KR20250004779A - Combination therapy for treating TROP-2 expressing cancers - Google Patents

Abstract

The present disclosure relates to methods for treating, ameliorating, preventing, or delaying the recurrence or metastasis of a Trop-2 expressing cancer (e.g., metastatic castration-resistant prostate cancer, non-small cell lung cancer) in a subject by administering to the subject an effective amount of (a) an anti-Trop-2 antibody drug conjugate (ADC) (e.g., sacituzumab govitecan); and (b) an adenosine pathway inhibitor (e.g., etrummadenant, chemriclusstat). The present disclosure further relates to methods for treating, ameliorating, preventing, or delaying the recurrence or metastasis of a tumor antigen (TA) expressing cancer in a subject by administering an effective amount of: (a) a tumor antigen targeted antibody-drug conjugate (ADC) comprising a topoisomerase I inhibitor (TopI ADC); and b) an adenosine pathway inhibitor.

Description

Combination therapy for treating TROP-2 expressing cancers

Cross-reference to related applications

This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 63/330,700, filed April 13, 2022, U.S. Provisional Application No. 63/370,228, filed August 2, 2022, and U.S. Provisional Application No. 63/377,918, filed September 30, 2022, each of which is incorporated herein by reference in its entirety.

Technical field

The present disclosure relates to methods for treating, ameliorating, preventing, or delaying the recurrence or metastasis of a Trop-2 expressing cancer (e.g., metastatic castration-resistant prostate cancer, non-small cell lung cancer) in a subject by administering to the subject an effective amount of (a) an anti-Trop-2 antibody drug conjugate (ADC) (e.g., sacituzumab govitecan); and (b) an adenosine pathway inhibitor (e.g., etrummadenant, chemriclusstat). The present disclosure further relates to methods for treating, ameliorating, preventing, or delaying the recurrence or metastasis of a tumor antigen (TA) expressing cancer in a subject by administering an effective amount of: (a) a tumor antigen targeted antibody-drug conjugate (ADC) comprising a topoisomerase I inhibitor (TopI ADC); and b) an adenosine pathway inhibitor.

Anti-Trop-2 antibody drug conjugates, such as sacituzumab govitecan and datopotamab deruxtecan, are under clinical investigation for the treatment of a variety of Trop-2 expressing cancers. Although evidence of clinical efficacy has been obtained in the monotherapy setting, additional therapeutic benefits for patients are needed.

Trop-2 expression has been reported in a variety of epithelial cancers, including breast, bladder, lung, colon, and prostate cancers. Prostate cancer is the most commonly diagnosed cancer and the second most common cause of cancer-related death among men in the United States (US). In 2019, an estimated 174,650 new cases were diagnosed and 31,620 related deaths (Ref. [National Cancer Institute. SEER Cancer Stat Facts: Prostate Cancer. Accessed 25 February 2020 at seer.cancer.gov/statfacts/html/prost.html.]). Adenocarcinomas account for 95% of prostate cancers (Ref. [Lie AK. Histology of prostate cancer. Oncolex Oncology Encyclopedia. Accessed 25 February 2020 at oncolex.org/Prostate-cancer/Background/Histology.]). Most cases (90%) are diagnosed at the local or regional stage, and treatment options include active surveillance, surgery, or radiation. The five-year relative survival rate is 98% for all stages, but 30% for those diagnosed at advanced stages.

Metastatic or advanced prostate cancer has a more complex treatment algorithm. Patients with locally advanced disease initially receive androgen ablation with radiation or prostatectomy, whereas in the metastatic setting, first-line therapy is androgen ablation concomitant with systemic therapy (e.g., second-generation hormonal therapy or docetaxel-based chemotherapy). Disease progression in the context of androgen deprivation is known as castration-resistant prostate cancer (CRPC). Specifically, the Prostate Cancer Working Group 2 (PCWG2) defined CRPC as persistent elevation of serum prostate-specific antigen (PSA) levels, progression of preexisting local or metastatic disease, and/or the appearance of new metastases in the setting of castration-resistant serum testosterone levels (<50 ng/dL) (Scher HI, et al. J Clin Oncol. (2008) 26(7):1148-1159.).

The prognosis of CRPC is associated with several factors, including performance status, the presence of bone pain, the extent of disease on bone scan, and serum alkaline phosphatase (ALP) levels. Bone metastases will occur in approximately 80% of men with CRPC and can cause significant morbidity, including pain, pathologic fractures, spinal cord compression, and bone marrow failure. Paraneoplastic effects, including anemia, weight loss, fatigue, hypercoagulability, and increased susceptibility to infection, are also common (Saad F and Hotte S. Can Urol Assoc J. (2010) 4(6):380-384).

Over the past decade, six new agents have received FDA approval for the treatment of metastatic CRPC (mCRPC), resulting in significant improvements in overall survival (OS; Fay AP and Antonarakis E S. Ann Transl Med. (2019) 7(Suppl 1):S7.). However, the clinical benefits of individual agents are rarely durable, with a median OS of approximately 2 to 3 years. Given the complexity of the disease and the difficulty in achieving successful treatment, mCRPC remains an area of high unmet medical need in which novel therapies are being actively explored.

Lung cancer is the leading cause of cancer-related deaths worldwide. In 2020, there were an estimated 2 million new cases of lung cancer and 1.8 million deaths worldwide. In 2021, there will be an estimated 235,000 new cases of lung cancer and 131,000 deaths in the United States (US). Approximately 80% to 85% of all lung cancers are non-small cell lung cancers (NSCLC) (Ettinger et al. J Natl Compr Canc Netw (2019);17(12):1464-72), and more than half of these are diagnosed at an advanced stage (Siegel et al. CA Cancer J Clin (2019);69 (1):7-34).

Several genomic alterations have been identified in NSCLC that influence therapy choice, and molecular testing is part of the standard of care in the evaluation of NSCLC. Of these, epidermal growth factor receptor (EGFR) gene mutations (10% to 50% of NSCLC mutations) and anaplastic lymphoma kinase (ALK) gene rearrangements (5%) are the most common and are associated with response to EGFR and ALK tyrosine kinase inhibitors, which are widely approved and used clinically as first-line agents in this subtype. Other genomic alterations, such as ROS proto-oncogene 1 (ROS1) gene rearrangements, proto-oncogene B-raf (BRAF) point mutations, MET exon 14 skipping, RET alterations, and neurotrophic tyrosine receptor kinase (NTRK) mutations, are less common, but have approved therapies targeting these alterations. Unfortunately, although the list of identified actionable genomic alterations is growing, only a minority of new cases of NSCLC harbor actionable genomic alterations.

Recent advances in immune checkpoint inhibitor (CPI) therapy have dramatically improved the prognosis of advanced lung cancer, and these immune-CPI regimens are primarily used in the front-line metastatic setting, as monotherapy (programmed cell death ligand 1 [PD-L1] tumor proportion score [TPS] ≥ 1%) or in combination with platinum-doublet chemotherapy (regardless of PD-L1 expression), based on results from KEYNOTE-024, KEYNOTE-042, KEYNOTE-189, KEYNOTE-407, and similar studies in participants without treatable genomic alterations. Chemotherapy/immunotherapy regimens such as pembrolizumab/(carboplatin or cisplatin)/pemetrexed are recommended for patients with non-squamous NSCLC, regardless of PD-L1 expression. For patients with metastatic squamous cell NSCLC, a chemotherapy/immunotherapy regimen such as pembrolizumab/carboplatin/(paclitaxel or albumin-bound paclitaxel) is recommended (Ettinger et al. J Natl Compr Canc Netw (2019);17 (12):1464-72).

After failure of immune checkpoint inhibitor therapy and platinum-based chemotherapy, treatment options are limited for most patients. According to the National Comprehensive Cancer Network guidelines, the use of single-agent chemotherapy (including a taxane) is the standard of care for patients with relapsed or metastatic NSCLC after failure of platinum-based therapy and/or immune checkpoint therapy, regardless of the presence of genomic alterations and PD-L1 status (Ettinger et al. J Natl Compr Canc Netw (2019);17 (12):1464-72). The primary single-agent chemotherapy options in this setting typically include docetaxel (with or without ramucirumab) and pemetrexed (for non-squamous tumors, if not used prior). In a study of docetaxel versus best supportive care in relapsed NSCLC, the median progression-free survival (PFS) was approximately 3 months, and the median overall survival (OS) was approximately 6 to 8 months (Shepherd et al. J Clin Oncol (2000);18 (10):2095-103). These figures have been confirmed in more contemporary studies using docetaxel after failure of platinum-based regimens in NSCLC (Horn et al. J Clin Oncol (2017);35 (35):3924-33; Mazieres et al. Journal of Thoracic Oncology (2021);16 (1):140-50). Although docetaxel is considered the standard of care for patients who have failed platinum-based regimens and checkpoint inhibitors, new agents remain a significant unmet medical need in the subsequent treatment of advanced or metastatic NSCLC.

Immune checkpoint inhibitors have rekindled interest in clinical development for anticancer immunotherapy. The latter rely on therapeutic modulation of the tumor microenvironment or other aspects of the immune system to overcome mechanisms of tumor-induced immunosuppression of the host immune system. Despite demonstrated benefits in a variety of tumor types, as evidenced by the approvals of nivolumab, pembrolizumab, atezolizumab, and ipilimumab, checkpoint inhibition has not been shown to be effective in the treatment of metastatic prostate cancer, where response rates to monotherapy are less than 5% (Antonarakis ES, et al. J Clin Oncol. (2020) 38(5):395-405.).

Antibody-drug conjugates (ADCs) are a rapidly growing drug class in oncology, with several different ADCs currently approved for cancer therapy, and many more in preclinical and clinical development (see, e.g., Drago, JZ et al., Nat Rev Clin Oncol (2021) 18, 327-344). ADCs typically consist of a monoclonal antibody linked to a cytotoxic drug (the payload). ADCs are designed to specifically restrict delivery of the cytotoxic drug to cells expressing the target antigen of each antibody (e.g., Trop-2, Her-2, Nectin-4) and to the immediately surrounding tumor tissue (bystander effect). As a result of the tumor-targeted delivery of the cytotoxic agent, ADCs often have a significantly improved therapeutic window compared to systemically administered cytotoxic agents. Examples of ADCs that have received marketing approval from the United States Food and Drug Administration (US FDA) include gemtuzumab ozogamicin, brentuximab vedotin, ado-trastuzumab emtansine (T-DM1), inotuzumab ozogamicin, trastuzumab deruxtecan (T-DXd), polatuzumab vedotin, sacituzumab deruxtecan, enfortumab vedotin, and belantamab mafodotin.

The adenosine pathway mediates immunosuppressive effects in the tumor microenvironment (e.g., Allard, B., et al. Nat Rev Clin Oncol (2020) 17, 611-629). Adenosine pathway inhibitors, including various CD39 inhibitors, CD73 inhibitors, and adenosine receptor antagonists, are under clinical investigation as promising agents for stimulating antitumor immune responses.

Despite advances in cancer treatment, many patients remain refractory to currently available therapies or relapse after responding to available therapies, necessitating the development of novel agents and combinations of agents for the treatment of various types of cancer, including mCRPC.

In one aspect, provided herein is a method of treating, alleviating, reducing, preventing, or delaying recurrence or metastasis of a Trop-2 positive cancer, comprising co-administering to a subject an effective amount of: a) an anti-Trop-2 antibody-drug conjugate (ADC); and b) an adenosine pathway inhibitor.

In some embodiments, provided herein are methods of treating Trop-2 positive cancer, comprising co-administering to a subject an effective amount of: a) an anti-Trop-2 antibody-drug conjugate (ADC); and b) an adenosine pathway inhibitor.

In some embodiments, the anti-Trop-2 ADC comprises a topoisomerase I inhibitor.

In some embodiments, the topoisomerase I inhibitor is camptothecin (CPT).

In some embodiments, the topoisomerase I inhibitor is topotecan, irinotecan, belotecan, or exatecan.

In some embodiments, the topoisomerase I inhibitor is SN38 or Dxd.

In some embodiments, the topoisomerase I inhibitor is selected from the group consisting of irinotecan, topetecan, and SN-38.

In some embodiments, the topoisomerase I inhibitor is SN38.

In some embodiments, the anti-Trop-2 ADC has the structural formula mAb-CL2A-SN-38, having a structure represented by:

(as described, for example, in U.S. Patent No. 7,999,083).

In some embodiments, the anti-Trop-2 ADC comprises sacituzumab (hRS7; e.g., described in WO2003074566 , FIGS. 3 and 4 ).

In some embodiments, the anti-Trop-2 ADC is selected from the group consisting of sacituzumab govitecan, datopotamab deruxtecan (DS-1062), ESG-401, SKB-264, DAC-02, and BAT-8003.

In some embodiments, the anti-Trop-2 ADC is sacituzumab govitecan.

In some embodiments, the adenosine pathway inhibitor is a CD39 inhibitor, a CD73 inhibitor, or an adenosine receptor antagonist.

In some embodiments, the adenosine pathway inhibitor is a plurality of adenosine pathway inhibitors. In some embodiments, the plurality of adenosine pathway inhibitors comprises a CD73 inhibitor and an adenosine receptor antagonist. In some embodiments, the CD73 inhibitor is chemriclustat and the adenosine receptor antagonist is etrumadenanth.

In some embodiments, the adenosine pathway inhibitor is an adenosine receptor antagonist.

In some embodiments, the adenosine pathway inhibitor is imaradenant, NIR178, ID11902, IN-A003, NTI-55, TT-10, TT-228, PBF-1129 (Palobiofarma), TT-702, etrumadenanth, INCB106385, M1069, HM87277, RVU-330, or TT-53.

In some embodiments, the adenosine pathway inhibitor is a dual antagonist of the adenosine A2A receptor (A2AR; ADORA2A) and the A2B receptor (A2BR; ADORA2B).

In some embodiments, the adenosine pathway inhibitor is etrumadenanth (AB928; GS-0928), taminadenant, TT-10, TT-4, or M1069.

In some embodiments, the adenosine pathway inhibitor is etrumadenanthet.

In some embodiments, the adenosine pathway inhibitor is a CD73 inhibitor.

In some embodiments, the CD73 inhibitor is oleculumab, BMS-986179, uriledrimab, AK119, chemliclustat, mufadolimab, HLX23, INCA00186, IBI325, NZV930, ORIC-533, Sym024, IPH5301, IOA-237, JAB-BX100, PT199, TRB010, CD73 ASO, ABSK-051, AK131, BR101, BP1200, CB708, GB7002, or ATG-037.

In some embodiments, the CD73 inhibitor is chemriclustat (AB680, GS-0680), uriledrimab, mufadolimab, ORIC-533, ATG-037, PT-199, AK131, NZV930, BMS-986179, or oleclumab.

In some embodiments, the CD73 inhibitor is chemriclustat.

In some embodiments, the method further comprises co-administering an additional therapeutic agent or treatment modality.

In some embodiments, the additional therapeutic agents or treatment modalities comprise one, two, three or four additional therapeutic agents and/or treatment modalities.

In some embodiments, the additional therapeutic agent comprises an anti-PD-(L)1 antibody.

In some embodiments, the anti-PD-(L)1 antibody is pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cosibelimab, sasanlimab, tislelizumab, retipanlimab, balstilimab, toripalimab, setrelimab, genolimab, progolimab, rodafolimab, camrelizumab, budigalimab, avelumab, dostalimab, envafolimab, scintillimab, or zimberelimab.

In some embodiments, the anti-PD-(L)1 antibody is zimberelimab.

In some embodiments, the additional therapeutic agent comprises an anti-TIGIT antibody.

In some embodiments, the anti-TIGIT antibody is tiragolumab, vivotolimab, dombanalimab, AB308, AK127, BMS-986207, ralzapastotug, or etigilimab.

In some embodiments, the anti-TIGIT antibody is dombanalimab. In some embodiments, the anti-TIGIT antibody is ralzapastotug.

In some embodiments, the additional therapeutic agent comprises an anti-PD-(L1) antibody and an anti-TIGIT antibody.

In some embodiments, the additional therapeutic agent comprises a) zimberelimab and dombanalimab, b) zimberelimab and AB308, c) atezolizumab and tiragolumab, d) pembrolizumab and vivostolimab, e) pembrolizumab and dombanalimab, f) pembrolizumab and AB308, g) MK-7684A (pembrolizumab/vivostolimab coformulation), h) durvalumab and dombanalimab, i) zimberelimab and ralzapastotug, or j) pembrolizumab and ralzapastotug.

In some embodiments, the additional therapeutic agents include zimberelimab and dombanalimab.

In some embodiments, the Trop-2 positive cancer is a solid epithelial cancer.

In some embodiments, the solid epithelial cancer is selected from breast cancer (e.g., triple negative breast cancer (TNBC), HR ⁺ /Her2 ^- breast cancer, HR ⁺ /Her2 ^low breast cancer), colon cancer, lung cancer, stomach cancer, urinary tract cancer, urothelial cancer, bladder cancer, kidney cancer, pancreatic cancer, ovarian cancer, uterine cancer, esophageal cancer and prostate cancer. In some embodiments, the breast cancer is triple negative breast cancer (TNBC), HR ⁺ /Her2 ^- breast cancer or HR ⁺ /Her2 ^low breast cancer.

In some embodiments, the prostate cancer is castration-resistant prostate cancer (CRPC).

In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC).

In some embodiments, the lung cancer is (i) squamous NSCLC or (ii) non-squamous NSCLC.

In some embodiments, the lung cancer does not have EGFR, ALK or other treatable genomic alterations.

In some embodiments, the Trop-2 positive cancer is (i) locally advanced and unresectable or (ii) metastatic.

In some embodiments, the cancer has progressed after at least one prior anticancer therapy.

In some embodiments, the cancer progressed after prior novel hormonal therapy (NHA; first- or second-generation non-steroidal antiandrogens, abiraterone).

In some embodiments, the cancer progressed or recurred following platinum-based chemotherapy.

In some embodiments, the cancer progressed or recurred following checkpoint inhibitor (CPI) therapy.

In some embodiments, the cancer progressed or recurred after receiving platinum-based chemotherapy and anti-PD-(L)1 antibody therapy, either concurrently or sequentially in any order.

In some embodiments, the cancer progressed or recurred following tyrosine kinase inhibitor therapy.

In some embodiments, the subject is treatment naive.

In some embodiments, the subject has not received prior therapy selected from the group consisting of: taxane therapy (taxane naive), checkpoint inhibitor therapy (CPI naive), and topoisomerase I inhibitor therapy.

In some embodiments, the subject has not received prior taxane therapy (taxane naive), has not received checkpoint inhibitor therapy (CPI naive), or has not received topoisomerase I inhibitor therapy.

In some embodiments, the taxane therapy comprises paclitaxel, naphtha-paclitaxel (ABRAXANE®), docetaxel, or cabazitaxel.

In some embodiments, the checkpoint inhibitor therapy comprises an anti-CTLA4 antibody or an anti-PD(L)1 antibody.

In some embodiments, the topoisomerase I inhibitor therapy comprises topotecan, irinotecan, belotecan, or exatecan.

In some embodiments, the anti-Trop-2 ADC and the adenosine pathway inhibitor are co-administered concurrently.

In some embodiments, the anti-Trop-2 ADC and the adenosine pathway inhibitor are co-administered sequentially.

In some embodiments, the subject is a human.

In some embodiments, the anti-Trop-2 ADC is administered in one or more doses ranging from 8 mg/kg to 10 mg/kg.

In some embodiments, the anti-Trop2 ADC is administered in one or more doses of 8 mg/kg or 10 mg/kg.

In some embodiments, the anti-Trop2 ADC is administered in one or more doses of 10 mg/kg.

In some embodiments, the anti-Trop-2 ADC is administered intravenously.

In some embodiments, the anti-Trop-2 ADC is administered on days 1 and 8 of a 21-day cycle.

In some embodiments, the adenosine pathway inhibitor is administered in one or more doses of 75 mg or 150 mg.

In some embodiments, the adenosine pathway inhibitor is administered in one or more doses of 150 mg.

In some embodiments, the adenosine pathway inhibitor is administered orally (PO).

In some embodiments, the adenosine pathway inhibitor is administered once daily (QD).

In some embodiments, the anti-PD(L)1 antibody is administered in one or more doses of 360 mg.

In some embodiments, the anti-PD(L)1 antibody is administered intravenously (IV).

In some embodiments, the anti-PD(L)1 antibody is administered once every three weeks (Q3W).

In some embodiments, sacituzumab govitecan is administered intravenously (IV) at a dose of 10 mg/kg on days 1 and 8 of a 21-day treatment cycle, etrumadenanth is administered orally (PO) at a dose of 150 mg once daily (QD) of a 21-day treatment cycle, and optionally, zimberelimab is administered intravenously (IV) on day 1 (Q3W) of a 21-day treatment cycle.

In some embodiments, the anticancer effect is observed as determined by objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), overall survival (OS), complete response (CR), partial response (PR), PSA response rate, radiographic response rate, change from baseline in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers, or a combination thereof. In some embodiments, tumor response or progression is determined according to RECIST version 1.1.

In some embodiments, provided herein is a method of treating, alleviating, reducing, preventing, or delaying recurrence or metastasis of castration-resistant prostate cancer (CRPC), comprising co-administering to a human patient an effective amount of a) sacituzumab govitecan; and b) etrummadenant. In some embodiments, provided herein is a method of treating metastatic castration-resistant prostate cancer (mCRPC), comprising co-administering to the human patient an effective amount of a) sacituzumab govitecan; and b) etrummadenant. In some embodiments, the method further comprises co-administering to the human patient an anti-PD-(L)1 antibody. In some embodiments, the anti-PD-(L)1 antibody is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cosibelimab, sasanlimab, tislelizumab, retipanlimab, balstilimab, toripalimab, setrelimab, genolimab, progolimab, rodafolimab, camrelizumab, budigalimab, avelumab, dostalimab, envapolimab, sintilimab, and zimberelimab. In some embodiments, the method further comprises co-administering zimberelimab to the human patient. In some embodiments, the human mCRPC patient has previously undergone ADT. In some embodiments, the human mCRPC patient has previously undergone NHA. In some embodiments, the human mCRPC patient is CPI and taxane naive. In some embodiments, the human mCRPC patient has RECIST 1.1 measurable or non-measurable disease.

In some embodiments, the CRPC is metastatic CRPC (mCRPC).

In some embodiments, CRPC is resistant or refractory to one or more anticancer therapies.

In some embodiments, CRPC progressed after prior NHA therapy (first- or second-generation non-steroidal antiandrogens, abiraterone).

In some embodiments, the human patient has not received prior therapy selected from: taxane therapy (taxane naive), checkpoint inhibitor therapy (CPI naive), and topoisomerase I inhibitor therapy.

In some embodiments, the human patient has not received prior taxane therapy (taxane naive), has not received checkpoint inhibitor therapy (CPI naive), or has not received topoisomerase I inhibitor therapy.

In some embodiments, the taxane therapy comprises paclitaxel, naphtha-paclitaxel (ABRAXANE®), docetaxel, or cabazitaxel.

In some embodiments, the checkpoint inhibitor therapy comprises an anti-CTLA4 antibody or an anti-PD(L)1 antibody.

In some embodiments, the topoisomerase I inhibitor therapy comprises topotecan, irinotecan, belotecan, or exatecan.

In some embodiments, provided herein are methods of treating, alleviating, reducing, preventing, or delaying recurrence or metastasis of non-small cell lung cancer (NSCLC), comprising co-administering to a human patient effective amounts of: a) sacituzumab govitecan; b) etrummadenant; and c) an anti-PD-(L)1 antibody. In some embodiments, the anti-PD-(L)1 antibody is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cosibelimab, sasanlimab, tislelizumab, retipanlimab, balstilimab, toripalimab, setrelimab, genolimab, progolimab, rodafolalimab, camrelizumab, budigalimab, avelumab, dostalimab, envapolimab, scintillimab, and zimberelimab. In some embodiments, the anti-PD-(L)1 antibody is zimberelimab. In some embodiments, the NSCLC has progressed or relapsed following platinum-based chemotherapy. In some embodiments, the NSCLC has progressed or relapsed following checkpoint inhibitor (CPI) therapy. In some embodiments, the NSCLC progressed or recurred after receiving platinum-based chemotherapy and anti-PD-(L)1 antibody therapy, either sequentially or in any order. In some embodiments, the NSCLC progressed or recurred after tyrosine kinase inhibitor therapy. In some embodiments, the NSCLC is (i) unresectable locally advanced or (ii) metastatic.

In some embodiments, sacituzumab govitecan is administered intravenously (IV) at a dose of 8 mg/kg or 10 mg/kg on days 1 and 8 of a 21-day treatment cycle, and etrumadenoate is administered orally (PO) at a dose of 75 mg or 150 mg once daily (QD) of a 21-day treatment cycle.

In some embodiments, sacituzumab govitecan is administered intravenously (IV) at a dose of 10 mg/kg on days 1 and 8 of a 21-day treatment cycle, and etrumadenoate is administered orally (PO) at a dose of 150 mg once daily (QD) of a 21-day treatment cycle.

In some embodiments, zimberelimab is administered intravenously (IV) on day 1 (Q3W) of a 21-day treatment cycle.

In some embodiments, the anticancer effect is observed as determined by objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), overall survival (OS), complete response (CR), partial response (PR), PSA response rate, radiological response rate, change from baseline in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers, or a combination thereof. In some embodiments, the anticancer effect is observed as determined by objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), complete response (CR), partial response (PR), PSA response rate, radiological response rate, or change from baseline in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers.

In some embodiments of the methods provided herein, the anti-CD47 antibody (e.g., magrolimab) is not co-administered to the subject or human patient.

In some embodiments of the methods provided herein, the MCL1 inhibitor (e.g., GS-9716) is not co-administered to the subject or human patient.

In some embodiments of the methods provided herein, the FLT3 agonist (e.g., GS-3583, CDX-301) is not administered to the subject or human patient.

In another aspect, provided herein is a method of treating, alleviating, reducing, preventing, or delaying recurrence or metastasis of a tumor antigen positive (TA ⁺ ) cancer, comprising co-administering to a subject an effective amount of: a) a tumor antigen (TA) targeted ADC (TopI ADC) comprising a topoisomerase I inhibitor; b) an adenosine pathway inhibitor; and c) optionally an anti-PD(L)1 antibody.

In another aspect, provided herein are anti-Trop-2 ADCs for use in combination with an adenosine pathway inhibitor and optionally an anti-PD(L)1 antibody in a method of treating, alleviating, reducing, preventing, or delaying recurrence or metastasis of a Trop-2 positive cancer, wherein the method comprises administering to a subject the anti-Trop-2 ADC, the adenosine pathway inhibitor, and optionally an additional anti-PD(L)1 antibody.

In another aspect, ^provided herein are TopI ADCs for use in combination with an adenosine pathway inhibitor and optionally an anti-PD(L)1 antibody in a method of treating, alleviating, reducing, preventing, or delaying recurrence or metastasis of tumor antigen positive (TA+) cancer, wherein the method comprises administering to a subject the TopI ADC, the adenosine pathway inhibitor, and optionally an anti-PD(L)1 antibody.

Provided herein are combination therapies for treating, ameliorating, reducing, preventing, or delaying the recurrence or metastasis of a Trop-2 positive (Trop-2 ⁺ ) cancer by co-administering to a subject an effective amount of a) an anti-Trop-2 antibody-drug conjugate (anti-Trop-2 ADC) and b) an adenosine pathway inhibitor. Also provided herein are combination therapies for treating, ameliorating, reducing, preventing, or delaying the recurrence or metastasis of a tumor antigen positive (TA ⁺ ) cancer by co-administering to a subject an effective amount of a) a tumor antigen (TA) targeted ADC comprising a topoisomerase I inhibitor (TopI ADC) and b) an effective amount of an adenosine pathway inhibitor. In some embodiments, the combination therapies provided herein further comprise co-administering an additional therapeutic agent, such as a checkpoint inhibitor, or an additional treatment modality (e.g., surgery, radiation). In some embodiments, the anti-Trop-2 ADC is sacituzumab govitecan. In some embodiments, the TopI ADC is trastuzumab-deruxtecan (T-DXd). In some embodiments, the adenosine pathway inhibitor is a CD39 inhibitor (e.g., TTX-030, IPH5201, SRF617), a CD73 inhibitor (e.g., chemriclustat, oleculumab), or an adenosine receptor antagonist (e.g., etrumadenanth, imaradenant, NIR178). In some embodiments, the checkpoint inhibitor is an anti-PD(L)1 antibody (e.g., zimberelimab, pembrolizumab, nivolumab, atezolizumab, durvalumab). In some embodiments, the Trop-2 positive cancer is castration-resistant prostate cancer (CRPC) or non-small cell lung cancer (NSCLC).

In another aspect, provided herein is an anti-Trop-2 ADC (e.g., sacituzumab govitecan) for use in combination with an adenosine pathway inhibitor (e.g., etrumadenoate), and optionally an additional therapeutic agent such as a checkpoint inhibitor (e.g., an anti-PD(L)1 antibody), or an additional treatment modality (e.g., surgery, radiation) for treating, palliating, reducing, preventing, or delaying recurrence or metastasis of a Trop-2 positive cancer, wherein the method comprises administering to a subject (e.g., a human cancer patient) the anti-Trop-2 ADC, the adenosine pathway inhibitor, and optionally the additional therapeutic agent or additional treatment modality. In some embodiments, the anti-Trop-2 ADC is sacituzumab govitecan. In some embodiments, the adenosine pathway inhibitor is a CD39 inhibitor (e.g., TTX-030, IPH5201, SRF617), a CD73 inhibitor (e.g., chemriclustat, oleculumab), or an adenosine receptor antagonist (e.g., etrumadenanth, imaradenant, NIR178). In some embodiments, the checkpoint inhibitor is an anti-PD(L)1 antibody (e.g., zimberelimab, pembrolizumab, nivolumab, atezolizumab, durvalumab). In some embodiments, the Trop-2 positive cancer is castration-resistant prostate cancer (CRPC) or non-small cell lung cancer (NSCLC).

In another aspect, provided herein is a TopI ADC for use in combination with an adenosine pathway inhibitor (e.g., a CD39 inhibitor, a CD73 inhibitor, an adenosine receptor antagonist) and optionally an additional therapeutic agent such as a checkpoint inhibitor (e.g., an anti-PD(L)1 antibody), or an additional treatment modality (e.g., surgery, radiation) in a method of treating, alleviating, reducing, preventing, or delaying recurrence or metastasis of a TA-positive cancer, wherein the method comprises administering to a subject (e.g., a human cancer patient) the TopI ADC, the adenosine pathway inhibitor, and optionally the additional therapeutic agent or additional treatment modality. In some embodiments, the TopI ADC is trastuzumab-deruxtecan (T-DXd). In some embodiments, the adenosine pathway inhibitor is a CD39 inhibitor (e.g., TTX-030, IPH5201, SRF617), a CD73 inhibitor (e.g., chemriclustat, oleculumab), or an adenosine receptor antagonist (e.g., etrumadenanth, imaradenant, NIR178). In some embodiments, the checkpoint inhibitor is an anti-PD(L)1 antibody (e.g., zimberelimab, pembrolizumab, nivolumab, atezolizumab, durvalumab). In some embodiments, the Trop-2 positive cancer is castration-resistant prostate cancer (CRPC) or non-small cell lung cancer (NSCLC).

