.3) 276 (5.6) TEAEs leading to dose reduction 515 (20.4) 0 515 (10.4) TEAEs leading to dosing interruption 1823 (72.2) 182 (7.4) 2005 (40.4) TEAEs requiring additional treatment 1926 (76.3) 1576 (64.5) 3502 (70.5) Grade 3 or worse TEAE 1579 (62.6) 436 (17.8) 2015 (40.6) TEAEs of Special Concern 2160 (85.6) 1140 (46.6) 3300 (66.4) NOTE: Only one AE was counted per patient. [ Table B5.1-2 ] Severe treatment-emergent adverse events (regardless of causality) listed by preferred terminology and worst toxicity grade ( ≥ 0.5% in each group ) ET + Riboxili N = 2524 ET N = 2444 Preferred terminology All levels n ( % ) Level 3 n ( % ) Level 4 n ( % ) Level 5 n ( % ) All levels n ( % ) Level 3 n ( % ) Level 4 n ( % ) Level 5 n ( % ) Number of patients experiencing at least one TEAE 336 (13.3) 232 (9.2) 44 (1.7) 12 (0.5) 242 (9.9) 180 (7.4) 25 (1.0) 4 (0.2) COVID-19 20 (0.8) 13 (0.5) 0 3 (0.1) 12 (0.5) 8 (0.3) 0 1 (0.0) pneumonia 15 (0.6) 12 (0.5) 0 1 (0.0) 7 (0.3) 6 (0.2) 0 0 Pulmonary embolism 13 (0.5) 11 (0.4) 1 (0.0) 1 (0.0) 2 (0.1) 2 (0.1) 0 0 Difficulty breathing 13 (0.5) 10 (0.4) 0 0 5 (0.2) 3 (0.1) 0 0 - The preferred term is ranked based on decreasing frequency in the ET + Riboxil group. - MedDRA version 25.1 has been used for reporting. [ Table B5.1-3 ] Treatment-emergent adverse events leading to treatment discontinuation ( > 0.5% in either group ) by system organ class and preferred term and worst toxicity grade ET + Riboxili N = 2524 ET N = 2444 Preferred terminology All levels n ( % ) Level 3 n ( % ) Level 4 n ( % ) Level 5 n ( % ) All levels n ( % ) Level 3 n ( % ) Level 4 n ( % ) Level 5 n ( % ) Number of patients experiencing at least one TEAE 523 (20.7) 202 (8.0) 35 (1.4) 6 (0.2) 129 (5.3) 35 (1.4) 5 (0.2) 3 (0.1) Elevated alanine aminotransferase 176 (7.0) 77 (3.1) 19 (0.8) 0 2 (0.1) 1 (0.0) 0 0 Elevated aspartate aminotransferase 71 (2.8) 29 (1.1) 7 (0.3) 0 0 0 0 0 Joint pain 34 (1.3) 4 (0.2) 0 0 46 (1.9) 9 (0.4) 0 0 Fatigue 24 (1.0) 5 (0.2) 0 0 2 (0.1) 0 0 0 Neutropenia 16 (0.6) 13 (0.5) 2 (0.1) 0 0 0 0 0 Decreased neutrophil count 14 (0.6) 12 (0.5) 0 0 0 0 0 0 Nausea 13 (0.5) 1 (0.0) 0 0 2 (0.1) 0 0 0 - The preferred term is ranked in descending order of frequency based on the ET + ribociclib group. - MedDRA version 25.1 has been used for reporting. [ Table B5.1-4 ] Treatment-emergent adverse events leading to ribociclib discontinuation (irrespective of causality) listed by preferred term and worst toxicity grade ( > 0.5% in either group ) [ Table B5.1-5 ] Treatment-emergent adverse events of special concern by group and highest grade (safety analysis set) (> 1% in any group) ET + Riboxili N = 2524 ET N = 2444 AESI Grouping Preferred Terminology All levels n ( % ) Level 3 n ( % ) Level 4 n ( % ) Level 5 n ( % ) All levels n ( % ) Level 3 n ( % ) Level 4 n ( % ) Level 5 n ( % ) Hepatobiliary toxicity 641 (25.4) 166 (6.6) 43 (1.7) 0 (0.0) 260 (10.6) 36 (1.5) 1 (0.0) 0 (0.0) Elevated alanine aminotransferase 478 (18.9) 154 (6.1) 31 (1.2) 0 (0.0) 128 (5.2) 15 (0.6) 1 (0.0) 0 (0.0) Elevated aspartate aminotransferase 408 (16.2) 96 (3.8) 16 (0.6) 0 (0.0) 131 (5.4) 12 (0.5) 0 (0.0) 0 (0.0) Elevated γ-glutamyl transferase 114 (4.5) 24 (1.0) 3 (0.1) 0 (0.0) 63 (2.6) 20 (0.8) 0 (0.0) 0 (0.0) Elevated blood alkaline phosphatase 75 (3.0) 3 (0.1) 0 (0.0) 0 (0.0) 60 (2.5) 2 (0.1) 0 (0.0) 0 (0.0) Elevated hemoglobin 66 (2.6) 4 (0.2) 1 (0.0) 0 (0.0) 27 (1.1) 1 (0.0) 0 (0.0) 0 (0.0) ILD_Pneumonia ​ 39 (1.5) 0 (0.0) 0 (0.0) 0 (0.0) 19 (0.8) 2 (0.1) 0 (0.0) 0 (0.0) Infect 1199 (47.5) 115 (4.6) 9 (0.4) 7 (0.3) 836 (34.2) 67 (2.7) 3 (0.1) 2 (0.1) COVID-19 477 (18.9) 18 (0.7) 0 (0.0) 3 (0.1) 314 (12.8) 11 (0.5) 0 (0.0) 1 (0.0) Urinary tract infection 155 (6.1) 9 (0.4) 0 (0.0) 0 (0.0) 121 (5.0) 5 (0.2) 0 (0.0) 0 (0.0) Nasopharyngitis 121 (4.8) 0 (0.0) 0 (0.0) 0 (0.0) 84 (3.4) 0 (0.0) 0 (0.0) 0 (0.0) Upper respiratory tract infection 118 (4.7) 2 (0.1) 0 (0.0) 0 (0.0) 57 (2.3) 0 (0.0) 0 (0.0) 0 (0.0) Sinusitis 62 (2.5) 0 (0.0) 0 (0.0) 0 (0.0) 38 (1.6) 0 (0.0) 0 (0.0) 0 (0.0) Herpes zoster 58 (2.3) 3 (0.1) 0 (0.0) 0 (0.0) 51 (2.1) 2 (0.1) 0 (0.0) 0 (0.0) Suspected COVID-19 40 (1.6) 1 (0.0) 0 (0.0) 0 (0.0) 21 (0.9) 1 (0.0) 0 (0.0) 0 (0.0) pneumonia 36 (1.4) 12 (0.5) 0 (0.0) 1 (0.0) 18 (0.7) 7 (0.3) 0 (0.0) 0 (0.0) Cystitis 34 (1.3) 0 (0.0) 0 (0.0) 0 (0.0) 24 (1.0) 0 (0.0) 0 (0.0) 0 (0.0) Oral herpes 34 (1.3) 0 (0.0) 0 (0.0) 0 (0.0) 12 (0.5) 0 (0.0) 0 (0.0) 0 (0.0) Cellulitis 33 (1.3) 12 (0.5) 0 (0.0) 0 (0.0) 17 (0.7) 8 (0.3) 0 (0.0) 0 (0.0) influenza 30 (1.2) 2 (0.1) 0 (0.0) 0 (0.0) 20 (0.8) 0 (0.0) 0 (0.0) 0 (0.0) Tooth infection 30 (1.2) 2 (0.1) 0 (0.0) 0 (0.0) 20 (0.8) 0 (0.0) 0 (0.0) 0 (0.0) Bronchitis 29 (1.1) 1 (0.0) 0 (0.0) 0 (0.0) 29 (1.2) 0 (0.0) 0 (0.0) 0 (0.0) Gastroenteritis 29 (1.1) 1 (0.0) 0 (0.0) 0 (0.0) 17 (0.7) 0 (0.0) 0 (0.0) 0 (0.0) Respiratory virus 29 (1.1) 1 (0.0) 0 (0.0) 0 (0.0) 27 (1.1) 0 (0.0) 0 (0.0) 0 (0.0) Conjunctivitis 28 (1.1) 0 (0.0) 0 (0.0) 0 (0.0) 12 (0.5) 0 (0.0) 0 (0.0) 0 (0.0) Mastitis 27 (1.1) 7 (0.3) 0 (0.0) 0 (0.0) 17 (0.7) 4 (0.2) 0 (0.0) 0 (0.0) Myelosuppression - Anemia 209 (8.3) 7 (0.3) 0 (0.0) 0 (0.0) 74 (3.0) 5 (0.2) 1 (0.0) 0 (0.0) Anemia 203 (8.0) 7 (0.3) 0 (0.0) 0 (0.0) 70 (2.9) 5 (0.2) 1 (0.0) 0 (0.0) Myelosuppression - leukopenia 583 (23.1) 193 (7.6) 4 (0.2) 0 (0.0) 110 (4.5) 8 (0.3) 1 (0.0) 0 (0.0) Leukopenia 329 (13.0) 90 (3.6) 0 (0.0) 0 (0.0) 49 (2.0) 2 (0.1) 0 (0.0) 0 (0.0) Low white blood cell count 243 (9.6) 91 (3.6) 1 (0.0) 0 (0.0) 37 (1.5) 5 (0.2) 1 (0.0) 0 (0.0) Lymphocytopenia 65 (2.6) 11 (0.4) 1 (0.0) 0 (0.0) 16 (0.7) 0 (0.0) 0 (0.0) 0 (0.0) Decreased lymphocyte count 59 (2.3) 17 (0.7) 2 (0.1) 0 (0.0) 25 (1.0) 1 (0.0) 0 (0.0) 0 (0.0) Myelosuppression - neutropenia 1568 (62.1) 1054 (41.8) 52 (2.1) 0 (0.0) 110 (4.5) 17 (0.7) 3 (0.1) 0 (0.0) Neutropenia 1034 (41.0) 665 (26.3) 33 (1.3) 0 (0.0) 71 (2.9) 12 (0.5) 1 (0.0) 0 (0.0) Decreased neutrophil count 606 (24.0) 421 (16.7) 19 (0.8) 0 (0.0) 40 (1.6) 5 (0.2) 2 (0.1) 0 (0.0) Myelosuppression - thrombocytopenia 161 (6.4) 6 (0.2) 0 (0.0) 0 (0.0) 53 (2.2) 2 (0.1) 1 (0.0) 0 (0.0) Thrombocytopenia 110 (4.4) 5 (0.2) 0 (0.0) 0 (0.0) 43 (1.8) 0 (0.0) 1 (0.0) 0 (0.0) Decreased platelet count 52 (2.1) 1 (0.0) 0 (0.0) 0 (0.0) 10 (0.4) 2 (0.1) 0 (0.0) 0 (0.0) QT interval prolongation 132 (5.2) 23 (0.9) 1 (0.0) 1 (0.0) 30 (1.2) 13 (0.5) 0 (0.0) 0 (0.0) Prolonged QT interval on electrocardiogram 106 (4.2) 5 (0.2) 0 (0.0) 0 (0.0) 16 (0.7) 1 (0.0) 0 (0.0) 0 (0.0) Renal toxicity 144 (5.7) 6 (0.2) 1 (0.0) 0 (0.0) 49 (2.0) 0 (0.0) 0 (0.0) 0 (0.0) Increased serum creatinine 91 (3.6) 2 (0.1) 0 (0.0) 0 (0.0) 21 (0.9) 0 (0.0) 0 (0.0) 0 (0.0) Decreased glomerular filtration rate 40 (1.6) 2 (0.1) 0 (0.0) 0 (0.0) 9 (0.4) 0 (0.0) 0 (0.0) 0 (0.0) Elevated blood urea 26 (1.0) 0 (0.0) 0 (0.0) 0 (0.0) 24 (1.0) 0 (0.0) 0 (0.0) 0 (0.0) Reproductive toxicity 32 (1.3) 8 (0.3) 0 (0.0) 0 (0.0) 25 (1.0) 5 (0.2) 0 (0.0) 0 (0.0) Mastitis 27 (1.1) 7 (0.3) 0 (0.0) 0 (0.0) 17 (0.7) 4 (0.2) 0 (0.0) 0 (0.0) Second primary malignancy 46 (1.8) 25 (1.0) 3 (0.1) 0 (0.0) 45 (1.8) 20 (0.8) 8 (0.3) 0 (0.0) - AESI categories are listed in alphabetical order; preferred terms are sorted in decreasing frequency within the AESI category for the ET + Ribociclib group. - AESIs may belong to more than one category, but each AESI category is reported only once. - MedDRA version 25.1 has been used for reporting. - AESI grouping is based on the eCRS (version date December 16, 2022). [ Table B5.1-7 ] Comprehensive summary of death (safety analysis set) Number of patients ET + Riboxili N = 2524 ET N = 2444 Total N = 4968 Total number of deaths 60 (2.4) 74 (3.0) 134 (2.7) Main cause of death Disease recurrence/progression 41 (1.6) 61 (2.5) 102 (2.1) Adverse Events 13 (0.5) 4 (0.2) 17 (0.3) Covid-19 3 (0.1) 1 (0.0) 4 (0.1) Covid-19 pneumonia 3 (0.1) 0 3 (0.1) Acute myocardial infarction 1 (0.0) 0 1 (0.0) Brain edema 1 (0.0) 0 1 (0.0) Cardiac arrest 1 (0.0) 0 1 (0.0) Cardiogenic shock 1 (0.0) 0 1 (0.0) pneumonia 1 (0.0) 0 1 (0.0) Pulmonary embolism 1 (0.0) 0 1 (0.0) Road traffic accidents 1 (0.0) 0 1 (0.0) Congestive heart failure 0 1 (0.0) 1 (0.0) Myocardial infarction 0 1 (0.0) 1 (0.0) Pseudotoxin 0 1 (0.0) 1 (0.0) other 6 (0.2) 9 (0.4) 15 (0.3) Six patients who died from COVID 19 were not vaccinated. One patient in the ET + Riboxil group was vaccinated. [ Table B5.1-8 ] Summary of deaths during treatment (safety analysis set) Number of patients ET + Riboxili N = 2524 ET N = 2444 Total N = 4968 Number of patients who died during treatment 19 (0.8) 9 (0.4) 28 (0.6) Main cause of death Disease recurrence/progression 7 (0.3) 4 (0.2) 11 (0.2) Adverse Events 12 (0.5) 4 (0.2) 16 (0.3) Covid-19 3 (0.1) 1 (0.0) 4 (0.1) Covid-19 pneumonia 3 (0.1) 0 3 (0.1) Brain edema 1 (0.0) 0 1 (0.0) Cardiac arrest 1 (0.0) 0 1 (0.0) Cardiogenic shock 1 (0.0) 0 1 (0.0) pneumonia 1 (0.0) 0 1 (0.0) Pulmonary embolism 1 (0.0) 0 1 (0.0) Road traffic accidents 1 (0.0) 0 1 (0.0) Congestive heart failure 0 1 (0.0) 1 (0.0) Myocardial infarction 0 1 (0.0) 1 (0.0) Septicemia 0 1 (0.0) 1 (0.0) other 0 1 (0.0) 1 (0.0) Six patients who died from COVID 19 were not vaccinated. One patient in the ET + Riboxil group was vaccinated. 