Quinoline derivatives for combination therapy of small cell lung cancer

Abstract

A combination pharmaceutical composition for treating small cell lung cancer comprising: (i) Compound I or a pharmaceutically acceptable salt thereof; and (ii) at least one second therapeutic agent, wherein Compound I has the chemical name 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl]cyclopropylamine.

Description

[Technical Field]

[0001] The present application belongs to the pharmaceutical field and relates to the use of quinoline derivatives for antitumor purposes. Specifically, the present application relates to the use of quinoline derivatives for combination therapy of small cell lung cancer. [Background technology]

[0002] Small cell lung cancer (SCLC) is the most malignant type of lung cancer, characterized by rapid progression, early metastasis, and a high recurrence rate. It accounts for approximately 15-20% of new lung cancers, and its occurrence is closely related to long-term smoking. SCLC is highly invasive, has a low early detection rate, and lacks effective treatment, resulting in a poor prognosis. Untreated SCLC patients have a median survival time from diagnosis of only 2-4 months, with a 5-year survival rate of less than 5%.

[0003] The SCLC staging system established by the Veterans Administration Lung Study Group (VALG) has been widely used due to its ease of use. This system broadly classifies SCLC into limited disease (LD) and extensive disease (ED). The former refers to disease limited to one side of the pleural cavity, including metastases to the contralateral mediastinum and bilateral supraclavicular lymph nodes, ipsilateral pleural effusion, and a fully tolerated radiation field. Extensive disease is defined as disease extending beyond these limits. The former accounts for approximately 30–40% of cases. The median survival time (MST) for untreated SCLC patients is only 2–4 months. After treatment, the MST for limited-stage patients is approximately 15–20 months, while the MST for extensive-stage patients is 8–13 months. Compared to other types of lung cancer, SCLC is highly sensitive to chemotherapy and radiation therapy. However, high rates of recurrence and drug resistance mean that treatment remains challenging. Summary of the Invention [Problem to be solved by the invention]

[0004] In one aspect of the present application, there is provided a combination pharmaceutical composition for treating small cell lung cancer, comprising: (i) Compound I or a pharmaceutically acceptable salt thereof; and (ii) at least one second therapeutic agent.

[0005] In another aspect of the present application, there is further provided a use of the pharmaceutical composition for manufacturing a medicament for treating small cell lung cancer. The present application also provides a use of the pharmaceutical composition for treating small cell lung cancer.

[0006] In a further aspect, the present application further provides a method for treating small cell lung cancer, comprising administering to a patient a pharmaceutical composition of the present application, the pharmaceutical composition comprising (i) Compound I or a pharmaceutically acceptable salt thereof, and (ii) at least one second therapeutic agent. [Means for solving the problem]

[0007] In one aspect of the present application, [ka] The present invention provides a combination pharmaceutical composition for treating small cell lung cancer, comprising (i) Compound I or a pharmaceutically acceptable salt thereof, and (ii) at least one second therapeutic agent.

[0008] In some embodiments of the present application, the pharmaceutical composition comprises (i) a pharmaceutical composition of Compound I or a pharmaceutically acceptable salt thereof, and (ii) a pharmaceutical composition of at least one second therapeutic agent. In some embodiments, a pharmaceutical composition for treating small cell lung cancer is provided, comprising (i) Compound I or a pharmaceutically acceptable salt thereof, and (ii) at least one chemotherapeutic agent, optionally in combination with radiation therapy. In some embodiments, a pharmaceutical composition for treating small cell lung cancer is provided, comprising (i) Compound I or a pharmaceutically acceptable salt thereof, and (ii) at least one small molecule targeted anti-tumor agent, optionally in combination with radiation therapy. In some embodiments, a pharmaceutical composition for treating small cell lung cancer is provided, comprising (i) Compound I or a pharmaceutically acceptable salt thereof, and (ii) at least one immunotherapeutic agent, optionally in combination with radiation therapy. In some embodiments, a pharmaceutical composition for treating small cell lung cancer is provided, comprising: (i) Compound I or a pharmaceutically acceptable salt thereof; and (ii) at least one large molecule antibody drug, optionally in combination with radiation therapy.

[0009] In certain embodiments, a pharmaceutical composition for treating small cell lung cancer is provided, comprising (i) Compound I or a pharmaceutically acceptable salt thereof, and (ii) a fluoropyrimidine derivative, optionally in combination with radiation therapy. In certain embodiments, a pharmaceutical composition for treating small cell lung cancer is provided, comprising (i) Compound I or a pharmaceutically acceptable salt thereof, and (ii) tegafur, gimeracil, and oteracil potassium, optionally in combination with radiation therapy. In certain embodiments, a pharmaceutical composition for treating small cell lung cancer is provided, comprising (i) Compound I or a pharmaceutically acceptable salt thereof, and (ii) a podophyllum system and at least one platinum-based drug, optionally in combination with radiation therapy. In certain embodiments, a pharmaceutical composition for treating small cell lung cancer is provided, comprising (i) Compound I or a pharmaceutically acceptable salt thereof, and (ii) etoposide and at least one platinum-based drug, optionally in combination with radiation therapy. In certain embodiments, a pharmaceutical composition for treating small cell lung cancer is provided, comprising (i) Compound I or a pharmaceutically acceptable salt thereof, and (ii) etoposide and cisplatin, optionally in combination with radiation therapy. In certain embodiments, a pharmaceutical composition for treating small cell lung cancer is provided, comprising (i) Compound I or a pharmaceutically acceptable salt thereof, and (ii) etoposide and carboplatin, optionally in combination with radiation therapy. In certain embodiments, a pharmaceutical composition for treating small cell lung cancer is provided, comprising (i) Compound I or a pharmaceutically acceptable salt thereof, and (ii) etoposide and lobaplatin, optionally in combination with radiation therapy. In certain embodiments, a pharmaceutical composition for treating small cell lung cancer is provided, comprising (i) Compound I or a pharmaceutically acceptable salt thereof, and (ii) an anti-PD-1 antibody, optionally in combination with radiation therapy. In some specific embodiments, a pharmaceutical composition for treating small cell lung cancer is provided, comprising: (i) Compound I or a pharmaceutically acceptable salt thereof; and (ii) sintilimab, optionally in combination with radiation therapy.In certain embodiments, there is provided a pharmaceutical composition for treating small cell lung cancer, comprising (i) Compound I or a pharmaceutically acceptable salt thereof, and (ii) a camptothecin-based drug, optionally in combination with radiation therapy. In certain embodiments, there is provided a pharmaceutical composition for treating small cell lung cancer, comprising (i) Compound I or a pharmaceutically acceptable salt thereof, and (ii) irinotecan, optionally in combination with radiation therapy.

[0010] In another aspect of the present application, there is provided a use of a 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, for the manufacture of a medicament for the treatment of small cell lung cancer. The present application further provides a use of the pharmaceutical composition for the treatment of small cell lung cancer.

[0011] In a further aspect, the present application further provides a method for treating small cell lung cancer, comprising administering to a patient a pharmaceutical composition of the present application, the pharmaceutical composition comprising (i) Compound I or a pharmaceutically acceptable salt thereof, and (ii) at least one second therapeutic agent.

[0012] The present application provides a method for treating a subject suffering from small cell lung cancer. In some embodiments of the present application, the subject has undergone surgery, chemotherapy, and / or radiation therapy. In some specific embodiments, the subject has experienced disease progression after achieving complete remission with surgery, chemotherapy, and / or radiation therapy. In some specific embodiments, the subject has not achieved complete or partial remission after surgery, chemotherapy, and / or radiation therapy.

[0013] The present application provides a method for treating small cell lung cancer, comprising administering Compound I or a pharmaceutically acceptable salt thereof and at least one second therapeutic agent to a patient in need of treatment. In some embodiments of the present application, a method for treating chemotherapy-naive small cell lung cancer is provided, comprising administering Compound I or a pharmaceutically acceptable salt thereof and at least one second therapeutic agent to a patient in need of treatment. In some embodiments of the present application, a method for treating small cell lung cancer that has progressed or recurred after at least one chemotherapy is provided, comprising administering Compound I or a pharmaceutically acceptable salt thereof and at least one second therapeutic agent to a patient in need of treatment. In some embodiments of the present application, a method for treating small cell lung cancer that has undergone at least two chemotherapy regimens is provided, comprising administering Compound I or a pharmaceutically acceptable salt thereof and at least one second therapeutic agent to a patient in need of treatment. In one embodiment of the present application, a method for treating refractory or recurrent small cell lung cancer is provided, comprising administering Compound I or a pharmaceutically acceptable salt thereof and at least one second therapeutic agent to a patient in need of treatment. In some embodiments, Compound I or a pharmaceutically acceptable salt thereof and at least one second therapeutic agent are used in combination to treat primary small cell lung cancer or secondary small cell lung cancer. In some embodiments, the small cell lung cancer is chemotherapy-intolerant small cell lung cancer. In some embodiments of the present application, the subject has not received systemic chemotherapy. In some embodiments, the subject has received surgery, radiation therapy, induction chemotherapy, concurrent chemotherapy, and / or adjuvant chemotherapy. In some specific embodiments, the subject has not received systemic chemotherapy but has received surgery, radiation therapy, induction chemotherapy, concurrent chemotherapy, and / or adjuvant chemotherapy. In some specific embodiments, the subject has experienced disease progression again after achieving complete remission with surgery, radiation therapy, induction chemotherapy, concurrent chemotherapy, and / or adjuvant chemotherapy. In some specific embodiments, the subject does not achieve complete or partial remission after surgery, radiation therapy, induction chemotherapy, concurrent chemotherapy, and / or adjuvant chemotherapy.In certain embodiments, the subject has metastasized cancer following surgical treatment, radiation therapy, induction chemotherapy, concomitant chemotherapy, and / or adjuvant chemotherapy.

