CN112043831A - Quinolines for use in the combined treatment of breast cancer - Google Patents

Abstract

The application belongs to the technical field of medicines, provides a quinoline compound for combined treatment of breast cancer, and particularly provides application of the combination of a compound I or a pharmaceutically acceptable salt thereof and a second therapeutic agent in preparation of a medicine for treating breast cancer, and a combined pharmaceutical composition for treating colorectal cancer, wherein the combined pharmaceutical composition comprises: (i) compound I or a pharmaceutically acceptable salt thereof; and (ii) at least one second therapeutic agent, compound I having the chemical name 1- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl ] oxy ] methyl ] cyclopropylamine.

Description

Quinolines for use in the combined treatment of breast cancer

Technical Field

The invention belongs to the field of medicines, belongs to the technical field of pharmaceutical preparations, and particularly relates to a quinoline compound or pharmaceutically acceptable salt thereof for combined treatment of breast cancer.

Background

Breast Cancer (Breast Cancer) is one of the most common malignancies in women worldwide. The female breast consists of skin, fibrous tissue, breast glands and fat, and breast cancer occurs in the mammary gland epithelial tissue. Because the mammary gland is not an important organ for maintaining the life activity of a human body, the in-situ breast cancer is not fatal, but free cancer cells can be scattered to the whole body along with blood or lymph fluid, and are easy to transfer in organs such as lung, liver, bone, brain and the like, so that normal tissues of the organs are damaged, and the life is threatened. According to the International Agency for Research on Cancer (IARC) of the world health organization, about 120 million breast Cancer patients are counted worldwide each year, wherein about 54 million of the breast Cancer patients are new cases and 50 million death cases.

The treatment means of the breast cancer comprises methods such as operation treatment, chemotherapy, radiotherapy, endocrine treatment, immunotherapy, molecular targeted therapy, traditional Chinese medicine and the like. Surgery is the most prominent method for treating breast cancer at present, but is only a local treatment, and causes pain to patients with different degrees. Chemotherapy plays an important role in the treatment of different types of breast cancer as a systemic treatment means. The commonly used breast cancer chemotherapy drugs are cyclophosphamide, 5-fluorouracil, methotrexate, adriamycin, epirubicin, mitomycin, vincristine, vinblastine and cisplatin, and the existing breast cancer chemotherapy mostly adopts combined chemotherapy of more than three drugs in consideration of drug resistance and treatment effect, so that the effective rate is improved, but stronger toxic and side effects are caused. Endocrine therapy is to regulate the endocrine function in the body by using drugs or a method of removing endocrine glands, and reduce the secretion of endocrine hormones, thereby achieving the purpose of treating breast cancer. Molecular targeted therapy is one of the most active research fields in recent years, and is a novel antitumor therapeutic drug with a multi-link action mechanism.

Breast cancer is highly heterogeneous at a molecular level, and different molecular typing has a large difference in treatment response, so in recent years, breast cancer is treated mainly by performing comprehensive treatment without schemes such as surgery, chemotherapy, radiotherapy, endocrine therapy, immunotherapy and the like according to the molecular typing of breast cancer, so that the curative effect of breast cancer is effectively improved.

According to molecular typing, Breast cancer is classified into Luminal a (Luminal a Subtype), Luminal B (Luminal B Subtype), HER-2 overexpression HER-2(+) type, Basal-Like Subtype (BLBC, also called triple negative Breast cancer TNBC), and Normal Breast-Like Subtype (Normal Breast disease-Like). Wherein, Luminal type A mainly adopts endocrine therapy; luminal type B adopts endocrine therapy combined with chemotherapy or chemotherapy, endocrine therapy and targeted therapy; HER-2 overexpression type adopts targeted therapy combined chemotherapy; however, the targeted drugs are ineffective in treating triple negative breast cancer, so the main treatment means of triple negative breast cancer is only chemotherapy.

Since the clinical application of each treatment mode of breast cancer is still limited by the treatment effect and side effect, the necessity and urgency of providing a new scheme for treating breast cancer are suggested.

Summary of The Invention

In one aspect, the present application provides the use of a combination of compound I, or a pharmaceutically acceptable salt thereof, and a second therapeutic agent in the manufacture of a medicament for the treatment of breast cancer, in another aspect, the present application provides a combination pharmaceutical composition for the treatment of breast cancer comprising (I) compound I, or a pharmaceutically acceptable salt thereof; and (ii) at least one second therapeutic agent. In another aspect, the present application also provides the use of a pharmaceutical composition in the manufacture of a medicament for the treatment of breast cancer.

In yet another aspect, the present application also provides a method of treating breast cancer comprising administering to a subject a pharmaceutical composition of the present application. The pharmaceutical composition comprises (I) compound I or a pharmaceutically acceptable salt thereof; and (ii) at least one second therapeutic agent.

Disclosure of Invention

In one aspect, the present application provides the use of a combination of compound I, or a pharmaceutically acceptable salt thereof, and a second therapeutic agent in the manufacture of a medicament for the treatment of breast cancer, in another aspect, the present application provides a combination pharmaceutical composition for the treatment of breast cancer comprising (I) compound I, or a pharmaceutically acceptable salt thereof; and (ii) at least one second therapeutic agent

In some embodiments, the breast cancer is non-invasive breast cancer, early invasive breast cancer, invasive specific breast cancer, invasive non-specific breast cancer. In some embodiments, the breast cancer is invasive non-specific breast cancer.

In some embodiments, the breast cancer is advanced and/or metastatic breast cancer.

In some embodiments, the breast cancer is ductal carcinoma, classical lobular carcinoma, invasive ethmoid carcinoma, neuroendocrine carcinoma, myxoma, apocrine adenocarcinoma, pleomorphic lobular carcinoma, medullary carcinoma, anaplastic carcinoma, or adenoid cystadenocarcinoma. In some embodiments, the breast cancer is ductal breast cancer.

In some embodiments, the breast cancer is luminal a (luminal a subtype), luminal B (luminal B subtype), HER-2(+) type (or HER-2 overexpressing type), basal-like type (BLBC, including Triple Negative Breast Cancer (TNBC)), or normal breast-like type (normal breast-like subtype). In some embodiments, the breast cancer is a triple negative breast cancer.

In some embodiments, the breast cancer is primary breast cancer and/or secondary breast cancer. In some embodiments, the breast cancer is advanced and/or metastatic triple negative breast cancer.

In some embodiments, the breast cancer is a breast cancer that has failed prior therapy, preferably, the breast cancer has failed surgery and/or radiotherapy and/or a chemotherapeutic drug and/or endocrine therapy and/or immunotherapy and/or molecular targeted therapy. In some embodiments, the breast cancer is a triple negative breast cancer with prior treatment failure.

In some embodiments of the present application, the combination pharmaceutical composition comprises: (i) a pharmaceutical composition of compound I or a pharmaceutically acceptable salt thereof; and (ii) at least one second therapeutic agent, optionally in combination with radiation therapy. In some embodiments, there is provided a combination pharmaceutical composition for the treatment of breast cancer, comprising: (i) compound I or a pharmaceutically acceptable salt thereof; and (ii) at least one small molecule targeted antineoplastic drug, optionally in combination with radiation therapy. In some embodiments, there is provided a combination pharmaceutical composition for the treatment of breast cancer, comprising: (i) compound I or a pharmaceutically acceptable salt thereof; and (ii) at least one macromolecular antibody drug, optionally in combination with radiotherapy. In some embodiments, there is provided a combination pharmaceutical composition for the treatment of breast cancer, comprising: (i) compound I or a pharmaceutically acceptable salt thereof; and (ii) at least one immunotherapeutic drug, optionally in combination with radiation therapy. In some embodiments, there is provided a combination pharmaceutical composition for the treatment of breast cancer, comprising: (i) compound I or a pharmaceutically acceptable salt thereof; and (ii) at least one endocrine drug, optionally in combination with radiation therapy.

In another aspect, the present application provides a combination pharmaceutical composition comprising: (i) compound I or a pharmaceutically acceptable salt thereof; and (ii) at least one second therapeutic agent, optionally in combination with radiation therapy, in the manufacture of a medicament for the treatment of breast cancer.

In yet another aspect, the present application also provides a method of treating breast cancer comprising administering to a subject a combination pharmaceutical composition of the present application. The combination pharmaceutical composition comprises (I) compound I or a pharmaceutically acceptable salt thereof; and (ii) at least one second therapeutic agent.