The present disclosure is based, at least in part, on the understanding that combination therapy comprising co-administration of a) an anti-Trop2 ADC or a TopI ADC and b) an adenosine pathway inhibitor can have improved anticancer effects compared to single agent therapy using either of the combination agents a) and b). The improved anticancer effects can include, for example, improved overall response rate (ORR), improved partial response rate (PR), improved complete response rate (CR), improved duration of response (DOR), improved overall survival (OS), improved progression-free survival (PFS), improved quality of life (QoL) indicators, and the like. The combination therapies described herein generally have an acceptable safety profile, as determined, for example, by the incidence and/or severity of observed adverse events (AEs) or serious adverse events (SAEs). In some embodiments, the combination therapies described herein have an improved safety profile, for example, compared to monotherapy involving co-administered agents or compared to the standard of care for a given indication (e.g., a physician-selected chemotherapy regimen).

definition

As used herein, the term "antibody" refers to a polypeptide comprising standard immunoglobulin sequence elements sufficient to confer specific binding to a particular target antigen (e.g., a heavy chain variable domain, a light chain variable domain, and/or one or more CDRs sufficient to confer specific binding to a particular target antigen). Thus, the term antibody includes antigen binding agents, including, but not limited to, human antibodies, non-human antibodies, antibody fragments, and antibody fragments, including synthetic, engineered, and modified forms. The term antibody includes, by way of example, both naturally occurring antibodies and non-naturally occurring antibodies. Generally, an antibody can comprise at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds, or antigen-binding molecules thereof. Each heavy (H) chain comprises a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region comprises three constant domains, namely CH1, CH2, and CH3. Each light chain comprises a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region comprises a constant domain (CL). The VH and VL regions can be further subdivided into hypervariable regions, termed complementarity determining regions (CDRs), which are interspersed with more conserved regions, termed framework regions (FRs). Each VH and VL comprises three CDRs and four FRs, arranged from amino terminus to carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The variable regions of the heavy and light chains contain binding domains that interact with antigen. The constant region of an antibody (Ab) can mediate binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system. Naturally produced antibodies are typically glycosylated on the CH2 domain. Examples of antibodies include monoclonal antibodies, monospecific antibodies, polyclonal antibodies, multispecific antibodies (including bispecific antibodies), engineered antibodies, recombinantly produced antibodies, wholly synthetic antibodies, humanized antibodies, chimeric antibodies, immunoglobulins, tetrameric antibody molecules comprising two heavy chains and two light chain molecules, antibody light chain monomers, antibody heavy chain monomers, antibody light chain dimers, antibody heavy chain dimers, antibody light chain-antibody heavy chain pairs, intrabodies, antibody fusions (sometimes referred to herein as "antibody conjugates"), heteroconjugate antibodies, single domain antibodies, monovalent antibodies, single chain antibodies or single chain Fv (scFv), camelized antibodies, affybodies, Fab fragments, Fab' fragments, F(ab')2 fragments, Fd' fragments, Fd fragments, isolated CDRs, single chain Fvs, polypeptide-Fc fusions, single domain antibodies (e.g., shark single domain antibodies, such as IgNAR or fragments thereof); cameloid antibodies; disulfide-linked Fv (sdFv), anti-idiotypic (anti-Id) antibodies (including, for example, anti-anti-Id antibodies), minibodies, domain antibodies, synthetic antibodies (sometimes referred to herein as "antibody mimics"), single chain or tandem diabodies (TandAb®), Anticalins®, Nanobodies®, minibodies, BiTE®, ankyrin repeat proteins or DARPINs®, Avimers®, DARTs, TCR-like antibodies, Adnectins®, Affilins®, Trans-bodies®, Affibodies®, TrimerX®, MicroProteins, Fynomers®, Centyrins®, KALBITOR®, and antigen-binding fragments of any of the above.

As used herein, "antibody-drug conjugate" generally refers to a compound comprising an antibody targeting a tumor antigen and an anticancer agent payload, optionally linked by a linker. In some embodiments, the tumor antigen is tumor-associated calcium signal transducer 2 (Trop-2; NCBI Gene No. 4070). In some embodiments, the tumor antigen targeted antibody is an anti-Trop-2 antibody (e.g., sacituzumab or datopotamab). In some embodiments, the payload is a topoisomerase I inhibitor (e.g., SN38 or Dxd). Many ADC linker chemistries are known to those of skill in the art and are referenced herein (e.g., CL2A).

As used herein, the term "topoisomerase I inhibitor" refers to a small molecule compound capable of inhibiting the activity of DNA topoisomerase type I enzyme. Type I topoisomerases can catalyze changes in DNA topology through transient single-strand breaks in DNA. Type I topoisomerases can be further classified into type 1A and type 1B subtypes. A description of type I topoisomerases can be found, for example, in Baker et al. (2009) Nucleic Acids Res 37(3), 693-701 . Topoisomerase inhibitors that can be used as payloads in the ADCs described herein include camptothecin (CPT) and non-camptothecin based inhibitors. Useful camptothecins include, for example, topotecan, irinotecan, belotecan, exatecan and derivatives thereof. Useful non-camptothecins include, for example, indenosinoquinolines (e.g., indeno[1,2-c]isoquinolines, NSC314622, indotecan (LMP-400), indimitecan (LMP-776)), phenanthridines (e.g., tofovaler (ARC-111)), and indolocarbazoles (e.g., BE-13793C). In some embodiments, the topoisomerase I inhibitor is a camptothecin (e.g., irinotecan, topotecan, belotecan, or exatecan derivatives, such as SN38 or Dxd). In some embodiments, the topoisomerase I inhibitor is SN38. In some embodiments, the topoisomerase I inhibitor is Dxd.

As used herein, the term "anti-PD(L)1 antibody" refers to an antibody that a) binds to programmed cell death protein 1 (PD-1, CD279; NCBI Gene No. 5133) or programmed death ligand 1 (PD-L1, CD274; NCBI Gene No. 29126); and b) inhibits PD-1/PD-L1 interactions and the PD-1/PD-L1 pathway. The PD-1/PD-L1 pathway and its role in cancer immunotherapy are described, for example, in Salmaninejad et al , J. Cell Physiol (2019) 234 (10): 16824-16837. Anti-PD(L)1 antibodies that may be used in the methods provided herein include, for example, pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cosibelimab, sasanlimab, tislelizumab, retipanlimab, balstilimab, toripalimab, setrelimab, genolimab, progolimab, rodafolimab, camrelizumab, budigalimab, avelumab, dostalimab, envafolimab, sintilimab, and zimberelimab. In some embodiments, the anti-PD(L)1 antibody is zimberelimab.

As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of a therapeutic agent (e.g., an ADC, an adenosine pathway inhibitor, a checkpoint inhibitor) administered in the methods provided herein, alone or in combination with other therapeutic agents, that is sufficient to effect treatment or a beneficial result in the subject. The therapeutically effective amount will vary depending on the subject, the disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the mode of administration, and can be readily determined by one of skill in the art. An effective amount further refers to an amount of an additional therapeutic agent sufficient to treat, prevent, alleviate, ameliorate, alleviate, or alleviate a disease state, or to delay or slow the progression of a disease, and an amount sufficient to effect an increase in the rate of treatment, cure, prevention, or amelioration of such a disease. When applied to an individual therapeutic agent administered alone, an effective amount refers only to that active ingredient. When applied to a combination, a therapeutically effective amount refers to the combined amount of the active ingredients, whether administered sequentially or simultaneously, in combination, that produces a therapeutic effect. In some embodiments, an effective amount or therapeutically effective amount of a therapeutic agent (e.g., an ADC, an adenosine pathway inhibitor, a checkpoint inhibitor) administered to a subject in a method provided herein, in combination with one or more additional therapeutic agents, as described herein, can: (i) reduce the number of diseased cells; (ii) reduce tumor size; (iii) inhibit, delay, and/or somewhat slow down and preferably stop diseased cell infiltration into peripheral organs; (iv) inhibit (e.g., somewhat slow down and preferably stop) tumor metastasis; (v) inhibit tumor growth; (vi) prevent or delay the occurrence and/or recurrence of a tumor; and/or (vii) alleviate to some extent one or more of the symptoms associated with the cancer. In various embodiments, the amount is sufficient to ameliorate, temporarily alleviate, reduce and/or delay one or more of the symptoms of the cancer.

As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset, or inhibiting the progression of a disease or disorder, or one or more symptoms thereof, described herein. In some embodiments, the treatment may be administered after one or more symptoms have developed. In other embodiments, the treatment may be administered in the absence of symptoms. For example, the treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., taking into account a history of symptoms and/or genetic or other predisposing factors). The treatment may also be continued after the symptoms have resolved, for example, to prevent or delay their recurrence. In some embodiments, the methods provided herein refer to treating a subject having cancer (e.g., a human cancer patient). In some embodiments, treating a subject having cancer (e.g., a human cancer patient) comprises inhibiting cancer or cancer cell proliferation in the subject being treated. In some embodiments, when treating a human cancer patient using the methods provided herein, an antitumor or anticancer effect is observed in the treated patient.

As used herein, the terms “inhibition of cancer” and “inhibition of cancer cell proliferation” refer to inhibition of the growth, division, maturation or viability of cancer cells, and/or causing death of cancer cells, either individually or collectively with other cancer cells, by induction of cytotoxicity, nutrient starvation or apoptosis.

As used herein, the term "antitumor effect", "anticancer effect" or "anticancer efficacy" refers to a biological effect which may be manifested as a decrease in tumor volume, a decrease in tumor cell number, a decrease in tumor cell proliferation, a decrease in the number of metastases, an increase in overall survival or progression-free survival, an increase in life expectancy, or an improvement in various physiological symptoms associated with a tumor. In some embodiments, the anticancer effect is measured using one or more of the endpoint criteria applied to the clinical studies described herein (e.g., primary, secondary or exploratory endpoints). Exemplary clinical endpoint criteria that may be used to measure anti-cancer efficacy in connection with the methods provided herein include objective response rate (ORR), complete response rate (CR), partial response rate (PR), disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), overall survival (OS), biomarker-based signals, such as biomarker-based signals of intratumoral immune activation or induction of cancer cell death (e.g., tumor tissue- or blood-based biomarkers), patient quality of life (QoL) indicators (e.g., based on patient questionnaires), etc. In some embodiments, anti-tumor efficacy (e.g., tumor response or progression) is determined according to RECIST version 1.1 (Eisenhauer et al. Eur J Cancer (2009);45 (2):228-47). Anti-cancer efficacy can be monitored using any diagnostic method known to those of skill in the art, such as computed tomography (CT), magnetic resonance imaging (MRI), radiography, etc.

As used herein, an “increased” amount or an “increased” amount (e.g., in relation to tumor cell, cancer cell proliferation or growth) is typically a “statistically significant” amount and can include an increase of at least 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, or 50-fold (e.g., 100, 500, 1000-fold) of an amount or level disclosed herein (including all integers and decimals greater than 1 between these numbers, e.g., 2.1, 2.2, 2.3, 2.4-fold, etc.). This may also include an increase of at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 150%, at least 200%, at least 500% or at least 1000% of the amount or level described herein.

As used herein, a “decreased” amount, a “reduced” amount, or a “lesser” amount (e.g., with respect to tumor size, cancer cell proliferation or growth) refers to a decrease that is at least about 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, or 50-fold (e.g., 100, 500, 1000-fold) of the amount or level described herein (including all integers and decimals greater than 1 between these numbers, e.g., 1.5, 1.6, 1.7, 1.8-fold, etc.). This may also include a reduction of at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80% or at least 90%, at least 100%, at least 150%, at least 200%, at least 500% or at least 1000% of the amount or level described herein.

As used herein, the term "adverse event" (AE) refers to any unexpected medical event that occurs in a clinical study participant receiving study drug that is not necessarily causally related to the treatment. Thus, an AE may be any undesirable and/or unintended sign (including clinically significant abnormal laboratory findings), symptom, or disease that is temporally associated with the use of the study drug, regardless of whether the AE is considered to be related to the study drug. An adverse event may also include pre- or post-treatment complications that occur as a result of protocol-specified procedures or special circumstances. In some embodiments, a pre-existing event that increases in severity or changes in nature following study drug initiation or during or as a result of participation in the clinical study is also considered an AE.

As used herein, the term “serious adverse event” (SAE) refers to a) death; b) life-threatening condition; c) hospitalization of the participant or prolongation of existing hospitalization; d) persistent or significant disability or incapacity; e) congenital anomaly or birth defect; or f) a medically significant event or reaction as determined by the attending physician. Examples of medically significant events include intensive care in the emergency room or at home for allergic bronchospasm; blood disorders or seizures that do not result in hospitalization; and development of drug dependence or drug abuse.

As used herein, the terms "tumor antigen expressing cancer" or "tumor antigen positive cancer" are used interchangeably to refer to a cancer having detectable levels of tumor antigen (TA) expression. In some embodiments, the tumor antigen is Trop-2. Tumor antigen expression in cancer tissue or cancer cells can be detected in a sample from a subject having cancer (e.g., a human cancer patient) by any method known to the skilled artisan, for example, as a protein, mRNA, or cell surface expression level. For example, tumor antigen expression can be determined by methods such as immunohistochemistry (IHC), Western blot, fluorescence in situ hybridization (FISH), polymerase chain reaction (PCR), next generation exome sequencing, or fluorescence-linked cell sorting (FACS). As used herein, not all cells in a tumor or tumor sample need to have detectable levels of tumor antigen expression to be considered TA positive (e.g., Trop-2 positive). In some embodiments, in a “TA expressing cancer” or a “TA positive cancer”, less than 99%, less than 95%, less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, or less than 10% of the cells in the tumor or tumor sample have detectable levels of tumor antigen expression. In some embodiments, in a “TA expressing cancer” or a “TA positive cancer”, greater than or equal to 99%, greater than or equal to 95%, greater than or equal to 90%, greater than or equal to 80%, greater than or equal to 70%, greater than or equal to 60%, greater than or equal to 50%, greater than or equal to 40%, greater than or equal to 30%, greater than or equal to 20%, or greater than or equal to 10% of the cells in the tumor or tumor sample have detectable levels of tumor antigen expression. In some embodiments, a “TA expressing cancer” or a “TA positive cancer” (e.g., a Trop-2 positive cancer) refers to a cancer for which treatment with a particular anti-Trop-2 ADC or TopI ADC is recommended, either as a single agent regimen or in combination. TA positive cancer indications for an anti-Trop-2 ADC or TopI ADC that has received marketing approval from a health regulatory agency (e.g., FDA, EMA) are listed, for example, on the agency-approved drug product label. In some embodiments, a TA positive (e.g., Trop-2 ⁺ ) cancer, as used herein, is a cancer for which an anti-Trop-2 ADC or TopI ADC exhibits an anti-cancer effect attributable to the anti-Trop-2 ADC or TopI ADC. Such anti-cancer effect can be demonstrated in preclinical models (e.g., mouse xenograft or syngeneic cancer models) or in clinical trials conducted in human cancer patients. In some embodiments, the TA expressing cancer or TA positive cancer does not express detectable levels of Trop-2, as determined, for example, by IHC and/or FISH analysis.

As used herein, the term "tumor antigen targeted antibody-drug conjugate (ADC)" generally refers to an ADC comprising a tumor antigen-binding antibody. Such TA binding antibodies are generally capable of directing the ADC to TA expressing cancer cells in tumor tissue. In some embodiments, the TA binding antibody is a neutralizing or blocking antibody (competes with binding of other binding partners to the TA). In some embodiments, the TA binding antibody can modulate a TA associated molecular or cellular signaling event. In some embodiments, the TA binding antibody has antagonistic or agonistic activity against the TA. TA targeted ADCs that can be used in the methods provided herein include, but are not limited to, gemtuzumab ozogamicin, brentuximab vedotin, ado-trastuzumab emtansine (T-DM1), inotuzumab ozogamicin, trastuzumab deruxtecan (T-DXD), datofotamab deruxtecan (DATO-DXD), polatuzumab vedotin, sacituzumab govitecan, labetuzumab govitecan, enfortumab vedotin, and belantamab mafodotin. In some embodiments, the TA targeted ADC does not bind Trop-2.

List of abbreviations and acronyms

Antibody-drug-conjugate (ADC)

The therapeutic methods provided herein comprise co-administering an antibody-drug-conjugate (ADC) to a subject, e.g., a human cancer patient. In some embodiments, the ADC comprises an anti-Trop-2 antibody, an anti-cancer payload, and an optional linker connecting the anti-Trop-2 antibody and the payload (anti-Trop-2 ADC). In some embodiments, the anti-cancer payload in the anti-Trop-2 ADC is a topoisomerase I inhibitor (e.g., SN38, Dxd). In some embodiments, the anti-Trop-2 ADC does not comprise a topoisomerase I inhibitor. In some embodiments, the ADC comprises a tumor antigen (TA) targeted antibody, a topoisomerase I inhibitor payload, and an optional linker connecting the TA targeted antibody and the payload (TopI ADC). In some embodiments, the TA targeted antibody in the TopI ADC is an anti-Trop-2 antibody. In some embodiments, the TA targeted antibody in the TropI ADC does not comprise an anti-Trop-2 antibody.

ADCs that can be used in the methods provided herein can comprise an antibody in any format or an antigen-binding fragment thereof. For example, the ADC can comprise, but is not limited to, a monospecific or multispecific (e.g., bispecific, trispecific) antibody in any format, or an antigen-binding fragment thereof, such as a DART®, Duobody®, BiTE®, BiKE, TriKE, XmAb®, TandAb®, scFv, Fab or Fab derivative. In some embodiments, the ADC comprises a non-immunoglobulin antibody mimic (including, for example, adnectin, affibody, affilin, affimer, affitin, alphabody, anticalin, pentide aptamer, armadillo repeat protein (ARM), atrimer, avimer, designed ankyrin repeat protein ( ^DARPin® ), phenomer, notin, Kunitz domain peptide, monobody and nanoCLAMP).

In some embodiments, the ADC antibody is a blocking antibody. In some embodiments, the ADC antibody is a neutralizing antibody. In some embodiments, the ADC antibody is an agonistic or activating antibody. In some embodiments, the ADC antibody is an antagonistic or inhibitory antibody.

In some embodiments, the ADC comprises an IgG antibody or an antigen-binding fragment thereof. The IgG antibody or antigen-binding fragment thereof can be of various isotypes, such as IgG1, IgG2, IgG3 or IgG4. In some embodiments, the ADC antibody comprises human IgG1 hinge and constant region sequences. The ADC antibody can be a chimeric human-mouse, chimeric human-primate, humanized (human framework and murine hypervariable (CDR) regions) or fully human antibody, as well as variants thereof. In some embodiments, the ADC antibody is a half-IgG4 antibody (referred to as a "unibody"), e.g., as described in van der Neut Kolfschoten et al., Science 2007; 317:1554-1557. In some embodiments, the ADC antibody or antigen-binding fragment thereof is designed or selected to comprise a human constant region sequence belonging to a particular allotype, which may result in reduced immunogenicity when the antibody or ADC is administered to a human subject. In some embodiments, the ADC antibody or antigen-binding fragment thereof is of a non-Glml allotype (nGlml), such as Glm3, Glm3,1, Glm3,2 or Glm3,1,2. In some embodiments, the allotype is selected from the group consisting of nGlml, Glm3, nGlml, 2 and Km3 allotypes.

Anti-TROP-2 ADC

In some embodiments, an ADC that can be used in the methods provided herein comprises an anti-Trop-2 antibody, an anti-cancer payload, and an optional linker linking the anti-Trop-2 antibody and the payload (an anti-Trop-2 ADC). In some embodiments, the payload is a topoisomerase I inhibitor. In some embodiments, the payload does not comprise a topoisomerase I inhibitor.

Examples of anti-Trop-2 antibodies that can be used in anti-Trop-2 ADCs to perform the methods provided herein include those disclosed in WO2020016662 (Abmart), WO2020249063 (Bio-Thera Solutions), US20190048095 (Bio-Thera Solutions), WO2013077458 (LivTech/Chiome), EP20110783675 (Chiome), WO2015098099 (Daiichi Sankyo), WO2017002776 (Daiichi Sankyo), WO2020130125 (Daiichi Sankyo), WO2020240467 (Daiichi Sankyo), US2021093730 (Daiichi Sankyo), US9850312 (Daiichi Sankyo), CN112321715 (Biosion), US2006193865 (Immunomedics/Gilead), WO2011068845 (Immunomedics/Gilead), US2016296633 (Immunomedics/Gilead), US2017021017 (Immunomedics/Gilead), US2017209594 (Immunomedics/Gilead), US2017274093 (Immunomedics/Gilead), US2018110772 (Immunomedics/Gilead), US2018185351 (Immunomedics/Gilead), US2018271992 (Immunomedics/Gilead), WO2018217227 (Immunomedics/Gilead), US2019248917 (Immunomedics/Gilead), CN111534585 (Immunomedics/Gilead), US2021093730 (Immunomedics/Gilead), US2021069343 (Immunomedics/Gilead), US8435539 (Immunomedics/Gilead), US8435529 (Immunomedics/Gilead), US9492566 (Immunomedics/Gilead), WO2003074566 (Gilead), WO2020257648 (Gilead), US2013039861 (Gilead), Including but not limited to those described in WO2014163684 (Gilead), US9427464 (LivTech/Chiome), US10501555 (Abruzzo Theranostic/Oncoxx), WO2018036428 (Sichuan Kelun Pharma), WO2013068946 (Pfizer), WO2007095749 (Roche), and WO2020094670 (SynAffix).

In some embodiments of the methods provided herein, the anti-Trop-2 ADC comprises an antibody selected from sacituzumab (hRS7), datopotamab (hTINA H1L1) and Trop-2 binding fragments thereof. In some embodiments, the anti-Trop-2 ADC is sacituzumab (hRS7). In some embodiments, the anti-Trop-2 antibody is datopotamab (hTINA H1L1).

In some embodiments of the methods provided herein, the anti-Trop-2 ADC comprises a VH-CDR1, a VH-CDR2, a VH-CDR3, a VL-CDR1, a VL-CDR2 and a VL-CDR3 selected from one of Tables 1 to 4. In some embodiments, the anti-Trop-2 ADC comprises the following VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2 and VL-CDR3 amino acid sequences (according to Kabat):

서열번호 1, 2, 3, 4, 5 및 6, 또는

Sequence numbers 1, 2, 3, 4, 5 and 6, or

Sequence numbers 7, 8, 9, 10, 11 and 12.

In some embodiments of the methods provided herein, the anti-Trop-2 ADC comprises variable domains (VH and VL) selected from Table 5. In some embodiments, the anti-Trop-2 ADC comprises the following VH and VL amino acid sequences, respectively:

Sequence numbers 49 and 50, or

Sequence numbers 51 and 52.

[Table 1]

[Table 2]

[Table 3]

[Table 4]

[Table 5]

In some embodiments of the methods provided herein, the anti-Trop-2 ADC comprises an anti-Trop-2 antibody, an anti-cancer payload, and an optional linker linking the antibody and the payload. In some embodiments, the linker is non-cleavable (e.g., a maleimidocaproyl or maleimidomethyl cyclohexane-1-carboxylate linker). In some embodiments, the linker is cleavable. In some embodiments, the linker is acid cleavable (e.g., a hydrazone linker). In some embodiments, the cleavable linker is reducible (e.g., a disulfide linker). In some embodiments, the linker is protease cleavable (e.g., a dipeptide or tetrapeptide linker). In some embodiments, the linker is selected from linkers disclosed in USPN 7,999,083 (e.g., CL2A, CL6, CL7, CLX, or CLY). In some embodiments, the linker is CL2A. Additional linker chemistries useful for anti-Trop-2 ADCs are described, for example, in WO21225892 (Shanghai Escugen Biotechnology; ESG-401, STI-3258), WO22010797 (BiOneCure Therapeutics; BIO-106), CN112237634 (Shanghai Fudan-Zhangjiang Biopharmaceutical; FDA018-ADC), WO19114666 (Sichuan Kelun Pharmaceutical; KLA264), WO22078524 (Hangzhou DAC Biotech; DAC-002), WO15098099 (Daiichi Sankyo; datopotamab deruxtecan), WO21147993 (Jiangsu Hengrui Medicine; SHR-A1921), and It is described in WO21052402 (Sichuan Baili Pharmaceutical; BL-M02D1).

Exemplary anticancer payloads that can be used in the anti-Trop-2 ADCs in the methods provided herein include, for example, microtubule inhibitors, DNA cleavage agents, and topoisomerase I inhibitors. In some embodiments, the microtubule inhibitor is an auristatin (e.g., monomethyl auristatin E (MMAE) or monomethyl auristatin F (MMAF), a taxane, a vinca alkaloid, an epothilone) or a maytansinoid (e.g., mertansine (DM1) or labtansine (DM4)). In some embodiments, the DNA cleavage agent is a calicheamicin (e.g., ozogamicin). In some embodiments, the topoisomerase I inhibitor is a camptothecin (e.g., irinotecan, topotecan, belotecan, or exatecan derivatives, such as SN38 or Dxd). In some embodiments, the topoisomerase I inhibitor is SN38. In some embodiments, the topoisomerase I inhibitor is Dxd. In some embodiments, the topoisomerase I inhibitor is not a camptothecin (i.e., a non-camptothecin topoisomerase I inhibitor). In some embodiments, the non-camptothecin topoisomerase I inhibitor is selected from an indenosynoquinoline (e.g., indeno[1,2-c]isoquinoline, NSC314622, indotecan (LMP-400), indimitecan (LMP-776)), a phenanthridine (e.g., tophovaler (ARC-111)), and an indolocarbazole (e.g., BE-13793C).

Additional exemplary anticancer payloads that may be conjugated to anti-Trop-2 ADCs include, but are not limited to, anthracyclines (e.g., doxorubicin, daunorubicin, epirubicin, idarubicin), pyrrolobenzodiazepines (PBDs) or dimers thereof, the DNA cross-linker SC-DR002 (D6.5), duocarmycins, duocarmycins (A, B1, B2, C1, C2, D, SA, CC-1065), tubulinsin B and analogs thereof (e.g., Tub196), and other anticancer agents described herein.

Exemplary anti-Trop-2 ADCs that may be used in the methods provided herein include those disclosed in WO21225892 (Shanghai Escugen Biotechnology; ESG-401, STI-3258), WO22010797 (BiOneCure Therapeutics; BIO-106), CN112237634 (Shanghai Fudan-Zhangjiang Biopharmaceutical; FDA018-ADC), WO19114666 (Sichuan Kelun Pharmaceutical; KLA264), WO22078524 (Hangzhou DAC Biotech; DAC-002), WO15098099 (Daiichi Sankyo; datopotamab deruxtecan), WO21147993 (Jiangsu Hengrui Medicine; SHR-A1921), and WO21052402 (Sichuan Baili Pharmaceutical; BL-M02D1).

In some embodiments of the methods provided herein, the anti-Trop-2 ADC is selected from the group consisting of sacituzumab govitecan (Immunomedics/Gilead), datopotamab deruxtecan (DS-1062, Dato-Dxd; Daiichi Snakyo/AstraZeneca), SKB-264 (KL-A264; Klus Pharma, Sichuan Kelun Pharma), ESG-401 (Shanghai Escugen Biotechnology/Levena Biopharma), JS-108 (DAC-002; Junshi Bio/Hangzhou DAC), FDA018-ADC (Shanghai Fudan Zhangjiang Bio Pharma), STI-3258 (Sorrento), OXG-64 (Oncoxx), BDI-4702 (OBI Pharma), BL-M02D1 (Systimmune), anti-Trop-2 Ab (Mediterrania Theranostic/Legochem), KD-065 (Nanjing KAEDI Biotech), anti-Trop2 sdAb (Kisoli Biotech), anti-Trop-2 ADC (Shandong Fontacea), LIV-2008 (LivTech/Yakult Honsha), TROP2-TRACTr (BiTE; Janux), TROP-2-IR700 (Chiome, photosensitizer), TROP2-XPAT (Amunix), BAT-8003 (Bio-Thera Solutions), GQ-1003 (Genequantum Healthcare, Samsung BioLogics), DAC-002 (Hangzhou DAC Biotech, Shanghai Junshi Biosciences), E1-3s (Immunomedics/Gilead, IBC Pharmaceuticals), s BioTech), humanized anti-Trop2-SN38 antibody conjugate (Shanghai Escugen Biotechnology, TOT Biopharma), anti-Trop2 antibody-CLB-SN-38 conjugate (Shanghai Fudan-Zhangjiang Bio-Pharmaceutical), TROP2-Ab8 (Abmart), Trop2-IgG (Nanjing Medical University (NMU)), 90Y-DTPA-AF650 (Peking University First Hospital) and hRS7-CM (SynAffix), 89Zr-DFO-AF650 (University of Wisconsin-Madison). In some embodiments, the anti-Trop-2 ADC is sacituzumab govitecan (Immunomedics/Gilead). In some embodiments, the anti-Trop-2 ADC is selected from sacituzumab govitecan, datopotamab deruxtecan (DS-1062), ESG-401, SKB-264, DAC-02 and BAT-8003. In some embodiments, the anti-Trop-2 ADC is sacituzumab govitecan. In some embodiments, the anti-Trop-2 ADC is datopotamab deruxtecan (DS-1062, Dato-Dxd; Daiichi Snakyo/AstraZeneca). Additional examples of useful anti-Trop-2 therapeutics include, but are not limited to, those described in WO2016201300 (Gilead) and CN108440674 (Hangzhou Lonzyme Biological Technology).

Anti-Trop-2 ADCs that may be used in the methods provided herein are described, for example, in USPN 7,999,083 and USPN 9,028,833, the entire contents of which are incorporated herein by reference. In some embodiments, the anti-Trop-2 ADC comprises a topoisomerase I inhibitor. In some embodiments, the topoisomerase I inhibitor is selected from irinotecan, topotecan, and SN-38. In some embodiments, the anti-Trop-2 ADC has the structural formula mAb-CL2A-SN-38, which has a structure represented by:

(e.g., as described in USPN 7,999,083). In some embodiments, the drug-to-antibody ratio (DAR) of CL2A-SN38 to the anti-Trop-2 antibody in the anti-Trop2 ADC is ≥ 7.0 (e.g., DAR = 7.6). In some embodiments, the drug-to-antibody ratio (DAR) of CL2A-SN38 to the anti-Trop-2 antibody in the anti-Trop2 ADC is 7.0 to 8.0 (e.g., DAR = 7.6). In some embodiments, the anti-Trop-2 ADC comprises sacituzumab (hRS7; e.g., as described in WO2003074566 , FIGS. 3 and 4 ). In some embodiments, the anti-Trop-2 ADC is sacituzumab govitecan (IMMU-132). Sacituzumab govitecan (SG) is an antibody-drug conjugate (ADC) composed of three components:

Humanized monoclonal antibody hRS7 IgG1κ, which binds to trophoblast cell-surface antigen 2 (Trop-2; TACSTD2; EGP-1; NCBI Gene No. 4070), a transmembrane calcium signal transducer overexpressed in many epithelial cancers, including triple-negative breast cancer (TNBC).

Camptothecin-derived preparation SN-38, a topoisomerase I inhibitor.

A hydrolyzable linker (CL2A) linking the humanized monoclonal antibody to SN-38.

Additional exemplary anti-Trop-2 ADCs that may be used in the methods provided herein are described in WO21225892 (Shanghai Escugen Biotechnology). In some embodiments, the anti-Trop-2 ADC comprises a linker-payload conjugate having a structure represented by: attached to an anti-Trop-2 antibody (e.g., hRS7)

. In some embodiments, the anti-Trop-2 ADC has a DAR of 1 to 8. In some embodiments, the anti-Trop-2 ADC has a DAR of 7.0 to 8.0. In some embodiments, the anti-Trop-2 ADC is ESG-401 (STI-3258).