[0014] The administration method may be determined comprehensively based on the activity, toxicity, tolerability, etc. of the drug. In some embodiments of the present application, in the above-mentioned uses or treatment methods, the second therapeutic agent may be administered, but is not limited to, once daily (qd), once every other day (qod), once every three days (q3d), once every four days (q4d), once every five days (q5d), once a week (q1w), once every two weeks (q2w), once every three weeks (q3w), or once every four weeks (q4w), or twice a day (bid), twice a week (biw), three times a day (tid), four times a day (qid), etc. In some embodiments of the present application, in the above-mentioned uses or treatment methods, the second therapeutic agent may be administered by interval dosing. The interval administration may include an administration period and a rest period, e.g., administering the second therapeutic agent daily during the administration period, followed by a rest period during which administration is discontinued, followed by an administration period, followed by a rest period, and may be repeated multiple times.

[0015] In some embodiments of the present application, the uses or treatments include, but are not limited to, administering Compound I or a pharmaceutically acceptable salt thereof at a dose of 6 mg, 8 mg, 10 mg, or 12 mg once daily on a two week on, one week off regimen, and / or two week on, two weeks off regimen.

[0016] In some embodiments, the second therapeutic agent and Compound I or a pharmaceutically acceptable salt thereof may have the same or different treatment cycles. In some particular embodiments, the second therapeutic agent and Compound I or a pharmaceutically acceptable salt thereof have the same treatment cycle, e.g., a 1-week, 2-week, 3-week, or 4-week treatment cycle. In some particular embodiments, the second therapeutic agent and Compound I or a pharmaceutically acceptable salt thereof both have a 3-week treatment cycle.

[0017] In some embodiments of the present application, a combination pharmaceutical composition is provided that contains 84-168 mg, preferably 112-168 mg, of Compound I or a pharmaceutically acceptable salt thereof and at least one second therapeutic agent, as a formulation suitable for administration within one treatment cycle (e.g., a 3-week treatment cycle). Compound I or a pharmaceutically acceptable salt thereof may be divided equally into multiple portions (e.g., 2 equal portions, 7 equal portions, 14 equal portions, 28 equal portions, or more equal portions) and packaged separately.

[0018] In yet another aspect of the present application, a kit for treating small cell lung cancer is provided, the kit comprising Compound I or a pharmaceutically acceptable salt thereof and at least one second therapeutic agent, each packaged individually, and optionally, instructions for use.

[0019] "Small cell lung cancer" In some embodiments of the present application, the small cell lung cancer is recurrent. In some embodiments, the small cell lung cancer is refractory. In some embodiments, the small cell lung cancer is unresectable. In some embodiments, the small cell lung cancer is late-stage small cell lung cancer. In some embodiments, the small cell lung cancer is small cell lung cancer that has failed treatment with chemotherapy and / or targeted drugs. In some embodiments, the small cell lung cancer is small cell lung cancer that has received at least two types of chemotherapy. In one embodiment, the small cell lung cancer is refractory recurrent small cell lung cancer, and the "refractory recurrent small cell lung cancer" refers to small cell lung cancer that does not achieve remission with chemotherapy, or small cell lung cancer that has been effective with chemotherapy but has progressed within 3 months after the end of chemotherapy. In one embodiment, the small cell lung cancer is sensitive recurrent small cell lung cancer. In one embodiment, the small cell lung cancer is drug-resistant recurrent small cell lung cancer. In some embodiments, the clinical stage of the small cell lung cancer includes, but is not limited to, locally late, and / or late (e.g., stage IIIB / IV), and / or metastatic small cell lung cancer. Metastatic small cell lung cancer includes, but is not limited to, single organ metastasis, disseminated metastasis, and diffuse metastasis, and the metastatic organs include, but are not limited to, lymph nodes, pleura, bone, brain, pericardium, adrenal gland, and liver. In some embodiments, the small cell lung cancer is small cell lung cancer with brain metastasis. In some embodiments, the small cell lung cancer is small cell lung cancer that is intolerant to chemotherapy. As will be understood by those skilled in the art, patients can receive radiation therapy simultaneously or sequentially with the chemotherapy.

[0020] In some embodiments, the small cell lung cancer is extensive-stage small cell lung cancer.

[0021] In some embodiments, the small cell lung cancer is limited-stage small cell lung cancer.

[0022] In some embodiments, the small cell lung cancer is metastatic small cell lung cancer, and the organs of metastasis include, but are not limited to, lymph nodes, pleura, bone, pericardium, adrenal gland, liver, and brain. In some embodiments, the small cell lung cancer is small cell lung cancer with brain metastasis.

[0023] In some embodiments, the small cell lung cancer is refractory / recurrent small cell lung cancer that has been treated with one or more of irinotecan, platinum-based drugs, paclitaxel, and docetaxel.

[0024] In some embodiments, the small cell lung cancer is refractory or recurrent small cell lung cancer that has been treated with irinotecan and a platinum-based drug (e.g., including but not limited to, oxaliplatin, cisplatin, carboplatin, nedaplatin, dicycloplatin, lobaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, miriplatin, and satraplatin).

[0025] "Second treatment drug" Second therapeutic agents described herein include, but are not limited to, chemotherapeutic agents, small molecule targeted anti-tumor agents, immunotherapeutic agents, and large molecule antibody agents.

[0026] In some embodiments, the second therapeutic agent is a chemotherapeutic agent, including, but not limited to, one or more of platinum-based agents, fluoropyrimidine derivatives, camptothecins, taxanes, vinblastines, anthracyclines, antibiotics, podophyllums, and antimetabolite anti-tumor agents, examples of which include, but are not limited to, platinum-based agents (e.g., oxaliplatin, cisplatin, carboplatin, nedaplatin, dicycloplatin, lobaplatin (L), and the like. obaplatin), triplatin tetranitrate, phenanthriplatin, picoplatin, miriplatin, satraplatin), fluoropyrimidine derivatives (e.g., gemcitabine, capecitabine, ancitabine, fluorouracil, tegadifur, doxifluridine, tegafur, carmofur, trifluridine, tegafur-gimeracil-oteracil potassium), taxanes (e.g., paclitaxel, albumin-bound paclitaxel, docetaxel), camptothecins (e.g., camptothecins camptothecin, hydroxycamptothecin, 9-aminocamptothecin, 7-ethylcamptothecin, irinotecan, topotecan), vinblastine thread (vinorelbine, vinblastine, vincristine, vindesine, vinflunine), anthracycline thread (epirubicin, adriamycin, daunorubicin, pirarubicin, amrubicin, idarubicin, mitoxantrone, aclarubicin, valrubicin, zorubicin, pixantrone), pemetrexed, calm statin, melphalan, etoposide (Lastet), teniposide, mitomycin, ifosfamide, cyclophosphamide, azacitidine, methotrexate, bendamustine, liposomal adriamycin, actinomycin D (dactinomycin), bleomycin, pingyangmycin, temozolomide, dacarbazine, peplomycin, eribulin, plinabulin, sapacitabine, treosulfan, 153 Sm-EDTMP, encequidar.

[0027] In certain embodiments, the second therapeutic agent is one or more of platinum-based drugs, including, but not limited to, cisplatin, carboplatin, nedaplatin, oxaliplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, satraplatin, miriplatin, lobaplatin, and the like.

[0028] In some embodiments, the chemotherapeutic agent is one or more selected from etoposide, irinotecan, cisplatin, carboplatin, lobaplatin, nedaplatin, topotecan, paclitaxel, docetaxel, temozolomide, vinorelbine, gemcitabine, cyclophosphamide, adriamycin, vincristine, bendamustine, epirubicin, methotrexate, amrubicin, tegafur, gimeracil, oteracil, and tegafur-gimeracil-oteracil potassium.

[0029] Optionally, the second therapeutic agent is used in combination with a chemotherapy adjunct, including, but not limited to, calcium folinate (CF), folinic acid, mesna, bisphosphonates, amifostine, and colony-stimulating factors (CSFs). In some embodiments, the chemotherapy adjunct is calcium folinate (CF), mesna, or folinic acid.

[0030] In some embodiments, the second therapeutic agent is an immunotherapeutic agent, including, but not limited to, one or more of interferon (interferon alpha, interferon alpha-1b, interferon alpha-2b), interleukin, sirolimus, everolimus, ridaforolimus, and temsirolimus.