The present application provides a method for treating a subject having breast cancer. In some versions of the present application, the subject has previously received surgery, chemotherapy, and/or radiation therapy. In some embodiments, the subject has re-developed disease progression after achieving complete remission following surgery, chemotherapy, and/or radiation therapy. In some embodiments, the subject has failed to complete remission or failed to partial remission following surgery, chemotherapy, and/or radiation therapy.

The present application provides a method of treating breast cancer comprising administering to a patient in need thereof compound I or a pharmaceutically acceptable salt thereof and at least one second therapeutic agent. In some embodiments, the present application provides a method of treating breast cancer that has not received a chemotherapeutic regimen comprising administering to a patient in need thereof compound I, or a pharmaceutically acceptable salt thereof, and at least one second therapeutic agent. In some embodiments, the present application provides a method of treating breast cancer that has progressed or recurred after receiving at least one chemotherapy, the method comprising administering to a patient in need thereof compound I, or a pharmaceutically acceptable salt thereof, and at least one second therapeutic agent. In some embodiments, the present application provides a method of treating breast cancer that has failed second-line and beyond, comprising administering to a patient in need of treatment compound I, or a pharmaceutically acceptable salt thereof, and at least one second therapeutic agent. In one embodiment, the present application provides a method of treating refractory relapsed breast cancer, comprising administering to a patient in need thereof compound I, or a pharmaceutically acceptable salt thereof, and at least one second therapeutic agent. In some embodiments, the compound I or a pharmaceutically acceptable salt thereof and a second therapeutic agent are used to treat primary breast cancer or secondary breast cancer. In some embodiments, the breast cancer is a breast cancer that is intolerant to chemotherapy.

In some embodiments of the present application, the subject has not previously received systemic chemotherapy. In some embodiments, the subject has previously received surgical treatment, radiation therapy, induction chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy. In some embodiments, the subject has not previously received systemic chemotherapy, but has received surgical treatment, radiation therapy, induction chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy. In some embodiments, the subject has complete remission following surgical treatment, radiation therapy, induction chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy before disease progression occurs again. In some embodiments, the subject has failed to complete remission or failed to partial remission following surgical treatment, radiation therapy, induction chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy. In some embodiments, the subject undergoes metastasis following surgical treatment, radiation treatment, induction chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy.

In some embodiments of the present application, the method of treating breast cancer comprises administering compound I or a pharmaceutically acceptable salt thereof to a subject concurrently, intermittently, or sequentially with at least one second therapeutic agent.

The method of administration can be determined comprehensively on the basis of the activity, toxicity of the drug, tolerance of the subject, and the like. In some embodiments of the present application, the use or method of treatment, including but not limited to, the second therapeutic agent may be administered daily (qd), every other day (qod), every 3 days (q3d), every 4 days (q4d), every 5 days (q5d), weekly (q1w), every 2 weeks (q2w), every 3 weeks (q3w), or every 4 weeks (q4w), or twice daily (bid), twice weekly (biw), three times daily (tid), four times daily (qid), etc. In some embodiments of the present application, the use or method of treatment may also be administered with a second therapeutic agent in an intermittent dosing regimen. The intermittent administration includes a dosing period and a rest period, for example, administration of the second therapeutic agent daily during the dosing period followed by a rest period followed by a dosing period followed by a rest period, and so on, which may be repeated multiple times.

In some embodiments of the present application, the use or method of treatment, including but not limited to the compound I or pharmaceutically acceptable salt thereof, may be in a dose of 6mg, 8mg, 10mg or 12mg once daily; 2 weeks with continuous dosing and 1 week off dosing schedule; and/or, in a dosing regimen of 2 weeks on continuous dosing, and 2 weeks off.

In some embodiments, the second therapeutic agent and compound I, or a pharmaceutically acceptable salt thereof, each have the same or different treatment cycles. In some specific embodiments, the second therapeutic agent and compound I or a pharmaceutically acceptable salt thereof have the same treatment cycle, e.g., one treatment cycle every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks. In some specific embodiments, the second therapeutic agent and compound I, or a pharmaceutically acceptable salt thereof, are each one treatment cycle every 3 weeks.

Breast cancer

In some embodiments of the present application, breast cancer includes, but is not limited to, non-invasive breast cancer, early invasive breast cancer, invasive specific breast cancer, invasive non-specific breast cancer, according to morphological classification.

In some embodiments, the breast cancer includes, but is not limited to, ductal carcinoma, classic lobular carcinoma, invasive ethmoid carcinoma, neuroendocrine carcinoma, mucinous carcinoma, apocrine adenocarcinoma, pleomorphic lobular carcinoma, medullary carcinoma, anaplastic carcinoma, or adenoid cystadenocarcinoma, based on histological typing.

In some embodiments, the breast cancer includes, but is not limited to, luminal a (luminal a subtype), luminal B (luminal B subtype), HER-2(+) type (or HER-2 overexpressing type), basal-like type (BLBC, including Triple Negative Breast Cancer (TNBC)), normal breast-like type (normal breast-like), depending on molecular typing.

In some embodiments, the breast cancer is a triple negative breast cancer. Triple negative breast cancer in the present application refers in particular to breast cancer in which the ER, PR, HER2 immunohistochemical markers are all negative.

In some embodiments, the breast cancer is primary breast cancer and/or secondary breast cancer; in some embodiments, the breast cancer, clinical stage of which includes, but is not limited to, locally advanced, and/or advanced (e.g., stage IIIB/IV) breast cancer. In some embodiments, in some embodiments metastatic breast cancer. Wherein metastatic breast cancer includes, but is not limited to, distant metastasis, focal single metastasis, disseminated metastasis, diffuse metastasis; the metastatic lesions include, but are not limited to, lung, lymph node, pleura, bone, brain, pericardium, adrenal gland, liver; in some embodiments, the breast cancer is lung metastatic breast cancer. In some embodiments, the breast cancer is brain metastatic breast cancer. In some embodiments, the breast cancer is lymph node metastatic breast cancer. In some embodiments, the breast cancer is advanced and/or metastatic triple negative breast cancer.

In some embodiments of the present application, the breast cancer is recurrent; in certain embodiments, the breast cancer is refractory; in certain embodiments, the breast cancer is unresectable. In some embodiments, the breast cancer is a breast cancer that has failed chemotherapy and/or targeted drug therapy. In some embodiments, the chemotherapeutic agents include, but are not limited to, camptothecin and its derivatives, platinum complexes, pyrimidine antagonists; in some embodiments, the targeted drug includes, but is not limited to, one or more of an EGFR inhibitor. In some embodiments, the breast cancer is a breast cancer that has received at least two chemotherapy regimens. In some embodiments, the breast cancer is a breast cancer that has received at least two chemotherapeutic drugs. In some embodiments, the breast cancer is a breast cancer that has failed second-line and above-second-line chemotherapy. In one embodiment, the breast cancer is refractory relapsed breast cancer, wherein the "refractory relapsed breast cancer" refers to breast cancer that is not remitted by chemotherapy, and breast cancer that is effective by chemotherapy but shows disease progression within 3 months after the end of chemotherapy.

In some embodiments, the breast cancer is a breast cancer that has failed prior therapy, preferably, the breast cancer has failed surgery and/or radiotherapy and/or a chemotherapeutic drug and/or endocrine therapy and/or immunotherapy and/or molecular targeted therapy. In some embodiments, the breast cancer is a triple negative breast cancer with prior treatment failure.

A second therapeutic agent

The second therapeutic agent described herein includes, but is not limited to, chemotherapeutic drugs, small molecule targeted antineoplastic drugs, macromolecular antibody drugs, immunotherapeutic drugs, endocrine drugs.