5.2 Laboratory Data (r) Table B5.2-1 Worst Treatment Period CTCAE Grade of Hematology Laboratory Data (Safety Analysis Set) ET + Riboxili N = 2524 ET N = 2444 Parameters 1/2 level n ( % ) Level 3 n ( % ) Level 4 n ( % ) 1/2 level n ( % ) Level 3 n ( % ) Level 4 n ( % ) Activated partial thromboplastin time (sec) is high 9 (0.4) 0 0 8 (0.3) 0 0 Hemoglobin (g/L) is high 90 (3.6) 14 (0.6) 0 152 (6.2) 18 (0.7) 0 Hemoglobin (g/dL) is low 1156 (45.8) 11 (0.4) 0 611 (25.0) 6 (0.3) 0 White blood cell (10E9/L) is high 0 49 (1.9) 0 0 32 (1.3) 0 White blood cell (10E9/L) is low 1718 (68.1) 678 (26.9) 9 (0.4) 1091 (44.6) 13 (0.5) 3 (0.1) Lymphocytes (10E9/L) high level 33 (1.3) 74 (2.9) 0 56 (2.3) 62 (2.5) 0 Lymphocytes (10E9/L) low level 1967 (77.9) 404 (16.0) 84 (3.3) 1990 (81.4) 95 (3.9) 65 (2.7) Neutrophils (10E9/L) low level 1235 (48.9) 1071 (42.4) 55 (2.2) 807 (33.0) 34 (1.4) 7 (0.3) Platelets (10E9/L) are low 696 (27.6) 9 (0.4) 2 (0.1) 307 (12.6) 7 (0.3) 1 (0.0) Prothrombin international normalized ratio (sec) is high 5 (0.2) 1 (0.0) 0 3 (0.1) 2 (0.1) 0 - Baseline was defined as the last nonmissing value before the start date of study treatment. - Percentages were determined based on N. - Patients were counted only for the worst grade observed after baseline. - Laboratory assessments performed more than 30 days after the last study treatment dose date were not summarized. - CTCAE version 4.03 was used for reporting. (s) Table B5.2-2 Worst CTCAE grade during treatment for biochemical laboratory data (safety analysis set) ET + Riboxili N = 2524 ET N = 2444 Parameters 1/2 level n ( % ) Level 3 n ( % ) Level 4 n ( % ) 1/2 level n ( % ) Level 3 n ( % ) Level 4 n ( % ) Alanine aminotransferase (IU/L) is high 900 (35.7) 161 (6.4) 37 (1.5) 817 (33.4) 23 (0.9) 1 (0.0) Albumin (g/dL) low level 178 (7.1) 14 (0.6) 0 138 (5.7) 8 (0.3) 0 Alkaline phosphatase (IU/L) is high 882 (34.9) 4 (0.2) 0 875 (35.8) 5 (0.2) 0 Amylase (IU/L) High 346 (13.7) 24 (1.0) 8 (0.3) 326 (13.3) 32 (1.3) 2 (0.1) Aspartate aminotransferase (IU/L) high 952 (37.7) 108 (4.3) 19 (0.8) 761 (31.1) 26 (1.1) 1 (0.0) Bilirubin (μmol/L) High 226 (9.0) 7 (0.3) 2 (0.1) 231 (9.5) 1 (0.0) 0 Corrected calcium (mmol/L) high 244 (9.7) 5 (0.2) 11 (0.4) 338 (13.8) 9 (0.4) 21 (0.9) Corrected Calcium (mmol/L) Low 494 (19.6) 6 (0.2) 32 (1.3) 369 (15.1) 8 (0.3) 39 (1.6) Creatinine (mg/dL) is high 797 (31.6) 9 (0.4) 2 (0.1) 267 (10.9) 0 1 (0.0) Direct bilirubin (μmol/L) High 442 (17.5) 27 (1.1) 11 (0.4) 420 (17.2) 16 (0.7) 4 (0.2) γ-Glucosyltransferase (IU/L) high level 857 (34.0) 85 (3.4) 8 (0.3) 748 (30.6) 82 (3.4) 5 (0.2) Glomerular filtration rate (mL/min/1.73m2) is low 1038 (41.1) 14 (0.6) 8 (0.3) 651 (26.6) 4 (0.2) 5 (0.2) Glucose (mmol/L) is high 1452 (57.5) 45 (1.8) 27 (1.1) 1381 (56.5) 34 (1.4) 23 (0.9) Glucose (mmol/L) is low 219 (8.7) 3 (0.1) 21 (0.8) 163 (6.7) 1 (0.0) 22 (0.9) Lipase (IU/L) is high 385 (15.3) 62 (2.5) 12 (0.5) 384 (15.7) 66 (2.7) 11 (0.5) Magnesium (mmol/L) High 83 (3.3) 28 (1.1) 1 (0.0) 100 (4.1) 26 (1.1) 2 (0.1) Magnesium (mmol/L) Low level 380 (15.1) 4 (0.2) 5 (0.2) 368 (15.1) 0 11 (0.5) Phosphate (mmol/L) Low level 190 (7.5) 12 (0.5) 6 (0.2) 162 (6.6) 11 (0.5) 2 (0.1) Potassium (mmol/L) High 346 (13.7) 15 (0.6) 2 (0.1) 372 (15.2) 14 (0.6) 6 (0.3) Potassium (mmol/L) low level 257 (10.2) 14 (0.6) 8 (0.3) 201 (8.2) 21 (0.9) 14 (0.6) Sodium (mmol/L) High 264 (10.5) 3 (0.1) 1 (0.0) 281 (11.5) 2 (0.1) 0 Sodium (mmol/L) low level 258 (10.2) 24 (1.0) 7 (0.3) 220 (9.0) 16 (0.7) 10 (0.4) Uric acid (mg/dL) is high 756 (30.0) 0 42 (1.7) 693 (28.4) 0 49 (2.0) - Baseline was defined as the last nonmissing value before the start date of study treatment. - Percentages were determined based on N. - Patients were counted only for the worst grade observed after baseline. - Laboratory assessments performed more than 30 days after the last study treatment dose date were not summarized. - CTCAE version 4.03 was used for reporting. (t) Table B5.2-3 Liver function parameters (safety analysis set) Riboxil + ET N = 2524 n/m （ % ） ET N = 2444 n /m ( % ) ALT or AST ＞ 3*ULN and TBL ＞ 2*ULN 14/2504 (0.6%) 1/2386 (0.0%) Biochemical Hy's rule: ALT or AST ＞ 3*ULN and TBL ＞ 2*ULN and ALP ＜ 2*ULN 8/2496 (0.3%) 1/2378 (0.0%) - Biochemical Hy's rule based on individual abnormalities occurring simultaneously at the same study visit - ALP: alkaline phosphatase - ALT: alanine aminotransferase - AST: aspartate aminotransferase - TBL: total bilirubin - ULN: upper limit of normal - Based on the worst treatment period value according to the Novartis AG Hepatotoxicity Guideline. - n: number of subjects meeting the specified criteria. - m: number of subjects with a specific category of risk. This is the number of patients with a non-missing value at baseline and at least one non-missing post-baseline value. - N: total number of patients in the treatment group in this analysis set. 5.3 Significant ECG values (u) Table B0.3-1 Significant ECG values - central assessment (safety analysis set) ECG values ET + Riboxil N = 2524 n/m （ % ） ET N = 2444 n /m ( % ) Total N = 4968 n/m ( % ) QTcF interval New value > 450 238/2489 (9.6) 66/2367 (2.8) 304/4856 (6.3) New value > 480 10/2505 (0.4) 4/2380 (0.2) 14/4885 (0.3) New value > 500 3/2505 (0.1) 1/2380 (0.0) 4/4885 (0.1) Increase relative to baseline> 30 476/2505 (19.0) 179/2380 (7.5) 655/4885 (13.4) Increase relative to baseline> 60 19/2505 (0.8) 2/2380 (0.1) 21/4885 (0.4) - Patients were counted based on any significant ECG post-baseline value. - ECG assessments were performed based on central laboratory results only. - Baseline was defined as the last assessment on or before the day of study treatment initiation. For any replicate/triplicate ECG at each time point, the mean of these measurements was calculated as baseline. - n: number of subjects meeting the specified criteria. - m: number of subjects with a specific category of risk. For new post-baseline abnormalities, this is the number of patients who had both baseline and post-baseline evaluations and did not meet the criteria at baseline. For abnormal changes from baseline, it refers to the number of patients who had both baseline and post-baseline evaluations. - N: total number of subjects in the treatment group in this analysis set. Appendix (v) Table B14.2-1.1 Follow-up duration from randomization to data cutoff (full analysis set) Total N = 5101 n ( % ) Tracking duration 0-3 months 308 (6.0) 3-6 months 86 (1.7) 6-12 months 114 (2.2) 12-18 months 78 (1.5) 18-24 months 705 (13.8) 24-30 months 1083 (21.2) 30-36 months 1401 (27.5) 36-42 months 1215 (23.8) 42-48 months 110 (2.2) 48-54 months 1 (0.0) Tracking duration n 5101 average value 29.0 SD 10.57 Minimum 0 Median 30.6 Maximum 48 Randomization (recruitment) phase 27.33 Duration between randomization and data cutoff date n 5101 average value 32.6 SD 5.97 Minimum twenty one Median 34.0 Maximum 48 - Follow-up duration is calculated as {min(cut-off date, death date, study exit date)-randomization date + 1}/30.4375 (months). - Randomization (recruitment) period = (last patient randomization date-first patient randomization date + 1)/30.4375 (months). - Duration between randomization and data cut-off date = (cut-off date-randomization date + 1)/30.4375 (months) (w) Table B14.2-1.2 Duration of iDFS tracking (full analysis set) Total N = 5101 n ( % ) Tracking duration 0-3 months 416 (8.2) 3-6 months 95 (1.9) 6-12 months 150 (2.9) 12-18 months 176 (3.5) 18-24 months 915 (17.9) 24-30 months 1171 (23.0) 30-36 months 1581 (31.0) 36-42 months 572 (11.2) 42-48 months 25 (0.5) Tracking duration n 5101 average value 25.97 SD 10.715 Minimum 0.0 Median 27.70 Maximum 45.1 - Follow-up duration was calculated as (date of event or last appropriate recurrence assessment - randomization date + 1)/30.4375 (months). (x) Table B14.2-1.3 OS follow-up duration (full analysis set)