[0031] In some embodiments, the second therapeutic agent is a small molecule targeted anti-tumor agent, including, but not limited to, a protein kinase inhibitor, such as a tyrosine kinase inhibitor, a serine and / or threonine kinase inhibitor, or a poly ADP-ribose polymerase (PARP) inhibitor. polymerase inhibitors, and targets of the inhibitors include, but are not limited to, Fascin-1 protein, HDAC (histone deacetylase), proteasome, CD38, SLAMF7 (CS1 / CD319 / CRACC), RANKL, EGFR (epidermal growth factor receptor), anaplastic lymphoma kinase (ALK), MET gene, ROS1 gene, HER2 gene, RET gene, BRAF gene, PI3K signaling pathway, DDR2 (discrete death receptor 2) gene, FGFR1 (fibroblast growth factor receptor 1), NTRK1 (neurotrophin tyrosine kinase receptor type 1) gene, and KRAS gene, and targets of the small molecule targeted anti-tumor drugs include, but are not limited to, COX-2 (cyclooxygenase 2). Further included are: APE1 (Apurinic / Apyrimidinic Site Endonuclease 1), VEGFR (Vascular Endothelial Growth Factor Receptor), CXCR-4 (Chemokine Receptor-4), MMP (Matrix Metalloproteinase), IGF-1R (Insulin-Like Growth Factor 1 Receptor), Ezrin, PEDF (Pigment Epithelium-Derived Factor), AS, ES, OPG (Osteoprotective Molecule), Src, IFN, ALCAM (Activated Leukocyte Cell Adhesion Molecule), HSP, JIP1, GSK-3 (Glycogen Synthase Kinase 3), CyclinD1 (Cyclin), CDK4 (Cyclin-Dependent Kinase), TIMP1 (Tissue Inhibitor of Metalloproteinase), THBS3, PTHR1 (Parathyroid Hormone-Related Peptide 1), TEM7 (Human Tumor Endothelial Marker 7), COPS3, and Cathepsin K. Examples of small molecule targeted antitumor drugs include imatinib, sunitinib, nilotinib, bosutinib, saracatinib, pazopanib, trabectedin,Regorafenib, Cediranib, Bortezomib, Panobinostat, Carfilzomib, Ixazomib, Apatinib, Erlotinib, Afatinib, Crizotinib, Ceritinib, Vemurafenib, Dabrafenib ), Cabozantinib, Gefitinib, Dacomitinib, Osimertinib, Olmutinib, Alectinib, Brigatinib, Lorlatinib, Trametinib, Larotrectinib, Icotinib, Lapatinib, Vandetanib, Selmetinib Selumetinib, Sorafenib, Olmutinib, Savolitinib, Fruquintinib, Entrectinib, Dasatinib, Ensartinib, Lenvatinib, Itacitinib, Pyrotinib, Binimetinib, Erdafitinib b), axitinib, neratinib, cobimetinib, acalabrutinib, famitinib, masitinib, ibrutinib, rociletinib, nintedanib, lenalidomide, LOXO-292, vorolanib, bemcentinib, capmatinib,Entrectinib, TAK-931, ALT-803, palbociclib, famitinib L-malate L-malate, LTT-462, BLU-667, ningetinib, tipifarnib, poziotinib, DS-1205c, capivasertib, SH-1028, metformin, seliciclib, OSE-2101, APL-101, berzosertib, idelalisib, lerociclib, ceralasertib, PLB-1003, tomivosertib, AST-2818, SKLB-1028, D-0316, LY-3023414, allitinib ), MRTX-849, AP-32788, AZD-4205, lifirafenib, vactosertib, mibebresib, napabucasin, sitravatinib, TAS-114, molibresib, CC-223, rivoceranib, CK-101, LXH-254, simotinib, GSK-3368715, TAS-0728, masitinib, tepotinib, HS-10296, AZD-4547, merestinib, olaptesed pegol pegol), galunisertib, ASN-003, gedatolisib, defactinib, 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, copanlisib, niraparib, olaparib, veliparib, talazoparib tosylate tosylate, DV-281, Siremadlin, Telaglenastat, MP-0250, GLG-801, ABTL-0812, bortezomib, tucidinostat, vorinostat, resminostat, epacadostat, tazemetostat, entinostat, mocetinostat, quisinostat, LCL-161, KML-001. In some embodiments, the small molecule targeted anti-tumor drug is sorafenib, erlotinib, afatinib, crizotinib, ceritinib, vemurafenib, dabrafenib, cabozantinib, gefitinib, dacomitinib, osimertinib, alectinib, brigatinib, lorlatinib, trametinib, larotrectinib, icotinib, lapatinib, vandetanib, selmetin ... The drug is one or more of the following: tinib, olmutinib, savolitinib, fruquintinib, entrectinib, dasatinib, ensartinib, lenvatinib, itacitinib, pyrotinib, binimetinib, erdafitinib, axitinib, neratinib, cobimetinib, acalabrutinib, famitinib, masitinib, ibrutinib, and nintedanib.

[0032] In some embodiments, the second therapeutic agent is a large molecule antibody drug, the targets of which include, but are not limited to, any one or more of PD-1, PD-L1, cytotoxic T-lymphocyte antigen 4 (CTLA-4), platelet-derived growth factor receptor alpha (PDGFR-α), vascular endothelial growth factor (VEGF), human epidermal growth factor receptor-2 (HER2), epidermal growth factor receptor (EGFR), ganglioside GD2, B cell surface immunoglobulin CD20, B cell surface immunoglobulin CD52, B cell surface immunoglobulin CD38, B cell surface immunoglobulin CD319, B cell surface immunoglobulin CD30, and B cell surface immunoglobulin CD19 / CD3.

[0033] 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 drug 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-α) inhibitor.

[0034] 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 to programmed death receptor 1 (PD-1) and / or inhibits PD-1 activity, or an antibody or antigen-binding portion thereof that binds to programmed death ligand 1 (PD-L1) and / or inhibits PD-L1 activity, e.g., an anti-PD-1 antibody or an anti-PD-L1 antibody. In some specific embodiments, the antibody or antigen-binding portion thereof is (a) an anti-PD-1 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) an anti-PD-L1 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.

[0035] In some embodiments, the anti-PD-1 or PD-L1 antibody is an anti-PD-1 or PD-L1 monoclonal antibody.

[0036] In some embodiments, the anti-PD-1 or PD-L1 antibody is a human antibody or a murine antibody.

[0037] In some embodiments, the anti-PD-1 antibody may be any one or more selected from nivolumab, pembrolizumab, durvalumab, toripalimab (JS-001), sintilimab (IBI308), camrelizumab, tislelizumab (BGB-A317), genolizumab (GB226), lizumab (LZM009), HLX-10, BAT-1306, AK103 (HX008), AK104 (Kangho Bio), CS1003, SCT-I10A, F520, SG001, and GLS-010.

[0038] In some embodiments, the anti-PD-L1 antibody may be any one or more selected from atezolizumab, avelumab, durvalumab, KL-A167, SHR-1316, BGB-333, JS003, STI-A1014 (ZKAB0011), KN035, MSB2311, HLX-20, and CS-1001.

[0039] In some specific embodiments, the anti-PD-1 antibody is toripalimab.

[0040] In some specific embodiments, the anti-PD-1 antibody is pembrolizumab.

[0041] In some embodiments, the cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitor is an anti-CTLA-4 antibody. In some specific embodiments, the anti-CTLA-4 antibody is an anti-CTLA-4 monoclonal antibody.

[0042] In some embodiments, the anti-CTLA-4 antibody may be any one or more selected from ipilimumab, tremelimumab, AGEN-1884, BMS-986249, BMS-986218, AK-104, and IBI310.

[0043] In certain embodiments, the anti-CTLA-4 antibody is ipilimumab.

[0044] In some embodiments, the platelet-derived growth factor receptor alpha (PDGFR-α) inhibitor is an anti-PDGFRα antibody. In some specific embodiments, the anti-PDGFRα antibody is an anti-PDGFRα monoclonal antibody.

[0045] In certain embodiments, the anti-PDGFRα antibody is Olaratumab.

[0046] In some specific embodiments, the antibody drug is selected from the group consisting of Bevacizumab, Ramucirumab, Pertuzumab, Trastuzumab, Cetuximab, Nimotuzumab, Panitumumab, Necitumumab, Dinutuximab, and the like. The therapeutic agent may further include, but is not limited to, any one or more of: Rituximab, Ibritumomab, Ofatumumab, Obinutuzumab, Alemtuzumab, Daratumumab, Gemtuzumab, Elotuzumab, Brentuximab, Inotuzumab Ozogamicin, Blinatumomab.

[0047] In certain embodiments, the second therapeutic agent is tegafur, gimeracil, and oteracil potassium.

[0048] In certain specific embodiments, the second therapeutic agent is etoposide and at least one platinum-based drug.