In some embodiments, the second therapeutic agent is a chemotherapeutic drug, including but not limited to one or more of taxanes, platinum complexes, pyrimidine antagonists, camptothecins and derivatives thereof, anthracyclines, podophyllides;

in the application, the chemotherapeutic drugs include, but are not limited to, one or more of taxanes, vinca alkaloids antitumor drugs, platinum complexes, pyrimidine antagonists, camptothecins and derivatives thereof, anthracyclines and podophyllum compounds; the taxanes include but are not limited to one or more of paclitaxel, albumin-bound paclitaxel and docetaxel;

the vinblastine antineoplastic agent comprises one or more of vinblastine, vincristine, vindesine, vinorelbine, vinfunin (vinflunine) and catharanthine;

the platinum complex comprises one or more of, but is not limited to, miboplatin, cisplatin, carboplatin, dicycloplatin, nedaplatin, oxaliplatin, leplatin (Lobaplatin), triplatin tetranitrate, phenanthroline, picoplatin and satraplatin;

the pyrimidine antagonist includes but is not limited to one or more of cytarabine, azacitidine, ancitabine, capecitabine, gemcitabine, fluorouracil, bifurofluorouracil, doxifluridine, trifluridine, tegafur, carmofur, and eufordine;

the camptothecin and the derivatives thereof include but are not limited to one or more of camptothecin, hydroxycamptothecin, irinotecan and topotecan;

the anthracycline compound includes, but is not limited to, one or more of epirubicin (epirubicin), doxorubicin, daunorubicin, pirarubicin, amrubicin, idarubicin, mitoxantrone, doxorubicin, valrubicin, zorubicin, pixantrone, doxorubicin pyrans, liposomal doxorubicin;

the podophyllum compound includes but is not limited to one or more of etoposide (etoposide), teniposide and epipodophyllotoxin glucopyranoside;

the chemotherapy medicine also comprises bleomycin, pingyangmycin, pelomomycin, mitomycin, actinomycin D (dactinomycin), amiloride, eribulin, lycium barbarum polysaccharide, methotrexate, thioguanine, pemetrexed, bendamustine, temozolomide, Sapacitabine, plin, trooshusufen, trolene, and a pharmaceutically acceptable salt thereof,¹⁵³One or more of Sm-EDTMP, tegafur and encequidar.

Optionally, the second therapeutic agent is used in combination with chemotherapeutic adjuvants, including, but not limited to, leucovorin (CF), aldehydo, mesna, bisphosphonates, amifostine, hematopoietic Colony Stimulating Factors (CSFs), ondansetron. In some embodiments, the chemotherapeutic adjuvant is calcium leucovorin (CF), mesna, aldehydic acid.

In some embodiments, the second therapeutic agent is a pyrimidine antagonist, in particular capecitabine.

In some embodiments, the second therapeutic agent is one, two or three of cyclophosphamide, methotrexate and fluorouracil, particularly a CMF regimen.

In some embodiments, the second therapeutic agent is one or both of doxorubicin and cyclophosphamide, in particular the AC regimen.

In some embodiments, the second therapeutic agent is one, two or three of doxorubicin, cyclophosphamide and paclitaxel, in particular an AC-T regimen.

In some embodiments, the second therapeutic agent is one or both of vinorelbine and doxorubicin, in particular a NA regimen.

In some embodiments, the second therapeutic agent is one, two or three of fluorouracil, doxorubicin and cyclophosphamide, in particular a CAF regimen.

In some embodiments, the second therapeutic agent is mitoxantrone, aldehydic acid and fluorouracil, in particular an MFL chemotherapy regimen.

In some embodiments, the second therapeutic agent is one or both of paclitaxel and doxorubicin, specifically a PA regimen.

In some embodiments, the second therapeutic agent is one, two or three of cyclophosphamide, doxorubicin and cisplatin, in particular a CAP regimen.

In some embodiments, the second therapeutic agent is one or both of gemcitabine and cisplatin, specifically a GC regimen.

In some embodiments, the second therapeutic agent is one or both of docetaxel and capecitabine, specifically an XD regimen.

In some embodiments, the second therapeutic agent is a small molecule targeted anti-tumor drug, including but not limited to protein kinase inhibitors. Wherein, the protein kinase inhibitor includes but is not limited to tyrosine kinase inhibitor, serine and/or threonine kinase inhibitor. Targets for such inhibitors include, but are not limited to, HER-2, mTOR, PIK3CA, PTEN, FGFR1, FGFR2, VEGF, EGFR, PARP, CDK4/6, COX-2, ARG2, AKT. In some specific embodiments, the second therapeutic agent is a small molecule targeted anti-tumor drug that is directed against HER-2 target drugs, including but not limited to Neratinib (Neratinib) lapatinib;

in some specific embodiments, the second therapeutic agent is a small molecule targeted anti-tumor drug that is a drug directed against a VEGF target, including but not limited to sunitinib, sorafenib, endostatin;

in some specific embodiments, the second therapeutic agent is a small molecule targeted anti-tumor drug that is an EGRF inhibitor, including but not limited to gefitinib, erlotinib;

in some embodiments, the second therapeutic agent is a small molecule targeted antineoplastic agent that is a PARP (poly adenosine diphosphate ribose polymerase) inhibitor against the Bcrab1/2 mutation, and in Triple Negative Breast Cancer (TNBC), due to the frequent deficiency or mutation of BRCA1/2, the PARP inhibitor (PARPI) inhibits BRCA 1/2-mediated homologous recombination DNA repair with the aim of promoting tumor cell apoptosis, thereby enhancing the therapeutic effects of radiation therapy and therapeutic agents such as alkylating agents and platinum complexes, including but not limited to iniparib, veliparib and olaparib;

in some specific embodiments, the second therapeutic agent is a small molecule targeted anti-tumor drug against CDK4/6 inhibitor as a post-menopausal ER positive, HER2 negative advanced breast cancer treatment regimen, including but not limited to palbociclib (palbociclib);

in some specific embodiments, the second therapeutic agent is a small molecule targeted anti-neoplastic agent that is a COX-2 inhibitor, including but not limited to celecoxib, aspirin;

small molecule targeted antineoplastic agents may also include, but are not limited to, lenatinib (Neratinib), Lapatinib (Lapatinib), Sunitinib (Sunitinib), endostatin (Endostar), Gefitinib (Gefitinib), Erlotinib (Erlotinib), ininib, Veliparib, Olaparib, Palbociclib (Palbociclib), Celecoxib (Celecoxib), Aspirin (asperin), Rapamycin (rapamicin), Imatinib (Imatinib), Tipifarnib, frataxidin (Flavopiridol), Apatinib (Apatinib), Aflibercept (aflibercitib), Afatinib (Afatinib), Crizotinib (critinib), chromotinib (Ceintinib), ravirinotecan (tratinib), Ventifertinib (vantifertib), vantifertinib (vantifertib), valcaninfertib (valcaninfertib), valcanitinib (valcanitinib), valcanitinib (e), valcanitinib (e), valcanitinib), valtinib (e), valcanitinib), valtinib), valcanitinib (e), valcanitinib), valtinib, Sermititinib (Selumitinib), Sorafenib (Sorafenib), ormotinib (Olmutinib), Volitinib (Savoltinib), Fujitinib (Fruquintinib), Entretinib (Entretinib), Dasatinib (Dasatinib), Ensartinib (Ensartinib), Lenvatinib (Lenvatinib), Itacitinib, pyrroltinib (Pyrotinib), Bimetinib (Binimetinib), Erdasatinib (Erdasatinib), Ascintinib (Axitinib), Cobimitinib (Cobimitinib), Acarabutinib, Famitininib (Famitininib), Masitinib (Masitinib), Ibritinib (Ibricinininib), Rorentinib (Sanilib), Veitnib (Boracitinib), Novacinib (Boracitinib), Nocardianib (Novacarbinib (Novacarbib), Novatinib (Nomadinib), Nomadinib (Nomadinib), Nomadinib (Nomadinib), Nomadinib (Nomadib), Nomadinib (Nomadib), Nomadicinbamide (Nomadicinbamide), Nomadicinbamide (Nomadib), Nomadicinbamide (Nomadinib (Nomadicib), Nomadib), Nomadicib), Nomadicinbamide (, Bemcentinib, Capmatinib, Entrectinib, TAK-931, ALT-803, Famitiniib L-Malate, LTT-462, BLU-667, Ningetiniib, Poziotiib, DS-1205c, Capivastib, SH-1028, metformin, Sericib, OSE-2101, APL-101, Berzostib, Idelalisib, Lerociclib, Ceralassib, PLB-1003, Tovostib, SklB-2818, SKLB-1028, D-0316, LY-3023414, Allitinib, MRTX-849, AP-32788, AZD-4205, Lirafenib, Vactostib, Mivebressib, Sipapavitibin, Sivatiniib, ASN-497, Germinib-32, Mastica-0796, Germinib-077, Germinib-11, Germinib-10200, Germinib-369, Mascasticib-369, Germinib-369, Germinib-3, Germinib-3, Ge, AZD-3759, Antroquinonol, SAF-189s, AT-101, TTI-101, Naputinib, LNP-3794, HH-SCC-244, ASK-120067, CT-707, Epitinib Succinate, Tesevatinib, SPH-1188-11, BPI-15000, Copalisib, Niraparib, Talazoparib Tosylate, DV-281, Siremainslin, Telaglenastat, MP-0250, GLG-801, ABTL-0812, Bortezomib, Panobinostat (Panobinostat), Tucidinostat, Vorinostat, Resminadostat, Epacstastat, Tamettamettat, Entostat, Mocesatintat, Quisinostat, LCL-001, KML-161.