without

[Figure 1] provides a schematic diagram of the study design of the NATALEE clinical trial.

[Figure 2] shows the simulated ANC mean curves for 3-week dosing/1-week rest of ribociclib 200 mg, 400 mg and 600 mg QD; the mean ANC curves were predicted by the ANC exposure-response model developed based on data from studies CLEE011X2101, CLEE011X1101, CLEE011X2107, CLEE011A2301, CLEE011E2301 and CLEE011F2301.

[Figure 3] provides a schematic diagram of the inclusion of patients according to anatomical stage groups in the NATALEE clinical trial.

[Figure 4] provides a schematic diagram of ECG and PK associated with drug administration (C1D15).

[Figure 5] shows a questionnaire used, for example, to assess quality of life and healthcare resource utilization (i.e., EORTC QLQ-C30).

[Figure 6] shows a questionnaire used, for example, to assess quality of life and healthcare resource utilization (i.e., EORTC QLQ-BR23).

[Figure 7] shows a questionnaire used to assess, for example, quality of life and healthcare resource utilization (i.e., EQ-5D-5L).

[Figure 8] shows a questionnaire used to assess, for example, quality of life and healthcare resource utilization (i.e., the Hospital Anxiety and Depression Scale (HADS)).

[ Fig. 9 ] shows the Kaplan-Meier Plot of primary invasive disease-free survival analysis (full analysis set).

[Figure 10] Forest plot of (q) iDFS (full analysis set) by stratum (per eCRF).

[ Fig. 11A ] shows the forest plot of iDFS-subgroup analysis.

[ Fig. 11B ] shows the forest plot of iDFS-subgroup analysis.

[ Fig. 11C ] shows the forest plot of iDFS-subgroup analysis.

[ Fig. 11D ] shows the forest plot of iDFS-subgroup analysis.

[ Fig. 12 ] The iDFS-Kaplan-Meier survival curves of iDFS according to II anatomical stage (eCRF layer) are shown (full analysis set).

[ Fig. 13 ] The iDFS-Kaplan-Meier survival curves of iDFS according to III anatomical stage (eCRF layer) are shown (full analysis set).

[Figure 14] shows the Kaplan-Meyer curve of RFS (full analysis set).

[Figure 15] shows the Kaplan-Meyer curve of DDFS (full analysis set).