[0049] In some specific embodiments, the second therapeutic agent is one or both of etoposide and cisplatin. In one specific embodiment, the second therapeutic agent is EP therapy (etoposide + cisplatin).

[0050] In some specific embodiments, the second therapeutic agent is one or both of carboplatin and etoposide. In one specific embodiment, the second therapeutic agent is EC therapy (carboplatin + etoposide).

[0051] In certain specific embodiments, the second therapeutic agent is one or two of etoposide and lobaplatin.

[0052] In some specific embodiments, the second therapeutic agent is one, two, three, or four of cyclophosphamide, vincristine, methotrexate, or etoposide. In one specific embodiment, the second therapeutic agent is COME (cyclophosphamide + vincristine + methotrexate + etoposide).

[0053] In some specific embodiments, the second therapeutic agent is one, two, or three of cyclophosphamide, adriamycin, and vincristine. In one specific embodiment, the second therapeutic agent is CAV therapy (cyclophosphamide + adriamycin + vincristine).

[0054] In some specific embodiments, the second therapeutic agent is one, two, or three of cyclophosphamide, adriamycin, and etoposide. In one specific embodiment, the second therapeutic agent is CAE therapy (cyclophosphamide + adriamycin + etoposide).

[0055] In some specific embodiments, the second therapeutic agent is one, two, or three of ifosfamide, etoposide, and cisplatin. In one specific embodiment, the second therapeutic agent is IEP therapy (ifosfamide + etoposide + cisplatin).

[0056] In some specific embodiments, the second therapeutic agent is one, two, or three of carboplatin, paclitaxel, and etoposide. In one specific embodiment, the second therapeutic agent is CPE therapy (carboplatin + paclitaxel + etoposide).

[0057] In some specific embodiments, the second therapeutic agent is one, two, three, or four of cisplatin, vincristine, adriamycin, or etoposide. In one specific embodiment, the second therapeutic agent is CODE therapy (cisplatin + vincristine + adriamycin + etoposide).

[0058] In certain embodiments, the second therapeutic agent is topotecan.

[0059] "Compound I or a pharmaceutically acceptable salt thereof" The chemical name of Compound I is 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl]cyclopropylamine, and its structural formula is as follows: [ka]

[0060] In this application, when anlotinib is referred to, it is Compound I.

[0061] Compound I may be administered in the form of its free base or in the form of a salt, hydrate, or prodrug, which is converted in vivo to the free base form of Compound I. For example, pharmaceutically acceptable salts of Compound I may be prepared within the scope of this application from different organic or inorganic acids by methods well known in the art.

[0062] In some embodiments, Compound I is administered in the form of a hydrochloride salt. In some embodiments, Compound I is administered in the form of a monohydrochloride salt. In some embodiments, Compound I is administered in the form of a dihydrochloride salt. In some embodiments, Compound I is administered in the form of a crystalline hydrochloride salt. In certain embodiments, Compound I is administered in the form of a crystalline dihydrochloride salt.

[0063] Compound I, or a pharmaceutically acceptable salt thereof, the second therapeutic agent may be administered by several routes, including, but not limited to, oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, inhalation, vaginal, intraocular, topical, subcutaneous, intraadipose, intraarticular, intraperitoneal, and intrathecal. In one particular embodiment, it is administered orally.

[0064] The dosage of Compound I or a pharmaceutically acceptable salt thereof, or the second therapeutic agent may be determined based on the severity of the disease, the response to the disease, any treatment-related toxicities, and the age and health of the patient. In some embodiments, the daily dosage of Compound I or a pharmaceutically acceptable salt thereof is 3-30 mg. In some embodiments, the daily dosage of Compound I or a pharmaceutically acceptable salt thereof is 5-20 mg. In some embodiments, the daily dosage of Compound I or a pharmaceutically acceptable salt thereof is 8-16 mg. In some embodiments, the daily dosage of Compound I or a pharmaceutically acceptable salt thereof is 10-14 mg. In some embodiments, the daily dosage of Compound I or a pharmaceutically acceptable salt thereof is 6-12 mg. In one particular embodiment, the daily dosage of Compound I or a pharmaceutically acceptable salt thereof is 6 mg. In one particular embodiment, the daily dosage of Compound I or a pharmaceutically acceptable salt thereof is 8 mg. In one particular embodiment, the daily dosage of Compound I or a pharmaceutically acceptable salt thereof is 10 mg. In a specific embodiment, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 12 mg. In this application, for example, in the case of a tablet or capsule, "containing 12 mg of Compound I or a pharmaceutically acceptable salt thereof on a unit dose basis" means that the final tablet or capsule contains 12 mg of Compound I per tablet.

[0065] Compound I or a pharmaceutically acceptable salt thereof, the second therapeutic agent may be administered one or more times daily. In some embodiments, Compound I or a pharmaceutically acceptable salt thereof is administered once daily. In one embodiment, the oral solid dosage form is administered once daily.

[0066] In the above-mentioned treatment method, the administration method may be comprehensively determined based on the activity, toxicity, and tolerability of the drug. Preferably, Compound I or a pharmaceutically acceptable salt thereof is administered at intervals. The interval administration includes an administration period and a rest period, and Compound I or a pharmaceutically acceptable salt thereof may be administered once or multiple times per day during the administration period. For example, Compound I or a pharmaceutically acceptable salt thereof is administered daily during the administration period, followed by a rest period during which administration is discontinued for a certain period, followed by an administration period and then a rest period. This cycle can be repeated multiple times. The ratio of the administration period to the rest period in terms of days is 2:(0.5-5), preferably 2:(0.5-3), more preferably 2:(0.5-2), and even more preferably 2:(0.5-1).

[0067] In some embodiments, the administration is for two consecutive weeks followed by two weeks off. In some embodiments, the administration is once daily, with the administration continuing for 14 days, followed by a 14-day rest period, followed by once daily, with the administration continuing for 14 days, followed by a 14-day rest period, and such two consecutive weeks of administration followed by a two-week rest period can be repeated multiple times.

[0068] In some embodiments, the administration is for two consecutive weeks followed by one week off. In some embodiments, the administration is once daily, with the administration continuing for 14 days, followed by a seven-day rest period, followed by once daily, with the administration continuing for 14 days, followed by a seven-day rest period, and such two consecutive weeks of administration followed by a one-week rest period can be repeated multiple times. In one particular embodiment, Compound I or a pharmaceutically acceptable salt thereof is administered on days 1-14 of each cycle, resulting in a 21-day administration cycle.

[0069] In some embodiments, the administration is for 5 consecutive days followed by 2 days off. In some embodiments, the administration is once daily, with the administration continuing for 5 days, followed by 2 days off, followed by once daily, with the administration continuing for 5 days, followed by 2 days off, and such intervals of 5 consecutive days on and 2 days off can be repeated multiple times.

[0070] In certain embodiments, it is administered orally at a dose of 12 mg once daily for two consecutive weeks on and one week off.

[0071] Drug combinations In some embodiments, Compound I or a pharmaceutically acceptable salt thereof is combined with surgical resection and / or radiation therapy.

[0072] Each component of the pharmaceutical combination described herein may optionally be combined with one or more pharmaceutically acceptable carriers, and the components may each independently, or some or all of them may simultaneously contain pharmaceutically acceptable carriers and / or excipients. Each component of the pharmaceutical combination described herein may be prepared alone, or some or all of them may simultaneously be prepared. Preferably, each component of the pharmaceutical composition is prepared alone or as a suitable pharmaceutical composition. In some embodiments, the pharmaceutical combination described herein may be prepared as a pharmaceutical composition suitable for single or multiple administration. In some specific embodiments, the pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt thereof may be selected from solid pharmaceutical compositions, including, but not limited to, tablets and capsules.

[0073] The components of the pharmaceutical combinations of the present application may be administered individually, or some or all of them may be administered simultaneously. The components of the pharmaceutical combinations of the present application may be administered substantially non-concurrently, or some or all of them may be administered substantially simultaneously.

[0074] The components of the drug combinations herein may be administered individually or in part or in whole simultaneously by any suitable route, including, but not limited to, oral, parenteral (intravenous, intramuscular, topical, or subcutaneous), hi some embodiments, the components of the pharmaceutical compositions herein may be administered individually or in part or in whole simultaneously by oral administration or injection, e.g., intravenous or intraperitoneal administration.

[0075] The components of the pharmaceutical combinations of the present application may each be independently, or some or all of them may be together, in any suitable dosage form, including, but not limited to, tablets, troches, pills, capsules (e.g., hard capsules, soft capsules, enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions, and sustained-release formulations for oral or parenteral administration.

[0076] In some embodiments of the present application, the drug combination is a defined combination. In some embodiments, the defined combination is in the form of a solid pharmaceutical composition or a liquid pharmaceutical composition.

[0077] In some embodiments of the present application, the drug combination is an open combination. In some embodiments, the second therapeutic agent of the open combination, Compound I, or a pharmaceutically acceptable salt thereof, is each in the form of a pharmaceutical composition.