In some embodiments, the second therapeutic agent is a macromolecular antibody drug. Wherein, the target of the antibody includes any one or more of PD-1, PD-L1, cytotoxic T lymphocyte antigen 4 (cytoxic T-lymphocyte antigen 4, CTLA-4), platelet derived growth factor receptor alpha (PDGFR-alpha), Vascular Endothelial Growth Factor (VEGF), human epidermal growth factor receptor-2 (HER2), Epidermal Growth Factor Receptor (EGFR), ganglioside GD2, B cell surface protein CD20, B cell surface protein CD52, B cell surface protein CD38, B cell surface protein CD319, B cell surface protein CD30, and B cell surface protein CD19/CD 3.

In some embodiments, the antibody drug is an inhibitor of the interaction between the PD-1 receptor and its ligand PD-L1; in some embodiments, the antibody agent is a cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitor. In some embodiments, the antibody drug is a platelet-derived growth factor receptor alpha (PDGFR-alpha) inhibitor.

In some embodiments, the inhibitor of the interaction between the PD-1 receptor and its ligand PD-L1 is an antibody or antigen-binding portion thereof that binds programmed death receptor 1(PD-1) and/or inhibits PD-1 activity, or an antibody or antigen-binding portion thereof that binds programmed death receptor 1(PD-L1) and/or inhibits PD-L1 activity, such as an anti-PD-1 antibody or an anti-PD-L1 antibody. In some embodiments, the antibody or antigen-binding portion thereof is (a) a monoclonal antibody, or antigen-binding fragment thereof, that specifically binds to human PD-1 and blocks the binding of human PD-L1 to human PD-1; or (b) a monoclonal antibody, or antigen-binding fragment thereof, that specifically binds to human PD-L1 and blocks the binding of human PD-L1 to human PD-1.

In some embodiments, the anti-PD-1 or PD-L1 antibody is an anti-PD-1 or PD-L1 monoclonal antibody.

In some embodiments, the anti-PD-1 or PD-L1 antibody is a human or murine antibody.

In some embodiments, the anti-PD-1 antibody may be selected from any one or more of Nivolumab, pamirumab (Pembrolizumab), debarville mab (Durvalumab), terilisib (toriplalimab, JS-001), Cedilizumab (IBI308), Carelix strain mab (Camrelizumab), Tirilizumab (BGB-A317), Jennuomab (GB226), Lizumab (LZM009), HLX-10, BAT-1306, AK103(HX008), AK104 (Kangfang organism), CS1003, SCT-I10A, F520, SG001, GLS-010.

In some embodiments, the anti-PD-L1 antibody may be selected from any one or more of Attributumab (Atezolizumab), Avelumab, Durvalumab, KL-A167, SHR-1316, BGB-333, JS003, STI-A1014(ZKAB0011), KN035, MSB2311, HLX-20, CS-1001.

In some specific embodiments, the anti-PD-1 antibody is nivolumetrizumab.

In some specific embodiments, the anti-PD-1 antibody is pembrolizumab.

In some embodiments, the inhibitor of cytotoxic T-lymphocyte antigen 4 (CTLA-4) is an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is an anti-CTLA-4 monoclonal antibody.

In some embodiments, the anti-CTLA-4 antibody may be selected from any one or more of Ipilimumab (Iplimumab), Tremelimumab (Tremelimumab), AGEN-1884, BMS-986249, BMS-986218, AK-104, IBI 310.

In some specific embodiments, the anti-CTLA-4 antibody is ipilimumab.

In some embodiments, the platelet-derived growth factor receptor alpha (PDGFR-alpha) inhibitor is an anti-PDGFR alpha antibody. In some embodiments, the anti-PDGFR α antibody is an anti-PDGFR α monoclonal antibody.

In some specific embodiments, the anti-PDGFR α antibody is Olaratumab (olarataumab).

In some specific embodiments, the antibody drug may further include, but is not limited to, Bevacizumab (Bevacizumab), Ramucirumab (Ramucirumab), Pertuzumab (Pertuzumab), trastuzumab (trastuzumab), trastuzumab-Emtansine (TDM1), cetuximab (Cotuximab), Nimotuzumab (Nimotuzumab), Panitumumab (Panitumumab), Matuzumab (Matuzumab), Nimotuzumab (Necitumumab), dinitumumab (Necitumumab), dinituximab, Rituximab (Rituximab), Ibritumomab (Ibritumomab), ofamab (ofatsumadumab), obib, Alemtuzumab (erbitumomab), obenzumab (erbitumomab), Alemtuzumab (Alemtuzumab), darumumab (darumumab), Gemtuzumab (Gemtuzumab), and optionally.

In some specific embodiments, the antibody drug is one or more of trastuzumab, trastuzumab-Emtansine (TDM1), pertuzumab, ramucirumab, bevacizumab, cetuximab, nimotuzumab, panitumumab, matuzumab.

In some embodiments, the second therapeutic agent is an immunotherapeutic agent including, but not limited to, one or more of interferon alpha, interferon alpha-1 b, interferon alpha-2 b, interleukins, tumor necrosis factor, anti-breast cancer RNA, paualr, LAK cells, sirolimus (Temsirolimus), everolimus (everolimus), Temsirolimus (Temsirolimus), ridaforolimus (ridaforolimus), Temsirolimus; preferred are Temsirolimus (Temsirolimus) and everolimus (everolimus).

In some embodiments, the second therapeutic agent is an endocrine drug, including but not limited to tamoxifen, amphetamine, megestrol, or megestrol.

Compound I or a pharmaceutically acceptable salt thereof

Compound I has the chemical name 1- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl ] oxy ] methyl ] cyclopropylamine, which has the following structural formula:

in the application, all references to erlotinib refer to compound I.

Compound I can be administered in its free base form, as well as in the form of its salts, hydrates, and prodrugs, which convert in vivo to the free base form of compound I. For example, pharmaceutically acceptable salts of compound I are within the scope of the invention, which salts can be produced from various organic and inorganic acids according to methods well known in the art.

Further, the pharmaceutically acceptable salt thereof is a salt of compound I with any of the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, p-toluenesulfonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, dodecylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid; preferably in the form of the hydrochloride or maleate salt, more preferably the dihydrochloride salt.

In some embodiments, compound I is administered as the hydrochloride salt of compound I. In some embodiments, compound I is administered as the monohydrochloride salt of compound I. In some embodiments, compound I is administered as the dihydrochloride salt. In some embodiments, the compound I is administered as a crystalline form of the hydrochloride salt of compound I. In a particular embodiment, compound I dihydrochloride is administered as a crystalline form. In some embodiments, compound I is administered as the maleate salt of compound I.

Further, the amount of compound I or a pharmaceutically acceptable salt thereof administered in a combination may be determined by the severity of the disease, the response to the disease, any treatment-related toxicity, the age and health of the patient. In some embodiments, the daily dose of compound I, or a pharmaceutically acceptable salt thereof, administered is from 3 mg to 30 mg. In some embodiments, the daily dose of compound I, or a pharmaceutically acceptable salt thereof, administered is from 5mg to 20 mg. In some embodiments, the daily dose of compound I, or a pharmaceutically acceptable salt thereof, administered is from 8mg to 16 mg. In some embodiments, the daily dose of compound I or a pharmaceutically acceptable salt thereof administered is from 8mg to 14 mg. In a particular embodiment, the daily dose of compound I, or a pharmaceutically acceptable salt thereof, administered is 8 mg. In a particular embodiment, compound I or a pharmaceutically acceptable salt thereof is administered in a daily dose of 10 mg. In a particular embodiment, the daily dose of compound I, or a pharmaceutically acceptable salt thereof, administered is 12 mg.

Compound I or a pharmaceutically acceptable salt thereof may be administered one or more times daily. In some embodiments, compound I, or a pharmaceutically acceptable salt thereof, is administered once daily.

The method of administration of compound I can be determined comprehensively on the basis of the activity, toxicity of the drug, tolerance of the patient, and the like.