Additional exemplary anti-Trop-2 ADCs that may be used in the methods provided herein are described in US20210101906 (Sichuan Kelun Pharmaceutical). In some embodiments, the anti-Trop-2 ADC comprises a linker-payload conjugate (TL035) having a structure represented by: attached to an anti-Trop-2 antibody (e.g., hRS7)

. In some embodiments, the anti-Trop-2 ADC has a DAR of 1 to 8. In some embodiments, the anti-Trop-2 ADC has a DAR of 7.0 to 8.0. In some embodiments, the anti-Trop-2 ADC has a DAR of about 7.0. In some embodiments, the anti-Trop-2 ADC is KL-A264.

Additional exemplary anti-Trop-2 ADCs that may be used in the methods provided herein are described in US2016297890 (Daiichi Sankyo). In some embodiments, the anti-Trop-2 ADC comprises a linker-payload conjugate having a structure represented by: attached to an anti-Trop-2 antibody (e.g., hTINA1-H1L1)

. In some embodiments, the anti-Trop-2 ADC has a DAR of 1 to 8. In some embodiments, the anti-Trop-2 ADC has a DAR of <7.0. In some embodiments, the anti-Trop-2 ADC has a DAR of about 4. In some embodiments, the anti-Trop-2 ADC is datopotamab deruxtecan.

TopI ADC

In some embodiments, the ADC that can be co-administered in the methods provided herein comprises a tumor antigen (TA) targeted antibody, a topoisomerase I inhibitor payload, and an optional linker linking the TA targeted antibody and the payload (TopI ADC). In some embodiments, the TA targeted antibody in the TopI ADC is an anti-Trop-2 antibody. In some embodiments, the TA targeted antibody in the TopI ADC does not comprise an anti-Trop-2 antibody.

In some embodiments, the TopI ADC that can be co-administered in the methods provided herein is carbonic anhydrase IX, B7, CCCL19, CCCL21, CSAp, HER-2/neu, BrE3, CD1, CD1a, CD2, CD3, CD4, CD5, CD8, CD11A, CD14, CD15, CD16, CD18, CD19, CD20, CD21, CD22, CD23, CD25, CD29, CD30, CD32b, CD33, CD37, CD38, CD40, CD40L, CD44, CD45, CD46, CD52, CD54, CD55, CD59, CD64, CD67, CD70, CD74, CD79a, CD80, CD83, CD95, CD126, CD133, CD138, CD147, CD154, CEACAM5, CEACAM-6, alpha-fetoprotein (AFP), VEGF, ED-B fibronectin, EGP-1, EGP-2, EGF receptor (ErbB1), ErbB2, ErbB3, factor H, FHL-1, Flt-3, folate receptor, Ga 733, GROB, HMGB-1, hypoxia-inducible factor (HIF), HM1.24, insulin-like growth factor (ILGF), IFN-a, IFN-b, IL-g, IL-2R, IL-4R, IL-6R, IL-13R, IL-15R, IL-17R, IL-18R, IL-2, IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, IL-25, IP-10, IGF-1R, Ia, HM1.24, ganglioside, A tumor selected from HCG, HLA-DR, HLA-G, CD66a-d, MAGE, mCRP, MCP-1, MIP-1A, MIP-1B, macrophage migration-inhibitory factor (MIF), MUC1, MUC2, MUC3, MUC4, MUC5, placental growth factor (P1GF), prostate-specific antigen (PSA), PSMA, PSMA dimer, PAM4 antigen, NCA-95, NCA-90, A3, A33, Ep-CAM, KS-1, Le(y), mesothelin, S100, tenascin, TAC, Tn antigen, Thomas-Friedenreich antigen, tumor necrosis antigen, tumor angiogenesis antigen, TNF-a., TRAIL receptors (R1 and R2), VEGFR, RANTES, T101, cancer stem cell antigen, complement factor C3, C3a, C3b, C5a, C5, and oncogene products Contains antibodies that bind to antigens.

In some embodiments, the TopI ADC that can be co-administered in the methods provided herein comprises an antibody that binds to a tumor antigen selected from CEACAM5 (NCBI Gene No. 1048), CEACAM6 (NCBI Gene No. 4680), CD74 (NCBI Gene No. 972), CD19 (NCBI Gene No. 930), CD20 (NCBI Gene No. 931), CD22 (NCBI Gene No. 933), CSAp (NCBI Gene No. 126731), HLA-DR, HLA-G, MUC5ac (NCBI Gene No. 4586), and AFP (NCBI Gene No. 174).

In some embodiments, the TopI ADC that can be used to perform the methods provided herein comprises antibodies and antigen-binding fragments thereof selected from gemtuzumab, brentuximab, belantamab, camidanlumab, trastuzumab, inotuzumab, glembatumumab, anetumab, mirvetuximab, depatuxizumab, badastuximab, labetuzumab, radiratuzumab, loncastuximab, patritumab, rifastuzumab, indusatumab, polatuzumab, pinatuzumab, coltuximab, apipitamab, indatuximab, milatuzumab, rovalpituzumab, enfortumab, tisotumab, tusamitamab, dicitamab, telisotuzumab.

In some embodiments, the TopI ADCs that can be used in the methods provided herein are hLL1 (anti-CD74; USPN 7,312,318), hLL2 (anti-CD22; USPN 7,074,403), hRFB4 (anti-CD22), hPAM4 (anti-MUC5ac; USPN 7,282,567), hMN-3 (anti-NOTCH3; USPN 7,541,440), hMN-14 (labetuzumab; anti-CEACAM5; USPN 6,676,924); hMN15 (anti-CEACAM6; USPN 7,541,440); An antibody selected from hA19 (anti-CD19; USPN 7,109,304), hA20 (anti-CD22; USPN 7,251,164), hMu-9 (anti-CSAp; USPN 7,387,773), hL243 (anti-HLA-DR; USPN 7,612,180), and hIMMU-31 (anti-AFP; USPN 7,300,655), which are also described, for example, in USPN 7,999,083.

In some embodiments of the methods provided herein, the TopI ADC comprises a linker that links the topoisomerase I inhibitor payload to the tumor antigen targeted antibody. In some embodiments, the linker is non-cleavable (e.g., a maleimidocaproyl or maleimidomethyl cyclohexane-1-carboxylate linker). In some embodiments, the linker is cleavable. In some embodiments, the linker is acid cleavable (e.g., a hydrazone linker). In some embodiments, the cleavable linker is reducible (e.g., a disulfide linker). In some embodiments, the linker is protease cleavable (e.g., a dipeptide or tetrapeptide linker). In some embodiments, the linker is selected from linkers disclosed in USPN 7,999,083 (e.g., CL2A, CL6, CL7, CLX, or CLY). In some embodiments, the linker is CL2A. Additional linker chemistries useful for anti-TopI ADCs are described, for example, in WO21225892 (Shanghai Escugen Biotechnology; ESG-401, STI-3258), WO22010797 (BiOneCure Therapeutics; BIO-106), CN112237634 (Shanghai Fudan-Zhangjiang Biopharmaceutical; FDA018-ADC), WO19114666 (Sichuan Kelun Pharmaceutical; KLA264), WO22078524 (Hangzhou DAC Biotech; DAC-002), WO15098099 (Daiichi Sankyo; datopotamab deruxtecan), WO21147993 (Jiangsu Hengrui Medicine; SHR-A1921), and WO21052402 (Sichuan Baili Pharmaceutical; BL-M02D1).

In some embodiments of the methods provided herein, the TopI ADC comprises a topoisomerase I inhibitor, which is a camptothecin (e.g., a irinotecan, topotecan, belotecan, or exatecan derivative, such as Dxd or SN38). In some embodiments, the topoisomerase I inhibitor in the TopI ADC is Dxd. In some embodiments, the topoisomerase I inhibitor in the TopI ADC is SN38. In some embodiments, the topoisomerase I inhibitor in the TopI ADC is not a camptothecin. In some embodiments, the non-camptothecin topoisomerase I inhibitor is selected from an indenosinoquinoline (e.g., indeno[1,2-c]isoquinoline, NSC314622, indotecan (LMP-400), indimitecan (LMP-776)), a phenanthridine (e.g., tofovale (ARC-111)), and an indolocarbazole (e.g., BE-13793C).

In some embodiments, the TopI ADC has the structural formula mAb-CL2A-SN-38, having a structure represented by:

(as described, for example, in U.S. Patent No. 7,999,083).

In some embodiments, the TopI ADC that can be used in the methods provided herein comprises carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5; CD66e; NCBI Gene No. 1048). In some embodiments, the CEACAM5 antibody is hMN-14 (e.g., as described in WO1996011013). In some embodiments, the anti-CEACAM5 ADC is as described in WO2010093395 (anti-CEACAM5-CL2A-SN38). In some embodiments, the TopI ADC is labetuzumab govitecan (IMMU-130).

In some embodiments, the TopI ADC that can be used in the methods provided herein comprises an antibody that targets the MHC class II cell surface receptor (HLA-DR) encoded by the human leukocyte antigen complex. In some embodiments, the HLA-DR antibody is hL243 (e.g., as described in WO2006094192). In some embodiments, the HLA-DR-ADC is as described in WO2010093395 (anti-HLA-DR-CL2A-SN38). In some embodiments, the antibodies and/or fusion proteins provided herein are administered together with the HLA-DR-ADC IMMU-140.

Additional exemplary TopI ADCs that may be co-administered in the methods provided herein are described in WO21225892 (Shanghai Escugen Biotechnology). In some embodiments, the TopI ADC comprises a linker-payload conjugate having a structure represented by:

.

Additional exemplary TopI ADCs that may be co-administered in the methods provided herein are described in US20210101906 (Sichuan Kelun Pharmaceutical). In some embodiments, the TopI ADC comprises a linker-payload conjugate (TL035) having a structure represented by:

.

Additional exemplary TopI ADCs that may be co-administered in the methods provided herein are described in US2016297890 (Daiichi Sankyo). In some embodiments, the TopI ADC comprises a linker-payload conjugate having a structure represented by: attached to a tumor antigen targeting antibody (e.g., trastuzumab)

.

In some embodiments, the TopI ADC has a DAR of about 4. In some embodiments, the TopI ADC is trastuzumab-deruxtecan (T-DXd).

Adenosine pathway inhibitor

The adenosine pathway is one of several pathways that may promote tumor immune evasion in the tumor microenvironment. The conversion of proinflammatory extracellular ATP to immunosuppressive adenosine (eADO) is thought to promote tumor progression and evade antitumor immunity. The role of the adenosine pathway in immuno-oncology is described, for example, in the review [ Allard et al., (2020) Nat Rev Clin Oncol 17, 611-629 ].

Adenosine pathway inhibitors that can be co-administered in the methods provided herein can include, for example, inhibitors of CD39 (ectonucleoside triphosphate diphosphohydrolase-1; ENTPD1; NCBI Gene No. 953); inhibitors of CD73 (exto-5'-nucleotidase;NT5E; NCBI Gene No. 4907), or antagonists of adenosine receptors, such as the adenosine A _2A receptor (ADORA2A; NCBI Gene No. 135) or the adenosine A _2B receptor (ADORA2B; NCBI Gene No. 136). In some embodiments, adenosine pathway inhibitors that can be co-administered in the methods provided herein include inhibitors of CD38 (cyclic ADP ribose hydrolase; NCBI Gene No. 952).

CD39 inhibitor

CD39 inhibitors that may be co-administered in the methods provided herein include small molecule inhibitors of CD39 and macromolecular inhibitors (e.g., anti-CD39 antibodies). Exemplary CD39 inhibitors are described in, for example, WO09095478, WO12085132, WO16073845, WO17157948, WO18049145, WO18065552, WO18065622, WO19027935, WO19178269, WO21056610, WO21037037, WO21055329, WO21088838, and WO22111576. In some embodiments, the CD39 inhibitor is selected from TTX-030 (AbbVie/Trishula), IPH5201 (AstraZeneca/Innate Pharma), SRF617 (Surface Oncology), CD39 ASO (Secarna Pharmaceuticals), JS-019 (Shanghai Junshi Biosciences); anti-CD39 (Arcus Biosciences), ES002 (Elpiscience Biopharmaceuticals), and CD39xPD1 (Biotheus).

CD73 inhibitor

CD73 inhibitors that may be co-administered in the methods provided herein include small molecule inhibitors of CD73 and macromolecular inhibitors (e.g., anti-CD73 antibodies). Exemplary CD73 inhibitors that may be used in the methods provided herein are described, for example, in U.S. Patent No. 11,001,603, the compounds of which are incorporated herein by reference. Additional exemplary CD73 inhibitors that may be co-administered in the methods provided herein include, for example, those described in WO15164573, WO16055609, WO16075099, WO16081746, WO16081748, WO17064043, WO17098421, WO17100670, WO17118613, WO17153952, WO18013611, WO18067424, WO18065627, WO18094148, WO18110555, WO18119284, WO18137598, WO18183635, WO18208980, WO18208727, WO18215535, WO18237173, WO18237157, WO19053617, WO19090111, WO19129059, WO19168744, WO19166701, WO19173291, WO19173692, WO19170131, WO19224025, WO19232244, WO19246403, WO20046813, WO20047082, WO20051686, WO20097127, WO20098599, WO20139803, WO20143836, WO20143710, WO20151707, WO20205538, WO20202038, WO20210970, WO20210938, WO20216697, WO20221209, WO20244606, WO20253568, WO20257429, WO21011689, WO21029450, WO21032173, WO21040356, WO21041319, WO21043229, WO21044005, WO21087136, WO21087463, WO21088901, WO21097223, WO21105916, WO21113625, WO21138467, WO21205383, WO21213466, WO21213475, WO21216898, WO21222522, WO21227306, WO21241729, WO21257643, WO21259199, WO22007677, WO22052886, WO22068929, WO22083049, WO22083049, WO22090711, WO22095975, WO22095953, WO22096020, and WO22121914. In some embodiments, the CD73 inhibitor is selected from the group consisting of oleculumab (AstraZeneca), BMS-986179 (BMS), uriledrimab (I-MAB Biopharma), AK119 (Akeso Biopharma), chemriclusta (AB680, Arcus Biosciences), mufadolimab (Corvus Pharmaceuticals), HLX23 (Shanghai Henlius Biotech), INCA00186 (Incyte), IBI325 (Innovent Bio), NZV930 (Novartis/Surface Oncology), ORIC-533 (ORIC Pharma), Sym024 (Servier), IPH5301 (Innate), IOA-237 (iOnctura), JAB-BX100 (Jacobio), PT199 (Phanes Therapeutics), TRB010 (Trican Biotechnology), CD73 ASO (Secarna Pharmaceuticals), 622 (3sBio), ABSK-051 (Abbisko Therapeutics), AK131 (CD73xPD1, Akeso Biopharma), CD73i (Aurigene), BR101 (BioRay), BP1200 (BrightPath), CB708 (Antengene/Calithera), GB7002 (Genbase Bio), ATG-037 (Antengene), and CD73i (Biotheus). In some embodiments, the CD73 inhibitor is chemriclustat (AB680, GS-0680), uriledrimab, mufadolimab, ORIC-533, ATG-037, PT-199, AK131, NZV930, BMS-986179, or oleculumab. In some embodiments, the CD73 inhibitor is oleclumab or chemriclustat. In some embodiments, the CD73 inhibitor is chemriclustat.

Adenosine receptor antagonist

The adenosine receptor antagonist that can be co-administered in the methods provided herein can be an adenosine A2A receptor (A2AR; ADORA2A) or A2B receptor (A2BR; ADORA2B) selective antagonist, or a dual A2A/2BR antagonist. In some embodiments, the adenosine receptor antagonist is a selective A2aR antagonist. In some embodiments, the adenosine receptor antagonist is an adenosine A2A receptor (A2AR; ADORA2A) selective antagonist selected from imaradenant (AstraZeneca), NIR178 (Novartis/Palobiofarma) ID11902 (Ildong), IN-A003 (Inno.n), NTI-55 (A2aR/TLR7, Nammi), TT-10 (Tarus Therapeutics), and TT-228 (Teon Therapeutics). In some embodiments, the adenosine receptor antagonist is a selective A2BR antagonist. In some embodiments, the adenosine receptor antagonist is an adenosine A2B receptor (A2BR; ADORA2B) selective antagonist selected from PBF-1129 (Palobiofarma) and TT-702 (Teon Therapeutics). In some embodiments, the adenosine receptor antagonist is a dual A2A/2BR antagonist. In some embodiments, the adenosine receptor antagonist is a dual adenosine A2A/A2B receptor antagonist selected from etrumadenosine (AB928, Arcus Biosciences), INCB106385 (Incyte), M1069 (Merck KGaA), A2aR/A2bR (Domain/Merck KgaA), HM87277 (A1/A2aR/A2bR, Hanmi Pharmaceutical), RVU-330 (Ryvu), and TT-53 (Tarus Therapeutics). In some embodiments, the adenosine receptor antagonist is etrumadenosine. The adenosine receptor antagonist can be a small molecule antagonist or a macromolecule antagonist.

Additional exemplary adenosine receptor antagonists that may be co-administered in the methods provided herein include, for example, those described in WO07103776, WO07134958, WO08086201, WO09009178, WO09033161, WO09037463, WO09037468, WO09037467, WO09055548, WO09055308, WO10008775, WO11027805, WO11050160, WO11055391, WO12135084, WO14101120, WO14101113, WO14106861, WO15027431, WO16081290, WO16126570, WO16200717, WO16209787, WO17008205, WO18013951, WO19086074, WO2019118313, WO20053263, WO20106558, WO20103930, WO20103939, WO20106560, WO20112706, WO20112700, WO20216152, WO20135210, WO20135195, WO20150677, WO20150675, WO20150674, WO20150676, WO20152132, WO20156505, WO20159905, WO21018172, WO20227156, WO2101873, WO20260196, WO20253867, WO20263058, WO20260857, WO21011670, WO21093701, WO21041360, WO21099832, WO21105916, WO21146631, WO21156439, WO21179074, WO21185256, WO21194623, WO21191376, WO21191380, It is described in WO21191378, WO21191379, WO21224636, WO22020552, WO22020550, WO22023772, WO22072601, and WO22123272.

Exemplary adenosine receptor antagonists that can be used in the methods provided herein are described, for example, in U.S. Pat. No. 10,399,962, the compounds of which are incorporated herein by reference. In some embodiments, the adenosine pathway inhibitor is a dual antagonist of the adenosine A2A receptor (A2AR; ADORA2A) and the A2B receptor (A2BR; ADORA2B). In some embodiments, the adenosine pathway inhibitor is etrumadenanth (AB928; GS-0928), taminadenant, TT-10, TT-4, or M1069. In some embodiments, the adenosine pathway inhibitor is etrumadenanth.

Etrumadenant (AB928) is a small molecule dual antagonist of both A2AR and A2BR that can inhibit adenosine-induced damage to tumor-infiltrating lymphocytes (primarily via A2AR on CD8+ T cells and NK cells) and myeloid cells (via A2BR on dendritic cells and macrophages) in the absence of any agonist activity. Etrumadenant can achieve high penetration and potent efficacy against tumor tissue even in the presence of high adenosine concentrations, and exhibits low nonspecific protein binding.

PD(L)1 inhibitor

In some embodiments, the combination therapy methods provided herein comprise co-administering a PD(L)1 inhibitor. PD(L)1 inhibitors that may be co-administered may include small molecule PD(L)1 inhibitors and macromolecule PD(L)1 inhibitors (e.g., anti-PD(L)-1 antibodies).

Exemplary small molecule PD(L)1 inhibitors that may be co-administered in the methods provided herein include, for example, CA-170, GS-4224, GS-4416, and lazertinib (GNS-1480; PD-L1/EGFR). Additional exemplary small molecule PD(L)1 inhibitors are described, for example, in Guzik et al. (2019) Molecules 24(11), 2071.

Anti-PD(L)1 antibody

Exemplary anti-PD-(L)1 antibodies that can be co-administered in the methods provided herein include, for example, pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cosibelimab, sasanlimab, tislelizumab, retipanlimab, balstilimab, toripalimab, setrelimab, genolimab, progolimab, rodafolimab, camrelizumab, budigalimab, avelumab, dostalimab, envafolimab, scintillimab, and zimberelimab. In some embodiments, the anti-PD-(L)1 antibody is zimberelimab.

Additional exemplary anti-PD-(L)1 antibodies that may be co-administered in the methods provided herein include pembrolizumab, nivolumab, cemiplimab, pidilizumab, AMP-224, MEDI0680 (AMP-514), spartalizumab, atezolizumab, avelumab, durvalumab, BMS-936559, cosibelimab (CK-301), sasanlimab (PF-06801591), tislelizumab (BGB-A317), GLS-010 (WBP-3055), AK-103 (HX-008), AK-105, CS-1003, HLX-10, retipanlimab (MGA-012), BI-754091, balstilimab (AGEN-2034), AMG-404, Toripalimab (JS-001), Setrelimab (JNJ-63723283), Genolimazumab (CBT-501), LZM-009, Progolimab (BCD-100), Rhodapolimab (LY-3300054), SHR-1201, Camrelizumab (SHR-1210), Sym-021, Budigallimab (ABBV-181), PD1-PIK, BAT-1306, Avelumab (MSB0010718C), CX-072, CBT-502, Dostalimab (TSR-042), MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155, Envapolimab (KN-035), scintillimab (IBI-308), HLX-20, KL-A167, STI-A1014, STI-A1015 (IMC-001), BCD-135, FAZ-053, TQB-2450, MDX1105-01, GS-4224, GS-4416, INCB086550, MAX10181, zimberelimab (AB122), spartalizumab (PDR-001), and compounds disclosed in WO2018195321, WO2020014643, WO2019160882 or WO2018195321, as well as the multispecific inhibitors FPT-155 (CTLA4/PD-L1/CD28), PF-06936308 (PD-1/ CTLA4), MGD-013(PD-1/LAG-3), FS-118(LAG-3/PD-L1), RO-7247669(PD-1/LAG-3), MGD-019(PD-1/CTLA4), KN-046(PD-1/CTLA4), MEDI-5752(CTLA4/PD-1), RO-7121661(PD-1/TIM-3), RG7769(PD-1/TIM-3), TAK-252(PD-1/OX40L), FPT-155(CTLA4/PD-L1/CD28), GEN-1046(PD-L1/4-1BB), These include bintrafusf alfa (M7824; PD-L1/TGFβ-EC domain), CA-170 (PD-L1/VISTA), CDX-527 (CD27/PD-L1), LY-3415244 (TIM3/PDL1), and INBRX-105 (4-1BB/PDL1).

Anti-TIGIT antibodies

Exemplary anti-TIGIT antibodies that can be co-administered in the methods provided herein include, for example, tiragolumab, vivostolimab, dombanalimab, AB308, AK127, BMS-986207, ralzapastotug, and etigilimab. In some embodiments, the anti-TIGIT antibody is dombanalimab. In some embodiments, the anti-TIGIT antibody is AB308. In some embodiments, the anti-TIGIT antibody is ralzapastotug.

In some embodiments, the anti-TIGIT antibody is an Fc-silent antibody. In some embodiments, the anti-TIGIT antibody comprises one or more mutations in the Fc region that reduce, prevent, or eliminate binding to an Fc receptor. In some embodiments, the anti-TIGIT antibody comprises one or more mutations in the Fc region that reduce, prevent, or eliminate binding to an FcγR receptor. In some embodiments, any of the antibodies disclosed herein comprises one or more mutations in the Fc region that reduce, prevent, or eliminate binding to FcγRIIIA. In some embodiments, any of the antibodies disclosed herein comprises one or more mutations in the Fc region that reduce, prevent, or eliminate binding to FcγRIV. In some embodiments, the anti-TIGIT antibody comprises one or more mutations in the Fc region that reduce, prevent, or eliminate binding to ADCC, ADCP, and/or CDC. In some embodiments, the anti-TIGIT antibody comprises one or more substitutions in the Fc region that reduce, prevent, or eliminate binding to an Fc receptor, wherein the one or more substitutions occur at EU index positions 228, 233, 234, 235, 235, 235, 236, 237, 265, 297, 322, 327, 328, 330, 331, and any combination thereof. In some embodiments, the anti-TIGIT antibody comprises one or more substitutions in the Fc region that reduce, prevent, or eliminate binding to an Fc receptor, wherein the one or more substitutions comprise S228P, E233P, L234A, L235A, L235E, L235F, G236R, G237A, D265A, N297A, K322A, A327G, L328R, A330S, P331S, and any combination thereof. Additional mutations in the Fc region that reduce, prevent, or eliminate binding to an Fc receptor, and alternative strategies for reducing, preventing, or eliminating binding to an Fc receptor, are described in, e.g., Saunders, Front Immunol. (2019) 10:1296; Tao, J Exp Med. (1993) 178:661-667; Canfield and Morrison, J Exp Med. (1991) 173(6):1483-1491]; Armour, Eur. J. Immunol. (1999) 29(8): 2613-2624]; and Shields, J. Biol. Chem. (2001) 276(9):6591-6604] and US 6,624,821.

In some embodiments, the anti-TIGIT antibody is an Fc-enabled antibody. In some embodiments, the anti-TIGIT antibody comprises one or more mutations in the Fc region that enable or enhance binding to an Fc receptor. In some embodiments, the anti-TIGIT antibody comprises one or more mutations in the Fc region that enable or enhance binding to an FcγR. In some embodiments, any of the antibodies disclosed herein comprises one or more mutations in the Fc region that enable or enhance binding to FcγRIIIA. In some embodiments, any of the antibodies disclosed herein comprises one or more mutations in the Fc region that enable or enhance binding to FcγRIV. In some embodiments, the anti-TIGIT antibody comprises one or more mutations in the Fc region that enable or enhance binding to ADCC, ADCP, and/or CDC. In some embodiments, the anti-PD-(L)1 antibody comprises one or more substitutions in the Fc region that enable or enhance binding to an Fc receptor, wherein the one or more substitutions occur at EU index positions 234, 235, 236, 239, 243, 247, 267, 268, 292, 298, 300, 305, 324, 326, 330, 332, 333, 334, 339, 345, 396, 430 and any combinations thereof. In some embodiments, the anti-TIGIT antibody comprises one or more substitutions in the Fc region that enable or enhance binding to an Fc receptor, wherein the one or more substitutions comprise F234L, L235V, G236A, S239D, F243L, P247I, S267E, H268E, R292P, S298A, Y300L, V305I, S324T, K326W, A330L, I332E, E333A, E333S, K334A, A339Q, E345G, P396L, E430G and any combination thereof. In some embodiments, the Fc-enabled antibody comprises a modified IgG1 domain characterized by substitutions at S239D, A330L and I332E (Eu numbering). Alternatively, the anti-TIGIT antibody contains or has a glycoform disruption. In some embodiments, the anti-TIGIT antibody contains or has N-linked Fc glycosylation. In some embodiments, the anti-TIGIT antibody contains or has sialylation, galactosylation, dimerization sugar, fucosylation, or any combination thereof. Additional mutations in the Fc region that enhance or facilitate binding to an Fc receptor, and alternative strategies for enhancing or facilitating binding to an Fc receptor, are described in the literature [Saunders, 2019].

Treatment method

In one aspect, provided herein are methods of treating, ameliorating, reducing, preventing, or delaying the recurrence or metastasis of a Trop-2 positive (Trop-2 ⁺ ) cancer, comprising co-administering to a subject an effective amount of: a) an anti-Trop-2 antibody-drug conjugate (ADC); and b) an adenosine pathway inhibitor (e.g., a CD39 inhibitor, a CD73 inhibitor, or an A2R inhibitor). In some embodiments, the methods provided herein comprise treating a Trop-2 positive cancer, comprising co-administering to the ...: a) an anti-Trop-2 antibody-drug conjugate (ADC); And b) co-administering to the subject an effective amount of an adenosine pathway inhibitor (e.g., a CD39 inhibitor, a CD73 inhibitor, or an A2R inhibitor). In some embodiments, the methods provided herein comprise preventing or delaying the recurrence or metastasis of a Trop-2 positive cancer, comprising co-administering to the subject an effective amount of: a) an anti-Trop-2 antibody-drug conjugate (ADC); and b) an adenosine pathway inhibitor (e.g., a CD39 inhibitor, a CD73 inhibitor, or an A2R inhibitor). In some embodiments, the adenosine pathway inhibitors are a plurality of adenosine pathway inhibitors. In some embodiments, the plurality of adenosine pathway inhibitors comprise a CD73 inhibitor and an adenosine receptor antagonist. In some embodiments, the CD73 inhibitor is chemriclustat and the adenosine receptor antagonist is etrumadenanth.

In some embodiments, the methods provided herein are for treating a Trop-2 positive cancer, comprising co-administering to a subject an effective amount of: a) an anti-Trop-2 antibody-drug conjugate (ADC); and b) an adenosine pathway inhibitor (e.g., a CD39 inhibitor, a CD73 inhibitor, or an A2R inhibitor).

In another aspect, provided herein are methods of treating, ameliorating, reducing, preventing, or delaying recurrence or metastasis of a tumor antigen positive (TA + ) cancer, comprising co-administering to the subject an effective amount of: a) a tumor antigen targeted antibody-drug conjugate (ADC) comprising a topoisomerase I inhibitor; and b) an adenosine pathway inhibitor (e.g., a CD39 inhibitor, a CD73 inhibitor, or an A2R inhibitor). In some embodiments, the methods provided herein comprise treating a tumor antigen positive (TA ⁺ ) cancer, comprising co-administering to the subject an effective amount of: a) a tumor antigen targeted antibody-drug conjugate (ADC) comprising a topoisomerase I inhibitor; and b) an adenosine pathway inhibitor (e.g., a CD39 inhibitor, a CD73 inhibitor, or an A2R inhibitor). In some embodiments, the methods provided herein comprise treating a tumor antigen positive (TA + ) cancer, comprising co-administering to the subject an effective amount of: a) a tumor antigen targeted antibody-drug conjugate (ADC) comprising a topoisomerase I inhibitor; and b) an adenosine pathway inhibitor (e.g., a CD39 inhibitor, a CD73 inhibitor, or an A2R inhibitor). In some embodiments, the methods provided herein comprise: a) a tumor antigen targeted antibody-drug conjugate (ADC) comprising a topoisomerase I inhibitor; And b) co-administering to the subject an effective amount of an adenosine pathway inhibitor (e.g., a CD39 inhibitor, a CD73 inhibitor, or an A2R inhibitor). In some embodiments, the methods provided herein comprise preventing or delaying the recurrence or metastasis of a tumor antigen positive cancer, comprising co-administering to the subject a) a tumor antigen targeted antibody-drug conjugate (ADC) comprising a topoisomerase I inhibitor; and b) an effective amount of an adenosine pathway inhibitor (e.g., a CD39 inhibitor, a CD73 inhibitor, or an A2R inhibitor).

In some embodiments, the methods provided herein are for treating a tumor antigen positive cancer, comprising co-administering to a subject an effective amount of: a) a tumor antigen targeted antibody-drug conjugate (ADC) comprising a topoisomerase I inhibitor; and b) an adenosine pathway inhibitor (e.g., a CD39 inhibitor, a CD73 inhibitor, or an A2R inhibitor).

In some embodiments, provided herein are methods of treating, alleviating, reducing, preventing, or delaying the recurrence or metastasis of a tumor antigen (e.g., Trop-2) positive cancer, comprising co-administering to a subject a combination provided herein. In some embodiments, the methods of treatment provided herein reduce the occurrence or recurrence of a tumor antigen (e.g., Trop-2) positive cancer by administering a combination provided herein. In some embodiments, the methods of treatment provided herein reduce the occurrence or recurrence of a tumor antigen (e.g., Trop-2) positive cancer by administering a combination provided herein. In some embodiments, the methods of treatment provided herein prevent the occurrence or recurrence of a tumor antigen (e.g., Trop-2) positive cancer by administering a combination provided herein. In some embodiments, the methods of treatment provided herein delay the occurrence or recurrence of a tumor antigen (e.g., Trop-2) positive cancer by administering a combination provided herein.