[0078] In some embodiments of the present application, Compound I or a pharmaceutically acceptable salt thereof is administered simultaneously or sequentially with one or more second therapeutic agents. In some embodiments, one or more second therapeutic agents have been administered to the recipient prior to administration of Compound I or a pharmaceutically acceptable salt thereof or prior to combination with Compound I or a pharmaceutically acceptable salt thereof. In some embodiments, one or more second therapeutic agents are administered to the recipient after administration of Compound I or a pharmaceutically acceptable salt thereof or after combination with Compound I or a pharmaceutically acceptable salt thereof. In some embodiments, Compound I or a pharmaceutically acceptable salt thereof has been administered to the recipient prior to administration of one or more second therapeutic agents or prior to combination with one or more second therapeutic agents. In some embodiments, Compound I or a pharmaceutically acceptable salt thereof is administered to the recipient after administration of one or more second therapeutic agents or after combination with one or more second therapeutic agents. In some embodiments, when Compound I or a pharmaceutically acceptable salt thereof is administered to an applicant in combination with one or more second therapeutic agents, Compound I or a pharmaceutically acceptable salt thereof and the one or more second therapeutic agents are administered to the applicant sequentially.

[0079] In some embodiments, a kit of pharmaceutical compositions for treating small cell lung cancer is provided, further comprising: (a) a first pharmaceutical composition comprising a chemotherapeutic agent as an active ingredient; and (b) a second pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt thereof as an active ingredient. In some embodiments, a kit of pharmaceutical compositions for treating small cell lung cancer is provided, further comprising: (a) a first pharmaceutical composition comprising a small molecule targeted anti-tumor agent as an active ingredient; and (b) a second pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt thereof as an active ingredient. In some embodiments, a kit of pharmaceutical compositions for treating small cell lung cancer is provided, further comprising: (a) a first pharmaceutical composition comprising an immunotherapeutic agent as an active ingredient; and (b) a second pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt thereof as an active ingredient. In some embodiments, a pharmaceutical composition kit for treating small cell lung cancer is provided, further comprising: (a) a first pharmaceutical composition comprising a large molecule antibody drug as an active ingredient; and (b) a second pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt thereof as an active ingredient. In some embodiments, a pharmaceutical composition kit for treating small cell lung cancer is provided, further comprising: (a) a first pharmaceutical composition comprising tegafur, gimeracil, and oteracil potassium as active ingredients; and (b) a second pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt thereof as an active ingredient. In some embodiments, a pharmaceutical composition kit for treating small cell lung cancer is provided, further comprising: (a) a first pharmaceutical composition comprising etoposide and a platinum-based drug as active ingredients; and (b) a second pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt thereof as an active ingredient. In some embodiments, a kit of pharmaceutical compositions for treating small cell lung cancer is provided, further comprising: (a) a first pharmaceutical composition comprising etoposide and cisplatin as active ingredients; and (b) a second pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt thereof as an active ingredient.In some embodiments, a kit of pharmaceutical compositions for treating small cell lung cancer is provided, further comprising: (a) a first pharmaceutical composition comprising etoposide and lobaplatin as active ingredients; and (b) a second pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt thereof as an active ingredient.

[0080] "Definitions and Explanations" For the purposes of this specification, unless otherwise specified, the following terms used in the specification and claims have the following meanings:

[0081] As used herein, the term "treatment" generally refers to obtaining a desired pharmacological and / or physiological effect. The effect is therapeutic if it partially or completely stabilizes or cures a disease and / or its associated side effects. As used herein, the term "treatment" includes any treatment of a disease in a recipient, such as (a) inhibiting the symptoms of the disease, i.e., preventing its progression, or (b) ameliorating the symptoms of the disease, i.e., eliminating the disease or symptoms.

[0082] As used herein, the term "treatment failure" refers to intolerable toxicity and side effects, disease progression during treatment, or recurrence after treatment has ended.

[0083] As used herein, the term "subject" refers to a mammal, such as a rodent, cat, dog, or primate. Preferably, the subject in this application is a human.

[0084] The term "administration" refers to the physical introduction of a composition containing a therapeutic agent into a subject using any one of a variety of methods and delivery systems known to those skilled in the art. Routes of administration include intravenous, intramuscular, subcutaneous, intraperitoneal, intrathecal, or other parenteral routes, e.g., injection, infusion. As used herein, the term "parenteral administration" refers to any route of administration other than enteral or topical administration, typically performed by injection, including, but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intravisceral, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injection and infusion, and in vivo electroporation. In some embodiments, drugs are administered by routes other than parenteral, and in some embodiments, orally. Other non-parenteral routes include topical, epidermal, and mucosal routes of administration, e.g., intranasal, intravaginal, rectal, sublingual, and topical. Administration may be once or multiple times and / or may occur over one or more extended periods of time.

[0085] A "subject" includes any human or non-human animal. The term "non-human animal" includes, but is not limited to, vertebrates (e.g., non-human primates, sheep, dogs) and rodents (e.g., mice, rats, guinea pigs). In some embodiments, the subject is a human. As used herein, the terms "subject" and "applicant" are used interchangeably in certain contexts.

[0086] As an example, an "anti-cancer drug" promotes the elimination of cancer or the prevention of further tumor growth in a subject. In some embodiments, the drug promotes the elimination of cancer until it disappears. "Promoting the elimination of cancer" refers to the reduction in tumor growth or size, tumor necrosis, reduction in the severity of at least one symptom, or an increase in the frequency and duration of symptom-free periods, when the drug is administered alone or in combination with an anti-tumor drug. Furthermore, the terms "effectiveness" and "efficacy" in relation to treatment include pharmacological efficacy and physiological safety. Pharmacological efficacy is the ability of a drug to promote the elimination of cancer in a subject. Physiological safety refers to the level of toxicity at the cellular, organ, and / or systemic level or other adverse physiological effects (adverse events) caused by the administration of the drug.

[0087] As an example of tumor treatment, an anti-cancer drug may inhibit cell or tumor growth by at least about 10%, at least about 20%, at least about 40%, at least about 60%, or at least about 80% compared to untreated controls, or in some embodiments, compared to patients receiving standard therapy. In other embodiments of the present application, tumors are visually determined to have resolved for at least about 20 days, at least about 40 days, or at least about 60 days. Despite these measures of therapeutic efficacy, "immune-related" response patterns must be considered when evaluating drugs.

[0088] "Immune-related" response patterns are commonly observed in cancer patients clinically treated with immunotherapeutic agents, which induce cancer-specific immune responses or alter innate immunity to produce antitumor effects. These response patterns are characterized by beneficial therapeutic effects after an initial increase in tumor burden or the appearance of new lesions, which, in the evaluation of conventional chemotherapeutic agents, is considered disease progression in the same sense as drug failure. Therefore, to properly evaluate immunotherapeutic agents, it is necessary to monitor the effects of these agents on the target disease over time.

[0089] As used herein, the term "antibody" refers to a binding protein that contains at least one antigen-binding domain. The antibodies and fragments thereof of the present application may be whole antibodies or any fragments thereof. Thus, the antibodies and fragments thereof of the present application include monoclonal antibodies or fragments thereof, antibody variants or fragments thereof, and immunoconjugates. Examples of antibody fragments include Fab fragments, Fab' fragments, F(ab)'2 fragments, Fv fragments, isolated CDR regions, single-chain Fv molecules (scFv), Fd fragments, and other antibody fragments known in the art. Antibodies and fragments thereof further 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.

[0090] The term "isotype" refers to the antibody species encoded by the heavy chain constant region genes. In one embodiment, the anti-PD-1 / PD-L1 antibodies and fragments thereof disclosed herein are of the IgG1 or IgG4 isotype. The anti-PD-1 / PD-L1 antibodies and fragments thereof herein may be derived from any species, including, but not limited to, mouse, rat, rabbit, primate, llama, human, etc. The PD-1 / PD-L1 antibodies and fragments thereof may be chimeric, humanized, or fully human.

[0091] The term "humanized" refers to an antibody in which the antigen-binding site is derived from a non-human species and the variable region framework is derived from a human immunoglobulin sequence. Because humanized antibodies may contain substitutions in the framework region, the framework may not be an exact copy of the expressed human immunoglobulin or germline gene sequence.

[0092] An "isolated antibody" is an antibody that is substantially free of other antibodies with different antigenic specificities (e.g., an isolated antibody that specifically binds to PD-1 / PD-L1 is substantially free of antibodies that specifically bind to antigens other than PD-1 / PD-L1). However, an isolated PD-1 / PD-L1 specific binding antibody may have cross-reactivity with other antigens (e.g., PD-1 / PD-L1 molecules from different species). An isolated antibody may also be substantially free of other cellular material and / or chemicals.