Preferably, compound I or a pharmaceutically acceptable salt thereof is administered in a spaced-apart manner. The intermittent administration includes a dosing period during which compound I or a pharmaceutically acceptable salt thereof may be administered one or more times per day and a rest period. For example, compound I or a pharmaceutically acceptable salt thereof is administered daily during a dosing period, then the administration is stopped for a period of time during a rest period, followed by a dosing period, then a rest period, and so on, which may be repeated multiple times. Wherein the ratio of the administration period to the withdrawal period in days is 2: 0.5-5, preferably 2: 0.5-3, more preferably 2: 0.5-2, and still more preferably 2: 0.5-1.

Further preferably, compound I or a pharmaceutically acceptable salt thereof is administered at intervals of one of the following: stopping the drug for 2 weeks after 2 weeks of continuous administration, for 1 week after 2 weeks of continuous administration, or for 2 days after 5 days of continuous administration; the intermittent administration mode may be repeated a plurality of times.

Further, the compound I or a pharmaceutically acceptable salt thereof, and the second therapeutic agent are administered simultaneously, or separately, in no sequential order;

further, the combination drug for breast cancer is a preparation suitable for any administration mode of oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, transbuccal, intranasal, inhalation, vaginal, intraocular, topical, subcutaneous, intraadipogenic, intraarticular, intraperitoneal or intrathecal administration.

Wherein, the compound I or the pharmaceutically acceptable salt thereof is preferably suitable for oral preparations, including tablets, capsules, powder, granules, dripping pills, pastes, powder and the like, and preferably tablets and capsules. Wherein the tablet can be common tablet, dispersible tablet, effervescent tablet, sustained release tablet, controlled release tablet or enteric coated tablet, and the capsule can be common capsule, sustained release capsule, controlled release capsule or enteric coated capsule. The oral preparation can be prepared by a conventional method using a pharmaceutically acceptable carrier well known in the art. Pharmaceutically acceptable carriers include fillers, absorbents, wetting agents, binders, disintegrants, lubricants, and the like. Fillers include starch, lactose, mannitol, microcrystalline cellulose, and the like; the absorbent comprises calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; wetting agents include water, ethanol, and the like; the binder comprises hypromellose, polyvidone, microcrystalline cellulose, etc.; the disintegrating agent comprises croscarmellose sodium, crospovidone, surfactant, low-substituted hydroxypropyl cellulose, etc.; the lubricant comprises magnesium stearate, pulvis Talci, polyethylene glycol, sodium laurylsulfate, silica gel micropowder, pulvis Talci, etc. The medicinal adjuvants also include colorant, sweetener, etc.

In one embodiment, the pharmaceutical composition is a solid formulation suitable for oral administration. The composition may be in the form of a tablet or capsule, for example. In a particular embodiment, the pharmaceutical composition is a capsule. In a particular embodiment of the invention, the pharmaceutically acceptable carrier of the oral solid formulation comprises mannitol, microcrystalline cellulose, hydroxypropylcellulose, magnesium stearate.

In certain particular embodiments, the administration is oral at a dose of 12mg once daily for 2 weeks with 1 week rest.

Combined pharmaceutical composition or pharmaceutical combination

In certain embodiments, compound I is combined with surgical resection and/or radiation therapy.

Each component of the pharmaceutical compositions described herein may optionally be used in combination with one or more pharmaceutically acceptable carriers, wherein the components may each independently, or some or all of them together contain a pharmaceutically acceptable carrier and/or excipient. The pharmaceutical compositions described herein may be formulated separately from each other, or some or all of them may be co-formulated. Preferably, the components of the pharmaceutical composition are formulated separately or each formulated into a suitable pharmaceutical composition. In some embodiments, the pharmaceutical compositions of the present application may be formulated as pharmaceutical compositions suitable for single or multiple administrations. In some particular embodiments, the pharmaceutical composition containing compound I or a pharmaceutically acceptable salt thereof may be selected from solid pharmaceutical compositions including, but not limited to, tablets or capsules.

The components of the pharmaceutical compositions of the present application may be administered each separately, or some or all of them may be co-administered. The components of the pharmaceutical compositions of the present application may be administered substantially simultaneously, or some or all of them may be administered substantially simultaneously.

The components of the pharmaceutical compositions of the present application may be administered independently of each other, or some or all of them together in a suitable route, including, but not limited to, oral or parenteral (by intravenous, intramuscular, topical or subcutaneous routes). In some embodiments, the components of the pharmaceutical compositions of the present application may be administered orally or parenterally, each independently, or some or all of them together, for example intravenously or intraperitoneally.

The components of the pharmaceutical compositions of the present application may each independently, or some or all of them together be in a suitable dosage form, including, but not limited to, tablets, troches, pills, capsules (e.g., hard capsules, soft capsules, enteric capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions and dosage forms for sustained release formulations for oral or non-oral administration.

In some embodiments of the present application, the pharmaceutical composition is a fixed combination. In some embodiments, the fixed combination is in the form of a solid pharmaceutical composition or a liquid pharmaceutical composition.

In some embodiments of the present application, the pharmaceutical composition is a non-fixed combination. In some embodiments, the second therapeutic agent and compound I in the non-fixed combination are each in the form of a pharmaceutical composition.

In some embodiments of the present application, compound I is administered simultaneously or sequentially with one or more second therapeutic agents. In certain embodiments, the one or more second therapeutic agents have been administered to the subject prior to administration of compound I or prior to combination with compound I. In certain embodiments, the one or more second therapeutic agents are administered to the subject again after administration of compound I or after combination with compound I. In certain embodiments, compound I has been administered to the subject prior to administration of the one or more second therapeutic agents or prior to combination with the one or more second therapeutic agents. In certain embodiments, compound I is administered to the subject again after administration of the one or more second therapeutic agents or after combination with the one or more second therapeutic agents. In some embodiments, compound I is administered to a subject sequentially after compound I and one or more second therapeutic agent compositions are administered to the subject. In certain embodiments, the one or more second therapeutic agents are not effective in treating cancer. In some embodiments, the second therapeutic agent is any anti-cancer agent described herein or known in the art.

In certain particular embodiments, compound I or a pharmaceutically acceptable salt thereof is used in combination with a CMF regimen. The method comprises the following steps: cyclophosphamide 600mg/m²Intravenous drip on day 1 and 8, or cyclophosphamide 100mg/m²Orally taken on day 1-14, methotrexate 30-40mg/m²Day 1, day 8 intravenous drip, fluorouracil 500mg/m²Intravenous drip on days 1 and 8; the compound I or the pharmaceutically acceptable salt thereof can be selected from oral administration with a dose of 3-30 mg once or more times per day, and is administered in a continuous administration mode for 2 weeks and a drug stopping mode for 1 week.

In certain particular embodiments, compound I or a pharmaceutically acceptable salt thereof is used in combination with the AC regimen. The method comprises the following steps: adriamycin 60mg/m²Day 1, intravenous drip, cyclophosphamide 600mg/m²Day 1, intravenous drip; the compound I or the pharmaceutically acceptable salt thereof can be selected from oral administration with a dose of 3-30 mg once or more times per day, and the administration is continued for 5 days and stopped for 2 days; one cycle of 21 days.

In certain specific embodiments, chemical combination is employedObject I or a pharmaceutically acceptable salt thereof, in combination with an AC-T combination radiotherapy regimen. The method comprises the following steps: adriamycin 60mg/m²Day 1, intravenous drip, cyclophosphamide 600mg/m²Intravenous drip on day 1, paclitaxel 175mg/m²Intravenous drip is carried out on days 1-5; the compound I or the pharmaceutically acceptable salt thereof can be selected from oral administration with a dose of 3-30 mg once or more times per day, and the administration is continued for 5 days and stopped for 2 days; one cycle of 21 days.

In certain particular embodiments, compound I or a pharmaceutically acceptable salt thereof is used in combination with the NA regimen. The method comprises the following steps: vinorelbine 25mg/m²Intravenous drip on days 1 and 8, doxorubicin 25mg/m²And intravenous drip on days 1 and 8. The compound I or the pharmaceutically acceptable salt thereof can be selected from oral administration with a dose of 3-30 mg once or more times per day, and the administration is continued for 5 days and stopped for 2 days; one cycle of 21 days.

In certain particular embodiments, compound I or a pharmaceutically acceptable salt thereof is used in combination with a CAF regimen. The method comprises the following steps: fluorouracil 500mg/m²Intravenous drip on days 1 and 8, doxorubicin 50mg/m²Day 1, intravenous drip, cyclophosphamide 600mg/m²Day 1, intravenous drip; the compound I or the pharmaceutically acceptable salt thereof can be selected from oral administration with a dose of 3-30 mg once or more times per day, and the administration is continued for 5 days and stopped for 2 days; one cycle of 21 days.