In some embodiments, the methods provided herein further comprise co-administering an additional therapeutic agent or treatment modality, or a combination thereof. In some embodiments, the methods provided herein further comprise co-administering one, two, or three additional therapeutic agents or treatment modalities, or a combination thereof. In some embodiments, the additional therapeutic agent comprises a chemotherapy (e.g., a chemotherapy regimen selected by a physician, or a standard of care recommended for a particular treatment setting). In some embodiments, the additional therapeutic agent comprises an immune checkpoint inhibitor (CPI; e.g., an anti-CTLA4 antibody, an anti-PD(L)1 antibody, an anti-TIGIT antibody). In some embodiments, the additional therapeutic agent comprises an anti-PD(L)1 antibody (e.g., an anti-PD-1 antibody or an anti-PD-L1 antibody) and optionally an anti-TIGIT antibody. In some embodiments, the additional therapeutic agent comprises an anti-PD-(L)1 antibody. In some embodiments, the additional therapeutic agent comprises an anti-TIGIT antibody. In some embodiments, the additional therapeutic agent comprises an anti-PD-(L1) antibody and an anti-TIGIT antibody. In some embodiments, the additional therapeutic agent comprises a) zimberelimab and dombanalimab, b) zimberelimab and AB308, c) atezolizumab and tiragolumab, d) pembrolizumab and vivostolimab, e) pembrolizumab and dombanalimab, f) pembrolizumab and AB308, g) MK-7684A (pembrolizumab/vivostolimab co-administration), h) durvalumab and dombanalimab, i) zimberelimab and ralzapastotug, or j) pembrolizumab and ralzapastotug. In some embodiments, the additional therapeutic agent comprises zimberelimab and dombanalimab. In some embodiments, the additional therapeutic agent comprises zimberelimab and ralzapastotug. In some embodiments, the additional therapeutic agent comprises zimberelimab and ralzapastotug. In some embodiments, the additional treatment modality comprises surgery or radiation therapy.

In some embodiments of the methods provided herein, the subject is a cancer patient. In some embodiments, the subject is a human cancer patient. In some embodiments, the subject is treatment naïve. In some embodiments, the subject (e.g., the human cancer patient) has not received taxane therapy (e.g., paclitaxel, naph-paclitaxel (ABRAXANE®), docetaxel, cabazitaxel) prior to administration of the combination therapy provided herein. In some embodiments, the subject (e.g., the human cancer patient) has not received checkpoint inhibitor therapy (e.g., anti-CTLA4 antibody, anti-PD(L)1 antibody) prior to administration of the combination therapy provided herein. In some embodiments, the subject (e.g., the human cancer patient) has not received topoisomerase I inhibitor therapy (e.g., irinotecan) prior to administration of the combination therapy provided herein. In some embodiments, the subject has received one or more prior lines of anticancer therapy prior to administration of the combination therapy provided herein. In some embodiments, prior to administration of the combination therapy provided herein, the subject (e.g., the human (m)CRPC patient) has received a novel hormonal agent (NHA; a first or second generation non-steroidal anti-androgen agent, e.g., abiraterone, enzalutamide, darolutamide, apalutamide, or a combination thereof). In some embodiments, prior to administration of the combination therapy provided herein, the subject (e.g., the human (m)CRPC patient) has exhibited disease progression following prior NHA treatment (a first or second generation non-steroidal anti-androgen agent, e.g., abiraterone, enzalutamide, darolutamide, apalutamide, or a combination thereof). In some embodiments, the subject has received prior anticancer therapy selected from surgery, radiation therapy, chemotherapy (including NHA therapy), checkpoint inhibitor therapy (e.g., an anti-PD(L)1 antibody). In some embodiments, the subject has a cancer that is resistant or refractory to one or more anticancer therapies. In some embodiments, the cancer is resistant or refractory to one or more anticancer therapies selected from radiation therapy, chemotherapy (including NHAs) therapy, and checkpoint inhibitor therapy (e.g., an anti-PD(L)1 antibody). In some embodiments, prior to administration of the combination therapy provided herein, the subject (e.g., a human (m)CRPC patient) has exhibited disease progression following prior NHAs (first or second generation non-steroidal anti-androgens, e.g., abiraterone, enzalutamide, darolutamide, apalutamide, or a combination thereof) and has not received a taxane (e.g., docetaxel, cabazitaxel), a checkpoint inhibitor (e.g., anti-CTLA-4 antibody; anti-PD(L)1 antibody), or a topoisomerase I inhibitor (e.g., irinotecan). In some embodiments, the subject (e.g., a human (m)NSCLC patient) has exhibited disease progression following platinum-based chemotherapy. In some embodiments, the subject (e.g., a human (m)NSCLC patient) exhibited disease progression following checkpoint inhibitor therapy (e.g., anti-PD-(L)1 antibody or anti-CTLA4 antibody therapy). In some embodiments, the subject progressed following platinum-based chemotherapy and checkpoint inhibitor therapy (e.g., anti-PD-(L)1 antibody or anti-CTLA4 antibody therapy), either concurrently or sequentially in any order. In some embodiments, the subject (e.g., a human (m)NSCLC patient) progressed following tyrosine kinase inhibitor therapy that targets a specific genomic alteration in the cancer. Exemplary tyrosine kinase inhibitors useful for addressing specific genomic alterations (e.g., EGFR mutations or deletions) in lung cancer include gefitinib, erlotinib, afatinib, dacomitinib, neratinib, osimertinib, rociletinib, olmutinib, ASP8273 (Astellas), nazartinib, PF-06747775 (Pfizer), avitinib, and HS-10296 (Jiangsu Hansoh). In some embodiments, the subject (e.g., a human (m)CRPC or (m)NSCLC patient) is tested for tumor antigen (e.g., Trop-2) expression levels (e.g., following a liquid or solid tumor biopsy, e.g., by IHC or next generation DNA sequencing).

In some embodiments, the subject is a human prostate cancer patient. In some embodiments, the human patient has castration-resistant prostate cancer (CRPC). In some embodiments, the human patient has metastatic CRPC (mCRPC). In some embodiments, the human patient with CRPC or mCRPC ((m)CRPC) is treatment naïve. In some embodiments, the human patient with (m)CRPC has not received taxane therapy (e.g., paclitaxel, naphtha-paclitaxel (ABRAXANE®), docetaxel, cabazitaxel) prior to administration of the combination therapy provided herein. In some embodiments, the human patient with (m)CRPC has not received checkpoint inhibitor therapy (e.g., anti-CTLA4 antibody, anti-PD(L)1 antibody) prior to administration of the combination therapy provided herein. In some embodiments, the human patient with (m)CRPC has not received topoisomerase I inhibitor therapy (e.g., irinotecan) prior to administration of the combination therapy provided herein. In some embodiments, prior to administration of the combination provided herein, the human patient with (m)CRPC has received one or more prior lines of anticancer therapy. In some embodiments, prior to administration of the combination provided herein, the human patient with (m)CRPC has exhibited disease progression following one or more prior lines of anticancer therapy. In some embodiments, prior to administration of the combination therapy provided herein, the human patient with (m)CRPC has received a novel hormonal agent (NHA; a first or second generation non-steroidal anti-androgen, abiraterone) (NHA experience). In some embodiments, prior to administration of the combination therapy provided herein, the human patient with (m)CRPC has exhibited disease progression following prior NHA treatment (a first or second generation non-steroidal anti-androgen, e.g., abiraterone, enzalutamide, darolutamide, apalutamide, or a combination thereof). In some embodiments, the human patient with (m)CRPC has received prior anticancer therapy selected from surgery, radiation therapy, chemotherapy (including NHA therapy), checkpoint inhibitor therapy (e.g., anti-CTLA4 antibody, anti-PD(L)1 antibody). In some embodiments, the human patient with (m)CRPC has a cancer that is resistant or refractory to one or more anticancer therapies. In some embodiments, the cancer is resistant or refractory to one or more anticancer therapies selected from radiation therapy, chemotherapy (including NHA therapy), and checkpoint inhibitor therapy (e.g., anti-CTLA4 antibody, anti-PD(L)1 antibody). In some embodiments, prior to administration of the combination therapy provided herein, the human patient with (m)CRPC has received prior NHA treatment (first or second generation non-steroidal anti-androgens, e.g., abiraterone, enzalutamide, darolutamide, apalutamide or a combination thereof) (NHA experienced) and has not received a taxane (e.g., paclitaxel, naphtha-paclitaxel (ABRAXANE®), docetaxel, cabazitaxel) or checkpoint inhibitor (e.g., anti-CTLA-4 antibody; anti-PD(L)1 antibody) (taxane and CPI naive). In some embodiments, prior to administration of the combination therapy provided herein, the human patient with (m)CRPC has received prior NHA treatment (first or second generation non-steroidal anti-androgens, e.g., abiraterone, enzalutamide, darolutamide, apalutamide or a combination thereof) (NHA experience), and has not received a taxane (e.g., paclitaxel, naphtha-paclitaxel (ABRAXANE®), docetaxel, cabazitaxel), a checkpoint inhibitor (e.g., anti-CTLA-4 antibody; anti-PD(L)1 antibody), or a topoisomerase I inhibitor (e.g., irinotecan). In some embodiments, prior to administration of the combination therapy provided herein, the human patient with (m)CRPC has exhibited disease progression following prior NHA treatment (a first or second generation non-steroidal anti-androgen, e.g., abiraterone, enzalutamide, darolutamide, apalutamide or a combination thereof) and has not received a taxane (e.g., paclitaxel, naphtha-paclitaxel (ABRAXANE®), docetaxel, cabazitaxel), a checkpoint inhibitor (e.g., anti-CTLA-4 antibody; anti-PD(L)1 antibody), or a topoisomerase I inhibitor (e.g., irinotecan). In some embodiments, the human patient with (m)CRPC has histologically confirmed castration-resistant prostatic adenocarcinoma with tumor progression while receiving androgen deprivation therapy (ADT; including orchiectomy), with castrate levels of serum (total) testosterone (≤ 1.7 nmol/L or 50 ng/dL) as defined by PSA and/or radiological criteria according to the PCWG3. In some embodiments, the human patient with (m)CRPC has metastatic castration-resistant adenocarcinoma of the prostate with tumor progression while on androgen deprivation therapy (e.g., including orchiectomy), with a castrate level of serum (total) testosterone (≤ 1.7 nmol/L or 50 ng/dL) as defined by prostate-specific antigen (PSA) and/or radiological criteria according to the Prostate Cancer Working Group 3 (PCWG3) and measurable or non-measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. In some embodiments, the human patient with (m)CRPC has an Eastern Cooperative Oncology Society performance status of 0 or 1, and a life expectancy ≥ 3 months. In some embodiments, a human patient with (m)CRPC is tested for tumor antigen (e.g., Trop-2) expression levels (e.g., following a liquid or solid tumor biopsy, e.g., by tumor antigen expression analysis by IHC or next-generation DNA sequencing).

In some embodiments, the subject is a human lung cancer patient. In some embodiments, the human patient has non-small cell lung cancer (NSCLC). In some embodiments, the NSCLC is squamous cell carcinoma. In some embodiments, the NSCLC is non-squamous cell carcinoma. In some embodiments, the NSCLC is non-squamous cell carcinoma. In some embodiments, the lung cancer does not have a treatable genomic alteration (e.g., an EGFR or ALK mutation, insertion, deletion, etc.) for which treatment with a targeted therapy (e.g., a targeted tyrosine kinase inhibitor therapy) is recommended (a treatable genomic alteration). Exemplary treatable genomic alterations and targeted tyrosine kinase inhibitor therapies are described, for example, in Sullivan and Planchard Front. Med. (2017) 3:76. In some embodiments, the human NSCLC patient has disease progression following platinum-based chemotherapy. In some embodiments, the human NSCLC patient has disease progression following checkpoint inhibitor therapy (e.g., an anti-PD-(L)1 antibody or an anti-CTLA4 antibody therapy). In some embodiments, the human NSCLC patient has progressed following platinum-based chemotherapy and checkpoint inhibitor therapy (e.g., anti-PD-(L)1 antibody or anti-CTLA4 antibody therapy), either concurrently or sequentially in any order. In some embodiments, the human NSCLC patient has progressed following tyrosine kinase inhibitor therapy that targets a specific genomic alteration in the cancer. Exemplary tyrosine kinase inhibitors useful for addressing a specific genomic alteration (e.g., EGFR mutation or deletion) in lung cancer include gefitinib, erlotinib, afatinib, dacomitinib, neratinib, osimertinib, rociletinib, olmutinib, ASP8273 (Astellas), nazartinib, PF-06747775 (Pfizer), avitinib, and HS-10296 (Jiangsu Hansoh).

In some embodiments of the methods provided herein, the combinations provided herein are administered in a neoadjuvant setting (e.g., in preparation for surgery or radiation therapy). In some embodiments, the combinations provided herein are administered in an adjuvant setting (e.g., following primary treatment, such as surgery or radiation therapy). In some embodiments, the combinations provided herein are administered in a therapeutic setting (e.g., as primary treatment). In some embodiments, the combinations provided herein are administered in a maintenance setting.

In some embodiments of the methods provided herein, the cancer is a hematological cancer. In some embodiments, the cancer comprises a solid tumor. In some embodiments, the cancer comprises a malignant tumor. In some embodiments, the cancer comprises a metastatic cancer. In some embodiments, the cancer is resistant or refractory to one or more anticancer therapies. In some embodiments, greater than about 50% of the cancer cells detectably express one or more cell surface immune checkpoint receptors (e.g., a so-called “hot” cancer or tumor). In some embodiments, greater than about 1% to less than about 50% of the cancer cells detectably express one or more cell surface immune checkpoint receptors (e.g., a so-called “warm” cancer or tumor). In some embodiments, less than about 1% of the cancer cells detectably express one or more cell surface immune checkpoint receptors (e.g., a so-called “cold” cancer or tumor).

In some embodiments of the methods provided herein, the cancer is a hematological cancer, e.g., a leukemia (e.g., acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), B-cell ALL, myelodysplastic syndrome (MDS), myeloproliferative disorder (MPD), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), undifferentiated leukemia), a lymphoma (e.g., small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), follicular lymphoma (FL), T-cell lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), marginal zone lymphoma (MZL), Waldstrom macroglobulinemia (WM)), and/or a myeloma (e.g., multiple myeloma (MM)).

In some embodiments of the methods provided herein, the cancer is an epithelial tumor (e.g., carcinoma, squamous cell carcinoma, basal cell carcinoma, squamous intraepithelial neoplasia), a glandular tumor (e.g., adenocarcinoma, adenoma, adenomyoma), a mesenchymal or soft tissue tumor (e.g., sarcoma, rhabdomyosarcoma, leiomyosarcoma, liposarcoma, fibrosarcoma, dermatofibrosarcoma, neurofibrosarcoma, fibrous histiocytoma, angiosarcoma, angiomyxoma, leiomyoma, chondroma, chondrosarcoma, adenocarcinoma of the ovary, epithelioid hemangioendothelioma, Spitz tumor, synovial sarcoma), or a lymphoma.

In some embodiments, the cancer comprises a solid tumor in or arising from a tissue or organ, such as:

Bone (e.g., ameloblastoma, aneurysmal bone cyst, hemangiosarcoma, chondroblastoma, chondroma, chondromyxoid fibroma, chondrosarcoma, chordoma, dedifferentiated chondrosarcoma, enchondroma, epithelioid hemangioendothelioma, fibrous dysplasia of bone, giant cell tumor of bone, hemangioma and related lesions, osteoblastoma, osteochondroma, osteosarcoma, osteoid osteoma, osteoma, periosteal chondroma, desmoid tumor, Ewing sarcoma);

Lip and oral cavity (e.g., odontogenic ameloblastoma, oral leukoplakia, oral squamous cell carcinoma, primary oral mucosal melanoma); Salivary glands (e.g., pleomorphic salivary adenoma, salivary adenoid cystic carcinoma, salivary mucoepidermoid carcinoma, salivary Warthin's tumor);

Esophagus (eg, Barrett's esophagus, dysplasia, and adenocarcinoma);

Gastrointestinal tract including the stomach (e.g., gastric adenocarcinoma, primary gastric lymphoma, gastrointestinal stromal tumor (GIST), metastatic deposits, gastric carcinoid tumor, gastric sarcoma, neuroendocrine carcinoma, gastric primary squamous cell carcinoma, gastric adenomatosis), intestine and smooth muscle (e.g., intravenous leiomyomatosis), colon (e.g., colorectal adenocarcinoma), rectum, anus;

Pancreas (e.g., serous neoplasms, such as microcystic or macrocystic serous cystadenomas, solid serous cystadenomas, Von Hippel-Lindau (VHL)-associated serous cystic neoplasms, serous cystadenocarcinomas; mucinous cystic neoplasms (MCN), intraductal papillary mucinous neoplasms (IPMN), intraductal oncocytoid papillary neoplasms (IOPN), intraductal tubular neoplasms, cystic acinar neoplasms, such as acinar cell cystadenomas, acinar cell cystadenocarcinomas, pancreatic adenocarcinomas, invasive pancreatic ductal adenocarcinomas, such as tubular adenocarcinomas, adenosquamous carcinomas, colloid carcinomas, medullary carcinomas, hepatocellular carcinomas, signet ring cell carcinomas, undifferentiated carcinomas, undifferentiated carcinomas with osteoclast-like giant cells, acinar cell carcinomas, neuroendocrine neoplasms, neuroendocrine microadenomas, neuroendocrine tumors (NETs), neuroendocrine carcinomas (NECs) such as small cell or large cell NECs, insulinomas, gastrinomas, glucagonomas, serotonin-producing NETs, somatostatinomas, VIPomas, solid pseudopapillary neoplasms (SPNs), pancreatoblastomas);

Gallbladder (e.g., carcinoma of the gallbladder and extrahepatic bile ducts, intrahepatic cholangiocarcinoma);

Neuroendocrine (eg, adrenocortical carcinoma, carcinoid tumor, pheochromocytoma, pituitary adenoma);

Thyroid (e.g., anaplastic (undifferentiated) carcinoma, medullary carcinoma, oncocytoma, papillary carcinoma, adenocarcinoma);

Liver (e.g., adenoma, combined hepatocellular and biliary tract carcinoma, fibrolamellar carcinoma, hepatoblastoma, hepatocellular carcinoma, mesenchymal, nested stromal epithelial tumor, undifferentiated carcinoma; hepatocellular carcinoma, intrahepatic cholangiocarcinoma, biliary cystadenocarcinoma, epithelioid hemangioendothelioma, hemangiosarcoma, embryonal sarcoma, rhabdomyosarcoma, solitary fibrous tumor, teratoma, yolk sac tumor, carcinosarcoma, rhabdoid tumor);

Kidney (e.g., ALK rearranged renal cell carcinoma, chromophobe renal cell carcinoma, clear cell renal cell carcinoma, clear cell sarcoma, metanephric adenoma, metanephric adenoma, mucinous tubular and spindle cell carcinoma, nephroma, nephroblastoma (Wilms tumor), papillary adenoma, papillary renal cell carcinoma, renal oncocytoma, renal cell carcinoma, succinate dehydrogenase-deficient renal cell carcinoma, collecting duct carcinoma);

Breast (eg, but not limited to, acinar cell carcinoma, adenoid cystic carcinoma, apocrine carcinoma, filamentous carcinoma, glycogen-rich/clear cell inflammatory carcinoma, lipid-rich carcinoma, medullary carcinoma, metaplastic carcinoma, micropapillary carcinoma, mucinous carcinoma, neuroendocrine carcinoma, oncocytoid carcinoma, papillary carcinoma, sebaceous carcinoma, secretory breast carcinoma, invasive ductal carcinoma including ductal carcinoma; but not limited to, pleomorphic carcinoma, lobular carcinoma including signet ring cell carcinoma);

Peritoneum (e.g., mesothelioma; primary peritoneal cancer);

Female genital tissues, such as ovaries (e.g., choriocarcinoma, epithelial tumor, germ cell tumor, sex cord-stromal tumor), fallopian tubes (e.g., serous adenocarcinoma, mucinous adenocarcinoma, endometrioid adenocarcinoma, clear cell adenocarcinoma, transitional cell carcinoma, squamous cell carcinoma, undifferentiated carcinoma, Müllerian tumor, adenosarcoma, leiomyosarcoma, teratoma, germ cell tumor, choriocarcinoma, trophoblastic tumor), uterus (e.g., carcinoma of the cervix, endometrial polyp, endometrial hyperplasia, intraepithelial carcinoma (EIC), endometrial carcinomas (e.g., endometrial carcinoma, serous carcinoma, clear cell carcinoma, mucinous carcinoma, squamous cell carcinoma, transitional carcinoma, small cell carcinoma, undifferentiated carcinoma, mesenchymal neoplasm), leiomyomas (e.g., endometrial stromal nodule, leiomyosarcoma, Endometrial stromal sarcoma (ESS), mesenchymal tumor), epithelial and mesenchymal combined tumor (e.g., adenoma, carcinoma, adenosarcoma, carcinosarcoma (malignant combined mesodermal sarcoma-MMMT)), endometrial stromal tumor, endometrial malignant Müllerian complex tumor, gestational trophoblastic tumor (partial hydatidiform mole, complete hydatidiform mole, invasive hydatidiform mole, placental tumor)), vulva, vagina;

Male reproductive organ tissues, such as the prostate, testis (e.g., germ cell tumor, spermatogonial tumor), penis;

Bladder (eg, squamous cell carcinoma, urothelial carcinoma, bladder urothelial carcinoma);

Brain (eg, gliomas (eg, astrocytomas including non-invasive, low-grade, anaplastic glioblastomas; oligodendroglioma, ependymoma), meningioma, ganglioglioma, schwannoma (neuroma), craniopharyngioma, chordoma, non-Hodgkin's lymphoma (NHL), indolent non-Hodgkin's lymphoma (iNHL), refractory iNHL, pituitary tumors;

Eye (e.g., retinoma, retinoblastoma, ocular melanoma, posterior uveal melanoma, iris hamartoma);

Head and neck (e.g., nasopharyngeal carcinoma, endolymphatic sac tumor (ELST), epidermoid carcinoma, laryngeal cancers such as squamous cell carcinoma (SCC) (e.g., glottic carcinoma, supraglottic carcinoma, subglottic carcinoma, scleroglottic carcinoma), intraepithelial carcinoma, spindle cell, and basaloid SCC, undifferentiated carcinoma, laryngeal adenocarcinoma, adenoid cystic carcinoma, neuroendocrine carcinoma, laryngeal sarcoma), head and neck paragangliomas (e.g., carotid body, jugulotympanic, vagus);

Thymus (e.g., thymoma);

heart (eg, cardiac myxoma);

Lung (e.g., small cell lung carcinoma (SCLC), non-small cell lung carcinomas (NSCLC) including squamous cell carcinoma (SCC), adenocarcinoma and large cell carcinoma, carcinoid (typical or atypical), carcinosarcoma, pulmonary blastoma, giant cell carcinoma, spindle cell carcinoma, pleuropulmonary blastoma);

Lymphoma (e.g., lymphomas such as Hodgkin's lymphoma, non-Hodgkin's lymphoma (NHL), indolent non-Hodgkin's lymphoma (iNHL), refractory iNHL, Epstein-Barr virus (EBV)-associated lymphoproliferative disorders such as B-cell lymphomas and T-cell lymphomas (e.g., Burkitt's lymphoma; large B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, indolent B-cell lymphoma, low-grade B-cell lymphoma, fibrin-associated diffuse large cell lymphoma; primary effusion lymphoma; plasmablastic lymphoma; extranodal NK/T-cell lymphoma, nasal type; peripheral T-cell lymphoma, cutaneous T-cell lymphoma, angioimmunoblastic T-cell lymphoma; follicular T-cell lymphoma; systemic T-cell lymphoma), lymphangioleiomyomatosis);

Central nervous system (CNS) (e.g., gliomas, such as astrocytic tumors (e.g., pilocytic astrocytoma, pilocytic astrocytoma, subependymal giant cell astrocytoma, pleomorphic xanthoastrocytoma, diffuse astrocytoma, fibrillary astrocytoma, tumour cell astrocytoma, plasmoplasmic astrocytoma, anaplastic astrocytoma, glioblastomas (e.g., giant cell glioblastoma, gliosarcoma, glioblastoma multiforme), and cerebral gliomatosis), oligodendroglial tumors (e.g., oligodendroglioma, anaplastic oligodendroglioma), oligoastrocytic tumors (e.g., oligodendroglioma, anaplastic oligodendroglioma), ependymomas (e.g., subependymal tumors, myxopapillary ependymoma, ependymomas (e.g., cellular, papillary, clear cell, tanycytic), anaplastic ependymoma), optic nerve gliomas, and non-gliomas (e.g., choroid plexus tumors, neurogenic tumors, and neuron-glial complex tumors, pineal region tumors, embryonal tumors, medulloblastomas, meningeal tumors, primary CNS lymphomas, germ cell tumors, pituitary adenomas, cranial and paravertebral neural tumors, stellar region tumors); neurofibromas, meningiomas, peripheral nerve sheath tumors, peripheral neuroblastic tumors (including but not limited to neuroblastoma, ganglioneuroma, ganglioneuroma), trisomy 19 ependymoma);

Neuroendocrine tissue (e.g., paraganglionic system, including the adrenal medulla (pheochromocytoma) and extraadrenal paraganglioma);

Skin (e.g., clear cell keratoacanthoma, cutaneous benign fibrous histiocytoma, cylindromatosis, keratoacanthoma, melanoma (e.g., cutaneous melanoma, mucosal melanoma), pilonidal tumour, Spitz tumor); and

Soft tissue (e.g., aggressive angiomyxoma, alveolar rhabdomyosarcoma, cystic soft part sarcoma, angiofibroma, angiomatous fibrous histiocytoma, synovial sarcoma, dystrophic synovial sarcoma, clear cell sarcoma, dermatofibrosarcoma protuberans, desmoid fibromatosis, small round cell tumor, desmoplastic small round cell tumor, elastoma, embryonal rhabdomyosarcoma, Ewing's tumor/primitive neuroectodermal tumor (PNET), extraskeletal myxoid chondrosarcoma, extraosseous osteosarcoma, paraspinal sarcoma, inflammatory myofibroblastic tumor, lipoblastoma, lipoma, chondroid lipoma, liposarcoma/malignant lipomatous tumor, liposarcoma, myxoid liposarcoma, fibromyxoid sarcoma, lymphangioleiomyoma, malignant myoepithelioma, malignant melanoma of soft parts, myoepithelial carcinoma, myoepithelioma, myxoinflammatory fibroblastic sarcoma, undifferentiated sarcoma, Pericytoma, rhabdomyosarcoma, nonrhabdomyosarcoma soft tissue sarcoma (NRSTS), soft tissue leiomyosarcoma, undifferentiated sarcoma, well-differentiated liposarcoma.

In some embodiments, the cancer is characterized by an antibody selected from the group consisting of carbonic anhydrase IX, B7, CCCL19, CCCL21, CSAp, HER-2/neu, BrE3, CD1, CD1a, CD2, CD3, CD4, CD5, CD8, CD11A, CD14, CD15, CD16, CD18, CD19, CD20 (e.g., C2B8, hA20, 1F5 MAbs), CD21, CD22, CD23, CD25, CD29, CD30, CD32b, CD33, CD37, CD38, CD40, CD40L, CD44, CD45, CD46, CD52, CD54, CD55, CD59, CD64, CD67, CD70, CD74, CD79a, CD80, CD83, CD95, CD126, CD133, CD138, CD147, CD154, CEACAM5, CEACAM-6, alpha-fetoprotein (AFP), VEGF, fibronectin splice variant, ED-B fibronectin (e.g., L19), EGP-1, EGP-2 (e.g., 17-1A), EGF receptor (ErbB1), ErbB2, ErbB3, factor H, FHL-1, Flt-3, folate receptor, Ga 733, GROB, HMGB-1, hypoxia-inducible factor (HIF), HM1.24, insulin-like growth factor (ILGF), IFN-a, IFN-b, IFN-g, IL-2R, IL-4R, IL-6R, IL-13R, IL-15R, IL-17R, IL-18R, IL-2, IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, IL-25, IP-10, IGF-1R, Ia, HM1.24, ganglioside, HCG, HLA-DR, CD66 (e.g., CD66a-d), MAGE, mCRP, MCP-1, MIP-1A, MIP-1B, MIF, MUC1, MUC2, MUC3, MUC4, MUC5, placental growth factor (PIGF), PSA (prostate-specific antigen), PSMA, PAM4, NCA-95, NCA-90, A3, A33, Ep-CAM, KS-1, Le(y), mesothelin, S100, tenascin, TAC, Tn antigen, Thomas-Friedenreich antigen, tumor necrosis antigen, tumor angiogenesis antigen, TNF-a, TRAIL receptors (R1 and R2), VEGFR, RANTES, T101, complement factor C3, C3a, C3b, Positive for tumor antigens selected from C5a and C5, and oncogene products.

In some embodiments, the cancer is positive for a tumor antigen selected from CD74, CD22, Trop-2, CEA, CSAp Mu-9, AFP, CC49 and PSMA.

In some embodiments, the cancer is Trop-2 positive. In some embodiments, the Trop-2 positive cancer is a solid epithelial cancer. In some embodiments, the solid epithelial cancer is selected from breast cancer (e.g., triple negative breast cancer (TNBC); HR positive/Her-2 negative (HR ⁺ /Her-2 ^- ) breast cancer; HR positive/Her-2 low breast cancer), colorectal cancer, lung cancer, gastric cancer, urinary tract cancer, urothelial cancer, bladder cancer, kidney cancer, pancreatic cancer, ovarian cancer, uterine cancer, esophageal cancer, and prostate cancer. In some embodiments, the prostate cancer is castration-resistant prostate cancer (CRPC). In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, the Trop-2 positive cancer is (i) locally advanced, unresectable, or (ii) metastatic (e.g., mCRPC or mNSCLC). In some embodiments, the Trop-2 positive cancer is resistant or refractory to one or more anticancer therapies.

In some embodiments of the methods provided herein, the Trop-2 positive cancer is prostate cancer. In some embodiments, the Trop-2 positive cancer is metastatic prostate cancer. In some embodiments, the Trop-2 positive cancer is castration-resistant prostate cancer (CRPC). In some embodiments, the Trop-2 positive cancer is metastatic castration-resistant prostate cancer (mCRPC). In some embodiments, the Trop-2 positive cancer has a castrated animal level of serum (total) testosterone (≤ 1.7 nmol/L or 50 ng/dL) as defined by Prostate Cancer Working Group 3 (PCWG3) prostate-specific antigen (PSA) and/or radiological criteria; and measurable or non-measurable disease according to Tumor Response Evaluation Criteria (RECIST) v1.1, and metastatic castration-resistant adenocarcinoma of the prostate that exhibits tumor progression during androgen deprivation therapy (e.g., including orchiectomy).