[ Fig. 16 ] shows the Kaplan-Meier curve of OS (full analysis set).

without

Claims (372)

A method for treating HR+/HER2- stage II or stage III early breast cancer in an adult patient in need thereof, the method comprising administering to the patient a treatment comprising a dose ranging from 150 mg/day to 450 mg/day of riboxil, its free base form or a pharmaceutically acceptable salt thereof on days 1-21 of a 28-day cycle in combination with an aromatase inhibitor administered daily in a 28-day cycle, the aromatase inhibitor preferably being letrozole or anastrozole. A method for preventing or alleviating the signs or symptoms of early breast cancer, the method comprising administering to the patient a treatment comprising ribociclib, its free base form or a pharmaceutically acceptable salt thereof, in combination with an aromatase inhibitor, preferably letrozole or anastrozole. The method of claim 2, wherein the reboxil, its free base form or a pharmaceutically acceptable salt thereof is administered to the patient at a dose ranging from 150 mg/day to 450 mg/day on days 1 to 21 of a 28-day cycle. The method of claim 2 or 3, wherein the aromatase inhibitor is administered on each day of the 28-day cycle. A method for preventing or alleviating the signs or symptoms of early breast cancer, the method comprising administering to the patient a treatment comprising a dose ranging from 150 mg/day to 450 mg/day of ribociclib, its free base form or a pharmaceutically acceptable salt thereof on days 1-21 of a 28-day cycle in combination with an aromatase inhibitor administered daily in a 28-day cycle, the aromatase inhibitor preferably being letrozole or anastrozole. The method of any one of claims 1 to 5, wherein the patient is in remission from HR+/HER2- stage II or stage III early breast cancer. A method of maintaining remission in an adult patient previously diagnosed with HR+/HER2- stage II or III early breast cancer, the method comprising administering to the patient a treatment comprising a dose of riboxil, its free base form or a pharmaceutically acceptable salt thereof, in combination with an aromatase inhibitor, preferably letrozole or anastrozole. The method of claim 6 or claim 7, wherein the relief is complete relief. The method of claim 6 or claim 7, wherein the relief is partial relief. The method of any one of claims 1 to 9, wherein the treatment reduces recurrence of HR+/HER2- stage II or stage III early breast cancer. The method of claim 10, wherein the treatment prevents recurrence for at least 3 months. The method of claim 11, wherein the treatment prevents recurrence for at least 6 months. The method of claim 12, wherein the treatment prevents recurrence for at least 1 year. The method of any one of claims 1 to 13, wherein the patient had no signs or symptoms of cancer prior to receiving the treatment. The method of any one of claims 1 to 14, wherein the treatment prevents the growth of HR+/HER2- breast cancer cells. The method of any one of claims 1 to 15, wherein the treatment is adjunctive therapy. The method of any one of claims 1 to 16, wherein the reboxili is a pharmaceutically acceptable reboxili salt. The method as described in claim 17, wherein the reboxili salt is reboxili succinate. The method of any one of claims 1 to 18, wherein the dose of riboxil is 200 mg/day or 400 mg/day. The method of any one of claims 1 to 18, wherein the reboxil is not administered at a dose of 600 mg/day. The method of any one of claims 1 to 19, wherein reboxili is administered in the form of reboxili succinate, and the total dose of reboxili is 200 mg/day. The method of any one of claims 1 to 19, wherein reboxili is administered in the form of reboxili succinate, and the total dose of reboxili is 400 mg/day. The method of any one of claims 1 to 19, wherein the reboxil is administered at a dose of 400 mg/day for a period of time, followed by administration of 200 mg/day of reboxil. The method of any one of claims 1 to 23, wherein the dose of Riboxil is administered orally. The method of any one of claims 1 to 24, wherein the dose of riboxil is administered in the form of a tablet. The method of any one of claims 1 to 24, wherein the aromatase inhibitor is letrozole or anastrozole. The method of any one of claims 1 to 26, wherein the aromatase inhibitor is administered orally. The method of claim 26 or 27, wherein the letrozole is administered in an amount ranging from 1 mg/day to 4 mg/day. The method of claim 28, wherein the letrozole is administered in a dosage of 2.5 mg/day. The method of claim 26 or 27, wherein the anastrozole is administered in an amount ranging from 0.5 mg/day to 1.5 mg/day. The method of claim 30, wherein the anastrozole is administered in a dose of 1 mg/day. The method of any one of claims 1 to 31, wherein the treatment comprises a gonadotropin-releasing hormone agonist. The method of claim 32, wherein the gonadotropin-releasing hormone agonist is goserelin. The method of claim 33, wherein the goserelin is administered in an amount ranging from 2 mg to 5 mg. The method of claim 34, wherein the dose of goserelin is 3.6 mg. The method of any one of claims 33 to 35, wherein the goserelin is administered subcutaneously. The method of any one of claims 33 to 36, wherein the goserelin is administered once every 4 weeks. The method of any one of claims 1 to 31, wherein the patient is a postmenopausal female. The method of any one of claims 1 to 37, wherein the patient is a premenopausal female or male. The method of any one of claims 1 to 39, wherein the treatment is administered to the patient for at least 12 months. The method of claim 40, wherein the treatment is administered to the patient for at least 24 months. The method of claim 40 or claim 41, wherein the treatment is administered to the patient for at least 36 months. The method of any one of claims 40 to 41, wherein the treatment is administered to the patient for at least 48 months. The method of any one of claims 40 to 41, wherein the treatment is administered to the patient for at least 60 months. The method of any one of claims 1 to 44, wherein the treatment continues until the patient is free of detectable cancer. The method of any one of claims 1 to 45, wherein the breast cancer is ER+ and PR+. The method of any one of claims 1 to 45, wherein the breast cancer is ER- and PR+. The method of any one of claims 1 to 45, wherein the breast cancer is ER+ and PR-. The method of any one of claims 1 to 48, wherein the histological subtype of the breast cancer is a ductal subtype or the histological subtype of the breast cancer is a lobular subtype. The method of any one of claims 1 to 49, wherein the breast cancer is stage IIA cancer or stage IIB cancer. The method of claim 50, wherein the breast cancer is stage IIA cancer. The method of claim 50, wherein the breast cancer is stage IIB cancer. The method of any one of claims 1 to 49, wherein the breast cancer is stage IIIA cancer, stage IIIB cancer, or stage IIIC cancer. The method of claim 53, wherein the breast cancer is stage IIIA cancer. The method of claim 53, wherein the breast cancer is stage IIIB cancer. The method of claim 53, wherein the breast cancer is stage IIIC cancer. The method of any one of claims 1 to 56, wherein the treatment is administered without regard to the lymph node status of the breast cancer. The method of any one of claims 1 to 57, wherein the breast cancer has a lymph node status selected from N0, N1, N2 and N3. The method of claim 57 or 58, wherein the breast cancer has a lymph node status of N0. The method of claim 57 or 58, wherein the breast cancer has a lymph node status of N1 to N3. The method of claim 57 or 58, wherein the breast cancer has a lymph node status of N1. The method of claim 57 or 58, wherein the breast cancer has a lymph node status of N2. The method of claim 57 or 58, wherein the breast cancer has a lymph node status of N3. The method of any one of claims 1 to 63, wherein the breast cancer comprises one or more cells having a histological grade selected from G1, G2 or G3. The method of claim 64, wherein the breast cancer comprises one or more cells having a G1 histological grade. The method of claim 64, wherein the breast cancer comprises one or more cells having a G2 histological grade. The method of claim 64, wherein the breast cancer comprises one or more cells having a G3 histological grade. The method of any one of claims 1 to 67, wherein the breast cancer comprises a tumor classified as T0, T1, T2, T3 or T4. The method of claim 68, wherein the breast cancer comprises a tumor classified as T1, T2, or T3. The method of claim 68, wherein the breast cancer comprises a T0 classification tumor. The method of claim 68 or 69, wherein the breast cancer comprises a T1 classification tumor. The method of claim 68 or 69, wherein the breast cancer comprises a T2 classification tumor. The method of claim 68 or 69, wherein the breast cancer comprises a T3 tumor. The method of claim 68, wherein the breast cancer comprises a T4 tumor. The method of any one of claims 1 to 74, wherein the breast cancer has a Ki67 status of 20 or less. The method of any one of claims 1 to 74, wherein the breast cancer has a Ki67 status greater than 20. The method of any one of claims 1 to 76, wherein prior to the administration, the patient has received a loading dose of (i) riboxil and/or (ii) endocrine therapy. The method of any one of claims 1 to 77, wherein the patient has received at least one prior treatment for cancer. The method of claim 78, wherein the prior treatment is an adjunct to another prior treatment. The method of claim 78 or 79, wherein the prior treatment was surgery. The method of claim 80, wherein the surgery comprises complete surgical resection of the cancer. The method of claim 80 or 81, wherein the surgery is a mastectomy. The method of claim 80 or 81, wherein the prior treatment is chemotherapy. The method of claim 83, wherein the prior treatment is adjuvant chemotherapy. The method of claim 83, wherein the prior treatment is neoadjuvant chemotherapy. The method of claim 78 or 79, wherein the prior treatment is endocrine therapy. The method of claim 78 or 79, wherein the prior treatment is radiation therapy. The method of any one of claims 78 to 87, wherein the patient is unresponsive to the prior treatment. The method of any one of claims 1 to 88, wherein the patient is located in a geographic region selected from North America, Western Europe, or Oceania. The method of any one of claims 1 to 89, wherein the patient is Asian. The method of any one of claims 1 to 90, wherein the patient is 18 to 45 years old. The method of any one of claims 1 to 90, wherein the patient is 45 to 54 years old. The method of any one of claims 1 to 90, wherein the patient is 54 to 64 years old. The method of any one of claims 1 to 90, wherein the patient is older than 64 years old. The method of any one of claims 1 to 94, wherein the patient has a BMI of 25 or greater. The method of any one of claims 1 to 94, wherein the patient has a BMI less than 25. The method of any one of claims 1 to 96, wherein the treatment improves the patient's condition relative to patients not