[0093] The term "monoclonal antibody (mAb)" refers to a single antibody molecule. Monoclonal antibody compositions exhibit a single binding specificity and affinity for a particular epitope, or, in the case of bispecific monoclonal antibodies, dual binding specificities for two different epitopes. mAbs are an example of isolated antibodies. mAbs can be produced by hybridoma technology, recombinant DNA technology, or other techniques well known to those skilled in the art. Examples of isolated monoclonal antibodies include nivolumab (Opdivo®), pembrolizumab (Keytruda®), durvalumab, avelumab, toripalimab (JS-001, Kimitsu Bio), sintilimab (IBI308, Shinda Bio), and camrelizumab ( SHR-1210, Camrelizumab, Hengrui Pharmaceutical, see CN105026428B or WO2015085847A1), tislelizumab (BGB-A317, Baekje Shenzhou), genolimuzumab (GB226, Jiahe Bio), lizumab (LZM009, Liju Pharmaceutical), HLX-10 (Fuhong Hanlin), BAT-1306 (Baiao Tai), HX008 (AK103, Kangfang Bio / Hanzhong Bio), AK104 (Zhongshan Kangfang), CS1003 (Basestone Pharmaceuticals), SCT-I10A (Shenzhou Cells), F520 (Shandong New Generation Pharmaceuticals / Lunan Pharmaceuticals), SG001 (Shangjian Biosciences), GLS-010 (Yuheng Pharmaceuticals), atezolizumab (Tecentriq®, F. Hoffmann-La Roche), avelumab (Bavencio®, Merck / Pfizer), durvalumab ab, Imfinzi®, AstraZeneca), KL-A167 (Kelun Pharmaceutical), SHR-1316 (Hengrui Pharmaceutical), BGB-333 (Baekje Shenzhou), JS003 (Junshi Bio), STI-A1014 (ZKAB0011, Zhaoke Pharmaceutical), KN035 (Kangning Jerui / Siludi), MSB2311 (Midori Bio), HLX-20 (Fuhong Hanlin), CS-1001 (Geishi Pharmaceutical), and the like.

[0094] An "antigen-binding portion" (also called an "antigen-binding fragment") of an antibody is one or more fragments of an antibody that retain the ability to specifically bind to an antigen bound by the intact antibody.

[0095] "Programmed death receptor-1 (PD-1)" is an immunosuppressive receptor belonging to the CD28 family. PD-1 is primarily expressed in vivo on preactivated T cells and binds to two ligands, PD-L1 and PD-L2. As used herein, the term "PD-1" includes human PD-1 (hPD-1), hPD-1 variants, homologs, interspecies homologs, and analogs that share at least one epitope with hPD-1.

[0096] Programmed cell death ligand-1 (PD-L1) is one of two cell surface glycoprotein ligands for PD-1 (the other is PD-L2), and upon binding to PD-1, it downregulates T cell activation and cytokine secretion.

[0097] "Recurrent" cancer is cancer that returns after responding to initial treatment (e.g., surgery), either locally or at a distant site. "Locally recurrent" cancer is cancer that appears after treatment in the same place as the previously treated cancer.

[0098] "Unresectable" cancer cannot be removed by surgery.

[0099] A "metastatic" cancer is one that has spread from one part of the body (for example, the lungs) to another.

[0100] The use of alternative embodiments (e.g., embodiments preceded by "or") is understood to refer to any one, two, or any combination of the alternative embodiments. As used herein, the open-ended modifier "a" or "one" is understood to refer to "one or more / one or more" of the listed components.

[0101] The term "pharmaceutically acceptable" refers to compounds, materials, compositions and / or dosage forms that are medically determined to be suitable for use in contact with human or animal tissues without toxicity, irritation, allergic reaction or other problem or complication, and that have a reasonable risk-to-benefit ratio.

[0102] The term "pharmaceutically acceptable salt" includes salts formed between base ions and free acids, and salts formed between acid ions and free bases, such as hydrochloride, hydrobromide, nitrate, sulfate, phosphate, formate, acetate, trifluoroacetate, fumarate, oxalate, maleate, citrate, succinate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, sodium salt, potassium salt, ammonium salt, and amino acid salts, and preferably hydrochloride, hydrobromide, sulfate, formate, acetate, trifluoroacetate, fumarate, maleate, methanesulfonate, p-toluenesulfonate, sodium salt, potassium salt, ammonium salt, and amino acid salt. In the present application, when a pharmaceutically acceptable salt is formed, the molar ratio of the free acid to the base ions is about 1:0.5-1:5, and 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 1:0.5-1:5, preferably 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7 or 1:8.

[0103] The term "defined combination" means that the active ingredients (e.g., chemotherapeutic agents or compound I) are administered to the recipient simultaneously in a defined total dose or dose ratio, or in the form of a single entity, pharmaceutical composition or formulation.

[0104] The term "indefinite combination" refers to two or more active ingredients administered to a patient as separate entities (e.g., pharmaceutical compositions, formulations) simultaneously or sequentially, without any time restriction, at a therapeutically effective dose level. An example of an indefinite combination is cocktail therapy, in which, for example, three or more active ingredients are administered. In an indefinite combination, each active ingredient may be packaged, sold, or administered as a completely separate pharmaceutical composition. The "indefinite combination" includes the use of multiple "definite combinations," or a "definite combination" in combination with a separate entity containing any one or more active ingredients.

[0105] As used herein, the term "combination" or "use in combination" refers to two or more active agents administered to a recipient in admixture, simultaneously in a single formulation, or sequentially in any order in a single formulation.

[0106] The term "pharmaceutical composition" refers to a mixture of one or more active ingredients of the present application (e.g., a second therapeutic agent or Compound I) or a pharmaceutical combination thereof, and pharmaceutically acceptable excipients. A pharmaceutical composition facilitates administration of the compound or pharmaceutical combination thereof to a recipient.

[0107] As used herein, "clinical benefit" includes, but is not limited to, an extension of progression-free survival (PFS), an extension of overall survival (OS), an improvement in objective response rate (ORR), an improvement in disease control rate (DCR), and a reduction in the number and / or severity of adverse events in clinical patients.

[0108] In this application, the term "about" refers to a range of ±5% of the specified numerical value, preferably ±2%, and more preferably ±1%.

[0109] In this specification, unless otherwise stated, the terms "comprise," "comprises," "comprising," or equivalent terms are intended to be open-ended and mean that the invention may include unspecified elements, components, or steps in addition to the listed elements, components, or steps.

[0110] Any patents, patent applications, or existing publications are incorporated herein by reference for purposes of explanation and disclosure. These publications are available because they were published prior to the filing date of the present application. Any statement as to the disclosure date of such documents or any representation as to their contents is based on the information known to the applicant and does not constitute an admission as to the correctness of the disclosure date or contents of such documents. Furthermore, the incorporation of such publications by reference does not constitute an admission that such publications constitute common general knowledge in the art in any country. DETAILED DESCRIPTION OF THE INVENTION

[0111] The present application will now be further described with some examples. However, these examples of the present application are for illustrative purposes only and do not limit the scope of the present application. The present application is also not limited to the specific preferred embodiments described herein. As understood by those skilled in the art, equivalent substitutions and corresponding improvements made to the technical features of the present application are still within the scope of protection of the present application. Unless otherwise specified, all reagents used in the following examples are commercially available products, and solutions are prepared using techniques common in the art.

[0112] Example 1 Patients with measurable lesions and pathologically confirmed small cell lung cancer (including extensive and limited stage) were assigned to two combination treatment groups: one group received EP or EC therapy (etoposide + cisplatin / carboplatin) + anlotinib, and the other group received EP or EC (etoposide + cisplatin / carboplatin) alone as a control group. The details of the treatment regimen are as follows: In the combination arm, patients received etoposide 100 mg / m 2 , iv, administered over 120 minutes on days 1-3 of each cycle, with cisplatin 75 mg / m2 Alternatively, carboplatin AUC 5, iv was administered over 120 minutes on day 1 of each cycle, with anlotinib 12 mg / day administered orally on an empty stomach after awakening in the morning on days 1-14 of each cycle, with each cycle lasting 21 days. When the combination therapy was continued for 4-6 cycles, maintenance treatment was with anlotinib 12 mg / day administered orally on an empty stomach after awakening in the morning on days 1-14 of each cycle, with each cycle lasting 21 days, until disease progression.

[0113] In the control arm, patients received etoposide 100 mg / m 2 , iv, administered over 120 minutes on days 1-3 of each cycle, with cisplatin 75 mg / m 2 Alternatively, carboplatin AUC 5, iv, was administered over 120 minutes on day 1 of each cycle, with each cycle lasting 21 days.

[0114] The primary endpoint was progression-free survival (PFS), and secondary endpoints were objective response rate (ORR), overall survival (OS), disease control rate (DCR), safety, and tolerability.

[0115] Thirty-one patients were enrolled in this clinical trial between February 2018 and October 2019. The efficacy evaluation results for the combination treatment group to date showed a median PFS of 8.9 months, with three patients (3 / 31) achieving a complete response (CR), 20 patients (20 / 31) achieving a partial response (PR), nine patients (9 / 31) achieving stable disease (SD), and no patients (0 / 31) experiencing progressive disease (PD). The objective response rate (ORR) was 74.2% (21 / 31), and the disease control rate (DCR) was 100% (31 / 31). The combination of anlotinib with EP or EC therapy was found to have excellent clinical efficacy and favorable clinical safety.