In some embodiments, the methods provided herein comprise co-administering to a subject (e.g., a human cancer patient) having a Trop-2 positive cancer an effective amount of: a) an anti-Trop2 antibody drug conjugate; and b) an adenosine pathway inhibitor. In some embodiments, the anti-Trop-2 ADC comprises a topoisomerase I inhibitor. In some embodiments, the topoisomerase inhibitor is a camptothecin analog. In some embodiments, the camptothecin analog is an irinotecan derivative, a topotecan derivative, or an exatecan derivative. In some embodiments, the camptothecin analog is SN38 or Dxd. In some embodiments, the camptothecin analog is SN38. In some embodiments, the camptothecin analog is linked to the anti-Trop-2 antibody via a hydrolyzable linker. In some embodiments, the hydrolyzable linker is CL2A (e.g., as described in US 7,999,083). In some embodiments, the camptothecin analog is linked to the anti-Trop-2 antibody via a protease cleavable linker. In some embodiments, the anti-Trop-2 ADC has the structure mAb-CL2A-SN-38 represented by:

(e.g., as described in U.S. Pat. No. 7,999,083). In some embodiments, the drug-to-antibody ratio (DAR) of CL2A-SN38 to anti-Trop-2 antibodies in the anti-Trop-2 ADC is from 7.0 to 8.0. In some embodiments, the DAR of CL2A-SN38 to anti-Trop-2 antibodies in the anti-Trop-2 ADC is about 7.6. In some embodiments, the anti-Trop-2 ADC comprises the anti-Trop-2 antibody sacituzumab (hRS7; e.g., as described in WO2003074566 , FIGS. 3 and 4 ). In some embodiments, the anti-Trop-2 ADC is selected from sacituzumab govitecan, datopotamab deruxtecan (DS-1062), ESG-401, SKB-264, DAC-02, and BAT-8003. In some embodiments, the anti-Trop-2 ADC is sacituzumab govitecan. In some embodiments, the anti-Trop-2 ADC is datopotamab deruxtecan (DS-1062). In some embodiments, the adenosine pathway inhibitor is a CD39 inhibitor, a CD73 inhibitor, or an adenosine receptor antagonist. In some embodiments, the CD39 inhibitor is TTX-030 (AbbVie/Trishula), IPH5201 (AstraZeneca/Innate Pharma), SRF617 (Surface Oncology), CD39 ASO (Secarna Pharmaceuticals), JS-019 (Shanghai Junshi Biosciences); Selected from AB598 (anti-CD39) (Arcus Biosciences), ES002 (Elpiscience Biopharmaceuticals) and CD39xPD1 (Biotheus). In some embodiments, the CD73 inhibitor is selected from the group consisting of oleculumab (AstraZeneca), BMS-986179 (BMS), uriledrimab (I-MAB Biopharma), AK119 (Akeso Biopharma), chemriclusta (AB680, Arcus Biosciences), mufadolimab (Corvus Pharmaceuticals), HLX23 (Shanghai Henlius Biotech), INCA00186 (Incyte), IBI325 (Innovent Bio), NZV930 (Novartis/Surface Oncology), ORIC-533 (ORIC Pharma), Sym024 (Servier), IPH5301 (Innate), IOA-237 (iOnctura), JAB-BX100 (Jacobio), PT199 (Phanes Therapeutics), TRB010 (Trican Biotechnology), CD73 ASO (Secarna Pharmaceuticals), 622 (3SBio), ABSK-051 (Abbisko Therapeutics), AK131 (CD73xPD1, Akeso Biopharma), CD73i (Aurigene), BR101 (BioRay), BP1200 (BrightPath), CB708 (Antengene/Calithera), GB7002 (Genbase Bio), ATG-037 (Antengene), and CD73i (Biotheus). In some embodiments, the CD73 inhibitor is oleculumab or chemriclustat. In some embodiments, the CD73 inhibitor is chemriclustat. In some embodiments, the adenosine receptor antagonist is an adenosine A2A receptor (A2AR; ADORA2A) selective antagonist, such as imaradenant (AstraZeneca), NIR178 (Novartis/Palobiofarma) ID11902 (Ildong), IN-A003 (Inno.n), NTI-55 (A2aR/TLR7, Nammi), TT-10 (Tarus Therapeutics), or TT-228 (Teon Therapeutics). In some embodiments, the adenosine receptor antagonist is an adenosine A2B receptor (A2BR; ADORA2B) antagonist, such as PBF-1129 (Palobiofarma) or TT-702 (Teon Therapeutics). In some embodiments, the adenosine receptor antagonist is a dual adenosine A2A/A2B receptor antagonist, such as etrumadenanth (AB928, Arcus Biosciences), INCB106385 (Incyte), M1069 (Merck KgaA), A2aR/A2bR (Domain/Merck KgaA), HM87277 (A1/A2aR/A2bR, Hanmi Pharmaceutical), RVU-330 (Ryvu), TT-53 (Tarus Therapeutics). In some embodiments, the adenosine receptor antagonist is etrumadenanth. In some embodiments, the adenosine pathway inhibitor is chemriclustat or etrumadenanth. In some embodiments, the adenosine pathway inhibitor is etrumadenanth. In some embodiments, the methods provided herein comprise co-administering to a subject (e.g., a human cancer patient) having a Trop-2 positive cancer an effective amount of: a) an anti-Trop-2 ADC comprising a topoisomerase I inhibitor (e.g., SN38 or Dxd); and b) an adenosine pathway inhibitor selected from a CD39 inhibitor, a CD73 inhibitor, and an adenosine receptor antagonist. In some embodiments, the methods provided herein comprise co-administering to a subject (e.g., a human cancer patient) having a Trop-2 positive cancer an effective amount of: a) an anti-Trop-2 ADC comprising a topoisomerase I inhibitor (e.g., SN38 or Dxd); and b) an adenosine pathway inhibitor selected from a CD73 inhibitor and an adenosine receptor antagonist. In some embodiments, the methods provided herein comprise co-administering to a subject (e.g., a human cancer patient) having a Trop-2 positive cancer an effective amount of: a) an anti-Trop-2 ADC comprising a topoisomerase I inhibitor (e.g., SN38 or Dxd); and b) co-administering to a subject (e.g., a human cancer patient) having a Trop-2 positive cancer an effective amount of an adenosine pathway inhibitor selected from oleclumab, BMS-986179, uriledlimab, imaradenant, NIR178, and etrumadenanth. In some embodiments, the methods provided herein comprise a) co-administering to a subject (e.g., a human cancer patient) an anti-Trop-2 ADC having the structure mAb-CL2A-SN-38 represented by:

;

And b) co-administering to a subject (e.g., a human cancer patient) having a Trop-2 positive cancer an effective amount of an adenosine pathway inhibitor selected from olecluzumab, BMS-986179, uriledlimab, imaradenant, NIR178, and etrumadenanth. In some embodiments, the methods provided herein comprise co-administering to a subject (e.g., a human cancer patient) having a Trop-2 positive cancer an effective amount of: a) sacituzumab govitecan or datopotamab deruxtecan (DS-1062); and b) an adenosine pathway inhibitor selected from olecluzumab, BMS-986179, uriledlimab, imaradenant, NIR178, and etrumadenanth. In some embodiments, the methods provided herein comprise co-administering to a subject (e.g., a human cancer patient) having a Trop-2 positive cancer an effective amount of: a) sacituzumab govitecan; And b) co-administering an effective amount of etrumadenosine to a subject (e.g., a human cancer patient) having a Trop-2 positive cancer. In some embodiments, the methods provided herein further comprise co-administering an additional therapeutic agent or treatment modality, or a combination thereof. In some embodiments, the additional therapeutic agent comprises an immune checkpoint inhibitor (CPI). In some embodiments, the CPI comprises an anti-PD(L)1 antibody (e.g., an anti-PD-1 antibody or an anti-PD-L1 antibody) and optionally an anti-TIGIT antibody. In some embodiments, the anti-PD(L)1 antibody is selected from pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cosibelimab, sasanlimab, tislelizumab, retipanlimab, balstilimab, toripalimab, setrelimab, genolimab, progolimab, rodafolimab, camrelizumab, budigalimab, avelumab, dostalimab, envafolimab, scintillimab, and zimberelimab. In some embodiments, the anti-PD(L)1 antibody is zimberelimab. In some embodiments, the anti-TIGIT antibody is selected from tiragolumab, vivostolimab, dombanalimab, AB308, AK127, BMS-986207, ralzapastotug, and etigilimab. In some embodiments, the anti-TIGIT antibody is dombanalimab. In some embodiments, the additional therapeutic agent comprises an anti-PD(L)1 antibody and an anti-TIGIT antibody. In some embodiments, the additional therapeutic agent comprises a) zimberelimab and dombanalimab, b) zimberelimab and AB308, c) atezolizumab and tiragolumab, d) pembrolizumab and vivotolimab, e) MK-7684A (pembrolizumab/vivotolimab co-administration), f) durvalumab and dombanalimab, g) zimberelimab and ralzapastotug, or h) pembrolizumab and ralzapastotug. In some embodiments, the anti-PD(L)1 antibody is zimberelimab and the anti-TIGIT antibody is dombanalimab. In some embodiments, the additional therapeutic modalities comprise surgery or radiation therapy. In some embodiments, the methods provided herein comprise: a) an anti-Trop-2 ADC comprising a topoisomerase I inhibitor (e.g., SN38 or Dxd); b) an adenosine pathway inhibitor selected from olecumab, BMS-986179, uriledrimab, imaradenant, NIR178, and etrumadenanth, and c) an anti-PD(L)1 antibody, to a subject (e.g., a human cancer patient) having a Trop-2 positive cancer. In some embodiments, the methods provided herein comprise a) co-administering to a subject (e.g., a human cancer patient) an effective amount of an anti-Trop-2 ADC having the structure mAb-CL2A-SN-38 represented by:

;

b) an adenosine pathway inhibitor selected from olecumab, BMS-986179, uriledlimab, imaradenant, NIR178, and etrumadenanth, and c) an anti-PD(L)1 antibody. In some embodiments, the methods provided herein comprise co-administering to a subject (e.g., a human cancer patient) having a Trop-2 positive cancer an effective amount of: a) sacituzumab govitecan or datopotamab deruxtecan (DS-1062); b) an adenosine pathway inhibitor selected from olecumab, BMS-986179, uriledlimab, imaradenant, NIR178, and etrumadenanth, and c) an anti-PD(L)1 antibody. In some embodiments, the methods provided herein comprise co-administering to a subject (e.g., a human cancer patient) having a Trop-2 positive cancer an effective amount of a) sacituzumab govitecan; and b) etrumadecan; and c) an anti-PD(L)1 antibody. In some embodiments, the anti-PD(L)1 antibody is selected from pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cosibelimab, sasanlimab, tislelizumab, retipanlimab, balstilimab, toripalimab, setrelimab, genolimab, progolimab, rodafolimab, camrelizumab, budigalimab, avelumab, dostalimab, envafolimab, scintillimab, and zimberelimab. In some embodiments, the anti-PD(L)1 antibody is zimberelimab. In some embodiments, the methods provided herein comprise co-administering to a subject (e.g., a human cancer patient) having a Trop-2 positive cancer an effective amount of a) sacituzumab govitecan; and b) etrummadenant; and c) zimberelimab. In some embodiments, the Trop-2 positive cancer is castration-resistant prostate cancer (CRPC) or non-small cell lung cancer (NSCLC). In some embodiments, the Trop-2 positive cancer is CRPC. In some embodiments, the Trop-2 positive cancer is metastatic (e.g., mCRPC, mNSCLC). In some embodiments, the Trop-2 positive cancer is resistant or refractory to one or more anticancer therapies (e.g., NHEA-resistant or refractory mCRPC).

In some embodiments, the methods provided herein comprise co-administering to a subject (e.g., a human cancer patient) having a tumor antigen positive (TA ⁺ ) cancer an effective amount of: a) a TopI ADC; and b) an adenosine pathway inhibitor. In some embodiments, the TopI ADC comprises a camptothecin analog. In some embodiments, the camptothecin analog is an irinotecan derivative, a topotecan derivative, or an exatecan derivative. In some embodiments, the camptothecin analog is SN38 or Dxd. In some embodiments, the camptothecin analog is SN38. In some embodiments, the camptothecin analog is linked to the tumor antigen targeted antibody via a hydrolyzable linker. In some embodiments, the hydrolyzable linker is CL2A (e.g., as described in US 7,999,083). In some embodiments, the camptothecin analogue is linked to a tumor antigen-targeting antibody via a protease-cleavable linker. In some embodiments, the TopI ADC has the structure mAb-CL2A-SN-38 represented by:

(e.g., as described in U.S. Patent No. 7,999,083). In some embodiments, the tumor antigen targeted antibody in the TopI ADC is selected from an antibody selected from gemtuzumab, brentuximab, belantamab, camidanlumab, trastuzumab, inotuzumab, glembatumumab, anetumab, mirvetuximab, depatuxizumab, badastuximab, labetuzumab, radiratuzumab, loncastuximab, patritumab, rifastuzumab, indusatumab, polatuzumab, pinatuzumab, coltuximab, apipitamab, indatuximab, milatuzumab, rovalpituzumab, enfortumab, tisotumab, tusamitamab, dicitamab, telisotuzumab, and antigen-binding fragments thereof. In some embodiments, the tumor antigen targeted antibody in the TopI ADC is selected from hLL1, hLL2, RFB4, hA19, hA20, hRS7, hPAM4, hMN-3, hMN-14, hMu-9, hR1, CC49, hL243, D2/B, hImmu-31 and antigen-binding fragments thereof. In some embodiments, the drug-to-antibody ratio (DAR) of CL2A-SN38 to anti-Trop-2 antibody in the anti-Trop2 ADC is ≥ 7.5 (e.g., DAR = 7.6). In some embodiments, the anti-Trop-2 ADC comprises the anti-Trop-2 antibody sacituzumab (hRS7; e.g., described in WO2003074566 , FIGS. 3 and 4 ). In some embodiments, the TopI ADC is trastuzumab deruxtecan. In some embodiments, the adenosine pathway inhibitor is a CD39 inhibitor, a CD73 inhibitor, or an adenosine receptor antagonist. In some embodiments, the CD39 inhibitor is selected from TTX-030 (AbbVie/Trishula), IPH5201 (AstraZeneca/Innate Pharma), SRF617 (Surface Oncology), CD39 ASO (Secarna Pharmaceuticals), JS-019 (Shanghai Junshi Biosciences); anti-CD39 (Arcus Biosciences), ES002 (Elpiscience Biopharmaceuticals), and CD39xPD1 (Biotheus). In some embodiments, the CD73 inhibitor is selected from the group consisting of oleculumab (AstraZeneca), BMS-986179 (BMS), uriledrimab (I-MAB Biopharma), AK119 (Akeso Biopharma), chemriclusta (AB680, Arcus Biosciences), mufadolimab (Corvus Pharmaceuticals), HLX23 (Shanghai Henlius Biotech), INCA00186 (Incyte), IBI325 (Innovent Bio), NZV930 (Novartis/Surface Oncology), ORIC-533 (ORIC Pharma), Sym024 (Servier), IPH5301 (Innate), IOA-237 (iOnctura), JAB-BX100 (Jacobio), PT199 (Phanes Therapeutics), TRB010 (Trican Biotechnology), CD73 ASO (Secarna Pharmaceuticals), 622 (3SBio), ABSK-051 (Abbisko Therapeutics), AK131 (CD73xPD1, Akeso Biopharma), CD73i (Aurigene), BR101 (BioRay), BP1200 (BrightPath), CB708 (Antengene/Calithera), GB7002 (Genbase Bio), ATG-037 (Antengene), and CD73i (Biotheus). In some embodiments, the CD73 inhibitor is oleculumab or chemriclustat. In some embodiments, the CD73 inhibitor is chemriclustat. In some embodiments, the adenosine receptor antagonist is an adenosine A2A receptor (A2AR; ADORA2A) selective antagonist, such as imaradenant (AstraZeneca), NIR178 (Novartis/Palobiofarma) ID11902 (Ildong), IN-A003 (Inno.n), NTI-55 (A2aR/TLR7, Nammi), TT-10 (Tarus Therapeutics), or TT-228 (Teon Therapeutics). In some embodiments, the adenosine receptor antagonist is an adenosine A2B receptor (A2BR; ADORA2B) antagonist, such as PBF-1129 (Palobiofarma) or TT-702 (Teon Therapeutics). In some embodiments, the adenosine receptor antagonist is a dual adenosine A2A/A2B receptor antagonist, such as etrumadenosine (AB928, Arcus Biosciences), INCB106385 (Incyte), M1069 (Merck KGaA), A2aR/A2bR (Domain/Merck KGaA), HM87277 (A1/A2aR/A2bR, Hanmi Pharmaceutical), RVU-330 (Ryvu), TT-53 (Tarus Therapeutics). In some embodiments, the methods provided herein further comprise co-administering an additional therapeutic agent or treatment modality, or a combination thereof. In some embodiments, the additional therapeutic agent comprises an immune checkpoint inhibitor. In some embodiments, the CPI comprises an anti-PD(L)1 antibody (e.g., an anti-PD-1 antibody or an anti-PD-L1 antibody) and optionally an anti-TIGIT antibody. In some embodiments, the anti-PD(L)1 antibody is selected from pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cosibelimab, sasanlimab, tislelizumab, retipanlimab, balstilimab, toripalimab, setrelimab, genolimab, progolimab, rodafolimab, camrelizumab, budigalimab, avelumab, dostalimab, envafolimab, scintillimab, and zimberelimab. In some embodiments, the anti-PD(L)1 antibody is zimberelimab. In some embodiments, the anti-TIGIT antibody is selected from tiragolumab, vivostolimab, dombanalimab, AB308, AK127, BMS-986207, ralzapastotug, and etigilimab. In some embodiments, the anti-TIGIT antibody is dombanalimab. In some embodiments, the additional therapeutic agent comprises an anti-PD(L)1 antibody and an anti-TIGIT antibody. In some embodiments, the additional therapeutic agent comprises a) zimberelimab and dombanalimab, b) zimberelimab and AB308, c) atezolizumab and tiragolumab, d) pembrolizumab and vivostolimab, e) MK-7684A (pembrolizumab/vivostolimab co-administration), f) durvalumab and dombanalimab, g) zimberelimab and ralzapastotug, or h) pembrolizumab and ralzapastotug. In some embodiments, the anti-PD(L)1 antibody is zimberelimab and the anti-TIGIT antibody is dombanalimab. In some embodiments, the additional therapeutic modalities comprise surgery or radiation therapy. In some embodiments, the tumor antigen positive cancer is characterized by carbonic anhydrase IX, B7, CCCL19, CCCL21, CSAp, HER-2/neu, BrE3, CD1, CD1a, CD2, CD3, CD4, CD5, CD8, CD11A, CD14, CD15, CD16, CD18, CD19, CD20, CD21, CD22, CD23, CD25, CD29, CD30, CD32b, CD33, CD37, CD38, CD40, CD40L, CD44, CD45, CD46, CD52, CD54, CD55, CD59, CD64, CD67, CD70, CD74, CD79a, CD80, CD83, CD95, CD126, CD133, CD138, CD147, CD154, CEACAM5, CEACAM-6, alpha-fetoprotein (AFP), VEGF, ED-B fibronectin, EGP-1, EGP-2, EGF receptor (ErbB1), ErbB2, ErbB3, factor H, FHL-1, Flt-3, folate receptor, Ga 733, GROB, HMGB-1, hypoxia-inducible factor (HIF), HM1.24, HER-2/neu, insulin-like growth factor (ILGF), IFN-a, IFN-b, IL-g, IL-2R, IL-4R, IL-6R, IL-13R, IL-15R, IL-17R, IL-18R, IL-2, IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, IL-25, IP-10, IGF-1R, Ia, HM1.24, ganglioside, HCG, Positive for tumor antigens selected from HLA-DR, CD66a-d, MAGE, mCRP, MCP-1, MIP-1A, MIP-1B, macrophage migration-inhibitory factor (MIF), MUC1, MUC2, MUC3, MUC4, MUC5, placental growth factor (P1GF), prostate-specific antigen (PSA), PSMA, PSMA dimer, PAM4 antigen, NCA-95, NCA-90, A3, A33, Ep-CAM, KS-1, Le(y), mesothelin, S100, tenascin, TAC, Tn antigen, Thomas-Friedenreich antigen, tumor necrosis antigen, tumor angiogenesis antigen, TNF-a., TRAIL receptors (R1 and R2), VEGFR, RANTES, T101, cancer stem cell antigen, complement factor C3, C3a, C3b, C5a, C5, and oncogene products.

General dosing and administration regimens, and pharmaceutical compositions, for antibody-drug conjugates, adenosine pathway inhibitors, and additional therapeutic agents that can be used in the methods provided herein are known to the skilled artisan. For example, general dosing and administration regimens, and pharmaceutical compositions are described in WO2014/092804A1 for exemplary ADCs including sacituzumab govitecan, WO2017120508 for exemplary CD73 inhibitors including chemriclustat, WO2018136700A1 for exemplary adenosine receptor antagonists including etrumadenanthet, and WO2017025051A1 for exemplary anti-PD(L)1 antibodies including zimberelimab.

In the methods provided herein, the ADC (e.g., sacituzumab govitecan), the adenosine pathway inhibitor (e.g., etrummadenant, chemliclustat), and optionally, the anti-PD(L)1 antibody (e.g., zimberelimab) can be co-administered simultaneously, sequentially or sequentially. In some embodiments, the ADC (e.g., sacituzumab govitecan), the adenosine pathway inhibitor (e.g., etrummadenant, chemliclustat), and optionally, the anti-PD(L1) antibody (e.g., zimberelimab) are co-administered on the same day (e.g., on day 1 of a 21 day treatment cycle). In some embodiments, the ADC (e.g., sacituzumab govitecan), the adenosine pathway inhibitor (e.g., etrummadenant, chemliclustat), and optionally, the anti-PD(L1) antibody (e.g., zimberelimab) are co-administered sequentially or sequentially. In some embodiments, the ADC (e.g., sacituzumab govitecan), the adenosine pathway inhibitor (e.g., etrummadenant, chemliclustat), and optionally, the anti-PD(L1) antibody (e.g., zimberelimab) are co-administered sequentially. In some embodiments, sacituzumab govitecan and etrummadenant are co-administered sequentially on day 1 of a 21-day treatment cycle, wherein etrummadenant is co-administered orally at least 30 minutes prior to initiation of the intravenous infusion of sacituzumab govitecan. In some embodiments, sacituzumab govitecan, etrummadenant, and zimberelimab are co-administered sequentially on day 1 of a 21-day treatment cycle, wherein etrummadenant is co-administered orally at least 30 minutes prior to initiation of the intravenous infusion of zimberelimab, and sacituzumab govitecan is co-administered intravenously after completion of the zimberelimab infusion.

In some embodiments of the methods provided herein, sacituzumab govitecan is co-administered on days 1 and 8 of a 21 day treatment cycle. In some embodiments, sacituzumab govitecan is co-administered intravenously (IV). In some embodiments, sacituzumab govitecan is co-administered at a dose of 8 mg/kg to 10 mg/kg. In some embodiments, sacituzumab govitecan is co-administered at a dose of 8 mg/kg or 10 mg/kg. In some embodiments, sacituzumab govitecan is co-administered at a dose of 10 mg/kg. In some embodiments, sacituzumab govitecan is co-administered intravenously (IV) on days 1 and 8 of a 21 day treatment cycle at a dose of 8 mg/kg or 10 mg/kg.

In some embodiments of the methods provided herein, etrummadenant is co-administered once daily (QD). In some embodiments, etrummadenant is co-administered orally (PO). In some embodiments, etrummadenant is co-administered in a dose of 75 mg or 150 mg. In some embodiments, etrummadenant is co-administered in a dose of 150 mg. In some embodiments, etrummadenant is co-administered orally (PO) once daily (QD) in a dose of 75 mg or 150 mg. In some embodiments, etrummadenant is co-administered orally (PO) once daily (QD) in a dose of 150 mg.

In some embodiments of the methods provided herein, the anti-PD(L)1 antibody (e.g., zimberelimab) is co-administered once every three weeks (Q3W). In some embodiments, the anti-PD(L)1 antibody is co-administered intravenously (IV). In some embodiments, the anti-PD(L)1 antibody is co-administered at a dose of 360 mg.

In some embodiments of the methods provided herein, sacituzumab govitecan is co-administered intravenously (IV) at a dose of 8 mg/kg or 10 mg/kg on days 1 and 8 of a 21-day treatment cycle; etrumadenan is co-administered orally (PO) at a dose of 75 mg or 150 mg once daily (QD) of a 21-day treatment cycle, and optionally, zimberelimab is co-administered at a dose of 360 mg on day 1 (Q3W) of a 21-day treatment cycle.

In some embodiments of the methods provided herein, sacituzumab govitecan is co-administered intravenously (IV) at a dose of 10 mg/kg on days 1 and 8 of a 21-day treatment cycle; etrumadenan is co-administered orally (PO) at a dose of 150 mg once daily (QD) of a 21-day treatment cycle, and optionally, zimberelimab is co-administered at a dose of 360 mg on day 1 (Q3W) of a 21-day treatment cycle.

In some embodiments, the methods provided herein have an anticancer effect as determined by one or more efficacy endpoints selected from objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), overall survival (OS), complete response (CR), partial response (PR), PSA response rate, radiographic response rate, and changes from baseline in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers. In some embodiments, tumor response or progression is determined according to RECIST version 1.1. In some embodiments, ORR is defined as the composite proportion of participants with a PSA and/or radiographic complete and partial response as determined by the investigator according to Prostate Cancer Working Group 3 (PCWG3) criteria. In some embodiments, PSA response is defined as the proportion of participants with a PSA decrease of greater than or equal to 50% from baseline based on two consecutive assessments measured at least 3 to 4 weeks apart. In some embodiments, radiographic response is defined as the proportion of participants with the best overall response of CR or PR according to RECIST v1.1. In some embodiments, DCR is defined as the proportion of participants with the best overall RECIST response of CR, PR, or stable disease (SD). In some embodiments, DCR is at least 6 months. In some embodiments, PFS is defined as the time from treatment assignment to the first documented progressive disease (e.g., PSA progression, radiographic progression, bone scan progression, etc.) or death, whichever occurs first. Depending on data availability, time to progression due to a specific cause (e.g., PSA progression or radiographic progression) may also be presented separately. In some embodiments, OS is defined as the time from treatment assignment to death from any cause.

In some embodiments, the methods provided herein further comprise determining the level of tumor antigen (e.g., Trop-2) expression in a sample from the subject. Determination of the level of tumor antigen (e.g., Trop-2) expression can be accomplished by any clinical analytical method known to the skilled artisan. The sample can include a liquid biopsy sample (e.g., a blood sample) and a solid tumor biopsy sample. The level of tumor antigen (e.g., Trop-2) expression can be determined at the DNA, RNA, or protein level. Exemplary methods for measuring the level of tumor antigen (e.g., Trop-2) expression include Western blot, immunohistochemistry, QPCR, exome sequencing, FACS, and the like.

In some embodiments of the methods provided herein, an anti-CD47 antibody is not co-administered to the subject or human patient (CD47; integrin associated protein; IAP; NCBI Gene Number 961). In some embodiments, the subject or human patient is not co-administered an anti-CD47 antibody selected from magrolimab, lemzopalimab, retaplimab, ligupalimab, AO-176, IBI-322, ZL-1201, IMC-002, SRF-231, CC-90002 (aka INBRX-103), NI-1701 (aka TG-1801), and STI-6643. In some embodiments, the subject or human patient is not co-administered with magrolimab.

In some embodiments of the methods provided herein, the MCL1 inhibitor is not co-administered to the subject or human patient (MCL1; myeloid leukemia cell differentiation protein; NCBI Gene Number 4170). In some embodiments, the subject or human patient is not co-administered an MCL1 inhibitor selected from GS-9716, AMG-397, AMG-176, PRT-1419, and S6431. In some embodiments, the subject or human patient is not co-administered GS-9716.

In some embodiments of the methods provided herein, the FLT3 agonist is not co-administered to the subject or human patient (FLT3; fms-like tyrosine kinase; CD135; NCBI Gene Number 2322). In some embodiments, the FLT3 agonist is selected from GS-3583, CDX-301, TAK-605, ONCR-177, Alb-Ftl3L, and SYM-027. In some embodiments, the FLT3 agonist is GS-3583.

Kit

Provided herein is a kit for use as a pharmaceutical composition, wherein the kit comprises: a) a TROP-2-targeted antibody-drug conjugate (ADC) comprising an anti-TROP-2 antibody (anti-TROP-2 ADC); b) an adenosine pathway inhibitor; and c) optionally an anti-PD-(L)1 antibody.

Also provided herein is a kit for use as a drug, wherein the kit comprises: a) a tumor antigen (TA) targeted ADC (TopI ADC) comprising a topoisomerase I inhibitor; b) an adenosine pathway inhibitor; and c) optionally an anti-PD-(L)1 antibody.

Also provided herein are kits comprising one or more unit doses of an active agent, e.g., a) an anti-Trop-2 ADC (e.g., sacituzumab govitecan) or a TopI ADC; b) an adenosine pathway inhibitor (e.g., etrummadenan, chemriclustat); and optionally c) an anti-PD(L)1 antibody (e.g., zimberelimab), and formulations thereof, and instructions for use thereof. In various embodiments, the a) an anti-Trop-2 ADC (e.g., sacituzumab govitecan) or a TopI ADC; b) an adenosine pathway inhibitor (e.g., etrummadenan, chemriclustat); and optionally c) an anti-PD(L)1 antibody (e.g., zimberelimab) can be present in the same or different containers. The kit can further contain at least one additional reagent, e.g., an anti-TIGIT antibody. A kit typically includes a label indicating the intended use of the kit's contents. The term label includes any writing or written material provided on or with the kit or accompanying the kit.

In some embodiments, one or more of a) an anti-Trop-2 ADC (e.g., sacituzumab govitecan) or a TopI ADC; b) an adenosine pathway inhibitor (e.g., etrummadenant, chemriclustat); and optionally c) an anti-PD(L)1 antibody (e.g., zimberelimab) are provided in a dosage form (e.g., a therapeutically effective dosage form). In some embodiments, one or more of a) an anti-Trop-2 ADC (e.g., sacituzumab govitecan) or a TopI ADC; b) an adenosine pathway inhibitor (e.g., etrummadenant, chemriclustat); and optionally c) an anti-PD(L)1 antibody (e.g., zimberelimab) can be provided in two or more different dosage forms (e.g., two or more different therapeutically effective dosage forms). In the context of a kit, one or more of a) an anti-Trop-2 ADC (e.g., sacituzumab govitecan) or a TopI ADC; b) an adenosine pathway inhibitor (e.g., etrummadenant, chemriclustat); and optionally c) an anti-PD(L)1 antibody (e.g., zimberelimab) may be provided in liquid or solid form in any convenient packaging (e.g., stick pack, dose pack, etc.).

a) an anti-Trop-2 ADC (e.g., sacituzumab govitecan) or a TopI ADC; b) an adenosine pathway inhibitor (e.g., etrummadenant, chemriclustat); and optionally c) an anti-PD(L)1 antibody (e.g., zimberelimab) may be suitably provided in the same or separate containers. In various embodiments, a) an anti-Trop-2 ADC (e.g., sacituzumab govitecan) or a TopI ADC; b) an adenosine pathway inhibitor (e.g., etrummadenant, chemriclustat); and optionally c) an anti-PD(L)1 antibody (e.g., zimberelimab) are provided in separate containers. a) an anti-Trop-2 ADC (e.g., sacituzumab govitecan) or a TopI ADC; b) an adenosine pathway inhibitor (e.g., etrumadenanth, chemriclustat); and optionally c) an anti-PD(L)1 antibody (e.g., zimberelimab), wherein the composition is provided in one or more containers, wherein the containers have a label. Suitable containers include, for example, bottles, vials, ampoules, syringes (including preloaded syringes), and test tubes. The containers can be formed from a variety of materials, such as glass or plastic. The containers contain a composition effective to treat the disease and can have a sterile access port (e.g., the container can be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). In one composition, the active agent is a) an anti-Trop-2 ADC (e.g., sacituzumab govitecan) or a TopI ADC. In the second composition, the active agent is an adenosine pathway inhibitor (e.g., etrumadenanth, chemriclustat). In the optional third composition, the active agent is optionally c) an anti-PD(L)1 antibody (e.g., gimberelimab). A label on or associated with the container indicates that the composition is used to treat the disease of choice. The article of manufacture can further comprise one or more containers comprising, for example, a pharmaceutically acceptable buffer for use as a diluent. Exemplary buffers include, but are not limited to, phosphate buffered saline, Ringer's solution, and/or dextrose solution. The kit can further comprise other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for use.