receiving the treatment and/or relative to the patient's condition before the treatment. The method of any one of claims 1 to 97, wherein the treatment reduces the risk of invasive disease. The method of claim 98, wherein the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than 1 when the risk is calculated relative to patients not receiving the treatment. The method of claim 99, wherein the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than or equal to 0.78 when the risk is calculated relative to patients not receiving the treatment. The method of any one of claims 1 to 37 and 39 to 100, wherein the patient is a premenopausal female or male and the treatment reduces the risk of the invasive disease corresponding to a hazard ratio of less than or equal to 0.72 when the risk is calculated relative to patients not receiving the treatment. The method of any of claims 98 to 100, wherein the patient has HR+/HER2- stage III early breast cancer and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than or equal to 0.74 when the risk is calculated relative to patients not receiving the treatment. The method of any of claims 98 to 100, wherein the patient has HR+/HER2- stage II early breast cancer and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than or equal to 0.76 when the risk is calculated relative to patients not receiving the treatment. The method of any one of claims 98 to 100, wherein the patient has HR+/HER2- stage III early breast cancer and the treatment reduces the risk of invasive disease by at least 25%, corresponding to a hazard ratio of 0.75 when the risk is calculated relative to patients not receiving the treatment. The method of any one of claims 1 to 104, wherein the treatment reduces the risk of invasive disease to similar levels in subgroups of patients including patients with stage II early breast cancer, patients with stage III early breast cancer, premenopausal female or male patients, and postmenopausal female patients. The method of any one of claims 1 to 105, wherein the treatment does not result in a reduction in overall survival corresponding to a hazard ratio of 0.76 when the risk is calculated relative to patients not receiving the treatment. The method of any one of claims 1 to 106, wherein the treatment reduces and/or prevents one or more of the risk of cancer recurrence, cancer spread, additional cancer development and/or growth, and death from cancer. The method of claim 107, wherein the treatment reduces cancer recurrence, wherein the recurrence is one or more of invasive ipsilateral breast tumor (IBTR) recurrence, loco-regional invasive recurrence, and distant recurrence. The method of claim 107 or claim 108, wherein the treatment reduces cancer spread, wherein the cancer spread is invasive contralateral breast cancer or another primary invasive cancer. The method of any one of claims 1 to 109, wherein the treatment prevents death from cancer. A method of maintaining remission in an adult patient previously diagnosed with HR+/HER2- stage II or stage III early breast cancer, the method comprising administering to the patient a treatment comprising a dose ranging from 150 mg/day to 450 mg/day of riboxil, its free base form or a pharmaceutically acceptable salt thereof on days 1-21 of a 28-day cycle in combination with an aromatase inhibitor administered daily in a 28-day cycle, preferably letrozole or anastrozole. A method for preventing recurrence of breast cancer in adult patients, the method comprising providing adjuvant therapy to a patient who has received prior treatment for HR+/HER2- stage II or stage III early breast cancer, wherein the adjuvant therapy comprises administering to the patient 400 mg of riboxil or a pharmaceutically acceptable salt thereof on days 1 to 21 of a 28-day cycle for at least 36 months, in combination with an aromatase inhibitor as defined in any of claims 26 to 31 administered daily during the 28-day cycle. The method of claim 112, wherein the prior treatment was surgical resection of the cancer. Reboxil or a pharmaceutically acceptable salt thereof and an aromatase inhibitor are used in a method for treating HR+/HER2- stage II or stage III early breast cancer in adult patients, wherein the method is a method as described in any one of claims 1 to 112. Use of ribociclib or a pharmaceutically acceptable salt thereof and an aromatase inhibitor in the manufacture of a medicament for treating HR+/HER2- stage II or stage III early breast cancer in adult patients, wherein the medicament is administered by the method described in any one of claims 1 to 112. A kit for use in performing a method of treating HR+/HER2- stage II or stage III early breast cancer in an adult patient as described in any one of claims 1 to 112. A method for treating HR+/HER2- stage II or stage III early breast cancer in an adult patient in remission, the method comprising administering to the adult patient a combination of riboxil and an aromatase inhibitor, whereby the administration maintains remission in the adult patient for at least 3 months. A method for treating HR+/HER2- stage II or III early breast cancer in an adult patient, the method comprising providing adjuvant treatment by administering a combination of riboxil and an aromatase inhibitor, wherein the patient is in complete remission at the start of the adjuvant treatment, and the administration of the combination of riboxil and the aromatase inhibitor maintains the adult patient in complete remission for at least 3 months. The method of claim 117 or 118, wherein the administration maintains complete remission in the adult patient for at least 6 months. The method of claim 117 or 118, wherein the administration maintains complete remission in the adult patient for at least 9 months. The method of claim 117 or 118, wherein the administration maintains complete remission in the adult patient for at least 12 months. The method of claim 117 or 118, wherein the administration maintains complete remission in the adult patient for at least 15 months. The method of claim 117 or 118, wherein the administration maintains complete remission in the adult patient for at least 18 months. The method of claim 117 or 118, wherein the administration maintains complete remission in the adult patient for at least 21 months. The method of claim 117 or 118, wherein the administration maintains complete remission in the adult patient for at least 24 months. The method of claim 117 or 118, wherein the administration maintains complete remission in the adult patient for at least 27 months. The method of claim 117 or 118, wherein the administration maintains complete remission in the adult patient for at least 30 months. The method of claim 117 or 118, wherein the administration maintains complete remission in the adult patient for at least 33 months. The method of claim 117 or 118, wherein the administration maintains complete remission in the adult patient for at least 36 months. The method of any one of claims 117 to 129, wherein reboxil and the aromatase inhibitor are administered for a duration of treatment and the administration maintains the adult patient in complete remission for at least the duration of treatment. The method of any one of claims 117 to 129, wherein 400 mg of riboxil is orally administered once daily on days 1-21 of a 28-day cycle, and the aromatase inhibitor is administered once daily on each day of the 28-day cycle. The method of any one of claims 117 to 129, wherein 400 mg of riboxil is orally administered once daily on days 1-21 of a 28-day cycle for up to three years, and the aromatase inhibitor is administered once daily on each day of the 28-day cycle for up to three years. The method of any one of claims 117 to 129, wherein 400 mg of riboxil is orally administered once daily on days 1-21 of a 28-day cycle for up to five years, and the aromatase inhibitor is administered once daily on each day of the 28-day cycle for up to five years. The method of any one of claims 117 to 133, wherein the pharmaceutically acceptable salt of riboxil is orally administered in an amount equivalent to 400 mg of riboxil. The method of claim 134, wherein the pharmaceutically acceptable salt is reboxili succinate. The method of any one of claims 117 to 135, wherein the adult patient has never been treated with 600 mg of riboxili. The method of any one of claims 117 to 136, wherein the adult patient has never been diagnosed with HR+/HER2- advanced or metastatic breast cancer. The method of any one of claims 117 to 137, wherein reboxil and an aromatase inhibitor are administered as adjunctive therapy. The method of any one of claims 117 to 138, wherein the reboxil is not administered at a dose of 600 mg/day. The method of any one of claims 117 to 139, wherein the dose of riboxil is administered in the form of a tablet. The method of any one of claims 117 to 139, wherein two tablets are orally administered to the adult patient once daily on days 1 to 21 of a 28-day cycle, repeated during the treatment duration, and each tablet contains an amount of a pharmaceutically acceptable salt of riboxili equivalent to 200 mg of riboxili. The method of claim 141, wherein the reboxili salt is reboxili succinate. The method of any one of claims 117 to 142, wherein the aromatase inhibitor is letrozole. The method of any one of claims 117 to 142, wherein the aromatase inhibitor is anastrozole. The method of any one of claims 117 to 144, wherein the aromatase inhibitor is letrozole, and the letrozole is administered in an amount ranging from 1 mg to 4 mg once daily. The method of any one of claims 117 to 144, wherein the aromatase inhibitor is letrozole, and the letrozole is administered in a dose of 2.5 mg once daily. The method of any one of claims 117 to 144, wherein the aromatase inhibitor is anastrozole, and the anastrozole is administered in an amount ranging from 0.5 mg once daily to 1.5 mg once daily. The method of any one of claims 117 to 144, wherein the aromatase inhibitor is anastrozole, and the anastrozole is administered in a dose of 1 mg once daily. The method of any one of claims 117 to 148, further comprising administering a gonadotropin-releasing hormone agonist to the adult patient. The method of claim 149, wherein the gonadotropin-releasing hormone agonist is goserelin. The method of claim 150, wherein the goserelin is administered in an amount ranging from 2 mg to 5 mg. The method of claim 151, wherein the dose of goserelin is 3.6 mg. The method of any one of claims 150 to 152, wherein the goserelin is administered subcutaneously. The method of any one of claims 150 to 153, wherein the goserelin is administered once every 4 weeks. The method of any one of claims 117 to 148, wherein the patient is a postmenopausal female. The method of any one of claims 117 to 154, wherein the patient is a premenopausal female or male. The method of any one of claims 117 to 156, wherein the histological subtype of the breast cancer is a ductal subtype or the histological subtype of the breast cancer is a lobular subtype. The method of any one of claims 117 to 156, wherein the breast cancer is stage IIA cancer or stage IIB cancer. The method of any