CN112121048A

CN112121048A - Quinolines for the combined treatment of esophageal cancer

Info

Publication number: CN112121048A
Application number: CN202010513543.9A
Authority: CN
Inventors: 王善春; 王峰
Original assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd
Current assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd
Priority date: 2019-06-06
Filing date: 2020-06-08
Publication date: 2020-12-25

Abstract

The application belongs to the technical field of medicines, provides a quinoline compound for combined treatment of esophageal cancer, and particularly provides application of combination of a compound I or pharmaceutically acceptable salt thereof and a second therapeutic agent in preparation of a medicine for treating esophageal cancer, and a combined pharmaceutical composition for treating esophageal cancer, wherein the combination comprises the following components in percentage by weight: (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 the combined treatment of esophageal 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 esophageal cancer.

Background

Esophageal Cancer (EC) is a common malignant tumor formed by abnormal hyperplasia of Esophageal squamous epithelium or glandular epithelium, accounting for 2% of all malignant tumors, and about 40-50 million people die of Esophageal cancer every year worldwide. The etiology of esophageal cancer is related to chronic nitrosamine stimulation, inflammation and trauma, genetic factors, and the content of trace elements in drinking water, food and vegetables. Smoking and drinking are common causes of esophageal cancer, and China is a high-incidence region of esophageal cancer and one of high-incidence countries of esophageal cancer in the world, and about 15 million people die each year.

Esophageal cancer has obvious geographical accumulation in China, areas with high incidence and high fatality rate are quite concentrated, northern diseases are more common than southern diseases, while males are more common than females, and most of the cancers are older than 40 years old. The esophageal cancer histology of China is divided into esophageal squamous cell carcinoma, esophageal adenocarcinoma and undifferentiated esophageal cancer, wherein the Esophageal Squamous Cell Carcinoma (ESCC) accounts for over 90 percent, the upper and middle esophageal cancers are mostly squamous cell carcinoma, and the lower esophageal cancer is mostly adenocarcinoma.

The esophageal cancer is divided into early stage, middle stage and middle stage, and the early symptoms of the esophageal cancer are not obvious, so that most of patients with the esophageal cancer have entered the middle and late stages of the esophageal cancer when in clinic, and the optimal treatment time is missed, so that the 5-year survival rate of the patients is low. According to the comprehensive factors of the occurrence part, stage, pathology and the like of the esophageal cancer, methods such as surgical treatment, endoscopic treatment, chemotherapy treatment, radiation treatment and the like are selected. At present, the main treatment method of the esophageal cancer is still surgical operation, wherein the 5-year survival rate of patients in the early stage can reach 30-35 percent, the 5-year survival rate of patients in the middle and late stages is not ideal, the patients are suffered from pains of different degrees in the surgical treatment, and complications are easily caused; radiotherapy is effective against undifferentiated carcinoma of the squamous cell carcinoma and relatively insensitive to adenocarcinoma.

In recent years, based on the deep research of the action mechanism of the antitumor drug, the chemotherapy level of esophageal cancer is continuously improved, but because the esophageal cancer has lower sensitivity to the chemotherapeutic drug, combined chemotherapy is more adopted. The DF scheme (DDP +5-FU) most commonly used for esophageal cancer has larger gastrointestinal toxicity, is easy to cause nausea, vomiting, stomatitis, gastrointestinal mucosal injury and the like; the DFT scheme (PTX + DDP +5-FU) is easy to generate myelosuppression, and meanwhile, cisplatin causes damage to a proximal renal tubule, so that cells are vacuolated, a lumen is expanded, a hyaline tube type is generated, and urea nitrogen and creatinine in blood are increased. Therefore, chemotherapy for esophageal cancer is still greatly limited in clinical application, and the necessity and urgency to provide new treatment regimens for esophageal cancer are also 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 esophageal cancer, in another aspect, the present application provides a pharmaceutical composition for use in a combination for the treatment of esophageal 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 combination pharmaceutical composition for the manufacture of a medicament for the treatment of esophageal cancer.

In yet another aspect, the present application also provides a method of treating esophageal cancer comprising administering to a subject the 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.

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

in some embodiments, the esophageal cancer is esophageal squamous carcinoma and/or esophageal adenocarcinoma and/or undifferentiated esophageal cancer.

In some embodiments, the esophageal cancer is latent esophageal cancer, erosive esophageal cancer, plaque-type esophageal cancer, papillary esophageal cancer, medullary esophageal cancer of intermediate/late esophageal cancer, mushroom-type esophageal cancer, ulcerative esophageal cancer, narrowed (sclerosing) esophageal cancer, luminal esophageal cancer, and/or indeterminate esophageal cancer of early esophageal cancer.

In some embodiments, the esophageal cancer is primary esophageal cancer and/or secondary esophageal cancer. In some embodiments, the esophageal cancer is advanced esophageal cancer. In some embodiments, metastatic esophageal cancer is detected.

In some embodiments, the esophageal cancer is esophageal cancer that failed prior treatment, preferably, the esophageal cancer failed surgical and/or radiation and/or chemotherapeutic drug treatment, more preferably, the esophageal cancer failed treatment with a taxane antineoplastic agent, a vinblastine antineoplastic agent, a platinum complex, and/or a pyrimidine antagonist.