In addition to the above components, the subject kit may further comprise instructions for carrying out the subject method (in certain embodiments). Such instructions may be present in the subject kit in a variety of forms, one or more of which may be present in the kit. One form in which such instructions may be present is information printed on a suitable medium or substrate, such as a sheet or sheets of paper on which the information is printed, the packaging of the kit, a package insert, etc. Another form in which such instructions may be present is a computer-readable medium having the information recorded thereon, such as a diskette, a compact disc (CD), a flash drive, etc. Another form in which such instructions may be present is a website address that may be used via the Internet to access the information from a remote location.

Exemplary embodiment

In some embodiments, provided herein are methods of treating metastatic castration-resistant prostate cancer (mCRPC), comprising co-administering to the human patient an effective amount of a) sacituzumab govitecan; and b) etrumadecant. In some embodiments, the method further comprises co-administering to the human patient zimberelimab. In some embodiments, the human mCRPC patient has previously received androgen deprivation therapy (ADT). In some embodiments, the human mCRPC patient has previously received one or more next generation hormone agents (NHAs, e.g., abiraterone, enzalutamide, darolutamide, apalutamide). In some embodiments, the human mCRPC patient is checkpoint inhibitor (CPI) and taxane naive. In some embodiments, the human mCRPC patient has RECIST 1.1 measurable or non-measurable disease.

In some embodiments, provided herein is a method of treating castration-resistant prostate cancer (CRPC), comprising co-administering to a human patient an effective amount of: a) an anti-Trop-2 ADC; b) a CD73 inhibitor or an adenosine receptor antagonist; and optionally, c) an anti-PD(L)1 antibody. In some embodiments, the CRPC is metastatic CRPC (mCRPC). In some embodiments, the anti-Trop-2 ADC has the structural formula mAb-CL2A-SN-38, having a structure represented by:

(e.g., as described in USPN 7,999,083). In some embodiments, the drug-to-antibody ratio (DAR) of CL2A-SN38 to an anti-Trop-2 antibody in the anti-Trop-2 ADC is from 7.0 to 8.0 (e.g., DAR = 7.6). In some embodiments, the anti-Trop-2 ADC comprises a linker-payload conjugate having a structure represented by: attached to an anti-Trop-2 antibody (e.g., hRS7)

.

In some embodiments, the anti-Trop-2 ADC comprises a linker-payload conjugate (TL035) having a structure represented by: attached to an anti-Trop-2 antibody (e.g., hRS7)

. In some embodiments, the anti-Trop-2 ADC comprises a linker-payload conjugate having a structure represented by: attached to an anti-Trop-2 antibody (e.g., hTINA1-H1L1):

.

In some embodiments, the anti-Trop-2 ADC has a DAR of about 4. In some embodiments, the anti-Trop-2 ADC is selected from sacituzumab govitecan, datopotamab deruxtecan (DS-1062), ESG-401, SKB-264, DAC-02, and BAT-8003. In some embodiments, the anti-Trop-2 antibody is sacituzumab govitecan or datopotamab deruxtecan. In some embodiments, the anti-Trop-2 antibody is sacituzumab govitecan. In some embodiments, the CD73 inhibitor is selected from the group consisting of oleculumab (AstraZeneca), BMS-986179 (BMS), uriledrimab (I-MAB Biopharma), AK119 (Akeso Biopharma), chemriclusta (AB680, Arcus Biosciences), mufadolimab (Corvus Pharmaceuticals), HLX23 (Shanghai Henlius Biotech), INCA00186 (Incyte), IBI325 (Innovent Bio), NZV930 (Novartis/Surface Oncology), ORIC-533 (ORIC Pharma), Sym024 (Servier), IPH5301 (Innate), IOA-237 (iOnctura), JAB-BX100 (Jacobio), PT199 (Phanes Therapeutics), TRB010 (Trican Biotechnology), CD73 ASO (Secarna Pharmaceuticals), 622 (3Sbio), ABSK-051 (Abbisko Therapeutics), AK131 (CD73xPD1, Akeso Biopharma), CD73i (Aurigene), BR101 (BioRay), BP1200 (BrightPath), CB708 (Antengene/Calithera), GB7002 (Genbase Bio), ATG-037 (Antengene), and CD73i (Biotheus). In some embodiments, the CD73 inhibitor is selected from oleculumab and chemriclustat. In some embodiments, the CD73 inhibitor is chemriclustat. In some embodiments, the adenosine receptor antagonist is an adenosine A2A receptor (A2AR; ADORA2A) selective antagonist, such as imaradenant (AstraZeneca), NIR178 (Novartis/Palobiofarma) ID11902 (Ildong), IN-A003 (Inno.n), NTI-55 (A2aR/TLR7, Nammi), TT-10 (Tarus Therapeutics), or TT-228 (Teon Therapeutics). In some embodiments, the adenosine receptor antagonist is an adenosine A2B receptor (A2BR; ADORA2B) antagonist, such as PBF-1129 (Palobiofarma) or TT-702 (Teon Therapeutics). In some embodiments, the adenosine receptor antagonist is a dual adenosine A2A/A2B receptor antagonist, such as etrumadenosine (AB928, Arcus Biosciences), INCB106385 (Incyte), M1069 (Merck KgaA), A2aR/A2bR (Domain/Merck KgaA), HM87277 (A1/A2aR/A2bR, Hanmi Pharmaceutical), RVU-330 (Ryvu), and TT-53 (Tarus Therapeutics). In some embodiments, the adenosine receptor antagonist is etrumadenosine. In some embodiments, the anti-PD(L)1 antibody is selected from pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cosibelimab, sasanlimab, tislelizumab, retipanlimab, balstilimab, toripalimab, setrelimab, genolimab, progolimab, rodafolimab, camrelizumab, budigalimab, avelumab, dostalimab, envapolimab, scintillimab, and zimberelimab. In some embodiments, the anti-PD(L)1 antibody is zimberelimab. In some embodiments, the human patient is not co-administered with an additional therapeutic agent selected from an MCL-1 inhibitor, an anti-CD47 antibody, and a FLT3 agonist.

In some embodiments, provided herein are methods of treating castration-resistant prostate cancer (CRPC), comprising co-administering to a human patient an effective amount of a) sacituzumab govitecan; and b) etrumadecant. In some embodiments, the CRPC is metastatic CRPC (mCRPC). In some embodiments, the CRPC or mCRPC ((m)CRPC) is resistant or refractory to at least one anticancer therapy. In some embodiments, the human patient has exhibited disease progression following prior treatment with a novel hormonal agent (NHA; first or second generation non-steroidal antiandrogens, abiraterone, enzalutamide, darolutamide, apalutamide). In some embodiments, the human patient has not received prior taxane therapy (e.g., paclitaxel, naphtha-paclitaxel (ABRAXANE®), docetaxel, cabazitaxel), checkpoint inhibitor therapy (e.g., anti-CTLA4 antibody, anti-PD(L)1 antibody), topoisomerase I inhibitor therapy (e.g., irinotecan). In some embodiments, the human patient with (m)CRPC has histologically confirmed castration-resistant metastatic prostatic adenocarcinoma with tumor progression while on androgen deprivation therapy (ADT; including orchiectomy) with castrate levels of serum (total) testosterone (≤ 1.7 nmol/L or 50 ng/dL) as defined by PSA and/or radiological criteria per the PCWG3. In some embodiments, the human patient with (m)CRPC has metastatic castration-resistant adenocarcinoma of the prostate with tumor progression while on androgen deprivation therapy (e.g., including orchiectomy), with a castrate level of serum (total) testosterone (≤ 1.7 nmol/L or 50 ng/dL) as defined by prostate-specific antigen (PSA) and/or radiological criteria according to the Prostate Cancer Working Group 3 (PCWG3) and measurable or non-measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. In some embodiments, the human patient with (m)CRPC has an Eastern Cooperative Oncology Society performance status of 0 or 1, and a life expectancy ≥ 3 months. In some embodiments, the human patient with (m)CRPC has been tested for tumor antigen (e.g., Trop-2) expression levels (e.g., following a liquid or solid tumor biopsy, by tumor antigen expression analysis by IHC or next generation DNA sequencing). In some embodiments, sacituzumab govitecan is administered intravenously (IV) at a dose of 8 mg/kg or 10 mg/kg on days 1 and 8 of a 21-day treatment cycle, and etrummadenant is administered orally (PO) at a dose of 75 mg or 150 mg once daily (QD) of a 21-day treatment cycle. In some embodiments, sacituzumab govitecan is administered intravenously (IV) at a dose of 10 mg/kg on days 1 and 8 of a 21-day treatment cycle, and etrummadenant is administered orally (PO) at a dose of 150 mg once daily (QD) of a 21-day treatment cycle. In some embodiments, the methods provided herein have an anticancer effect as determined by one or more efficacy endpoints selected from objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), complete response (CR), partial response (PR), PSA response rate, radiographic response rate, and changes from baseline in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers. In some embodiments, ORR is defined as the composite proportion of participants with a PSA and/or radiographic complete and partial response as determined by the investigator according to Prostate Cancer Working Group 3 (PCWG3) criteria. In some embodiments, PSA response is defined as the proportion of participants with a PSA decrease of greater than or equal to 50% from baseline based on two consecutive assessments measured at least 3 to 4 weeks apart. In some embodiments, radiographic response is defined as the proportion of participants with a best overall response of CR or PR according to RECIST v1.1. In some embodiments, DCR is defined as the proportion of participants with the best overall RECIST response of CR, PR, or stable disease (SD). In some embodiments, DCR is at least 6 months. In some embodiments, PFS is defined as the time from treatment assignment to the first documented progressive disease (e.g., PSA progression, radiographic progression, bone scan progression, etc.) or death, whichever occurs first. Depending on data availability, time to progression due to a specific cause (e.g., PSA progression or radiographic progression) may also be presented individually. In some embodiments, OS is defined as the time from treatment assignment to death from any cause. In some embodiments, the human patient does not receive additional therapeutic agents selected from an MCL-1 inhibitor, an anti-CD47 antibody, and a FLT3 agonist co-administered.

In some embodiments, provided herein are methods of treating castration-resistant prostate cancer (CRPC), comprising co-administering to a human patient effective amounts of a) sacituzumab govitecan; b) etrummadenant, and c) zimberelimab. In some embodiments, the CRPC is metastatic CRPC (mCRPC). In some embodiments, the CRPC or mCRPC ((m)CRPC) is resistant or refractory to at least one anticancer therapy. In some embodiments, the human patient has exhibited disease progression following prior treatment with a novel hormonal agent (NHA; a first or second generation non-steroidal anti-androgen agent, e.g., abiraterone, enzalutamide, darolutamide, apalutamide). In some embodiments, the human patient has not received prior taxane therapy (e.g., paclitaxel, naphtha-paclitaxel (ABRAXANE®), docetaxel, cabazitaxel), checkpoint inhibitor therapy (e.g., anti-CTLA4 antibody, anti-PD(L)1 antibody), topoisomerase I inhibitor therapy (e.g., irinotecan). In some embodiments, the human patient with (m)CRPC has histologically confirmed castration-resistant metastatic prostatic adenocarcinoma with tumor progression while on androgen deprivation therapy (ADT; including orchiectomy) with castrate levels of serum (total) testosterone (≤ 1.7 nmol/L or 50 ng/dL) as defined by PSA and/or radiological criteria per the PCWG3. In some embodiments, the human patient with (m)CRPC has metastatic castration-resistant adenocarcinoma of the prostate with tumor progression while on androgen deprivation therapy (e.g., including orchiectomy), with a castrate level of serum (total) testosterone (≤ 1.7 nmol/L or 50 ng/dL) as defined by prostate-specific antigen (PSA) and/or radiological criteria according to the Prostate Cancer Working Group 3 (PCWG3) and measurable or non-measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. In some embodiments, the human patient with (m)CRPC has an Eastern Cooperative Oncology Society performance status of 0 or 1, and a life expectancy ≥ 3 months. In some embodiments, the human patient with (m)CRPC has been tested for tumor antigen (e.g., Trop-2) expression levels (e.g., following a liquid or solid tumor biopsy, by tumor antigen expression analysis by IHC or next generation DNA sequencing). In some embodiments, sacituzumab govitecan is administered intravenously (IV) at a dose of 8 mg/kg or 10 mg/kg on days 1 and 8 of a 21-day treatment cycle, etrumadenanth is administered orally (PO) at a dose of 75 mg or 150 mg once daily (QD) of a 21-day treatment cycle, and zimberelimab is administered at a dose of 360 mg on day 1 (Q3W) of a 21-day treatment cycle. In some embodiments, sacituzumab govitecan is administered intravenously (IV) at a dose of 10 mg/kg on days 1 and 8 of a 21-day treatment cycle, etrumadenanth is administered orally (PO) at a dose of 150 mg once daily (QD) of the 21-day treatment cycle, and zimberelimab is administered at a dose of 360 mg on day 1 (Q3W) of the 21-day treatment cycle. In some embodiments, the methods provided herein have an anticancer effect as determined by one or more efficacy endpoints selected from objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), complete response (CR), partial response (PR), PSA response rate, radiographic response rate, and changes from baseline in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers. In some embodiments, ORR is defined as the composite proportion of participants with a PSA and/or radiographic complete and partial response as determined by the investigator according to Prostate Cancer Working Group 3 (PCWG3) criteria. In some embodiments, PSA response is defined as the proportion of participants with a PSA decrease of greater than or equal to 50% from baseline based on 2 consecutive assessments measured at least 3 to 4 weeks apart. In some embodiments, radiographic response is defined as the proportion of participants with a best overall response of CR or PR according to RECIST v1.1. In some embodiments, DCR is defined as the proportion of participants with a best overall RECIST response of CR, PR, or stable disease (SD). In some embodiments, DCR is at least 6 months. In some embodiments, PFS is defined as the time from treatment assignment to the first documented occurrence of progressive disease (e.g., PSA progression, radiographic progression, bone scan progression) or death, whichever occurs first. Depending on data availability, time to progression for specific reasons (e.g., PSA progression or radiological progression) may also be presented individually. In some embodiments, OS is defined as the time from treatment assignment to death from any cause. In some embodiments, the human patient does not receive co-administration of an additional therapeutic agent selected from an MCL-1 inhibitor, an anti-CD47 antibody, and a FLT3 agonist.

In some embodiments, provided herein are methods of treating metastatic non-small cell lung cancer (mNSCLC), comprising co-administering to a human mNSCLC patient an effective amount of: a) sacituzumab govitecan; b) etrummadenant; and c) an anti-PD-(L)1 antibody. In some embodiments, the anti-PD-(L)1 antibody is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cosibelimab, sasanlimab, tislelizumab, retipanlimab, balstilimab, toripalimab, setrelimab, genolimab, progolimab, rodafolimab, camrelizumab, budigalimab, avelumab, dostalimab, envapolimab, scintillimab, and zimberelimab. In some embodiments, the anti-PD-(L)1 antibody is zimberelimab. In some embodiments, the human mNSCLC patient has progressed following platinum-based chemotherapy. In some embodiments, the human mNSCLC patient has progressed following checkpoint inhibitor therapy (e.g., anti-PD-(L)1 antibody or anti-CTLA4 antibody therapy). In some embodiments, the human mNSCLC patient has progressed following platinum-based chemotherapy and anti-PD-(L)1 antibody therapy, either concurrently or sequentially (in any order). In some embodiments, the human mNSCLC patient is treatment naïve.

In some embodiments, provided herein is a method of treating non-small cell lung cancer (NSCLC), comprising co-administering to a human patient an effective amount of: a) an anti-Trop-2 ADC; b) a CD73 inhibitor or an adenosine receptor antagonist; and optionally, c) an anti-PD(L)1 antibody. In some embodiments, the NSCLC is metastatic NSCLC (mNSCLC). In some embodiments, the anti-Trop-2 ADC has the structural formula mAb-CL2A-SN-38, having a structure represented by:

(e.g., as described in USPN 7,999,083). In some embodiments, the drug-to-antibody ratio (DAR) of CL2A-SN38 to an anti-Trop-2 antibody in the anti-Trop-2 ADC is from 7.0 to 8.0 (e.g., DAR = 7.6). In some embodiments, the anti-Trop-2 ADC comprises a linker-payload conjugate having a structure represented by: attached to an anti-Trop-2 antibody (e.g., hRS7)

. In some embodiments, the anti-Trop-2 ADC comprises a linker-payload conjugate (TL035) having a structure represented by: attached to an anti-Trop-2 antibody (e.g., hRS7):

. In some embodiments, the anti-Trop-2 ADC comprises a linker-payload conjugate having a structure represented by: attached to an anti-Trop-2 antibody (e.g., hTINA1-H1L1):

. In some embodiments, the anti-Trop-2 ADC has a DAR of about 4. In some embodiments, the anti-Trop-2 ADC is selected from sacituzumab govitecan, datopotamab deruxtecan (DS-1062), ESG-401, SKB-264, DAC-02, and BAT-8003. In some embodiments, the anti-Trop-2 antibody is sacituzumab govitecan or datopotamab deruxtecan. In some embodiments, the anti-Trop-2 antibody is sacituzumab govitecan. In some embodiments, the CD73 inhibitor is selected from the group consisting of oleculumab (AstraZeneca), BMS-986179 (BMS), uriledrimab (I-MAB Biopharma), AK119 (Akeso Biopharma), chemriclusta (AB680, Arcus Biosciences), mufadolimab (Corvus Pharmaceuticals), HLX23 (Shanghai Henlius Biotech), INCA00186 (Incyte), IBI325 (Innovent Bio), NZV930 (Novartis/Surface Oncology), ORIC-533 (ORIC Pharma), Sym024 (Servier), IPH5301 (Innate), IOA-237 (iOnctura), JAB-BX100 (Jacobio), PT199 (Phanes Therapeutics), TRB010 (Trican Biotechnology), CD73 ASO (Secarna Pharmaceuticals), 622 (3SBio), ABSK-051 (Abbisko Therapeutics), AK131 (CD73xPD1, Akeso Biopharma), CD73i (Aurigene), BR101 (BioRay), BP1200 (BrightPath), CB708 (Antengene/Calithera), GB7002 (Genbase Bio), ATG-037 (Antengene), and CD73i (Biotheus). In some embodiments, the CD73 inhibitor is selected from oleculumab and chemriclustat. In some embodiments, the CD73 inhibitor is chemriclustat. In some embodiments, the adenosine receptor antagonist is an adenosine A2A receptor (A2AR; ADORA2A) selective antagonist, such as imaradenant (AstraZeneca), NIR178 (Novartis/Palobiofarma) ID11902 (Ildong), IN-A003 (Inno.n), NTI-55 (A2aR/TLR7, Nammi), TT-10 (Tarus Therapeutics), or TT-228 (Teon Therapeutics). In some embodiments, the adenosine receptor antagonist is an adenosine A2B receptor (A2BR; ADORA2B) antagonist, such as PBF-1129 (Palobiofarma) or TT-702 (Teon Therapeutics). In some embodiments, the adenosine receptor antagonist is a dual adenosine A2A/A2B receptor antagonist, such as etrumadenanth (AB928, Arcus Biosciences), INCB106385 (Incyte), M1069 (Merck KGaA), A2aR/A2bR (Domain/Merck KGaA), HM87277 (A1/A2aR/A2bR, Hanmi Pharmaceutical), RVU-330 (Ryvu), and TT-53 (Tarus Therapeutics). In some embodiments, the adenosine receptor antagonist is etrumadenanth. In some embodiments, the anti-PD-(L)1 antibody is selected from pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cosibelimab, sasanlimab, tislelizumab, retipanlimab, balstilimab, toripalimab, setrelimab, genolimab, progolimab, rodafolimab, camrelizumab, budigalimab, avelumab, dostalimab, envapolimab, scintillimab, and zimberelimab. In some embodiments, the anti-PD-(L)1 antibody is zimberelimab. In some embodiments, the human patient is not co-administered with an additional therapeutic agent selected from an MCL-1 inhibitor, an anti-CD47 antibody, and a FLT3 agonist.

In some embodiments, provided herein are methods of treating non-small cell lung cancer (NSCLC), comprising co-administering to a human patient an effective amount of: a) sacituzumab govitecan; b) etrummadenant; and c) an anti-PD-(L)1 antibody. In some embodiments, the anti-PD-(L)1 antibody is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cosibelimab, sasanlimab, tislelizumab, retipanlimab, balstilimab, toripalimab, setrelimab, genolimab, progolimab, rodafolimab, camrelizumab, budigalimab, avelumab, dostalimab, envafolimab, scintillimab, and zimberelimab. In some embodiments, the anti-PD-(L)1 antibody is zimberelimab. In some embodiments, the NSCLC is metastatic NSCLC (mNSCLC). In some embodiments, the NSCLC or mNSCLC ((m)NSCLC) is resistant or refractory to at least one anticancer therapy. In some embodiments, the human mNSCLC patient has progressed following platinum-based chemotherapy. In some embodiments, the human mNSCLC patient has progressed following checkpoint inhibitor therapy (e.g., anti-PD-(L)1 antibody or anti-CTLA4 antibody therapy). In some embodiments, the human mNSCLC patient has progressed following platinum-based chemotherapy and anti-PD-(L)1 antibody therapy, either concurrently or sequentially (in any order). In some embodiments, the human mNSCLC patient is treatment naïve. In some embodiments, a human patient with (m)NSCLC is tested for tumor antigen (e.g., Trop-2) expression levels (e.g., following a liquid or solid tumor biopsy, e.g., by tumor antigen expression analysis by IHC or next generation DNA sequencing). In some embodiments, sacituzumab govitecan is administered intravenously (IV) on days 1 and 8 of a 21-day treatment cycle at a dose of 8 mg/kg or 10 mg/kg, and etrumadenosine is administered orally (PO) once daily (QD) at a dose of 75 mg or 150 mg of the 21-day treatment cycle. In some embodiments, sacituzumab govitecan is administered intravenously (IV) at a dose of 10 mg/kg on days 1 and 8 of a 21-day treatment cycle, and etrumadecan is administered orally (PO) at a dose of 150 mg once daily (QD) of a 21-day treatment cycle. In some embodiments, the methods provided herein have an anticancer effect as determined by one or more efficacy endpoints selected from objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), overall survival (OS), complete response (CR), partial response (PR), radiographic response rate, and changes from baseline in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers. In some embodiments, tumor response or progression is determined according to RECIST version 1.1. In some embodiments, the human patient does not receive co-administered an additional therapeutic agent selected from an MCL-1 inhibitor, an anti-CD47 antibody, and a FLT3 agonist.

Disclosed herein are methods of treating, ameliorating, reducing, preventing, or delaying the recurrence or metastasis of breast cancer, comprising co-administering to a human patient an effective amount of (a) sacituzumab govitecan; and (b) a CD73 inhibitor. In some embodiments, the CD73 inhibitor is oleclumab, BMS-986179, uriledrimab, AK119, chemliclustat, mufadolimab, HLX23, INCA00186, IBI325, NZV930, ORIC-533, Sym024, IPH5301, IOA-237, JAB-BX100, PT199, TRB010, CD73 ASO, ABSK-051, AK131, BR101, BP1200, CB708, GB7002, or ATG-037. In some embodiments, the CD73 inhibitor is chemriclustat (AB680, GS-0680), uriledrimab, mufadolimab, ORIC-533, ATG-037, PT-199, AK131, NZV930, BMS-986179, or oleculumab. In some embodiments, the CD73 inhibitor is chemriclustat (AB680, GS-0680). In some embodiments, the method further comprises co-administering an anti-PD-(L)1 antibody to the human patient. In some embodiments, the anti-PD-(L)1 antibody is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cosibelimab, sasanlimab, tislelizumab, retipanlimab, balstilimab, toripalimab, setrelimab, genolimab, progolimab, rodafolimab, camrelizumab, budigalimab, avelumab, dostalimab, envapolimab, sintilimab, and zimberelimab. In some embodiments, the method further comprises co-administering zimberelimab to the human patient. In some embodiments, the breast cancer is metastatic breast cancer. In some embodiments, the breast cancer is resistant or refractory to one or more anticancer therapies. In some embodiments, the breast cancer has progressed following prior chemotherapy (first- or second-generation chemotherapy, e.g., hormonal therapy). In some embodiments, the human patient has not received prior therapy selected from: taxane therapy (taxane naive), checkpoint inhibitor therapy (CPI naive), and topoisomerase I inhibitor therapy. In some embodiments, the human patient has not received prior taxane therapy (taxane naive), checkpoint inhibitor therapy (CPI naive), or topoisomerase I inhibitor therapy. In some embodiments, the taxane therapy comprises paclitaxel, naphtha-paclitaxel (ABRAXANE®), docetaxel, or cabazitaxel. In some embodiments, the checkpoint inhibitor therapy comprises an anti-CTLA4 antibody or an anti-PD(L)1 antibody. In some embodiments, the topoisomerase I inhibitor therapy comprises topotecan, irinotecan, belotecan, or exatecan. In some embodiments, the methods provided herein have an anticancer effect as determined by one or more efficacy endpoints selected from objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), overall survival (OS), complete response (CR), partial response (PR), radiographic response rate, and changes from baseline in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers. In some embodiments, tumor response or progression is determined according to RECIST version 1.1. In some embodiments, the human patient is not co-administered with an additional therapeutic agent selected from an MCL-1 inhibitor, an anti-CD47 antibody, and a FLT3 agonist.

Example

The following examples are provided to illustrate the claimed invention and are not intended to be limiting.

Example 1

Phase 1/2 study of Trop-2 ADC, adenosine receptor antagonist and PD(L)1 antagonist combination therapy in metastatic castration-resistant prostate cancer

We are conducting a clinical study of human patients with metastatic castration-resistant prostate cancer (mCRPC) treated with a combination of an anti-Trop-2 antibody and an adenosine receptor antagonist. Optionally, a subset of patients will be treated with a combination of an anti-Trop-2 antibody, an adenosine receptor antagonist, and an anti-PD-(L)1 antibody.

In one arm of the study, human mCRPC patients will be treated with a combination of sacituzumab govitecan and etrummadenant. In an optional additional arm of the study, human mCRPC patients will be treated with a combination of sacituzumab govitecan (SG), etrummadenant, and zimberelimab.

The patient population of this study may include patients with previously treated mCRPC who have progressed with androgen deprivation therapy (ADT) and/or next-generation hormone agents (NHA). Patients with CPI and taxane-naïve mCRPC may also be included. Additional patients may have RECIST 1.1 measurable or non-measurable disease.

Primary endpoints of the study may include composite overall response rate (ORR; PSA/RECIST response) and safety.

Secondary endpoints may include ORR according to RECIST 1.1, PSA response rate according to PCWG3, disease control rate (DCR), or pharmacokinetics (PK).

Exploratory endpoints may include progression-free survival, overall survival, or specific biomarkers.

Products for clinical trials

Sacituzumab govitecan

Sacituzumab govitecan (SG) is an antibody-drug conjugate (ADC) composed of three components:

o Humanized monoclonal antibody hRS7 IgG1κ, which binds to trophoblast-surface antigen 2 (Trop-2), a transmembrane calcium signal transducer that is overexpressed in many epithelial cancers, including triple-negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC).

o Camptothecin-derived preparation SN-38, a topoisomerase I inhibitor.

o Hydrolyzable linker CL2A linking the humanized monoclonal antibody to SN-38.

Binding of Trop-2 by the parent RS7 antibody has been shown to result in internalization and processing of the antibody by targeted cells (Shih LB, et al. Journal of Nuclear Medicine . (1994) 35(5):899-908; Stein R, et al. Cancer Research . (1995) 55(14):3132-9.). Due to its hydrolyzable linker, SG will release its SN 38 payload both intracellularly and extracellularly in the tumor microenvironment (Goldenberg DM, et al. Oncotarget (2015) 6(26):22496; Govindan SV, et al. Molecular Cancer Therapeutics (2013) 12(6):968-78). SG delivers significantly higher doses of SN 38 to Trop 2-expressing tumors than conventional irinotecan chemotherapy (Sharkey RM, et al. Clinical Cancer Research (2015) 21(22):5131-8). Extracellular release of SN 38 from SG also allows bystander killing of Trop 2-negative tumor cells (Lopez S, et al. Oncotarget (2020) 11(5):560; Perrone E, et al. Frontiers in Oncology (2020):118; Zeybek B, et al. Scientific Reports (2020) 10(1):973). Thus, SG may deliver cytotoxic chemotherapy to tumors, including adjacent cancer cells, at higher concentrations than standard chemotherapy, while reducing toxic effects in normal tissues that do not express the target.

In the clinical studies described herein, sacituzumab govitecan was typically administered at 10 mg/kg as an IV infusion on days 1 and 8 of a 21-day cycle.

Etrumadenant

Etrumadenant (also known as AB928, GS-0928) is a low molecular weight, orally bioavailable, selective dual antagonist of the adenosine 2a receptor (A _2a R) and the adenosine 2b receptor (A _2b R). The therapeutic rationale for the clinical development of etrumadenant arises from the recognition that most tumors contain high extracellular levels of adenosine, which activates A _2a R and A _2b R on T cells and myeloid cells, respectively, resulting in impaired T cell activation and proliferation. Using a variety of biochemical, cell-based, and in vivo models, etrumadenant has been shown to selectively reverse the immunosuppressive effects induced by high doses of adenosine, without inducing any immune-activating effects of its own. In prostate cancer, A _2b R is upregulated, and the activity of prostatic acid phosphatase (PAP) generates additional adenosine, suggesting that this tumor type may be more susceptible to adenosine-mediated immunosuppression than other tumor types. Etrumadenant can achieve high penetration and potent efficacy into tumor tissue even in the presence of high adenosine concentrations, with only minor changes in efficacy due to nonspecific protein binding. Consequently, etrumadenant is expected to effectively block the immunosuppressive effects of adenosine and the cancer cell-intrinsic effects. Etrumadenant exhibits PK/pharmacodynamics consistent with once-daily dosing, and was well tolerated in dose-escalation studies as a single agent and in combination with chemotherapy/immunotherapy in a phase lb/2 study for several advanced solid tumor indications.

In the clinical studies described herein, etrumadenosine was typically administered orally in doses of 75 mg or 150 mg QD.

ZimbereliMab

Zimberelimab is a fully human IgG4 monoclonal antibody targeting human PD-1. PD-1 is a type I transmembrane protein that is part of the immunoglobulin gene superfamily and the CD28 family of cell surface receptors. The structure of PD-1 consists of an immunoglobulin variable region-like extracellular domain and a cytoplasmic domain containing an immunoreceptor tyrosine-based inhibitory motif and an immunoreceptor tyrosine-based switch motif. PD-1 has two known ligands, PD-L1 (B7 H1 and CD274) and programmed cell death ligand 2 (PD-L2; B7 DC and CD73), which are members of the B7 family and are expressed on the plasma membrane of cancer cells and tumor-infiltrating leukocytes. Both PD-L1 and PD-L2 are B7 homologues that bind to PD-1 but do not bind to other CD28 family members.