[0116] Example 2 Patients who were diagnosed with small cell lung cancer by histopathological or cytological examination, who had received one round of systematic chemotherapy and platinum-based chemotherapy, and who were found to have recurred or failed treatment after treatment, including patients with mixed small cell and non-small cell lung cancer, excluding those with non-small cell lung cancer, were divided into two groups: a combination treatment group and a single-agent chemotherapy control group, and the details of the treatment plan are as follows. The combination group received anlotinib hydrochloride capsules 12 mg qd po d1-14 + irinotecan 60-80 mg / m 2 The chemotherapy was given iv on days 1 and 8, q3w, with a maximum of 6 chemotherapy cycles. The single-agent chemotherapy control group was irinotecan 60-80 mg / m 2 The chemotherapy was given iv on days 1 and 8, q3w, with a maximum of 6 chemotherapy cycles.

[0117] Patients who achieved complete response (CR), partial response (PR), or stable disease (SD) continued treatment until disease progression (PD), intolerance to toxicity, or patient requested rest, or treatment was discontinued for patients with disease progression (PD).Efficacy evaluation observation endpoints included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), duration of remission (DOR), quality of life score, and drug safety.

[0118] This study demonstrated that the combination of anlotinib and irinotecan was clinically beneficial for patients with small cell lung cancer.

[0119] Example 3 Patients with extensive small cell lung cancer who were pathologically diagnosed with small cell lung cancer and who had failed second-line chemotherapy (having previously received two types of chemotherapy) were administered a combination of anlotinib and etoposide, with the details of the administration schedule being as follows: Etoposide soft capsules were orally administered once daily before breakfast, 100 mg (calculated by weight of etoposide) on days 1-10 of each cycle, with one treatment cycle lasting 21 days. Anlotinib hydrochloride capsules were administered orally once daily before breakfast, 12 mg per capsule, on days 1-14 of each cycle, with one treatment cycle lasting 21 days.

[0120] The interval between the administration of the two drugs should be at least 30 minutes. If a dose is missed, it should be taken within 12 hours of the next dose, otherwise it need not be taken. During the administration process, the dose can be adjusted based on the degree of drug-related toxic reactions in the patient and the expected beneficial effect. Anlotinib can be adjusted to two dose levels: 10 mg and 8 mg. If a dose reduction of two or more levels is required, treatment will be terminated. The dose of etoposide can be reduced to 50 mg.

[0121] Efficacy evaluation observation indicators include progression-free survival (PFS), overall survival (OS), objective response rate (ORR = CR + PR), disease control rate (DCR = CR + PR + SD), and safety indicators.

[0122] This study demonstrated that the combination of anlotinib and etoposide was clinically beneficial for patients with small cell lung cancer.

[0123] Example 4 Patients were diagnosed with small cell lung cancer histologically or cytologically (regardless of whether it was limited or extensive stage), had received at least platinum-based first-line standard treatment for SCLC, and had progressed as confirmed by imaging. [1] Sensitive recurrence: Progression is recognized when it has been more than 90 days since the last chemotherapy. [2] Drug-resistant relapse: Progression recognized during chemotherapy or progression recognized within 90 days after the last chemotherapy. The combination therapy consists of six 3-week cycles of anlotinib and S-1 (tegafur, gimeracil, and oteracil potassium) followed by maintenance therapy with S-1. Each cycle consists of sequential administration of the two drugs on the first day of each cycle, with the administration time window allowed to vary ±3 days. However, within three days prior to each administration, patients must undergo various tests, including vital signs, physical examination, laboratory tests, and performance status scores, in addition to imaging tests. Patients must also undergo imaging tumor assessments every 6 weeks (±7 days) within 48 weeks after the first administration, and every 9 weeks (±7 days) after 48 weeks after the first administration (either CT or MRI). The details of the administration schedule are as follows: Combination therapy (6 cycles): Anlotinib hydrochloride capsules 12 mg once daily + S-1 60 mg / m 2 The dose was administered bid for 2 consecutive weeks followed by 1 week off. Maintenance treatment: After the induction treatment is completed, the maintenance treatment phase begins. Patients are required to continue S-1 maintenance treatment (20 mg / m 2 Patients were treated bid (administered in 21-day cycles consisting of 2 consecutive weeks on and 1 week off) until disease progression, intolerable toxicity and side effects, withdrawal of informed consent, investigator-ordered withdrawal of the subject, noncompliance with treatment or study procedures, or other pre-specified circumstances.

[0124] Combination treatment of recurrent small cell lung cancer with S-1 and anlotinib hydrochloride was evaluated using efficacy indicators such as progression-free survival (PFS), objective response rate (ORR), overall survival (OS), disease control rate (DCR), PFS rate at 6 months and 1 year, OS rate at 1 year and 2 years, and safety.

[0125] Example 5 Patients with histologically or cytologically determined, pathologically confirmed small cell lung cancer who had relapsed after at least one prior line of systemic chemotherapy were administered anlotinib and sintilimab in combination. The details of the administration schedule are as follows: Anlotinib hydrochloride capsules were administered orally once daily before breakfast, at a dose of 12 mg, on days 1-14 of each cycle. One treatment cycle consisted of 21 days, consisting of two consecutive weeks of administration and one week of rest. Sintilimab was administered intravenously at 200 mg on day 1 of each cycle, with a 21-day treatment cycle.

[0126] All patients were treated for a maximum of 12 months or until disease progression, intolerable toxic reactions, withdrawal of informed consent, death, or other pre-specified events that led to the end of treatment. Only the first occurrence of any of these events was considered valid.

[0127] Efficacy evaluation observation endpoints included progression-free survival (PFS), overall survival (OS), objective response rate (ORR = CR + PR), disease control rate (DCR = CR + PR + SD), and safety endpoints. This study showed that the combination of anlotinib and sintilimab was clinically beneficial for patients with small cell lung cancer, prolonging progression-free survival (PFS), with some patients experiencing a 6-month PFS extension.

[0128] In the above examples of this application, the amount of anlotinib hydrochloride capsules is calculated by the weight of anlotinib free base contained therein.

[0129] Although this disclosure describes the compositions and methods of the present application in preferred embodiments, those skilled in the art will recognize that variations in the compositions and / or methods, as well as the steps or order of steps of the methods, may be made without departing from the basic principles and spirit of the present application.