In certain particular embodiments, compound I or a pharmaceutically acceptable salt thereof is used in combination with an MFL regimen. The method comprises the following steps: mitoxantrone 12mg/m²Day 1, intravenous drip; aldehyde hydrofolic acid 300mg/m²Intravenous drip on day 1-3, fluorouracil 350mg/m²And intravenous drip on days 1-3. The compound I or the pharmaceutically acceptable salt thereof can be selected from oral administration with a dose of 3-30 mg once or more times per day, and is administered in an administration mode of 2 weeks of continuous administration and 1 week of drug stopping; one cycle of 21 days.

In certain particular embodiments, compound I or a pharmaceutically acceptable salt thereof is used in combination with a PA regimen. The method comprises the following steps: paclitaxel 35-225 mg/m²Day 1, intravenous drip, doxorubicin 60mg/m²Day 1, intravenous injection; associationThe compound I or the pharmaceutically acceptable salt thereof can be selected from oral administration with a dose of 3-30 mg once or more times per day, and the administration is continued for 5 days and stopped for 2 days; one cycle of 21 days.

In certain specific embodiments, compound I or a pharmaceutically acceptable salt thereof is used in combination with a CAP combination radiation therapy regimen. The method comprises the following steps: cyclophosphamide 500mg/m²Intravenous injection on days 1 and 8, doxorubicin at 40mg/m²Day 2, intravenous drip, cisplatin 100mg/m²On day 3, the combination compound I or a pharmaceutically acceptable salt thereof may be selected from, but not limited to, oral administration at a dose of 3-30 mg once or more times per day, with 5 consecutive days of administration and 2 days of rest; one cycle of 21 days.

In certain particular embodiments, compound I or a pharmaceutically acceptable salt thereof is used in combination with a GC regimen. The method comprises the following steps: gemcitabine 800-1000 mg/m²Day 1,8 intravenous drip, cisplatin 30mg/m²Day 1, day 8; the combination compound I or the pharmaceutically acceptable salt thereof can be selected from oral administration with a dose of 3-30 mg once or more times per day, wherein the administration lasts for 5 days and is stopped for 2 days; one cycle of 28 days.

In certain particular embodiments, compound I or a pharmaceutically acceptable salt thereof is used in combination with an XD regimen. The method comprises the following steps: docetaxel 75mg/m²The capecitabine is administrated by intravenous drip on day 1, 1275mg/d of capecitabine and oral administration on days 1-14; the combination compound I or the pharmaceutically acceptable salt thereof can be selected from oral administration with a dose of 3-30 mg once or more times per day, wherein the administration lasts for 5 days and is stopped for 2 days; one cycle of 21 days.

In some embodiments, a kit of pharmaceutical compositions for treating breast cancer is also provided, which comprises (a) a first pharmaceutical composition comprising a small molecule targeted anti-tumor drug as an active ingredient; and (b) a second pharmaceutical composition comprising compound I as an active ingredient. In some embodiments, a kit of pharmaceutical compositions for treating breast cancer is also provided, which comprises (a) a first pharmaceutical composition comprising a macroantibody drug as an active ingredient; and (b) a second pharmaceutical composition comprising compound I as an active ingredient. In some embodiments, there is also provided a kit of pharmaceutical compositions for treating breast cancer, comprising (a) a first pharmaceutical composition comprising an immunotherapeutic agent as an active ingredient; and (b) a second pharmaceutical composition comprising compound I as an active ingredient. In some embodiments, there is also provided a kit of pharmaceutical compositions for treating breast cancer, which comprises (a) a first pharmaceutical composition comprising an endocrine drug as an active ingredient; and (b) a second pharmaceutical composition comprising compound I as an active ingredient.

Compared with the prior art, the invention has the beneficial effects that: the compound I or the pharmaceutically acceptable salt thereof and the second therapeutic agent are combined for application, and the compound I or the pharmaceutically acceptable salt thereof can obviously enhance the killing effect of medicaments, particularly chemotherapeutic medicaments, on breast cancer, enhance the curative effect and reduce the dosage of the chemotherapeutic medicaments, thereby reducing the side effect. The invention provides a new idea for treating the breast cancer, in particular to the second-line treatment of the breast cancer which fails to be treated by the first-line radiotherapy and chemotherapy medicaments.

Definitions and explanations

Unless otherwise indicated, the following terms used in the specification and claims shall have the following meanings for the purposes of this application.

As used herein, the term "treating" generally refers to obtaining a desired pharmacological and/or physiological effect. The effect may be therapeutic in terms of partially or completely stabilizing or curing the disease and/or side effects due to the disease. As used herein, "treatment" encompasses any treatment of a disease in a subject, including: (a) inhibiting the symptoms of the disease, i.e., arresting its development; or (b) alleviating a symptom of the disease, i.e., causing regression of the disease or symptom.

As used herein, the term "treatment failure" refers to intolerance of toxic side effects, disease progression during treatment, or relapse after treatment is concluded.

By "administering" is meant physically introducing a composition comprising a therapeutic agent to a subject using any of a variety of methods and delivery systems known to those skilled in the art. Routes of administration include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal, or other parenteral routes of administration, for example by injection or infusion. The phrase "parenteral administration" as used herein refers to modes of administration other than enteral and topical administration, typically by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion, and in vivo electroporation. In certain embodiments, the drug is administered by a non-parenteral route, and in certain embodiments, orally. Other non-parenteral routes include topical, epidermal or mucosal routes of administration, e.g., intranasally, vaginally, rectally, sublingually or topically. Administration may also be performed, for example, once, multiple times, and/or over one or more extended periods of time.

"subject" includes any human or non-human animal. The term "non-human animal" includes, but is not limited to, vertebrates such as non-human primates, sheep, dogs, and rodents such as mice, rats, and guinea pigs. In certain embodiments, the subject is a human. The terms "subject", "patient" and "patient" are used interchangeably herein in certain contexts.

As used herein, the term "antibody" refers to a binding protein having at least one antigen binding domain. The antibodies and fragments thereof of the present application can be whole antibodies or any fragment thereof. Thus, the antibodies and fragments of the present application include monoclonal antibodies or fragments thereof and antibody variants or fragments thereof, as well as immunoconjugates. Examples of antibody fragments include Fab fragments, Fab 'fragments, f (ab)' fragments, Fv fragments, isolated CDR regions, single chain Fv molecules (scFv), and other antibody fragments known in the art. Antibodies and fragments thereof can also include recombinant polypeptides, fusion proteins, and bispecific antibodies. The anti-PD-L1 antibodies and fragments thereof disclosed herein may be of the IgG1, IgG2, IgG3, or IgG4 isotype.

The term "monoclonal antibody" ("mAb") refers to an antibody molecule of a single molecular composition. Monoclonal antibody compositions showA single binding specificity and affinity for a particular epitope, or in the case of a bispecific monoclonal antibody, a dual binding specificity for two different epitopes, is shown. mabs are an example of an isolated antibody. Mabs can be produced by hybridoma techniques, recombinant techniques, transgenic techniques, or other techniques known to those of skill in the art. Examples of isolated monoclonal antibodies include, but are not limited to, Nivolumab

Pabolizumab (Pembrolizumab)

Durvalumab, Avelumab, Terepriamab (JS-001, Juniperus organism), Cedilimab (Sintilimab, IBI308, Nedar organism), Carrilizumab (SHR-1210, Camrelizumab, Henry medicine, see CN105026428B or WO2015085847A1), Tereli monoclonal antibody (BGB-A317, Baiji Shenzhou), Jennuomab (GB226, Jia and biol.), Lizhuzumab (LZM009, Lizhu pharmaceutical), HLX-10 (Rehong Han), BAT-1306 (Baiotai), HX008 (HX AK103, Kangfang organism/Han midbody), AK104 (Zhongshan Kangfang), CS1003 (Kishiyayao pharmaceutical industry), SCTP-I10A (Shenzhou cell era), F (Shandong Xinnanyao pharmaceutical industry/SG), SG001 (GLS-010 (Glen Jian Yam pharmaceutical industry), Atiza-Z (Atiza), Sammuzu pharmaceutical industry) (Tanza), Tanzozu (Tanzu-K) and Tanzu (Tanzu), Tanzu

Roche), Avelumab (

Merck/fevere), Durvalumab (

Aslicarban) KL-A167 (Konlun pharmaceutical industry), SHR-1316 (Henry medicine), BGB-333 (Baiji Shenzhou), JS003 (Junshi organism), STI-A1014(ZKAB0011, Megaku pharmaceutical industry), KN035 (kang Ning Jie Rui/Cidi), MSB2311 (Meubo Si organism), HLX-20 (Fuhong Hanlin), CS-1001 (Kishi pharmaceutical industry), and the like.