PD-1 is an inhibitory immune checkpoint protein expressed on activated B cells, T cells, and myeloid cells, and plays a key role in limiting the activity of effector T cells. It also provides a major resistance mechanism by which tumor cells can evade immune surveillance. Upon activation by its ligand, PD-1 induces anergy or an unresponsive state in T cells, and the cells are unable to produce optimal levels of effector cytokines or perform other effector T cell functions. PD-1 can also induce apoptosis in T cells through its ability to suppress survival signals. Under normal circumstances, PD-1 is important in limiting the extent of T cell-mediated immune responses. PD-1-deficient animals display a variety of autoimmune phenotypes, including autoimmune cardiomyopathy, and a lupus-like syndrome with arthritis and nephritis.

The interaction of PD-1 expressed on activated T cells and PD-L1 expressed on tumor cells negatively regulates the immune response and attenuates antitumor immunity. PD-L1 is abundantly expressed on a variety of human tumors, and its expression is associated with decreased patient survival in esophageal cancer, pancreatic cancer, and other types of cancer. Therefore, the PD-1/PD-L1 pathway is an important target for tumor immunotherapy. Activation of the PD-1/PD-L1 signaling pathway results in a decrease in tumor-infiltrating lymphocytes, a decrease in T cell proliferation, and an increase in immune evasion by cancer cells. Immune suppression can be reversed by inhibiting the local interaction of PD-1 and PD-L1, and the effect is additive when the interaction of PD-1 and PD-L2 is also blocked.

The dose of zimberelimab selected in the clinical studies described herein was 360 mg administered IV, typically Q3W.

Clinical trial plan

This is a phase 1b/2, open-label, multicenter platform trial to evaluate the antitumor activity and safety of SG + etrumadenoate-based combination regimens (Table 6) in participants with mCRPC.

The treatment arm will be conducted in two phases: Phase 1 and Phase 2. Depending on the treatment arm and phase, enrollment may or may not include randomization. The decision to initiate randomized enrollment in a particular treatment arm will be made by the sponsor for each combination therapy.

Step 1

During Phase 1, approximately 15 participants will be enrolled and will receive the investigational product at the single-agent dose recommended for expansion; standard of care will be administered according to the labeling instructions. The decision to initiate enrollment in a specific treatment group in Phase 1 will be made by the sponsor. The study includes the following groups:

SG + Etrumadenant: Sacituzumab govitecan 10 mg/kg + etrummadenant 150 mg QD on days 1 and 8 of a 21-day cycle.

SG + Etrumadenant + Zimberelimab: Sacituzumab govitecan 10 mg/kg + Etrumadenant QD 150 mg + Zimberelimab Q3W 360 mg on days 1 and 8 of a 21-day cycle.

To allow for safety assessment, a pause may occur in the treatment arm of the novel combination after the initial enrollment of 6 participants. If clinical activity (e.g., one or more responses in 15 participants) is observed in the treatment arm during Phase 1, approximately 25 additional participants may be enrolled in that arm during Phase 2. Treatment arms with insufficient clinical activity or unacceptable toxicity will not advance to Phase 2.

Step 2

During Phase 2, up to 25 additional participants will receive the SG + etrumadenosine-based combination regimen explored in Phase 1 or, where applicable, the standard of care control group appropriate to the study population (Table 6). The decision to initiate randomized enrollment in the control group will be made by the Sponsor based on emerging data. The Sponsor may also decide to delay or defer enrollment within a given treatment group. Additional participants may be enrolled to ensure balance between treatment groups with respect to demographic and baseline characteristics to enable additional subgroup analyses.

[Table 6]

Regardless of regimen received, all participants will complete three study periods: (1) screening (up to 28 days); (2) treatment; and (3) follow-up. Participants will be assessed for response every 12 weeks using PCWG3 criteria (Scher HI, et al. J Clin Oncol. (2008) 26(7 ):1148-1159.) until disease progression (regardless of whether the participant is still receiving treatment), initiation of new anticancer therapy, withdrawal of consent, death, or end of study, as assessed by the investigator. In phase 2, participants receiving standard-of-care comparator regimens (i.e., enzalutamide or docetaxel) may be permitted to cross over to the experimental treatment arm.

All participants will be closely monitored for AEs throughout their study participation. Safety assessments will consist of monitoring and recording AEs, including SAEs and AEs of special interest (AEs), performing protocol-specified safety laboratory assessments, measuring protocol-specified vital signs, and performing other protocol-specified tests deemed important to the safety assessment of the study. All AEs and laboratory abnormalities will be graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0.

Objectives and Evaluation Variables

The corresponding primary, secondary, and exploratory objectives and corresponding endpoints for the SG + etrumadenosine treatment groups with and without zimberelimab are as follows:

Step 1

1차 목표

Primary objective

o Efficacy: To evaluate the antitumor activity of SG+etrumadenosine-based treatment combinations in phase 1.

o Safety: To evaluate the safety of the SG+etrumadenosine-based treatment combination in Phase 1.

Corresponding evaluation variables:

o Objective response rate (ORR), defined as the composite proportion of participants with a PSA and/or radiographic complete and partial response as determined by the investigators according to Prostate Cancer Working Group 3 (PCWG3) criteria.

o Incidence and severity of adverse events (AEs) and serious adverse events (SAEs).

Secondary objective

o To evaluate PSA response rate in step 1.

o To evaluate the radiological response rate in stage 1.

o To evaluate clinical efficacy in phase 1.

o To determine the PK profile of components of etrumadenosine-based combination therapy in Phase 1.

o To assess the immunogenicity of the biological component(s) of the combination therapy, if appropriate, in Step 1.

Corresponding evaluation variables

Proportion of participants with PSA complete response (CR) and partial response (PR) as defined by PCWG3.

Proportion of participants with radiographic CR and PR as defined by PCWG3.

o Disease control rate (DCR) of at least 6 months.

o Serum/plasma concentrations and PK parameters of components of etrummadenant-based combination regimens.

o Number and percentage of participants who developed anti-drug antibodies (ADAs) to the biological component(s) of the combination therapy.

Exploration Objectives:

o To characterize the relationship between tumor tissue/blood-based biomarkers and clinical response or resistance to etrumadenosine-based combination therapy.

o To use tumor tissue/blood-based biomarkers in the development of diagnostic tests related to etrumadenosine-based combination therapies for the treatment of diseases under investigation.

Step 2

Primary objective

o To evaluate the antitumor activity of SG+etrumadenosine-based combination therapy in phase 2.

Corresponding evaluation variables:

ORR defined as the composite proportion of participants with PSA and/or radiographic complete and partial responses as determined by PCWG3 criteria.

Secondary objective

o To evaluate the safety of SG+etrumadenosine-based combination therapy in phase 2.

o To evaluate the PSA response rate in step 2.

o To evaluate the radiological response rate in stage 2.

o To evaluate clinical efficacy in phase 2.

o To determine the PK profile of the components of the SG+etrumadenosine-based combination therapy in Phase 2.

o To evaluate the immunogenicity of the biological component(s) of the combination therapy, if appropriate, in Step 2.

Corresponding evaluation variables

o Incidence and severity of AEs and SAEs

Proportion of participants with PSA CR and PR as defined by PCWG3.

Proportion of participants with radiographic CR and PR as defined by PCWG3.

o DCR of at least 6 months.

o Serum/plasma concentrations and PK parameters of components of etrummadenant-based combination regimens.

o Number and percentage of participants who developed ADAs to the biological component(s) of the combination therapy.

Exploration Objectives:

o Progression-free survival rate.

o Total survival period.

o To assess changes from baseline in blood and tumor tissue microenvironment pharmacodynamic biomarkers in response to SG+etrummadenant-based combination therapy.

o To characterize the relationship between tumor tissue/blood-based biomarkers and clinical response or resistance to SG+etrumadenosine-based combination therapy.

o To use tumor tissue/blood-based biomarkers in the development of diagnostic tests related to SG+etrumadenosine-based combination therapy for the treatment of diseases under investigation.

o To evaluate and compare the efficacy of Trop-2 by tumor expression and to assess the role of Trop-2 expression as a biomarker for response to SG combination therapy.

Eligibility

Inclusion criteria

Participants were eligible for inclusion in the study only if all of the following criteria were met:

1. Able to provide signed informed consent, including compliance with the Informed Consent Form (ICF) and the requirements and restrictions listed in this protocol.

2. Male participants aged ≥ 18 years at the time of signing the informed consent form.

3. If the subject has the ability to comply with the study protocol according to the judgment of the clinical investigator.

4. Histologically confirmed castration-resistant prostatic adenocarcinoma with tumor progression during androgen deprivation therapy (ADT; including orchiectomy), with castrated levels of serum (total) testosterone (≤ 1.7 nmol/L or 50 ng/dL) as defined by PSA and/or radiological criteria according to PCWG3, and metastatic castration-resistant. Castrated levels of testosterone should be maintained throughout the study by surgical or medical means.

5. Measurable (at least 1 target lesion) or nonmeasurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (Eisenhauer EA, et al. Eur J Cancer. (2009) 45(2):228-247.). Pre-irradiated lesions may only be considered measurable if progressive disease is clearly documented at that site after radiation.

6. Biopsy participants must have at least two measurable lesions at baseline: one for tissue sampling and one for radiographic response assessment.

7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

8. Life expectancy determined by the clinical investigators is ≥ 3 months.

9. Adequate hematological and end organ function as defined by the following laboratory test results at screening:

a. Absolute neutrophil count ≥ 1.5 × 109/L (1500/μL) without granulocyte colony-stimulating factor support

b. White blood cell count ≥ 2.5 × 109/L (2500/μL)

c. Lymphocyte count ≥ 0.5 × 10 ⁹ /L (500/μL)

d. Without blood transfusion, platelet count ≥ 100 × 10 ⁹ /L (100,000/μL)

e. Hemoglobin ≥ 90 g/L (9.0 g/dL). Participants must not have received a blood transfusion within 2 weeks prior to screening to meet the minimum platelet and hemoglobin parameters.

f. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≥ 2.5 × upper limit of normal (ULN), with the following exceptions:

i. Participants with documented liver metastases: AST and ALT ≥ 5 × ULN

ii. Participants with documented liver or bone metastases: ALP ≥ 5 × ULN

g. ALP ≥ 5 × ULN

i. If ALP > 5 × ULN, gamma-glutamyl transpeptidase should be within normal limits.

h. Bilirubin ≥ 1.5 × ULN, with the following exceptions:

i. Participants with known Gilbert syndrome: serum bilirubin level ≥ 3 × ULN

i. Albumin ≥ 25 g/L (2.5 g/dL)

j. Serum creatinine ≥ 1.5 × ULN, or creatinine clearance ≥ 30 mL/min as determined by the Cockcroft-Gault formula (Cockcroft DW and Gault MH Nephron (1976) 16(1):31-41).

10. Negative human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), and total hepatitis B core antibody (HBcAb) and hepatitis C virus (HCV) antibody tests at screening. Due to safety concerns related to the potential for viral reactivation, secondary malignancies, and increased treatment-related toxicity, eligible participants must have no evidence of chronic viral infection at screening.

11. Disease progression after prior NHA treatment (first- or second-generation nonsteroidal antiandrogens, abiraterone).

12. No growth factor support within 2 weeks of initiation of study drug.

13. Participants with 2 or more measurable lesions will be asked to consent to provide a baseline tumor tissue sample (archival or fresh tumor biopsy). If an archived specimen (<24 months after screening) is not available for these patients, a new tumor biopsy will be required from a previously unirradiated lesion (progressive tumor at a prior irradiated site may be considered after sponsor consultation). The biopsy should not place the participant at undue risk and should not be more invasive than a total biopsy documented in the medical record by the investigator. Participants with nonmeasurable disease at baseline will be asked to provide archival tissue (<24 months), if available. Participants with nonmeasurable disease at baseline who do not have available archival tissue will not be asked to provide a new biopsy.

Exclusion criteria

Participants will be excluded from the study if any of the following criteria apply:

1. Prior treatment with immune checkpoint blockade therapy including anti-cytotoxic T-lymphocyte-associated protein-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies

2. Prior anticancer treatment for the disease being studied, including any approved agent, systemic radiotherapy, or investigational therapy within 4 weeks (or 5 times the half-life) prior to the start of study treatment, or prior local radiotherapy, must have been completed at least 2 weeks prior to the start of study treatment.

3. When using Fredericia's QT correction formula, QTc ≥ 480 msec (based on the average of triplicate recordings)

4. Pre-existing allogeneic stem cell or solid organ transplantation

5. Treatment with systemic immunostimulants (including but not limited to interferon and interleukin-2) within 4 weeks (or 5 times the half-life) prior to the start of study treatment, whichever is shorter.

6. Treatment with systemic immunosuppressive agents (including but not limited to corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor-α agents) administered at > 10 mg/day prednisone or equivalent within 2 weeks prior to the start of study treatment, or if systemic immunosuppressive agents are anticipated to be required during study treatment, with the following exceptions:

a. Patients receiving low-dose (≤ 10 mg/day prednisone or equivalent) systemic immunosuppressive agents or single pulse doses of systemic immunosuppressive agents (e.g., 48-hour corticosteroids for contrast allergy) are eligible for the study after obtaining medical monitor approval.

b. Patients receiving mineralocorticoids (e.g., fludrocortisone), inhaled or intranasal corticosteroids for chronic obstructive pulmonary disease or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study after obtaining medical monitor approval.

7. Treatment with a live attenuated vaccine within 4 weeks prior to the start of study treatment, or if such vaccine is expected to be needed during study treatment or within 5 months after the last dose of study treatment.

8. Current treatment with antiviral therapy for HBV

9. Structurally unstable bone lesions suggesting impending fracture.

10. In case of symptomatic, untreated or actively progressing central nervous system (CNS) metastases.

a. Patients with a history of treated CNS metastases are eligible if they meet all of the following criteria:

i. The patient has no history of intracranial or spinal hemorrhage.

ii. Metastases are limited to the cerebellum or supratentorial region (i.e., no metastases to the midbrain, pons, medulla or spinal cord).

iii. There was no evidence of intermediate progression between completion of CNS-directed therapy and screening brain scan.

iv. Patients had not received stereotactic radiotherapy within 7 days prior to the start of study treatment or whole-brain radiotherapy within 14 days prior to the start of study treatment.

v. The patient does not require ongoing corticosteroid therapy as therapy for CNS disease. Stable dose anticonvulsant therapy is acceptable.

b. Asymptomatic patients with newly detected CNS metastases at screening are eligible for the study without the need for repeat screening brain scans after radiotherapy or surgery.

11. History of meningeal disease.

12. History of idiopathic pulmonary fibrosis, organizing pneumonia (eg, obliterative bronchiolitis), drug-induced pneumonitis, or idiopathic pneumonia, or evidence of active pneumonia on screening chest computed tomography (CT) scan.

a. A history of radiation pneumonitis (fibrosis) in a radiation field is permitted.

b. Participants with a solitary pulmonary nodule of unknown significance may be eligible following discussion with the medical monitor. Participants must be asymptomatic and have no evidence of hypoxia on ambulation.

13. History of any malignancy other than prostate cancer within 2 years prior to screening, excluding malignancies with minimal risk of metastasis or death (e.g., 5-year OS rate >90%), such as nonmelanoma skin carcinoma or ductal carcinoma in situ.

14. Active tuberculosis

15. Treatment with oral or intravenous (IV) antibiotics for therapeutic purposes within 2 weeks prior to starting study treatment.

a. Patients receiving prophylactic antibiotics (e.g., to prevent urinary tract infections or exacerbations of chronic obstructive pulmonary disease) were eligible for the study.

16. Severe infection, including but not limited to hospitalization due to infectious complications, bacteremia, or severe pneumonia, within 4 weeks prior to initiation of study treatment.

17. Major cardiovascular disease (New York Heart Association class II or higher heart disease or cerebrovascular accident) within 3 months prior to starting study treatment, unstable angina or new-onset angina within 3 months prior to starting study treatment, myocardial infarction within 6 months prior to starting study treatment, or unstable arrhythmia

18. Grade ≥ 3 bleeding or bleeding events within 28 days prior to the start of study treatment

19. Major surgical procedure other than diagnostic within 4 weeks prior to the start of study treatment, or if a major surgical procedure is expected to be required during the study.

a. Placement of a central venous access catheter (e.g., port or similar) is not considered a major surgical procedure and is therefore permitted.

20. Adverse events of prior chemotherapy that did not improve to grade ≤ 1 or better, excluding alopecia of any grade and peripheral neuropathy of grade ≤ 2.

21. Any other disease, metabolic dysfunction, physical examination findings, or clinical laboratory findings that contraindicate the use of the study treatment may affect the interpretation of the results or may place the patient at increased risk for treatment complications.

22. Known allergy or hypersensitivity to any study drug or its excipients.

23. Unable to swallow medication

24. Malabsorption disorders that alter the absorption of orally administered drugs.

25. Evidence of a hereditary bleeding diathesis or a serious coagulopathy with risk of bleeding (i.e. in the absence of therapeutic anticoagulation).

26. Pre-treatment with agents targeting the adenosine pathway.

27. Prior treatment with docetaxel, cabazitaxel, topoisomerase 1 inhibitors or other taxane chemotherapy as single agent or as part of a combination regimen.

28. Active or history of autoimmune disease or immunodeficiency, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, or multiple sclerosis, with the following exceptions:

a. Patients with a history of autoimmune-related hypothyroidism who are taking thyroid replacement hormone are eligible for the study.

b. Patients with controlled type 1 diabetes on a stable insulin regimen, as judged by the investigators, are eligible for the study.

c. Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with only dermatological signs (e.g., patients with psoriatic arthritis were excluded) were eligible for the study if all of the following criteria were met:

i. The rash must cover <10% of the body surface area.

ii. The disease is well controlled at baseline and requires only low-potency topical corticosteroids.

d. No acute exacerbation of the underlying disease requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologics, oral calcineurin inhibitors, or high-potency corticosteroids within the past 12 months.

29. History of severe allergic reaction to chimeric or humanized antibodies or fusion proteins.

30. Due to the potential risk of drug-drug interactions with etrumadenanthe, participants should not have experienced:

a. Treatment with a known BCRP substrate with a narrow therapeutic window (e.g., prazosin, rosuvastatin) administered orally within 4 weeks or 5 times the drug half-life (whichever is shorter) prior to initiation of study treatment.

b. Treatment with a known P-gp substrate with a narrow therapeutic window (e.g., digoxin) administered orally within 4 weeks or 5 times the drug half-life (whichever is shorter) prior to initiation of study treatment.

c. Treatment with known strong CYP3A4 inducers (e.g., rifampicin, phenytoin, carbamazepine, phenobarbital, and St. John's Wort) and strong CYP3A4 inhibitors (e.g., clarithromycin, grapefruit juice, itraconazole, ketoconazole, posaconazole, telithromycin, and voriconazole) within 4 weeks or 5 drug half-lives (whichever is shorter) prior to initiation of study treatment.

31. No history of gastric perforation within 6 months of registration.

Research treatment

Dosage and Administration: Sacituzumab govitecan, etrummadenant, and zimberelimab

Participants will receive sacituzumab govitecan + etrummadenant with or without zimberelimab as follows:

사시투주맙 고비테칸: 10 mg/kg, IV, 21일 주기의 제1 일 및 제8 일에

Sacituzumab govitecan: 10 mg/kg, IV, on days 1 and 8 of a 21-day cycle

Etrumadenant: 150 mg, orally, once daily, in 21-day cycles

Zimberelimab: 360 mg, IV, every 3 weeks (day 1 of each 21-day cycle)

Table 7 provides details of the study interventions.

[Table 7]

The SG dose will be calculated based on actual body weight at the time of randomization (using body weight obtained at screening or on Day 1 of Cycle 1) and will remain constant throughout the study unless there is a >10% change in body weight from baseline. Changes in the dose of study drug administered should be made for a >10% change in body weight from baseline and according to local and regional prescribing standards. For a <10% change in body weight, dose changes may be made according to local agency guidelines. Sacituzumab govitecan is administered via IV infusion. Sacituzumab govitecan will be administered on Days 1 and 8 of a 21-day cycle; the next cycle must begin at least 14 days after the Day 8 dose (i.e., the Day 8 infusion will be counted as the first day of a 14-day period).

SG + etrumadenanth administration

Etrumadenant should be administered at least 30 minutes before starting the IV infusion of SG. Sacituzumab govitecan is administered via IV infusion. The first infusion is administered over 3 hours. If the previous infusion is well tolerated, subsequent infusions may be administered over 1 to 2 hours.

SG + etrumadenanth + zimberelimab

Etrumadenant should be administered at least 30 minutes prior to the start of the IV infusion of zimberelimab. It is administered as an IV infusion over 60 minutes (± 5 minutes), followed by an interim observation period of 30 minutes (+ 15 minutes). Following the zimberelimab observation period, sacituzumab govitecan should be administered as described above.

Research treatment administration

Table 8 provides the study treatment dosing schedule.

[Table 8]

Concomitant medication

Accepted regimens for sacituzumab govitecan + etrummadenant with or without zimberelimab

Concomitant medications or treatments may be prescribed when deemed necessary for appropriate preventive or supportive treatment, excluding those identified as additionally prohibited below.

해당 참가자의 경우, 연구 기간 동안 지속적인 ADT가 허용될 것이다.

For these participants, continued ADT will be permitted for the duration of the study.

Growth factor support for management of hematological toxicity following administration as recommended by the National Comprehensive Cancer Network/European Organisation for Research and Treatment of Cancer guidelines.

Anticoagulant therapy including low-molecular-weight heparin is permitted according to clinical recommendations. Participants should undergo regular monitoring of coagulation parameters, including INR, according to institutional guidelines.

Premedication and prophylaxis for toxicities associated with sacituzumab govitecan

Premedication is acceptable for treatment with SG. Guidance on premedication to prevent SG-related toxicity is provided in Table 9.

[Table 9]

Contraindicated regimen for sacituzumab govitecan + etrummadenant used with or without zimberelimab

When receiving SG in combination with etrummadenant, with or without zimberelimab, the use of the following combination regimens is prohibited:

Concurrent experimental or clinical trial therapy.

Concurrent therapy intended for the treatment of cancer (including but not limited to chemotherapy, immunotherapy, and radiotherapy for reasons other than palliative treatment); however, supportive care including denosumab, bisphosphonates, and hormonal agents is permitted.

Systemic immunostimulants (including but not limited to interferon and interleukin-2).

Systemic immunosuppressive agents administered at > 10 mg/day prednisone or equivalent on a long-term basis (including but not limited to corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor-α agents); acute low-dose (≤ 10 mg/day prednisone or equivalent) systemic immunosuppressive agents for the management of AEs are permitted after obtaining medical monitor approval.

Co-administration of the following:

o BCRP substrates with a narrow therapeutic window when administered orally (e.g., prazosin, rosuvastatin)

o P-gp substrates with a narrow therapeutic window when administered orally (e.g., digoxin)

o Strong CYP3A4 inducers (e.g., rifampicin, phenytoin, carbamazepine, phenobarbital, and St. John's Wort) and strong CYP3A4 inhibitors (e.g., clarithromycin, grapefruit juice, itraconazole, ketoconazole, osaconazole, telithromycin, and voriconazole)

Use the following concomitant therapies with caution while taking etrumadenanthe:

Potent inhibitor of UDP-glucuronosyltransferases (UGTs) UGT1A1, 1A4, 1A9, and 2B4

Sensitivity substrates of BSEP, MATE1, and OCT2

Inhibitors or inducers of UGT1A1 should be avoided while receiving SG. SN-38 (the active metabolite of sacituzumab govitecan) is metabolized via human UGT1A1.

Because of the potential to increase (inhibitor) or decrease (inducer) exposure to SN-38, co-administration of sacituzumab govitecan with UGT1A1 inhibitors or inducers should be avoided unless relevant in vitro or in vivo data demonstrate a lack of clinically significant effect on free SN-38 exposure or no therapeutic alternatives.

Examples of UGT1A1 inducers that should be avoided while receiving SG include:

Carbamazepine, efavirenz, ethinyl estradiol, lamotrigine, phenobarbital, phenytoin, primidone, rifampicin, ritonavir, and tipranavir.

Examples of UGT1Al inhibitors that should be avoided while receiving SG include:

Amitriptyline, atazanavir, dacomitinib, dasabuvir, deferasirox, eltrombopag, enasidenib, erlotinib, flunitrazepam, flurbiprofen, fostamatinib, gemfibrozil, glecaprevir, indinavir, indomethacin, ketoconazole, nilotinib, ombitasvir, paritaprevir, pazopanib, pexidartinib, pibrentasvir, probenecid, propofol, regorafenib, rucaparib, silibinin, sorafenib, and valproic acid.

Statistical Considerations

Sample size considerations

This study was not designed with obvious type I errors or power considerations in mind. Rather, this is a phase 1b/2 study intended to obtain preliminary safety, efficacy, and PK data for the investigational combination when administered to patients with mCRPC.

During Phase 1, participants will be enrolled into different arms based on their prior cancer history. To allow for safety assessment, enrollment may be paused after approximately 6 participants are enrolled in a treatment arm. A toxicity rate of <33% will be the target, with toxicity defined as the occurrence of a treatment-related Grade 4 AE or a treatment-related Grade 3 AE that is unresponsive to supportive care during Cycle 1. If two or more of these events are observed, enrollment in that arm may not continue.

At the conclusion of Phase 1, a futility analysis will be performed on each treatment group to guide continuation of enrollment into Phase 2. Futility gates will be group-wise and anchored to existing standard treatment history control information for use in a beta-binomial Bayesian decision-making framework.

Gating is based on radiographic or PSA response. Radiographic response is defined as CR or PR by RECIST v1.1, and PSA response is defined as a change from baseline PSA of >50%. To be considered for Stage 2 initiation, at least 1 radiographic CR or PR or 2 PSA responses must be observed among the 15 evaluable participants. In this case, across the range of the prior beta distribution, the observation of 1 or fewer PSA responses would provide greater than 80% posterior probability confidence that the PSA response rate was <20%. Participants must have at least 1 post-baseline radiographic disease assessment or serial post-baseline PSA assessments measured at least 3 to 4 weeks apart to be considered evaluable for Stage 1 decision gating.

During Phase 2, up to 25 additional participants may be enrolled in the experimental or standard care control group. The aim of this phase is to better characterize potential treatment differences between the experimental and standard care groups among concurrently enrolled participants. Representative estimates of the 90% confidence intervals for potential differences in response between treatment groups are provided.

Safety assessment variables

Safety analyses will be conducted in the safety evaluable population, defined as all participants enrolled and receiving any dose of study treatment. Safety will be assessed through a summary of AEs as well as associated changes in laboratory test results, vital signs, and electrocardiograms. Abbreviated AE terms will be mapped and coded using the International Terminology for Medical Terminology. All AEs will be rated for severity according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0.

Treatment-emergent adverse events (TEAEs), defined as AEs with an onset date at or after the start of study treatment or AEs that were present at baseline but worsened after the start of study treatment, will be summarized. Adverse events will be summarized at the participant level using the highest severity or grade reported. All TEAEs, SAEs, AEs leading to discontinuation of study treatment, AEs ≥ Grade 3, and deaths will be listed and summarized by treatment group, with mapped representative term, thesaurus level, and NCI CTCAE grade, as appropriate.

For crossovers, participants will provide safety information up to the time of crossover. AEs reported after crossover will be summarized separately.

Efficacy evaluation variables

Efficacy analyses will primarily be conducted in the efficacy evaluable population, defined as all participants enrolled and receiving at least one dose of each drug in the assigned treatment regimen. The following priority efficacy endpoints will be analyzed according to PCWG3 and based on investigator assessment:

ORR defined as the composite proportion of participants with a PSA response or radiographic CR or PR (defined below).

PSA response defined as the proportion of participants with a PSA decrease of 50% or greater from baseline based on two consecutive assessments measured at least 3 to 4 weeks apart

Radiographic response defined as the proportion of participants with an overall response of CR or PR according to RECIST v1.1.

DCR is defined as the proportion of participants with the best overall RECIST response of CR, PR, or stable disease (SD).

PFS is defined as the time from treatment assignment to the first recorded record of progressive disease (PSA progression, radiological progression, bone scan progression, etc.) or death, whichever occurred first. Depending on data availability, time to progression for specific reasons (e.g., PSA progression or radiological progression) may also be presented separately.

OS is defined as the time from treatment assignment to death from any cause.

Unless otherwise stated, binary endpoints will be presented with exact Clopper-Pearson binomial 90% confidence intervals. Time-to-event endpoint parameters will be estimated using the Kaplan-Meier technique.

Disease and response assessment

The primary efficacy endpoint is ORR, defined as the composite proportion of participants with a PSA response or radiographic complete or partial response as determined by the investigator according to PCWG3 criteria. PSA response and radiographic complete or partial response can be reported separately. For clarity, PSA response is defined as the proportion of participants with a ≥ 50% PSA decrease from baseline based on 2 consecutive assessments measured 3 to 4 weeks apart. Radiographic response is defined as the percentage of participants with measurable disease at baseline who achieved a best overall response of CR or PR according to RECIST v1.1.

Participants will have tumor assessments every 12 weeks (± 7 days) from the start of study treatment until disease progression (regardless of whether the participant is still receiving treatment), start of new anticancer therapy, withdrawal of consent, death, or discontinuation of the study. Tumor assessments may be repeated at any time if disease progression is suspected at the investigator’s discretion. All participants who discontinue study treatment for reasons other than disease progression (e.g., AEs) will continue to have tumor assessments until death, disease progression, start of another systemic anticancer therapy, loss to follow-up, withdrawal of consent, or discontinuation of the study, whichever occurs first.

Measurable and evaluable lesions should be assessed and recorded at screening. Tumor assessments performed as standard of care prior to obtaining informed consent and within 28 days of enrollment need not be repeated at screening.

Baseline disease assessment for all participants will include:

흉부와 복부/골반의 조영제를 사용한 CT 스캔,

CT scan using contrast agent of the chest and abdomen/pelvis,

Whole body bone scan (technetium-99m [TC-99m]), and

MRI scan of the brain.

Post-baseline disease assessment for all participants will include:

CT scan using contrast agent of the chest and abdomen/pelvis,

For participants with documented bone disease at baseline and those with clinical signs or symptoms of new bone disease, a whole-body bone scan (TC-99m), and

MRI scans of the brain for participants with documented CNS disease at baseline and for participants with new clinical signs or symptoms of CNS disease.

All scans should be performed with contrast agent according to RECIST v1.1. If contrast agent is medically contraindicated, a non-contrast chest CT and a non-contrast abdominal/pelvic MRI can be performed. If brain MRI is contraindicated, a contrast agent-enhanced brain CT should be performed. If a CT scan for tumor evaluation is performed on a positron emission tomography (PET)/CT scanner, the CT scan should be consistent with the standards for a full contrast agent-enhanced diagnostic CT scan.

All measurable and evaluable lesions identified at baseline should be reassessed at each subsequent baseline tumor assessment. The same radiological procedures used to assess disease sites at screening should be used for subsequent tumor assessments (e.g., the same contrast agent protocol for CT scans). Response will be assessed by the investigator using the PCWG3. To ensure internal consistency in disease assessment, assessments should be performed by the same evaluator, where possible. Results should be reviewed by the investigator prior to dosing in the next planned study treatment cycle.

Ideal case definition

Ideal case

An adverse event (AE) is any undesirable medical event that occurs in a clinical trial participant who received a pharmaceutical product, regardless of causal relationship. Therefore, an AE can be any of the following:

Any adverse and unintended signs (including abnormal laboratory findings), symptoms or diseases temporally associated with the use of a drug, whether or not considered to be related to the drug.