one of claims 117 to 156, wherein the breast cancer is stage IIA cancer. The method of any one of claims 117 to 156, wherein the breast cancer is stage IIB cancer. The method of any one of claims 117 to 156, wherein the breast cancer is stage IIIA cancer, stage IIIB cancer, or stage IIIC cancer. The method of any one of claims 117 to 156, wherein the breast cancer is stage IIIA cancer. The method of any one of claims 117 to 156, wherein the breast cancer is stage IIIB cancer. The method of any one of claims 117 to 156, wherein the breast cancer is stage IIIC cancer. The method of any one of claims 117 to 156, wherein the treatment is administered without regard to the lymph node status of the breast cancer. The method of any one of claims 117 to 156, wherein treatment with riboxil and an aromatase inhibitor is not adjusted based on the lymph node status of the early stage breast cancer. The method of any one of claims 117 to 156, wherein the breast cancer has a lymph node status selected from N0, N1, N2 and N3. The method of any one of claims 117 to 156, wherein the breast cancer has a lymph node status of N0. The method of any one of claims 117 to 156, wherein the breast cancer has a lymph node status of N1-N3. The method of any one of claims 117 to 156, wherein the breast cancer has a lymph node status of N1. The method of any one of claims 117 to 156, wherein the breast cancer has a lymph node status of N2. The method of any one of claims 117 to 156, wherein the breast cancer has a lymph node status of N3. The method of any one of claims 117 to 156, wherein the breast cancer comprises one or more cells having a histological grade selected from G1, G2 or G3. The method of any one of claims 117 to 156, wherein the breast cancer comprises one or more cells having a G1 histological grade. The method of any one of claims 117 to 156, wherein the breast cancer comprises one or more cells having a G2 histological grade. The method of any one of claims 117 to 156, wherein the breast cancer comprises one or more cells having a G3 histological grade. The method of any one of claims 117 to 156, wherein the breast cancer comprises a tumor classified as T0, T1, T2, T3 or T4. The method of any one of claims 117 to 156, wherein the breast cancer comprises a tumor classified as T1, T2, or T3. The method of any one of claims 117 to 156, wherein the breast cancer comprises a tumor classified as T0. The method of any one of claims 117 to 156, wherein the breast cancer comprises a tumor classified as T1. The method of any one of claims 117 to 156, wherein the breast cancer comprises a tumor classified as T2. The method of any one of claims 117 to 156, wherein the breast cancer comprises a T3 classification tumor. The method of any one of claims 117 to 156, wherein the breast cancer comprises a T4 classification tumor. The method of any one of claims 117 to 156, wherein the breast cancer has a Ki67 status of 20 or less. The method of any one of claims 117 to 156, wherein the breast cancer has a Ki67 status greater than 20. The method of any one of claims 117 to 185, wherein prior to administering riboxil and an aromatase inhibitor to the adult patient, the patient underwent surgery for the early-stage breast cancer. The method of any of claims 117 to 185, wherein prior to administering riboxil and an aromatase inhibitor to the adult patient, the patient underwent (1) surgery for the early-stage breast cancer and then underwent (2) chemotherapy. The method of any of claims 117 to 185, wherein prior to administering riboxil and an aromatase inhibitor to the adult patient, the patient underwent (1) surgery for the early-stage breast cancer and then underwent (2) chemotherapy and/or endocrine therapy. The method of claim 188, wherein the endocrine therapy is therapy with a prior aromatase inhibitor. The method of claim 188, wherein the prior aromatase inhibitor is letrozole or anastrozole. The method of any one of claims 117 to 185, wherein immediately prior to administering riboxil and an aromatase inhibitor to the adult patient, the patient underwent surgery for the early stage breast cancer. The method of any one of claims 186 to 191, wherein the surgery comprises complete surgical resection of the cancer. The method of any of claims 186 to 191, wherein the surgery is a mastectomy. The method of any one of claims 186 to 191, wherein the patient is receiving a neoadjuvant therapy. The method of claim 194, wherein the new adjunctive therapy is chemotherapy. The method of any one of claims 117 to 195, wherein the adult patient is located in a geographic region selected from North America, Western Europe, or Oceania. The method of any one of claims 117 to 195, wherein the patient is Asian. The method of any one of claims 117 to 195, wherein the patient is 18 to 45 years old. The method of any one of claims 117 to 195, wherein the patient is 45 to 54 years old. The method of any one of claims 117 to 195, wherein the patient is 54 to 64 years old. The method of any one of claims 117 to 195, wherein the patient is older than 64 years old. The method of any one of claims 117 to 195, wherein the patient has a BMI of 25 or greater. The method of any one of claims 117 to 195, wherein the patient has a BMI less than 25. The method of any one of claims 117 to 203, wherein the treatment improves the patient's condition relative to patients not receiving the treatment and/or relative to the patient's condition prior to the treatment. The method of any one of claims 117 to 203, wherein the treatment reduces the risk of invasive disease. The method of any of claims 117 to 203, wherein the treatment reduces the risk of the invasive disease in the adult patient corresponding to a hazard ratio of less than 1 when the risk is calculated relative to other patients who have received the same treatment as the adult patient but have not received the ribociclib. The method of any of claims 117 to 203, wherein the treatment reduces the risk of the invasive disease in the adult patient corresponding to a hazard ratio of less than or equal to 0.78 when the risk is calculated relative to other patients who have received the same treatment as the adult patient but have not received the ribociclib. The method of any of claims 117 to 203, wherein the adult patient is a premenopausal female or male, and the treatment reduces the risk of the invasive disease, corresponding to a hazard ratio of less than or equal to 0.72 when the risk is calculated relative to other premenopausal females and males, respectively, who have received the same treatment as the premenopausal female or male but have not received riboxil. The method of any of claims 117 to 203, wherein the adult patient is diagnosed with HR+/HER2- stage III early breast cancer and the treatment reduces the risk of invasive disease in the adult patient, corresponding to a hazard ratio of less than or equal to 0.74 when the risk is calculated relative to other patients who have received the same treatment as the adult patient but have not received riboxil. The method of any of claims 117 to 203, wherein the adult patient is diagnosed with HR+/HER2- stage II early breast cancer and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than or equal to 0.76 when the risk is calculated relative to other patients who have received the same treatment as the adult patient but have not received riboxil. The method of any of claims 117 to 203, wherein the adult patient is diagnosed with HR+/HER2- stage III early breast cancer and the treatment reduces the risk of invasive disease by at least 25%, corresponding to a hazard ratio of 0.75 when the risk is calculated relative to other patients who have received the same treatment as the adult patient but have not received riboxil. The method of any one of claims 117 to 203, wherein the treatment reduces the risk of invasive disease to a similar level in subgroups of patients including patients with stage II early breast cancer, patients with stage III early breast cancer, premenopausal female or male patients, and postmenopausal female patients. The method of any of claims 117 to 203, wherein the treatment does not result in a shortening of overall survival corresponding to a hazard ratio of 0.76 when the risk is calculated relative to other patients who have received the same treatment as the adult patient but have not received the ribociclib. The method of any of claims 117 to 203, wherein the treatment reduces and/or prevents one or more of cancer recurrence, cancer spread, additional cancer development and/or growth, and risk of death from cancer. The method of any of claims 117 to 203, wherein the treatment reduces cancer recurrence, wherein the recurrence is one or more of invasive ipsilateral breast tumor (IBTR) recurrence, loco-regional invasive recurrence, and distant recurrence. The method of any one of claims 117 to 203, wherein the treatment reduces cancer spread, wherein the cancer spread is invasive contralateral breast cancer or another primary invasive cancer. Reboxil or a pharmaceutically acceptable salt thereof and an aromatase inhibitor are used in a method for treating HR+/HER2- stage II or stage III early breast cancer in adult patients, wherein the method is a method as described in any one of claims 117 to 216. Use of ribociclib or a pharmaceutically acceptable salt thereof and an aromatase inhibitor in the manufacture of a medicament for treating HR+/HER2- stage II or stage III early breast cancer in adult patients, wherein the medicament is administered by a method as described in any one of claims 117 to 216. A kit for use in performing a method of treating HR+/HER2- Stage II or Stage III early breast cancer in an adult patient according to any of claims 117 to 216. A method for treating an adult patient diagnosed with HER+/HER2- stage II or stage III early breast cancer, the method comprising administering to the patient an adjuvant therapy comprising (i) riboxil at a dose ranging from 150 mg/day to 450 mg/day administered on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily in a 28-day cycle, wherein the method results in an improvement in one or more of overall survival (OS), distant disease-free survival (DDFS), or relapse-free survival (RFS) in the patient. A method for improving one or more of overall survival (OS), distant disease-free survival (DDFS), or relapse-free survival (RFS) in a patient diagnosed with HR+/HER2- stage II or stage III early breast cancer, the method comprising administering to the patient an adjuvant therapy comprising (i) riboxil at a dose ranging from 150 mg/day to 450 mg/day on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily in a 28-day cycle. A method for reducing the risk of locally or regionally invasive recurrence of early breast cancer in an adult patient diagnosed with HR+/HER2- stage II or III early breast cancer, the method comprising administering to the patient an adjuvant therapy comprising (i) riboxil at a dose ranging from 150 mg/day to 450 mg/day on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily during the 28-day cycle. A method for reducing the risk of aggressive recurrence of early breast