An "antigen-binding portion" (also referred to as an "antigen-binding fragment") of an antibody refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen bound by an intact antibody.

"programmed death receptor-1 (PD-1)" means an immunosuppressive receptor belonging to the CD28 family. PD-1 is expressed predominantly on previously activated T cells in vivo and binds to both ligands PD-L1 and PD-L2. The term "PD-1" as used herein includes variants, homologs, and species homologs of human PD-1(hPD-1), hPD-1, and analogs having at least one common epitope with hPD-1.

"programmed death ligand-1 (PD-L1)" is one of two cell surface glycoprotein ligands for PD-1 (the other being PD-L2) that down-regulates T cell activation and cytokine secretion upon binding to PD-1.

A "recurrent" cancer is one that regenerates at the primary site or a distant site in response to an initial treatment (e.g., surgery). A "locally recurrent" cancer is one that occurs at the same location after treatment as a previously treated cancer.

A "non-resectable" cancer is one that cannot be removed by surgery.

"metastatic" cancer refers to cancer that spreads from one part of the body (e.g., the lungs) to another part of the body.

The use of alternatives (e.g., "or") should be understood to refer to either, both, or any combination of alternatives. The indefinite articles "a" or "an" as used herein shall be understood to mean "one or more" of any listed or enumerated component.

The term "pharmaceutically acceptable" is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" includes salts of the base ion with the free acid or salts of the acid ion with the free base, including, for example, hydrochloride, hydrobromide, nitrate, sulfate, phosphate, formate, acetate, trifluoroacetate, fumarate, oxalate, maleate, citrate, succinate, methanesulfonate, benzenesulfonate or p-methylbenzenesulfonate, preferably hydrochloride, hydrobromide, sulfate, formate, acetate, trifluoroacetate, fumarate, maleate, methanesulfonate, p-methylbenzenesulfonate, sodium salt, potassium salt, ammonium salt, amino acid salt and the like. In the present application, when forming a pharmaceutically acceptable salt, the molar amount of free acid to base ion is about 1:0.5 to 1:5, preferably 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, or 1: 8. In the present application, when forming a pharmaceutically acceptable salt, the molar ratio of the free base to the acid ion is about 1:0.5 to 1:5, preferably 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7 or 1: 8.

The term "fixed combination" means that the active ingredients (e.g. the chemotherapeutic drug or compound I) are administered to a subject simultaneously in a fixed total dose or dose ratio, or in the form of a single entity, pharmaceutical composition or formulation.

The term "non-fixed combination" means that two or more active ingredients are administered to a subject as separate entities (e.g. pharmaceutical compositions, formulations) simultaneously, concurrently or sequentially and without specific time constraints, wherein the active ingredients are administered to the subject at a therapeutically effective amount level. An example of an unfixed combination is cocktail therapy, e.g. 3 or more active ingredients are administered. In a non-fixed combination, the individual active ingredients may be packaged, sold or administered as a completely separate pharmaceutical composition. The term "non-fixed combination" also includes the use of "fixed combinations" in between, or "fixed combinations" in combination with, any one or more of the individual entities of the active ingredients.

As used herein, "in combination" or "in combination" means that two or more active substances may be administered to a subject together in a mixture, simultaneously as a single formulation, or sequentially in any order as a single formulation.

The term "pharmaceutical composition" refers to a mixture of one or more of the active ingredients of the present application (e.g., a chemotherapeutic second therapeutic agent or compound I) or a pharmaceutical combination thereof with pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate administration of the compounds of the present application or pharmaceutical combinations thereof to a subject.

"clinical benefit" in the present application includes, but is not limited to: clinical patients have prolonged Progression Free Survival (PFS), prolonged Overall Survival (OS), improved Objective Remission Rate (ORR), improved Disease Control Rate (DCR), reduced number and/or extent of adverse effects, decreased distant metastasis rates, decreased local control rates, and the like. In particular, in some particular embodiments of the present application, in particular embodiments of the present application, the rate of objective remission in clinical trials in human patients with breast cancer is above about 10%, preferably above about 15%, further preferably above about 20%, more preferably above about 30%, in particular above 35%; the disease control rate of the patient is 50% or more, preferably about 60% or more, more preferably about 70% or more, still more preferably about 80% or more, and particularly 90% or more.

Detailed Description

The following is a further illustration of the invention with reference to specific examples and experimental examples. These examples are only illustrative and not intended to limit the scope of the present invention. The experimental methods of the following examples, in which the specific experimental conditions are not specified, were carried out according to the usual conditions.

Combination administration of apratinib and capecitabine in patients with pathologically confirmed recurrent or metastatic triple negative breast cancer with measurable lesions and disease progression after at least prior treatment with anthracyclines and/or taxoids. The specific administration method is as follows:

capecitabine tablets: 1000mg/m²2 times daily within 30min after meal, and continuously orally taking for 2 weeks and stopping for 1 week, namely 3 weeks (21 days) is a treatment period until the disease progresses or adverse reactions are not tolerable;

anrotinib hydrochloride capsules: before breakfast, Arotinib hydrochloride capsule is taken on empty stomach 1 time daily, 1 granule (10mg) each time. Oral administration is continued for 2 weeks and 1 week, i.e., 3 weeks (21 days) as a treatment cycle until disease progression or adverse effects are not tolerated. If the time for next medication is shorter than 12 hours, the medicine is not taken again.

Observation indexes are as follows: objective Remission Rate (ORR), Progression Free Survival (PFS), Overall Survival (OS), quality of life (Qol), Disease Control Rate (DCR), safety index.

By implementing the clinical trial study, 8 patients were enrolled, 1 patient was dropped, and the efficacy evaluation result of the combination group was 14.3% (1 person) in Objective Remission Rate (ORR), wherein 0 patient in Complete Remission (CR), 1 patient in Partial Remission (PR), 4 patients with stable disease State (SD), 2 patients in disease Progression (PD), 71.4% in Disease Control Rate (DCR), and 4 months in median PFS, and clinical benefit of the anirtinib combined with capecitabine was found, and the clinical benefit was excellent in clinical safety and tolerability.

Among these, cases of patients with Partial Remission (PR) are as follows:

patients, women, pathological/clinical diagnosis of left breast invasive ductal carcinoma stage IV, left breast improvement radical surgery, radiotherapy and chemotherapy, and lung metastasis.

Treatment with fulvestrant + vinorelbine was performed between 28 months 11 and 5 months 2019 in 2018 and evaluated as SD.

Patients began the combined administration of aritinib and capecitabine in 6 months of 2019. The specific administration method is as follows:

capecitabine tablets: 1000mg/m²2 times daily within 30min after meal, and continuously orally taking for 2 weeks and stopping for 1 week, namely 3 weeks (21 days) is a treatment period until the disease progresses or adverse reactions are not tolerable;

anrotinib hydrochloride capsules: before breakfast, Arotinib hydrochloride capsule is taken on empty stomach 1 time daily, 1 granule (10mg) each time. Oral administration is continued for 2 weeks and 1 week, i.e., 3 weeks (21 days) as a treatment cycle until disease progression or adverse effects are not tolerated. If the time for next medication is shorter than 12 hours, the medicine is not taken again.

Prior to co-administration, CT scans showed that the sum of measurable target lesion diameters was 99 mm. After each treatment cycle, CT scan was performed immediately, and the results are shown in table 1 below, the subject had taken 6 cycles at present, after the doctor's assessment, the patient was advised to continue taking the drug, and the overall tolerance was good during the treatment period.

TABLE 1

Claims (10)

1. The combined use of the compound I or the pharmaceutically acceptable salt thereof and a second therapeutic agent, which is one or more of a chemotherapeutic drug and/or a small molecule targeted antitumor drug and/or a macromolecular antibody drug and/or an immunotherapy drug and/or an endocrine drug,

2. the use of claim 1, wherein the breast cancer is non-invasive breast cancer, early invasive breast cancer, invasive specific breast cancer, invasive non-specific breast cancer; or the breast cancer is a small tubular carcinoma, a classical lobular carcinoma, an invasive squamous carcinoma, a neuroendocrine carcinoma and a mucinous carcinoma, an apocrine adenocarcinoma and a pleomorphic lobular carcinoma, a medullary carcinoma, a anabolic carcinoma, or an adenoid cystadenocarcinoma; or the breast cancer is luminal A type, luminal B type, HER-2 overexpression type, basal cell type, triple negative breast cancer, normal breast type breast cancer.