[0130] All documents cited herein are incorporated herein to supplement the contents of this specification with illustrative details regarding the processes and other aspects to which they relate. The present invention includes the following aspects. [1] JPEG0007761490000003.jpg50159 A combination pharmaceutical composition for treating small cell lung cancer, comprising (i) Compound I or a pharmaceutically acceptable salt thereof, and (ii) at least one second therapeutic agent. [2] The pharmaceutical composition according to [1] above, wherein the small cell lung cancer is recurrent, and / or refractory, and / or unresectable, and / or late-stage, and / or metastatic small cell lung cancer, preferably small cell lung cancer for which treatment with chemotherapy drugs and / or targeted drugs has failed, small cell lung cancer that has received at least two types of chemotherapy, refractory recurrent small cell lung cancer, or locally late-stage and / or late-stage metastatic small cell lung cancer. [3] The pharmaceutical composition according to [1] or [2] above, wherein the second therapeutic agent is one or more of a chemotherapeutic agent, a small molecule targeted antitumor drug, an immunotherapeutic agent, and a large molecule antibody drug. [4] The chemotherapeutic agent is oxaliplatin, cisplatin, carboplatin, nedaplatin, dicycloplatin, lobaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, miriplatin, satraplatin, gemcitabine, capecitabine, ancitabine, fluorouracil, tegadifur, doxifluridine, tegafur, carmofur, trifluridine, paclitaxel, albumin-bound paclitaxel and docetaxel, camptothecin, hydroxycamptothecin, 9-aminocamptothecin, 7-ethylcamptothecin, irinotecan, topotecan, vinorelbine, vinblastine, vincristine ... Desine, vinflunine, epirubicin, adriamycin, daunorubicin, pirarubicin, amrubicin, idarubicin, mitoxantrone, aclarubicin, valrubicin, zorubicin, pixantrone, pemetrexed, carmustine, melphalan, etoposide, teniposide, mitomycin, ifosfamide, cyclophosphamide, azacitidine, methotrexate, bendamustine, liposomal adriamycin, actinomycin D, bleomycin, pingyangmycin, temozolomide, dacarbazine, peplomycin, eribulin, plinabulin, sapacitabine, treosulfan, 153 The pharmaceutical composition according to the above [3], which is one or more of Sm-EDTMP, tegafur, gimeracil, oteracil potassium, and encequidar. [5] The pharmaceutical composition according to [3] above, wherein the immunotherapeutic drug is one or more of interferon, interleukin, sirolimus, everolimus, ridaforolimus, and temsirolimus. [6] The small molecule targeted antitumor drugs include imatinib, sunitinib, nilotinib, bosutinib, saracatinib, pazopanib, trabectedin, regorafenib, cediranib, bortezomib, panobinostat, carfilzomib, ixazomib, apatinib, erlotinib, afatinib, crizotinib, ceritinib, and bem Rafenib, dabrafenib, cabozantinib, gefitinib, dacomitinib, osimertinib, olmutinib, alectinib, brigatinib, lorlatinib, trametinib, larotrectinib, icotinib, lapatinib, vandetanib, selumetinib, sorafenib, olmutinib, savolitinib, fruquintinib, Nutrectinib, dasatinib, ensartinib, lenvatinib, itacitinib, pyrotinib, binimetinib, erdafitinib, axitinib, neratinib, cobimetinib, acalabrutinib, famitinib, masitinib, ibrutinib, rociletinib, nintedanib, lenalidomide, LOXO-292, vorolanib, bemcentinib, capmatinib, entrectinib, TAK-931, ALT-803, palbociclib, famitinib L-malateL-malate, LTT-462, BLU-667, ningetinib, tipifarnib, poziotinib, DS-1205c, capivasertib, SH-1028, metformin, seliciclib, OSE-2101, APL-101, berzosertib, idelalisib, lerociclib, ceralasertib, PLB-1003, tomivosertib, AST-2818, SKLB-1028, D-0316, LY-3023414, allitinib ), MRTX-849, AP-32788, AZD-4205, lifirafenib, vactosertib, mibebresib, napabucasin, sitravatinib, TAS-114, molibresib, CC-223, rivoceranib, CK-101, LXH-254, simotinib, GSK-3368715, TAS-0728, masitinib, tepotinib, HS-10296, AZD-4547, merestinib, olaptesed pegol pegol, galunisertib, ASN-003, gedatolisib, defactinib, 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 succinatesuccinate, tesevatinib, SPH-1188-11, BPI-15000, copanlisib, niraparib, olaparib, veliparib, talazoparib tosylate The pharmaceutical composition according to [3] above, wherein the active ingredient is one or more of the following: tosylate, DV-281, siremadlin, telaglenstat, MP-0250, GLG-801, ABTL-0812, bortezomib, tucidinostat, vorinostat, resminostat, epacadostat, tazemetostat, entinostat, mocetinostat, quisinostat, LCL-161, and KML-001. [7] The pharmaceutical composition according to the above [3], wherein the large molecule antibody drug is any one or more of an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA-4 antibody, an anti-PDGFRα antibody, bevacizumab, ramucirumab, pertuzumab, trastuzumab, cetuximab, nimotuzumab, panitumumab, necitumumab, dinutuximab, rituximab, ibritumomab, ofatumumab, obinutuzumab, alemtuzumab, daratumumab, gemtuzumab, elotuzumab, brentuximab, inotuzumab ozogamicin, and blinatumomab. [8] The anti-PD-1 antibody is any one or more selected from nivolumab, pembrolizumab, durvalumab, toripalimab, sintilimab, camrelizumab, tislelizumab, genolimuzumab, lizumab, HLX-10, BAT-1306, AK103, AK104, CS1003, SCT-I10A, F520, SG001, and GLS-010, and the anti-PD-L1 antibody is atezolizumab, avelumab, durvalumab, scintilimab, genolimuzumab, lizumab, HLX-10, BAT-1306, AK103, AK104, CS1003, SCT-I10A, F520, SG001, and GLS-010. The pharmaceutical composition according to the above-mentioned [7], wherein the anti-CTLA-4 antibody is any one or more selected from durvalumab, KL-A167, SHR-1316, BGB-333, JS003, STI-A1014, KN035, MSB2311, HLX-20, and CS-1001, and the anti-CTLA-4 antibody is any one or more selected from ipilimumab, tremelimumab, AGEN-1884, BMS-986249, BMS-986218, AK-104, and IBI310. [9] The pharmaceutical composition according to [3] above, wherein the second therapeutic agent is one or more of a fluoropyrimidine derivative, a podophyllum drug, a platinum drug, a camptothecin drug, and an anti-PD-1 antibody.

[10] The second therapeutic agent is (1) tegafur, gimeracil, or oteracil potassium; (2) etoposide and at least one platinum-based drug; (3) one, two, three, or four of cyclophosphamide, vincristine, methotrexate, and etoposide; (4) one, two, or three of cyclophosphamide, adriamycin, and vincristine; (5) one, two, or three of cyclophosphamide, adriamycin, and etoposide; (6) one, two, or three of ifosfamide, etoposide, and cisplatin; (7) one, two, three or four of carboplatin, paclitaxel, and etoposide; (8) one, two, three or four of cisplatin, vincristine, adriamycin, and etoposide; (9) topotecan; (10) etoposide and lobaplatin; (11) etoposide and cisplatin; (12) etoposide and carboplatin; (13) sintilimab; and (14) irinotecan.

[11] The pharmaceutical composition according to any one of the above [1] to

[10] , wherein the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 3-30 mg, preferably 5-20 mg, more preferably 8-16 mg, even more preferably 8-14 mg, and most preferably 8 mg, 10 mg, or 12 mg.

[12] The pharmaceutical composition according to any one of the above [1] to

[11] , wherein Compound I or a pharmaceutically acceptable salt thereof is administered on days 1 to 14 of each cycle, and one administration cycle is 21 days.

[13] Use of the pharmaceutical composition according to any one of [1] to

[12] above for the manufacture of a drug for treating small cell lung cancer.

[14] A kit for treating small cell lung cancer, comprising: (a) a first type of pharmaceutical composition containing a chemotherapeutic agent and / or a small molecule targeted antitumor agent and / or an immunotherapeutic agent and / or a large molecule antibody drug as an active ingredient; and (b) a second type of pharmaceutical composition containing, as an active ingredient, compound I or a pharmaceutically acceptable salt thereof described in any of [1] to

[12] above.

[15] A method for treating small cell lung cancer, comprising administering to an individual in need thereof the pharmaceutical composition described in any one of [1] to

[12] above.

Claims

【Request Item 1】 【Chemistry 1】 1. A pharmaceutical combination for treating small cell lung cancer, comprising: (i) Compound I or a pharmaceutically acceptable salt thereof; and (ii) at least one second therapeutic agent, wherein the second therapeutic agent is selected from etoposide, a platinum-based agent, irinotecan, and sintilimab.

2. 2. The combination drug of claim 1, wherein the small cell lung cancer is recurrent, and / or refractory, and / or unresectable, and / or late-stage, and / or metastatic small cell lung cancer.

3. 2. The combination drug according to claim 1, wherein the small cell lung cancer is small cell lung cancer for which treatment with chemotherapy drugs and / or targeted drugs has failed, small cell lung cancer that has received at least two types of chemotherapy, refractory recurrent small cell lung cancer, or locally late and / or late metastatic small cell lung cancer.

4. The combination pharmaceutical of claim 1, wherein the platinum-based drug is one or more of oxaliplatin, cisplatin, carboplatin, nedaplatin, dicycloplatin, lobaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, miriplatin, and satraplatin.

5. The combination pharmaceutical according to any one of claims 1 to 4, wherein the second therapeutic agent is any one or more of (1) to (6), which are (1) etoposide and at least one platinum-based drug, (2) etoposide and lobaplatin, (3) etoposide and cisplatin, (4) etoposide and carboplatin, (5) sintilimab, and (6) irinotecan.

6. The combined pharmaceutical composition according to any one of claims 1 to 5, wherein the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 3 to 30 mg.

7. The combined pharmaceutical composition according to claim 6, wherein the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 5 to 20 mg.

8. The combined pharmaceutical composition according to claim 7, wherein the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 8 to 16 mg.

9. The combined pharmaceutical composition according to claim 8, wherein the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 8 to 14 mg.

10. 10. The combination pharmaceutical of claim 9, wherein the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 8 mg, 10 mg, or 12 mg.

11. The combination pharmaceutical of any one of claims 1 to 10, wherein Compound I or a pharmaceutically acceptable salt thereof is administered on days 1 to 14 of each cycle, resulting in a 21-day administration cycle.

12. A medicament for treating small cell lung cancer in combination with a quinoline derivative, the medicament comprising at least one selected from etoposide, a platinum-based drug, irinotecan, and sintilimab, the quinoline derivative being 【Chemistry 2】 The pharmaceutical agent is Compound I or a pharmaceutically acceptable salt thereof.

13. In the manufacture of a medicament for treating small cell lung cancer, 【Transformation 3】 Use of Compound I or a pharmaceutically acceptable salt thereof, which comprises The above use, wherein the medicament is one in which Compound I or a pharmaceutically acceptable salt thereof is administered in combination with at least one second therapeutic agent selected from etoposide, a platinum-based drug, irinotecan, and sintilimab.

14. A combination pharmaceutical composition for treating small cell lung cancer, comprising Compound I or a pharmaceutically acceptable salt thereof and at least one second therapeutic agent, wherein the second therapeutic agent is selected from etoposide, a platinum-based drug, irinotecan, and sintilimab, and Compound I or a pharmaceutically acceptable salt thereof is administered simultaneously or sequentially with the second therapeutic agent. 【Chemistry 4】

Images