cancer in one or more of the bone, liver, and lung or pleura in an adult patient diagnosed with HR+/HER2- Stage II or III early breast cancer, the method comprising administering to the patient an adjuvant therapy comprising (i) riboxil at a dose ranging from 150 mg/day to 450 mg/day on Days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily in a 28-day cycle. The method of any one of claims 220 to 223, wherein the treatment is administered without regard to the lymph node status of the breast cancer. A method for reducing the risk of early breast cancer recurrence in an adult patient diagnosed with HR+/HER2- stage II or stage III early breast cancer, the method comprising administering to the patient an adjuvant therapy comprising (i) riboxil at a dose ranging from 150 mg/day to 450 mg/day on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily during a 28-day cycle, wherein the treatment is administered without regard to the lymph node status of the breast cancer. The method of any one of claims 220 to 225, wherein the breast cancer has a lymph node status of N0, N1, N2, or N3. The method of claim 226, wherein the breast cancer has a lymph node status of N0. The method of any one of claims 220 to 227, wherein the early stage breast cancer is stage II, such as stage IIA. The method of any one of claims 220 to 227, wherein the early stage breast cancer is stage III, such as stage IIIB or stage IIIC. The method of any one of claims 220 to 229, wherein the breast cancer is of the ductal subtype. The method of any one of claims 220 to 230, wherein the patient is Asian. The method of any one of claims 220 to 231, wherein the method is adjuvant therapy because the patient has received at least one prior treatment for breast cancer selected from the group consisting of surgery, chemotherapy, and radiation therapy. The method of claim 232, wherein the patient has not undergone a mastectomy. The method of any one of claims 220 to 233, wherein the dose of riboxil is 400 mg/day. The method of any one of claims 220 to 234, wherein the reboxili is administered in the form of a salt, preferably reboxili succinate. The method of any one of claims 220 to 235, wherein the aromatase inhibitor is letrozole or anastrozole. The method of claim 236, wherein the aromatase inhibitor is letrozole, preferably administered at a dose of 2.5 mg/day. The method of claim 236, wherein the aromatase inhibitor is anastrozole, preferably administered at a dose of 1 mg/day. The method of any one of claims 220 to 238, wherein the dose of riboxili is 400 mg/day, the riboxili is administered in the form of riboxili succinate, and the aromatase inhibitor is letrozole or anastrozole, preferably 2.5 mg/day of letrozole or 1 mg/day of anastrozole. The method of any one of claims 220 to 239, wherein the patient achieves an improvement in OS, DDFS and/or RFS of at least 36 months or a reduction in the risk of breast cancer recurrence. Reboxil is for use in a method of improving one or more of overall survival (OS), distant disease-free survival (DDFS), or relapse-free survival (RFS) in adult patients diagnosed with HR+/HER2- stage II or stage III early breast cancer, wherein the method comprises administering to the patient an adjuvant therapy comprising (i) reboxil at a dose ranging from 150 mg/day to 450 mg/day on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily in a 28-day cycle. Reboxil is for use in a method of reducing the risk of locally or regionally invasive recurrence of early breast cancer in adult patients diagnosed with HR+/HER2- stage II or III early breast cancer, wherein the method comprises administering to the patient an adjuvant therapy comprising (i) reboxil at a dose ranging from 150 mg/day to 450 mg/day on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily in a 28-day cycle. Reboxil is for use in a method of reducing the risk of aggressive recurrence of early breast cancer in one or more of the bone, liver, and lung or pleura in adult patients diagnosed with HR+/HER2- Stage II or III early breast cancer, wherein the method comprises administering to the patient an adjuvant therapy comprising (i) reboxil at a dose ranging from 150 mg/day to 450 mg/day on Days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily in a 28-day cycle. The method of claim 241 , wherein the treatment is administered without regard to the lymph node status of the breast cancer. Reboxil is for use in a method of reducing the risk of early breast cancer recurrence in adult patients diagnosed with HR+/HER2- stage II or stage III early breast cancer, the method comprising administering to the patient an adjuvant therapy comprising (i) revocili administered at a dose ranging from 150 mg/day to 450 mg/day on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor administered daily during a 28-day cycle, wherein the treatment is administered without regard to the lymph node status of the breast cancer. The method of claim 241 , wherein the breast cancer has a lymph node status of N0, N1, N2 or N3. The method of claim 246 for use with Riboxil, wherein the breast cancer has a lymph node status of N0. The method of claim 241 , wherein the early breast cancer is stage II, such as stage IIA. The method of claim 241 , wherein the early breast cancer is stage III, such as stage IIIB or IIIC. The method of claim 241 or 249, wherein the breast cancer is of the ductal subtype. The method of claim 241 or 250, wherein the patient is Asian. The method of any of claims 241 to 251, wherein the method is adjuvant therapy because the patient has received at least one prior treatment for breast cancer selected from the group consisting of surgery, chemotherapy, and radiation therapy. As claimed in claim 252, the patient is provided with reboxil, wherein the patient has not undergone a mastectomy. The method of claim 241 to claim 253, wherein the dosage of the drug is 400 mg/day. The reboxili for use according to any one of claims 241 to 254, wherein the reboxili is administered in the form of a salt, and the salt is preferably reboxili succinate. The method of claim 241 , wherein the aromatase inhibitor is letrozole or anastrozole. The method of claim 256, wherein the aromatase inhibitor is letrozole, preferably administered at a dose of 2.5 mg/day. The method of claim 256, wherein the aromatase inhibitor is anastrozole, preferably administered in a dose of 1 mg/day. The ribociclib for use as claimed in any one of claims 241 to 258, wherein the dosage of ribociclib is 400 mg/day, the ribociclib is administered in the form of ribociclib succinate, and the aromatase inhibitor is letrozole or anastrozole, preferably 2.5 mg/day of letrozole or 1 mg/day of anastrozole. The method of claim 241 for use of Riboxil, wherein the patient achieves an improvement in OS, DDFS and/or RFS of at least 36 months or a reduction in the risk of breast cancer recurrence. Reboxilibe succinate is for use in a method of treating HR+/HER2- Stage II or III early breast cancer in adult patients who have received at least one prior treatment for early breast cancer and who have no signs or symptoms of cancer, wherein the method comprises administering to the patient an adjuvant therapy comprising (i) a dose of 400 mg/day of reboxilibe on days 1 to 21 of a 28-day cycle and (ii) 2.5 mg/day of letrozole or 1 mg/day of anastrozole administered daily in a 28-day cycle. The method of claim 261, wherein the adjunctive therapy comprises 2.5 mg/day of letrozole. The method of claim 261, wherein the adjunctive therapy comprises anastrozole at a dose of 1 mg/day. The ribociclib succinate for use as claimed in any one of claims 261 to 263, wherein the breast cancer has a lymph node status of N0, N1, N2 or N3. The method of claim 264 wherein the breast cancer has a lymph node status of N0. The ribociclib succinate for use as claimed in any one of claims 261 to 265, wherein the early breast cancer is stage II, such as stage IIA. The ribociclib succinate for use as claimed in any one of claims 261 to 265, wherein the early breast cancer is stage III, such as stage IIIB. The ribociclib succinate for use as claimed in any one of claims 261 to 265, wherein the early breast cancer is stage III, e.g., IIIC. The ribociclib succinate for use as claimed in any one of claims 261 to 268, wherein the breast cancer is of the ductal subtype. The method of claim 261 , wherein the patient is Asian. The method of claim 261 or 270, wherein the method is adjuvant therapy because the patient has received at least one prior treatment for breast cancer selected from the group consisting of surgery, chemotherapy, endocrine therapy, and radiation therapy. As claimed in claim 271, the patient is provided with riboxil succinate, wherein the patient has not undergone a mastectomy. The method of claim 261 or 272, wherein the method improves the patient's overall survival (OS), distant disease-free survival (DDFS) and/or recurrence-free survival (RFS) of breast cancer by at least 36 months; or the method reduces the patient's risk of breast cancer recurrence by at least 36 months. A method for preventing recurrence of breast cancer in an adult patient who has received prior treatment for HR+/HER2- stage II or III early breast cancer, the method comprising administering to the patient (i) an amount of riboxil, its free base form or a pharmaceutically acceptable salt thereof and (ii) an amount of an aromatase inhibitor, preferably letrozole or anastrozole. A method for treating an adult patient in remission from HR+/HER2- stage II or stage III early breast cancer, the method comprising administering to the patient (i) an amount of riboxil, its free base form or a pharmaceutically acceptable salt thereof and (ii) an amount of an aromatase inhibitor, preferably letrozole or anastrozole. A method for treating HR+/HER2- stage II or III early breast cancer in an adult patient in need thereof, the method comprising administering to the patient (i) a dose ranging from 150 mg/day to 450 mg/day of ribociclib, its free base form or a pharmaceutically acceptable salt thereof, administered on days 1-21 of a 28-day cycle, and (ii) an aromatase inhibitor, preferably letrozole or anastrozole, administered daily in a 28-day cycle. The method of any one of claims 274 to 276, wherein the reboxili is a pharmaceutically acceptable reboxili salt. The method of claim 277, wherein the reboxili salt is reboxili succinate. The method of any of claims 274, 275, 277 and 278, wherein the dose of riboxil is other than 600 mg/day. The method of any one of claims 274 to 278, wherein the dose of riboxil is 200 mg/day or 400 mg/day. The method of claim 280, wherein reboxili is administered in the form of reboxili succinate and the total dose of reboxili is 200 mg/day. The method of claim 280, wherein reboxili is administered in the form of reboxili succinate and the total dose of reboxili is 400 mg/day. The method of claim 280, wherein the reboxil is administered at a dose of 400 mg/day for a period of time, followed by administration of 200 mg/day of reboxil. The method of any one of claims 274 to 283, wherein the dose of Riboxil is administered orally. The method of any one