3. Use according to any one of claims 1 to 2, wherein the breast cancer is primary breast cancer and/or secondary breast cancer and/or breast cancer that has failed prior therapy, preferably the breast cancer is breast cancer that has failed surgery and/or radiotherapy and/or a chemotherapeutic agent and/or endocrine therapy and/or immunotherapy and/or molecular targeted therapy, advanced and/or metastatic triple negative breast cancer.

4. The use according to any one of claims 1 to 3, wherein the chemotherapeutic agent is one or more of taxanes, platinum complexes, pyrimidine antagonists, camptothecins and derivatives thereof, anthracyclines, podophyllides;

the taxane is one or more of paclitaxel, albumin-bound paclitaxel and docetaxel;

the vinblastine antineoplastic agent is selected from one or more of vinblastine, vincristine, vindesine and vinorelbine, vinblastine and catharanthine;

the platinum complex is selected from one or more of miriplatin, cisplatin, carboplatin, dicycloplatin, nedaplatin, oxaliplatin, leplatin, triplatin tetranitrate, phenanthroline, picoplatin and satraplatin;

the pyrimidine antagonist is selected from one or more of cytarabine, azacitidine, ancitabine, capecitabine, gemcitabine, fluorouracil, difurofluorouracil, doxifluridine, trifluridine, tegafur, carmofur and eufordine;

the camptothecin and the derivatives thereof are one or more of camptothecin, hydroxycamptothecin, irinotecan and topotecan;

the anthracycline compound is one or more of epirubicin, adriamycin, daunorubicin, pirarubicin, amrubicin, idarubicin, mitoxantrone, aclarubicin, valrubicin, zorubicin, pixantrone, pyrarubicin, and liposomal doxorubicin;

the podophyllum can be one or more of etoposide, teniposide, and epipodophyllotoxin glucopyranoside;

the chemotherapy medicine also comprises bleomycin, pingyangmycin, pellomycin, mitomycin, actinomycin D, amiloride, eribulin, lycium barbarum polysaccharide, methotrexate, thioguanine, pemetrexed, bendamustine, temozolomide, Sapacitapine, plinabulin, trooshusufan,¹⁵³One or more of Sm-EDTMP, tegafur and encequidar.

5. The use of any one of claims 1-3, wherein the small molecule targeted antineoplastic agent is lenatinib, lapatinib, sunitinib, sorafenib, endostatin, gefitinib, erlotinib, Iniparib, Veliparib, Olaparib, palbociclib, celecoxib, aspirin, rapamycin, imatinib, Tipifarnib, fraxidil, apartinib, aflibercept, afatinib, crizotinib, ceritinib, vemurafenib, dabrafenib, cabozertinib, dactinotinib, oxirtitinib, erlotinib, brigatinib, sorafenib, temotinib, voritinib, furazartinib, emtinib, dasatinib, tematinib, itatinib, itaconitinib, piriritinib, erlotinib, gefitinib, sorafenib, erlotinib, gefitinib, sorafenib, gefitinib, ge, Acertinib, cobicistinib, acartinib, Famitinib, masitinib, ibutinib, Rociletinib, nidanib, lenalidomide, nilotinib, bosutinib, Secardib, pazopanib, trabectinib, regorafenib, fuquintinib, cedanib, bortezomib, carfilzomib, ixazom, LOXO-292, Vorolanib, Bemcentinib, Capimatinib, Entretinib, TAK-931, ALT-803, Famitinib L-late, LTT-462, BLU-667, Ningetinib, Poziotiib, DS-1205, Capivastib, SH-1028, metformin, Seliciclib, OSE-2101, APL-101, Bertorib, Leibriib 1003, Szertib-4201028, Skibbib-1028, Skibbiib-358, Skyibb-2818, Torultibiib-1028-358, Skyibb-358, Skyibobrevib, Skyibb-358, Skyibb, Skyibobrevibratib, Skyi-358, Skyibb, Skyibobrevibratibb, Skyibb, Skyibobrevisburticib, S, Molibrescib, CC-223, Rivoceranib, CK-101, LXH-254, Simotiib, GSK-3368715, TAS-0728, Masitinib, Tepotiniib, HS-10296, AZD-4547, Merestinib, Olaptedepegol, Galunertinib, ASN-003, Gedatolisib, Defectinib, Lazertinib, CKI-27, S-49076, BPI-9016M, RF-A-089, RMC-4630, AZD-3759, Antroquinonol, SAF-189S, AT-101, TTI-101, Naputinib, LNP-3794, HH-SCC-244, ASK-120067, CT-707, Epitinib Succinate, Tesevatinib, SPH-1188-11, BPI-15000, Copalisib, Niraparib, Talazolepib Tosylate, DV-281, Siremaddin, Telaglenastat, MP-0250, GLG-801, ABTL-0812, Bortezomib, Panobinostat, Tucidinostat, Vorinostat, Resminostat, Epacadostat, Tazemetostat, Entinostat, Mocetinostat, Quisinostat, LCL-161, KML-001.

6. The use of any one of claims 1-3, wherein the macromolecular antibody drug is bevacizumab, ramucirumab, pertuzumab, trastuzumab-Emtansine, cetuximab, nimotuzumab, panitumumab, matuzumab, nimotuzumab, Dinutuximab, rituximab, temitumomab, ofatumumab, obituzumab ozitumumab, alemtuzumab, daratuzumab, gemtuzumab getuzumab, rituximab, obizumab ozotan, obikunituzumab, brazimab, tefuruzumab, terlipril, certolizumab, chariluzumab, tirilel strain, ibrituril strain, AK105 jikunmumab, HLX-10, BAT-1306, AK103, BAT 104, CS1003, SCT-I10A, SG 520, atlizumab, or giuzumab, Any one or more of Avelumab, Durvallub, KL-A167, SHR-1316, BGB-333, JS003, STI-A1014, KN035, MSB2311, HLX-20, CS-1001, ipilimumab, teximumab, AGEN-1884, BMS-986249, BMS-986218, AK-104, IBI 310.

7. The use according to any one of claims 1 to 3, wherein the immunotherapeutic agent is one or more of interferon alpha, interferon alpha-1 b, interferon alpha-2 b, interleukin, tumor necrosis factor, anti-breast cancer RNA, Bordeaux, LAK cells, sirolimus, everolimus, temsirolimus, diphospholimus, temsirolimus; the endocrine drug is one or more of tamoxifen, amfenadone, megestrol or megestrol.

8. The use according to any one of claims 1 to 3, wherein the second therapeutic agent is one, two or three of cyclophosphamide, methotrexate and fluorouracil;

or, the second therapeutic agent is one or both of doxorubicin and cyclophosphamide;

alternatively, the second therapeutic agent is one, two or three of doxorubicin, cyclophosphamide and paclitaxel;

alternatively, the second therapeutic agent is one or both of vinorelbine and doxorubicin;

or, the second therapeutic agent is one, two or three of fluorouracil, doxorubicin and cyclophosphamide;

or the second therapeutic agent is one, two or three of mitoxantrone, aldehydic acid and fluorouracil;

alternatively, the second therapeutic agent is one or both of paclitaxel and doxorubicin;

alternatively, the second therapeutic agent is one, two or three of cyclophosphamide, doxorubicin and cisplatin;

alternatively, the second therapeutic agent is one or both of gemcitabine and cisplatin;

alternatively, the second therapeutic agent is one or both of docetaxel and capecitabine.

9. The use according to any one of claims 1 to 8, wherein the daily dose for the administration of compound I or a pharmaceutically acceptable salt thereof is from 3 mg to 30mg, preferably from 5mg to 20 mg, more preferably from 8mg to 16 mg, even more preferably from 8mg to 14 mg, most preferably 8mg, 10mg, 12 mg.

10. The use according to any one of claims 1 to 9, wherein compound I or a pharmaceutically acceptable salt thereof is administered at intervals between an administration period and a rest period; the ratio of the administration period to the withdrawal period in days is preferably 2: 0.5-5, more preferably 2: 0.5-3, even more preferably 2: 0.5-2, and still more preferably 2: 0.5-1; as a further preferred mode of administration at intervals, one of the following modes is used: stopping the drug for 2 weeks after 2 weeks of continuous administration, for 1 week after 2 weeks of continuous administration, or for 2 days after 5 days of continuous administration; the intermittent administration mode may be repeated a plurality of times.