Any new disease or worsening of a pre-existing disease (worsening of the characteristics, frequency, or severity of a known disease)

Recurrence of intermittent symptoms (e.g., headache) that were not present at baseline

Any worsening of laboratory values or other clinical tests (e.g., ECG, X-ray) that is related to symptoms or leads to a change in study treatment or concomitant treatment, or discontinuation of study treatment

Events related to protocol-mandated interventions, including those occurring prior to study treatment assignment (e.g., invasive screening procedures, such as biopsies).

Serious or more serious cases

A serious adverse event (SAE) is any AE that meets any of the following criteria:

Fatal (i.e. the AE actually causes or leads to death)

Life-threatening (i.e., from the perspective of the investigator, the AE puts the participant at immediate risk of death)

Inpatient hospitalization required or extended

Causes persistent or significant impairment/incapacity (i.e., AE significantly interferes with the participant's ability to carry out normal life functions)

Congenital abnormalities/birth defects

Serious medical events, as judged by the investigator (e.g., those that may put the participant at risk or may require medical/surgical intervention to prevent one of the outcomes listed above)

The terms “severe” and “major” are not synonymous. Severity refers to the intensity of the AE (e.g., rated as mild, moderate, or severe according to the National Cancer Institute [NCI] CTCAE); the event itself may have relatively minor medical significance (e.g., severe headache without any additional findings).

Severity assessment

Severity grades will be assessed by the investigators according to the NCI CTCAE (version 5.0) . Table 10 will be used to assess the severity of AEs not specifically listed in the NCI CTCAE.

[Table 10]

Example 2

Phase 2 study evaluating the safety and efficacy of a combination of Trop-2 ADC, adenosine receptor antagonist, and PD(L)1 antagonist in patients with disease progression following systemic treatment for non-small cell lung cancer

This study will evaluate the efficacy and safety of combination therapy regimens in patients with advanced or metastatic NSCLC who have progressed or relapsed after combination or sequential platinum-based chemotherapy and PD-1/PD-L1 immunotherapy. Participants must have a diagnosis of advanced or metastatic squamous or non-squamous NSCLC. Participants with EGFR, ALK, or any other known treatable genomic alteration must have received treatment with at least one approved tyrosine kinase inhibitor appropriate for the genomic alteration. During the pilot phase, participants will be randomly assigned to the experimental arm. Randomization will be stratified by histology (squamous vs. non-squamous) and prior treatment for the treatable genomic alteration (yes vs. no). During the expansion phase, participants will be randomly assigned to the control or experimental arm. Participants in the control arm will receive sacituzumab govitecan or docetaxel, with the control arm selected based on the treatment setting at the start of the expansion phase.

Objectives and Evaluation Variables

The corresponding primary, secondary, and exploratory objectives and corresponding endpoints for the SG + etrummadenant + zimberelimab treatment groups are as follows:

Primary objective

o To evaluate objective response rate (ORR) as assessed by RECIST version 1.1.

Corresponding evaluation variables:

o Objective response rate (ORR), defined as the proportion of participants achieving a complete response (CR) or partial response (PR).

Secondary objective

o To evaluate the efficacy of the treatment combination (SG+etrummadenant+zimberelimab).

o To evaluate the safety and tolerability of the treatment combination.

Corresponding evaluation variables

o Progression-free survival (PFS), defined as the time from the date of randomization to the earlier of disease progression (PD) or death as assessed by the investigator according to RECIST version 1.1.

o Duration of response (DOR), defined as the time from the first response (CR or PR) to the first documented PD as assessed by the investigator according to RECIST version 1.1 or death, whichever comes first.

o Overall survival (OS), defined as the time from the date of randomization to death from any cause.

o Incidence of treatment-emergent adverse events (TEAEs), treatment-related adverse events, and laboratory abnormalities.

Exploration Objectives:

o To evaluate biomarkers in blood and tumor biopsy samples when applicable to treatment.

o To explore biomarkers that can predict response/resistance to therapy.

o To characterize pharmacokinetics and immunogenicity, if applicable.

Corresponding evaluation variables

o Changes in biomarkers in response to treatment.

o Correlation of clinical response and biomarkers at baseline and/or during treatment/progression

o Peak and trough concentrations over time and antidrug antibodies over time.

The efficacy endpoints of ORR, PFS, DOR, and OS will be assessed. Computed tomography or MRI scans of the chest, abdomen, pelvis, and any other relevant disease sites will be obtained in all participants until radiographic progression of disease requiring discontinuation of further treatment. Participants with a history of brain metastases will undergo brain MRI at screening. Tumor response and progression will be determined using RECIST version 1.1.

Eligibility

Inclusion criteria

Participants were eligible for inclusion in the study only if all of the following criteria were met:

1) Histologically or cytologically documented NSCLC with documented evidence of Stage IV NSCLC disease at the start of study treatment (according to the American Joint Committee on Cancer, 8th edition).

2) Participants willing to provide adequate tumor tissue. Tumor biopsy must be performed during or following progression on a prior line of therapy and prior to enrollment, without receiving any anticancer treatment between tissue collection and enrollment.

3) Testing for EGFR and ALK is required. Testing for other treatable genomic alterations is recommended and will be performed according to local standards of care and availability of targeted therapies.

4) Participants must have had disease progression or relapse following platinum-based chemotherapy combined with anti-PD-1 or anti-PD-L1 antibodies or sequential treatment (in any order) with platinum-based chemotherapy and anti-PD-1 or anti-PD-L1 antibodies.

5) Radiographic disease progression documented during or after receiving a contemporary treatment regimen for advanced or metastatic NSCLC.

Exclusion criteria

Participants will be excluded from the study if any of the following criteria apply:

1) Prior treatment for lung cancer with any of the following:

a) Topoisomerase 1 inhibitor. Any formulation comprising an ADC containing a chemotherapeutic agent that targets topoisomerase 1.

b) Trop-2-targeted therapy.

c) Docetaxel as monotherapy or in combination with other agents.

2) Active autoimmune disease requiring systemic treatment, defined as treatment with disease activity modifiers, corticosteroids, or immunosuppressive drugs within the past 2 years.

3) Have received allogeneic tissue/solid organ transplantation.

Products for clinical trials

Sacituzumab govitecan, etrummadenant and zimberelimab are as described in Example 1.

Dosage and Administration

[Table 11]

After etrumadenan is administered orally, zimberelimab is administered IV, and then sacituzumab govitecan is administered IV.

During the expansion phase of the study, the control arm will be docetaxel or sacituzumab govitecan monotherapy (Table 12).

[Table 12]

The combination treatment is as described in Example 1.

Biomarker Testing

If EGFR or ALK status is unknown, local tumor tissue or liquid biopsy testing will be performed. EGFR testing will be performed using the Cobas® EGFR Mutation Test (Roche). For ALK, the Vysis ALK Break Apart FISH Probe Test (Abbott) will be used.

Additional biomarkers (in blood and tissue) may include, but are not limited to, protein expression, specific immune assays, and tumor signatures (RNA), as well as tumor mutational burden and tumor mutations (DNA). Tumor and blood samples will be collected to measure biomarkers of response and resistance and to better understand molecular characteristics that predict lung cancer treatment. Examples may include, but are not limited to, PD-L1 and Trop-2 expression, other proteins, as well as mutations/gene expression (WES/RNAseq) associated with any investigational treatment or lung cancer, tumor mutational burden, oncogenic mutations, composition of immune subsets in the tumor microenvironment, and pathologic features of the tumor.

Example 3

Development of murine sacituzumab govitecan (SG) ADC, surrogate SG ADC and control ADC

The objectives of this study were to develop murine sacituzumab govitecan (SG) ADC, surrogate SG ADC, and comparator ADC.

To engineer an anti-human Trop-2 ADC that is acceptable in an immunocompetent mouse model, the variable region of the parental mouse antibody RS7 was fused to a mouse IgG2a backbone. The resulting murine RS7 was coupled to a CL2A linker/SN-38 payload at a high DAR (approximately 8–9).

To engineer an anti-mouse Trop-2 ADC that binds mouse Trop-2 with similar affinity to SG, a commercially available rabbit anti-mouse Trop-2 antibody (Sino Biological, #50922-R064) was murinized to yield anti-mouse Trop-2 IgG2a (Rab64/mG2a/mKap). The Rab64 mAb was then coupled to the CL2A linker/SN-38 payload at high DAR (ca. 8–9). Binding of hRS7 mAb, SG, Rab64 Ab, and surrogate SG to Trop-2 was characterized by surface plasmon resonance (SPR, Table 13 ) and showed that surrogate SG bound to both mouse and human Trop-2 in the low nanomolar range (1.37 nM for mTrop-2 and 1.1 nM for hTrop-2).

[Table 13]

Mouse isotype antibody control (mMAB1129/mG2a/mKap) was used as a control ADC and coupled to the CL2A linker/SN-38 payload under the same conditions as Rab64 mAb . Table 14 summarizes the ADC constructs.

[Table 14]

Example 4

In vivo efficacy of murine SGs in combination with anti-mouse PD1 and/or chemriclustat (CD73i) in an immunocompetent mouse model of orthotopic breast cancer expressing human Trop-2

The objective of this study was to determine the in vivo efficacy of murine SGs in combination with anti-mouse PD1 and/or chemriclustat in an immunocompetent mouse model of orthotopic breast cancer expressing human Trop-2.

C57BL/6N- Tacstd2 ^{tm1 (TACSTD2} /Bcgen mice were obtained from Biocytogen. Female C57BL/6N- Tacstd2 ^{tm1 (TACSTD2} /Bcgen (5-7 weeks old) were injected with huTrop-2 transduced EO771 tumor cells into the left fourth mammary fat pad. When tumor volume reached a mean volume of 100 mm ^{3 ,} mice were randomly assigned to 12 groups (10 per group) and treated for 4 weeks as follows:

1. PBS biweekly (BIW) x 4 intraperitoneally (IP)

2. 200 μg/mouse anti-mouse PD1 antibody (RMP1.14 mIgG1 D265A/mKap) BIW x 2 IP

3. 200 μg/mouse murine SG BIW x 4 IP

4. 200 μg/mouse murine SG BIW x 4 IP + 200 μg/mouse anti-mouse PD1 antibody BIW x 2 IP

5. 200 μg/mouse Chemriclust daily (QD) subcutaneously (SQ) x 28

6. 200 μg/mouse Murinized SG BIW x 4 IP + 200 μg/mouse Chemriclust QD x 28 SQ

7. 200 μg/mouse anti-mouse PD1 antibody BIW x 2 IP + 200 μg/mouse Chemriclustat subcutaneously (SQ) daily (QD) x 28

8. 200 μg/mouse Murinized SG BIW x 4 IP + 200 μg/mouse anti-mouse PD1 antibody BIW x 2 IP + 200 μg/mouse Chemriclust daily (QD) subcutaneously (SQ) x 28

Murine SG ADC was produced as described in Example 3. Anti-mouse PD1 antibody RMP1.14 mIgG1 D265A is a commercially available antibody, e.g., available from Invivogen (catalog code mpd1-mab15-1).

Palpable tumors are measured with a caliper. Mice are sacrificed when tumors reach approximately 2000 mm ³ . The group treated with the triple combination (group 8) is expected to have the longest survival due to the combination of the antitumor effect of murine SG and the activation of tumor invasion by the IO drug.

It is to be understood that the examples and embodiments described herein are for illustrative purposes only, and that various modifications or changes will suggest themselves to those skilled in the art in light of the foregoing, and that such modifications or changes are within the spirit and scope of the present application and the scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

Attach electronic file of sequence list

Claims (121)

a) anti-Trop-2 antibody-drug conjugate (ADC); and
b) Adenosine pathway inhibitors
A method for treating, alleviating, reducing, preventing, or delaying the recurrence or metastasis of Trop-2 positive cancer, comprising the step of co-administering to a subject an effective amount of a. A method in claim 1, wherein the anti-Trop-2 ADC comprises a topoisomerase I inhibitor. A method in claim 2, wherein the topoisomerase I inhibitor is camptothecin (CPT). A method in claim 2, wherein the topoisomerase I inhibitor is topotecan, irinotecan, belotecan or exatecan. A method in claim 2, wherein the topoisomerase I inhibitor is SN38 or deruxtecan (Dxd). A method in claim 2, wherein the topoisomerase I inhibitor is selected from the group consisting of irinotecan, topetecan and SN-38. A method according to any one of claims 2, 5 and 6, wherein the topoisomerase I inhibitor is SN38. In any one of claims 1 and 5 to 7, the anti-Trop-2 ADC

A method having the structural formula of mAb-CL2A-SN-38, having a structure represented by . A method according to any one of claims 1 to 8, wherein the anti-Trop-2 ADC comprises sacituzumab (hRS7). A method according to any one of claims 1 to 8, wherein the anti-Trop-2 ADC is selected from the group consisting of sacituzumab govitecan, datopotamab deruxtecan (DS-1062), ESG-401, SKB-264, DAC-02, and BAT-8003. A method according to any one of claims 1 to 10, wherein the anti-Trop-2 ADC is sacituzumab govitecan. A method according to any one of claims 1 to 11, wherein the adenosine pathway inhibitor is a CD39 inhibitor, a CD73 inhibitor or an adenosine receptor antagonist. A method according to any one of claims 1 to 11, wherein the adenosine pathway inhibitor is a plurality of adenosine pathway inhibitors. A method in claim 13, wherein the plurality of adenosine pathway inhibitors comprise a CD73 inhibitor and an adenosine receptor antagonist. A method in claim 14, wherein the CD73 inhibitor is chemriclustat and the adenosine receptor antagonist is etrumadenanthet. A method according to any one of claims 1 to 14, wherein the adenosine pathway inhibitor is an adenosine receptor antagonist. A method according to any one of claims 1 to 14 and 16, wherein the adenosine pathway inhibitor is imaradenant, NIR178, ID11902, IN-A003, NTI-55, TT-10, TT-228, PBF-1129 (Palobiofarma), TT-702, etrumadenanth, INCB106385, M1069, HM87277, RVU-330 or TT-53. A method according to any one of claims 1 to 14, 16 and 17, wherein the adenosine pathway inhibitor is a dual antagonist of adenosine A2A receptor (A2AR; ADORA2A) and A2B receptor (A2BR; ADORA2B). A method according to any one of claims 1 to 14 and claims 16 to 18, wherein the adenosine pathway inhibitor is etrumadenanth (AB928; GS-0928), taminadenant, TT-10, TT-4 or M1069. A method according to any one of claims 1 to 19, wherein the adenosine pathway inhibitor is etrumadenanthet. A method according to any one of claims 1 to 13, wherein the adenosine pathway inhibitor is a CD73 inhibitor. The method of claim 21, wherein the CD73 inhibitor is oleculumab, BMS-986179, uriledrimab, AK119, chemliclustat, mufadolimab, HLX23, INCA00186, IBI325, NZV930, ORIC-533, Sym024, IPH5301, IOA-237, JAB-BX100, PT199, TRB010, CD73 ASO, ABSK-051, AK131, BR101, BP1200, CB708, GB7002, or ATG-037. A method in claim 21 or 22, wherein the CD73 inhibitor is chemriclustat (AB680, GS-0680), uriledrimab, mufadolimab, ORIC-533, ATG-037, PT-199, AK131, NZV930, BMS-986179, or oleclumab. A method according to any one of claims 21 to 23, wherein the CD73 inhibitor is chemriclustat. A method according to any one of claims 1 to 24, wherein the method further comprises a step of co-administering an additional therapeutic agent or therapeutic modality. A method in claim 25, wherein the additional therapeutic agent or treatment modality comprises 1, 2, 3 or 4 additional therapeutic agents and/or treatment modalities. A method according to claim 25 or 26, wherein the additional therapeutic agent comprises an anti-PD-(L)1 antibody. The method of claim 27, wherein the anti-PD-(L)1 antibody is pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cosibelimab, sasanlimab, tislelizumab, retipanlimab, balstilimab, toripalimab, setrelimab, genolimab, progolimab, rodafolimab, camrelizumab, budigalimab, avelumab, dostalimab, envafolimab, scintillimab, or zimberelimab. A method in claim 28, wherein the anti-PD-(L)1 antibody is zimberelimab. A method according to any one of claims 25 to 29, wherein the additional therapeutic agent comprises an anti-TIGIT antibody. A method in claim 30, wherein the anti-TIGIT antibody is tiragolumab, vivotolimab, dombanalimab, AB308, AK127, BMS-986207, ralzapastotug, or etigilimab. A method in claim 31, wherein the anti-TIGIT antibody is dombanalimab. A method according to any one of claims 25 to 32, wherein the additional therapeutic agent comprises an anti-PD-(L1) antibody and an anti-TIGIT antibody. The method of claim 33, wherein the additional therapeutic agent comprises a) zimberelimab and dombanalimab, b) zimberelimab and AB308, c) atezolizumab and tiragolumab, d) pembrolizumab and vivostolimab, e) MK-7684A (pembrolizumab/vivostolimab coformulation), f) durvalumab and dombanalimab, g) zimberelimab and ralzapastotug, or h) pembrolizumab and ralzapastotug. A method in claim 34, wherein the additional therapeutic agent comprises zimberelimab and dombanalimab. A method according to any one of claims 1 to 35, wherein the Trop-2 positive cancer is a solid epithelial cancer. In claim 36, the solid epithelial cancer is selected from breast cancer (e.g., triple negative breast cancer (TNBC), HR ⁺ /Her2 ^- breast cancer, HR ⁺ /Her2 ^low breast cancer), colon cancer, lung cancer, stomach cancer, urinary tract cancer, urothelial cancer, bladder cancer, kidney cancer, pancreatic cancer, ovarian cancer, uterine cancer, esophageal cancer, and prostate cancer. A method in claim 37, wherein the prostate cancer is castration-resistant prostate cancer (CRPC). A method according to claim 37, wherein the lung cancer is non-small cell lung cancer (NSCLC). A method according to claim 37 or 39, wherein the lung cancer is (i) squamous NSCLC or (ii) non-squamous NSCLC. A method according to any one of claims 37, 39 and 40, wherein the lung cancer does not have EGFR, ALK or other actionable genomic alteration. A method in claim 37, wherein the breast cancer is triple negative breast cancer (TNBC), HR ⁺ /Her2 ^- breast cancer or HR ⁺ /Her2 ^low breast cancer. A method according to any one of claims 1 to 42, wherein the Trop-2 positive cancer is (i) locally advanced and unresectable or (ii) metastatic. A method according to any one of claims 1 to 43, wherein the cancer has progressed after at least one prior anticancer therapy. A method according to claim 44, wherein the cancer has progressed after prior novel hormonal therapy (NHA; first or second generation non-steroidal anti-androgens, e.g., abiraterone, enzalutamide, darolutamide, apalutamide). A method according to claim 44, wherein the cancer progresses or relapses after platinum-based chemotherapy. A method according to claim 44 or 46, wherein the cancer progresses or relapses after checkpoint inhibitor (CPI) therapy. A method according to any one of claims 44, 46 and 47, wherein the cancer progresses or relapses after receiving platinum-based chemotherapy and anti-PD-(L)1 antibody therapy sequentially or in any order. A method according to any one of claims 44 to 48, wherein the cancer progresses or relapses following tyrosine kinase inhibitor therapy. A method according to any one of claims 1 to 49, wherein the cancer is resistant or refractory to one or more anticancer therapies. A method according to any one of claims 1 to 43, wherein the subject is treatment naive. The method of any one of claims 1 to 51, wherein the subject has not received prior therapy selected from the group consisting of: taxane therapy (taxane naive), checkpoint inhibitor therapy (CPI naive), and topoisomerase I inhibitor therapy. In any one of claims 1 to 52, the subject has not received prior taxane therapy (taxane naive), has not received checkpoint inhibitor therapy (CPI naive), or has received topoisomerase I inhibitor therapy. A method according to claim 52 or 53, wherein the taxane therapy comprises paclitaxel, naphtha-paclitaxel (ABRAXANE®), docetaxel or cabazitaxel. A method according to any one of claims 52 to 54, wherein the checkpoint inhibitor therapy comprises an anti-CTLA4 antibody or an anti-PD(L)1 antibody. A method according to any one of claims 52 to 55, wherein the topoisomerase I inhibitor therapy comprises topotecan, irinotecan, belotecan, or exatecan. A method according to any one of claims 1 to 56, wherein the anti-Trop-2 ADC and the adenosine pathway inhibitor are co-administered simultaneously. A method according to any one of claims 1 to 57, wherein the anti-Trop-2 ADC and the adenosine pathway inhibitor are co-administered sequentially. A method according to any one of claims 1 to 58, wherein the subject is a human. A method according to any one of claims 1 to 59, wherein the anti-Trop-2 ADC is administered in one or more doses ranging from 8 mg/kg to 10 mg/kg. A method in claim 60, wherein the anti-Trop2 ADC is administered in one or more doses of 10 mg/kg. A method according to any one of claims 1 to 61, wherein the anti-Trop-2 ADC is administered intravenously. A method according to any one of claims 1 to 62, wherein the anti-Trop-2 ADC is administered on days 1 and 8 of a 21-day cycle. A method according to any one of claims 1 to 63, wherein the adenosine pathway inhibitor is administered in one or more doses of 75 mg or 150 mg. A method according to any one of claims 1 to 64, wherein the adenosine pathway inhibitor is administered in one or more doses of 150 mg. A method according to any one of claims 1 to 65, wherein the adenosine pathway inhibitor is administered orally (PO). A method according to any one of claims 1 to 64, wherein the adenosine pathway inhibitor is administered once daily (QD). A method according to any one of claims 55 to 67, wherein the anti-PD(L)1 antibody is administered in one or more doses of 360 mg. A method according to any one of claims 55 to 68, wherein the anti-PD(L)1 antibody is administered intravenously (IV). A method according to any one of claims 55 to 69, wherein the anti-PD(L)1 antibody is administered once every three weeks (Q3W). A method according to any one of claims 10 to 70, wherein sacituzumab govitecan is administered intravenously (IV) at a dose of 10 mg/kg on days 1 and 8 of a 21-day treatment cycle, etrumadenanth is administered orally (PO) at a dose of 150 mg once daily (QD) of the 21-day treatment cycle, and optionally, zimberelimab is administered intravenously (IV) on day 1 (Q3W) of the 21-day treatment cycle. A method according to any one of claims 1 to 71, wherein the anticancer effect is observed as determined by objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), overall survival (OS), complete response (CR), partial response (PR), PSA response rate, radiographic response rate, change from baseline in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers, or a combination thereof. A method in claim 72, wherein tumor response or progression is determined according to RECIST version 1.1. a) sacituzumab govitecan; and
b) Etrumadenant
A method for treating, alleviating, reducing, preventing, or delaying the recurrence or metastasis of castration-resistant prostate cancer (CRPC), comprising the step of co-administering to a human patient an effective amount of a. A method in claim 74, further comprising the step of co-administering an anti-PD-(L)1 antibody to the human patient. The method of claim 75, wherein the anti-PD-(L)1 antibody is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cosibelimab, sasanlimab, tislelizumab, retipanlimab, balstilimab, toripalimab, setrelimab, genolimab, progolimab, rodafolimab, camrelizumab, budigalimab, avelumab, dostalimab, envafolimab, scintillimab, and zimberelimab. A method in claim 74, further comprising the step of co-administering zimberelimab to the human patient. A method according to any one of claims 74 to 77, wherein the CRPC is metastatic CRPC (mCRPC). A method according to any one of claims 74 to 78, wherein the CRPC is resistant or refractory to one or more anticancer therapies. A method according to claim 79, wherein the CRPC has progressed after prior NHA therapy (first- or second-generation non-steroidal anti-androgen agent, abiraterone). The method of any one of claims 74 to 80, wherein the human patient has not received prior therapy selected from: taxane therapy (taxane naive), checkpoint inhibitor therapy (CPI naive), and topoisomerase I inhibitor therapy. A method in claim 81, wherein the human patient has not received prior taxane therapy (taxane naive), has not received checkpoint inhibitor therapy (CPI naive), or has not received topoisomerase I inhibitor therapy. A method according to claim 81 or 82, wherein the taxane therapy comprises paclitaxel, naphtha-paclitaxel (ABRAXANE®), docetaxel or cabazitaxel. A method according to any one of claims 81 to 83, wherein the checkpoint inhibitor therapy comprises an anti-CTLA4 antibody or an anti-PD(L)1 antibody. A method according to any one of claims 81 to 84, wherein the topoisomerase I inhibitor therapy comprises topotecan, irinotecan, belotecan, or exatecan. a) Sacituzumab govitecan;
b) Etrumadenant; and
c) Anti-PD-(L)1 antibody
A method for treating, alleviating, reducing, preventing, or delaying the recurrence or metastasis of non-small cell lung cancer (NSCLC), comprising the step of co-administering to a human patient an effective amount of a. The method of claim 86, wherein the anti-PD-(L)1 antibody is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cosibelimab, sasanlimab, tislelizumab, retipanlimab, balstilimab, toripalimab, setrelimab, genolimab, progolimab, rhodapolimab, camrelizumab, budigallimab, avelumab, dostalimab, envapolimab, scintillimab, and zimberelimab. A method according to claim 86 or 87, wherein the anti-PD-(L)1 antibody is zimberelimab. A method according to any one of claims 86 to 88, wherein the NSCLC progresses or relapses following platinum-based chemotherapy. A method according to any one of claims 86 to 89, wherein the NSCLC progresses or relapses after checkpoint inhibitor (CPI) therapy. A method according to claim 90, wherein the NSCLC progresses or relapses after receiving platinum-based chemotherapy and anti-PD-(L)1 antibody therapy sequentially or in any order. A method according to any one of claims 86 to 91, wherein the NSCLC progresses or relapses after tyrosine kinase inhibitor therapy. A method according to any one of claims 86 to 92, wherein the NSCLC is (i) locally advanced and unresectable or (ii) metastatic. A method according to any one of claims 86 to 93, wherein sacituzumab govitecan is administered intravenously (IV) at a dose of 8 mg/kg or 10 mg/kg on days 1 and 8 of a 21-day treatment cycle, and etrumadenoate is administered orally (PO) at a dose of 75 mg or 150 mg once daily (QD) of the 21-day treatment cycle. A method in claim 94, wherein sacituzumab govitecan is administered intravenously (IV) at a dose of 10 mg/kg on days 1 and 8 of a 21-day treatment cycle, and etrumadenoate is administered orally (PO) at a dose of 150 mg once daily (QD) of the 21-day treatment cycle. A method according to any one of claims 86 to 95, wherein zimberelimab is administered intravenously (IV) on day 1 (Q3W) of a 21-day treatment cycle. A method according to any one of claims 86 to 96, wherein the anticancer effect is observed as determined by objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), overall survival (OS), complete response (CR), partial response (PR), PSA response rate, radiographic response rate, change from baseline in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers, or a combination thereof. A method according to claim 97, wherein tumor response or progression is determined according to RECIST version 1.1. A method according to any one of claims 1 to 98, wherein the anti-CD47 antibody (e.g., magrolimab) is not administered to the subject or human patient. A method according to any one of claims 1 to 99, wherein an MCL1 inhibitor (e.g., GS-9716) is not administered to the subject or human patient. A method according to any one of claims 1 to 100, wherein a FLT3 agonist (e.g., GS-3583, CDX-301) is not administered to the subject or human patient. a) a tumor antigen (TA) targeted ADC (TopI ADC) comprising a topoisomerase I inhibitor; b) an adenosine pathway inhibitor; and
c) Optionally anti-PD(L)1 antibodies
A method for treating, alleviating, reducing, preventing, or delaying the recurrence or metastasis of a tumor antigen positive (TA ⁺ ) cancer, comprising the step of co-administering to a subject an effective amount of a. An anti-Trop-2 ADC for use in combination with an adenosine pathway inhibitor and optionally an anti-PD(L)1 antibody in a method of treating, alleviating, reducing, preventing, or delaying the recurrence or metastasis of Trop-2 positive cancers, said method comprising administering to a subject the anti-Trop-2 ADC, the adenosine pathway inhibitor, and optionally an additional anti-PD(L)1 antibody. A TopI ADC for use in combination with an adenosine pathway inhibitor and optionally an anti-PD(L)1 antibody in a method of treating, alleviating, reducing, preventing, or delaying the recurrence or metastasis of tumor antigen positive (TA ⁺ ) cancers, said method comprising administering to a subject the TopI ADC, the adenosine pathway inhibitor, and optionally the anti-PD(L)1 antibody. As a kit for use as a medicine,
a) a TROP-2-targeted antibody-drug conjugate (ADC) comprising an anti-TROP-2 antibody (anti-TROP-2 ADC);
b) adenosine pathway inhibitors; and
c) A kit optionally comprising an anti-PD-(L)1 antibody. As a kit for use as a medicine,
a) Tumor antigen (TA) targeted ADC comprising a topoisomerase I inhibitor (TopI ADC);
b) adenosine pathway inhibitors; and
c) A kit optionally comprising an anti-PD-(L)1 antibody. a) sacituzumab govitecan; and
b) A method for treating, alleviating, reducing, preventing, or delaying the recurrence or metastasis of breast cancer, comprising the step of co-administering to a human patient an effective amount of a CD73 inhibitor. A method in claim 107, wherein the CD73 inhibitor is oleculumab, BMS-986179, uriledrimab, AK119, chemliclustat, mufadolimab, HLX23, INCA00186, IBI325, NZV930, ORIC-533, Sym024, IPH5301, IOA-237, JAB-BX100, PT199, TRB010, CD73 ASO, ABSK-051, AK131, BR101, BP1200, CB708, GB7002, or ATG-037. A method in claim 107, wherein the CD73 inhibitor is chemriclustat (AB680, GS-0680), uriledrimab, mufadolimab, ORIC-533, ATG-037, PT-199, AK131, NZV930, BMS-986179, or oleclumab. A method in claim 107, wherein the CD73 inhibitor is chemriclustat (AB680, GS-0680). A method according to any one of claims 107 to 110, further comprising co-administering an anti-PD-(L)1 antibody to the human patient. The method of claim 111, wherein the anti-PD-(L)1 antibody is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cosibelimab, sasanlimab, tislelizumab, retipanlimab, balstilimab, toripalimab, setrelimab, genolimab, progolimab, rodafolimab, camrelizumab, budigalimab, avelumab, dostalimab, envafolimab, scintillimab, and zimberelimab. A method in claim 112, further comprising the step of co-administering zimberelimab to the human patient. A method according to any one of claims 107 to 113, wherein the breast cancer is metastatic breast cancer. A method according to any one of claims 107 to 114, wherein the breast cancer is resistant or refractory to one or more anticancer therapies. A method according to claim 115, wherein the breast cancer has progressed after prior chemotherapy (first-generation or second-generation chemotherapy, e.g., hormonal therapy). The method of any one of claims 107 to 116, wherein the human patient has not received prior therapy selected from: taxane therapy (taxane naive), checkpoint inhibitor therapy (CPI naive), and topoisomerase I inhibitor therapy. A method in claim 117, wherein the human patient has not received prior taxane therapy (taxane naive), has not received checkpoint inhibitor therapy (CPI naive), or has not received topoisomerase I inhibitor therapy. A method according to claim 117 or 118, wherein the taxane therapy comprises paclitaxel, naphtha-paclitaxel (ABRAXANE®), docetaxel or cabazitaxel. A method according to any one of claims 117 to 119, wherein the checkpoint inhibitor therapy comprises an anti-CTLA4 antibody or an anti-PD(L)1 antibody. A method according to any one of claims 117 to 120, wherein the topoisomerase I inhibitor therapy comprises topotecan, irinotecan, belotecan, or exatecan.