of claims 274 to 284, wherein the dose of riboxil is administered in the form of a tablet. The method of any one of claims 274 to 285, wherein the aromatase inhibitor is letrozole or anastrozole. The method of any one of claims 274 to 286, wherein the aromatase inhibitor is administered orally. The method of claim 286 or 287, wherein the letrozole is administered in an amount ranging from 1 mg/day to 4 mg/day. The method of claim 288, wherein the letrozole is administered in a dosage of 2.5 mg/day. The method of claim 286 or 287, wherein the anastrozole is administered in an amount ranging from 0.5 mg/day to 1.5 mg/day. The method of claim 290, wherein the anastrozole is administered in a dosage of 1 mg/day. A method for treating recurrence of breast cancer in an adult patient who has received at least one prior treatment for HR+/HER2- stage II or III early breast cancer and has no detectable signs or symptoms of breast cancer, the method comprising administering to the patient an adjuvant therapy comprising (i) riboxil succinate administered on days 1 to 21 of a 28-day cycle at a total dose of 400 mg/day and (ii) letrozole at a dose of 2.5 mg/day or anastrozole at a dose of 1 mg/day administered daily in a 28-day cycle. A method for treating an adult patient in remission from HR+/HER2- stage II or stage III early breast cancer who is in need of an adjuvant therapy, the method comprising administering to the patient an adjuvant therapy comprising (i) administering a dose of 400 mg/day of riboxil succinate on days 1-21 of a 28-day cycle, and (ii) administering 2.5 mg/day of letrozole or 1 mg/day of anastrozole on each day of the 28-day cycle. The method of any one of claims 274 to 293, wherein the treatment further comprises administering a gonadotropin-releasing hormone agonist. The method of claim 294, wherein the gonadotropin-releasing hormone agonist is goserelin. The method of claim 295, wherein the goserelin is administered in an amount ranging from 2 mg to 5 mg. The method of claim 296, wherein the dose of goserelin is 3.6 mg. The method of any one of claims 294 to 297, wherein the goserelin is administered subcutaneously. The method of any one of claims 294 to 298, wherein the goserelin is administered once every 4 weeks. The method of any one of claims 274 to 299, wherein the patient is a postmenopausal female. The method of any one of claims 274 to 293, wherein the patient is a premenopausal female or male. The method of any one of claims 274 to 301, wherein the treatment is administered to the patient for at least 12 months. The method of claim 302, wherein the treatment is administered to the patient for at least 24 months. The method of claim 302 or 303, wherein the treatment is administered to the patient for at least 36 months. The method of any of claims 302 to 304, wherein the treatment is administered to the patient for at least 48 months. The method of any one of claims 302 to 305, wherein the treatment is administered to the patient for at least 60 months. The method of any one of claims 274 to 306, wherein the breast cancer is ER+ and PR+. The method of any one of claims 274 to 306, wherein the breast cancer is ER- and PR+. The method of any one of claims 274 to 306, wherein the breast cancer is ER+ and PR-. The method of any one of claims 274 to 309, wherein the histological subtype of breast cancer is ductal subtype. The method of any one of claims 274 to 310, wherein the histological subtype of breast cancer is lobular subtype. The method of any one of claims 274 to 311, wherein the breast cancer is stage IIA cancer or stage IIB cancer. The method of claim 312, wherein the breast cancer is stage IIA cancer. The method of claim 312, wherein the breast cancer is stage IIB cancer. The method of any one of claims 274 to 311, wherein the breast cancer is a stage IIIA cancer, a stage IIIB cancer, or a stage IIIC cancer. The method of claim 315, wherein the breast cancer is stage IIIA cancer. The method of claim 315, wherein the breast cancer is stage IIIB cancer. The method of claim 315, wherein the breast cancer is stage IIIC cancer. The method of any one of claims 274 to 318, wherein the treatment is administered without regard to the lymph node status of the breast cancer. The method of any one of claims 274 to 319, wherein the breast cancer has a lymph node status selected from N0, N1, N2 and N3. The method of claim 319 or 320, wherein the breast cancer has a lymph node status of N0. The method of claim 319 or 320, wherein the breast cancer has a lymph node status of N1 to N3. The method of claim 319 or 320, wherein the breast cancer has a lymph node status of N1. The method of claim 319 or 320, wherein the breast cancer has a lymph node status of N2. The method of claim 319 or 320, wherein the breast cancer has a lymph node status of N3. The method of any one of claims 274 to 325, wherein the breast cancer comprises one or more cells having a histological grade selected from G1, G2 or G3. The method of claim 326, wherein the breast cancer comprises one or more cells having a G1 histological grade. The method of claim 326, wherein the breast cancer comprises one or more cells having a G2 histological grade. The method of claim 326, wherein the breast cancer comprises one or more cells having a G3 histological grade. The method of any one of claims 274 to 329, wherein the breast cancer comprises a tumor classified as T0, T1, T2, T3 or T4. The method of claim 330, wherein the breast cancer comprises a tumor classified as T1, T2, or T3. The method of claim 330, wherein the breast cancer comprises a tumor classified as T0. The method of claim 330 or claim 331, wherein the breast cancer comprises a tumor classified as T1. The method of claim 330 or claim 331, wherein the breast cancer comprises a T2 classification tumor. The method of claim 330 or claim 331, wherein the breast cancer comprises a T3 tumor. The method of claim 330, wherein the breast cancer comprises a T4 tumor. The method of any one of claims 274 to 336, wherein the breast cancer has a Ki67 status of 20 or less. The method of any one of claims 274 to 336, wherein the breast cancer has a Ki67 status greater than 20. The method of any one of claims 274 to 338, wherein prior to the administration, the patient has received a loading dose of (i) riboxil and/or (ii) endocrine therapy. The method of any one of claims 274 to 291 and 293 to 339, wherein the patient has received at least one prior treatment for cancer. The method of claim 292 or claim 340, wherein the prior treatment is an adjunct to another prior treatment. The method of claim 340 or 341, wherein the prior treatment was surgery. The method of claim 342, wherein the surgery comprises complete surgical resection of the cancer. The method of claim 342 or claim 343, wherein the surgery is a mastectomy. The method of claim 340 or claim 341, wherein the prior treatment is chemotherapy. The method of claim 345, wherein the prior treatment was adjuvant chemotherapy. The method of claim 345, wherein the prior treatment is neoadjuvant chemotherapy. The method of claim 340 or claim 341, wherein the prior treatment is endocrine therapy. The method of claim 340 or claim 341, wherein the prior treatment is radiation therapy. The method of any of claims 292 and 340 to 349, wherein the patient is unresponsive to the prior treatment. The method of any one of claims 274 to 350, wherein the patient is located in a geographic region selected from North America, Western Europe, or Oceania. The method of any one of claims 274 to 351, wherein the patient is Asian. The method of any one of claims 274 to 352, wherein the patient is 18 to 45 years old. The method of any one of claims 274 to 352, wherein the patient is 45 to 54 years old. The method of any one of claims 274 to 352, wherein the patient is 54 to 64 years old. The method of any one of claims 274 to 352, wherein the patient is older than 64 years old. The method of any one of claims 274 to 357, wherein the patient has a BMI of 25 or greater. The method of any one of claims 274 to 357, wherein the patient has a BMI less than 25. The method of any of claims 274 to 358, wherein the treatment improves the patient's condition relative to patients not receiving the treatment and/or relative to the patient's condition prior to the treatment. The method of any one of claims 274 to 359, wherein the treatment reduces the risk of invasive disease. The method of claim 360, wherein the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than 1 when the risk is calculated relative to patients not receiving the treatment. The method of claim 361, wherein the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than or equal to 0.78 when the risk is calculated relative to patients not receiving the treatment. The method of any of claims 274 to 299 and 301 to 362, wherein the patient is a premenopausal female or male and the treatment reduces the risk of the invasive disease corresponding to a hazard ratio of less than or equal to 0.72 when the risk is calculated relative to patients not receiving the treatment. The method of any of claims 360 to 362, wherein the cancer is HR+/HER2- stage III early breast cancer and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than or equal to 0.74 when the risk is calculated relative to patients not receiving the treatment. The method of any of claims 360 to 362, wherein the cancer is HR+/HER2- stage II early breast cancer and the treatment reduces the risk of invasive disease corresponding to a hazard ratio of less than or equal to 0.76 when the risk is calculated relative to patients not receiving the treatment. The method of any of claims 360 to 362, wherein the cancer is HR+/HER2- stage III early breast cancer and the treatment reduces the risk of invasive disease by at least 25%, corresponding to a hazard ratio of 0.75 when the risk is calculated relative to patients not receiving the treatment. The method of any one of claims 360 to 366, wherein the treatment reduces the risk of invasive disease to a similar level in subgroups of patients including patients with stage II early breast cancer, patients with stage III early breast cancer, premenopausal female or male patients, and postmenopausal female patients. The method of any of claims 274 to 367, wherein the treatment does not result in a reduction in overall survival corresponding to a hazard ratio of 0.76 when the risk is calculated relative to patients not receiving the treatment. The method of any of claims 274 to 368, wherein the treatment reduces and/or prevents one or more of cancer recurrence, cancer spread, additional cancer development and/or growth, and risk of death from cancer. The method of claim 369, wherein the treatment reduces cancer recurrence, wherein the recurrence is one or more of invasive ipsilateral breast tumor (IBTR) recurrence, loco-regional invasive recurrence, and distant recurrence. The method of claim 369, wherein the treatment reduces cancer spread, wherein the cancer spread is invasive contralateral breast cancer or another primary invasive cancer. The method of any of claims 274 to 371, wherein the treatment prevents death from cancer.