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 pharmaceutical composition for use in combination for the treatment of esophageal 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 pharmaceutical composition for use in combination for the treatment of esophageal 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 pharmaceutical composition for use in combination for the treatment of esophageal 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 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 radiotherapy, in the manufacture of a medicament for the treatment of esophageal cancer.

The present application provides a method for treating a subject having esophageal 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 esophageal cancer comprising administering to a patient in need thereof compound I or a pharmaceutically acceptable salt thereof and at least a second therapeutic agent. In some embodiments, the present application provides a method of treating esophageal 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 esophageal cancer that has progressed or recurred after receiving at least one chemotherapy, 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 esophageal 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 esophageal cancer comprising administering to a patient in need thereof compound I, or a pharmaceutically acceptable salt thereof, and at least a second therapeutic agent. In some embodiments, the compound I or a pharmaceutically acceptable salt thereof is administered in combination with at least one second therapeutic agent for the treatment of primary or secondary esophageal cancer. In some embodiments, the esophageal cancer is an esophageal 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 esophageal 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, in the use or method of treatment, including but not limited to the compound I or a pharmaceutically acceptable salt thereof, may be administered at 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.

In yet another aspect, the present application provides a kit for treating esophageal cancer, comprising compound I or a pharmaceutically acceptable salt thereof and at least one second therapeutic agent, each packaged separately, and optionally instructions.

Esophageal cancer

In some embodiments of the present application, the esophageal cancer includes, but is not limited to, esophageal squamous cell carcinoma, esophageal adenocarcinoma, and undifferentiated esophageal cancer, as classified by histopathology.

In some embodiments, the esophageal cancer is latent esophageal cancer, erosive esophageal cancer, plaque-type esophageal cancer, papillary esophageal cancer, medullary esophageal cancer of intermediate/late esophageal cancer, mushroom-type esophageal cancer, ulcerative esophageal cancer, narrowed (sclerosing) esophageal cancer, luminal esophageal cancer, and/or indeterminate esophageal cancer of the early esophageal cancer, as classified by the morphology of the tumor.

In some embodiments, the esophageal cancer is primary esophageal cancer and/or secondary esophageal cancer; in some embodiments, the esophageal cancer, clinical stage of which includes, but is not limited to, locally advanced, and/or advanced (e.g., stage IIIB/IV) esophageal cancer. In some embodiments, metastatic esophageal cancer is present in some embodiments. Wherein metastatic esophageal 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 esophageal cancer is metastatic esophageal cancer of the lung. In some embodiments, the esophageal cancer is brain metastatic esophageal cancer. In some embodiments, the esophageal cancer is lymph node metastatic esophageal cancer.

In some embodiments of the present application, the esophageal cancer is recurrent; in certain embodiments, the esophageal cancer is refractory; in certain embodiments, the esophageal cancer is unresectable. In some embodiments, the esophageal cancer is an esophageal cancer that failed a chemotherapeutic and/or targeted drug therapy. In some embodiments, the esophageal cancer is esophageal cancer that has received at least two chemotherapy regimens. In some embodiments, the esophageal cancer is esophageal cancer that has received at least two chemotherapeutic drugs. In some embodiments, the esophageal cancer is esophageal cancer that failed second-and beyond-second-line chemotherapy. In one embodiment, the esophageal cancer is refractory recurrent esophageal cancer, wherein "refractory recurrent esophageal cancer" refers to esophageal cancer that is not remitted by chemotherapy, and esophageal cancer that is effective by chemotherapy but shows progression within 3 months after chemotherapy is completed.

A second therapeutic agent

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

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

in the present application, the chemotherapeutic drug includes, but is not limited to, one or more of taxanes, platinum complexes, pyrimidine antagonists, camptothecin and derivatives thereof, anthracyclines, and podophyllum compounds.

Herein, the taxane compound includes but is not limited to one or more of paclitaxel, albumin-bound paclitaxel, paclitaxel liposome and docetaxel; the vinblastine antineoplastic agent comprises one or more of vinblastine, vincristine, vindesine and vinorelbine, vinfunin (vinflunine), nor vinblastine; the platinum complex comprises one or more of miboplatin, cisplatin, carboplatin, dicycloplatin, nedaplatin, oxaliplatin, lopaplatin (Lobalastatin), 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 comprises one or more of epirubicin (epirubicin), adriamycin, daunorubicin, pirarubicin, amrubicin, idarubicin, mitoxantrone, aclarubicin, valrubicin, zorubicin, pixantrone, pyrarubicin and liposome adriamycin; 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, trooshusufine, trooshusuo, dacarbazine, dactinomycin,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 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. The inhibitor includes but is not limited to EGRF inhibitor, HER-2 inhibitor, VEGF inhibitor, cyclooxygenase-2 inhibitor, mTOR kinase inhibitor, ubiquitin-proteasome inhibitor, IGFR1 kinase inhibitor, Bcrab1 tyrosine kinase inhibitor, farnesyl transferase inhibitor, BRAF inhibitor and cyclin dependent kinase inhibitor. Targets for such inhibitors include, but are not limited to, 8 genes of the EGFR signaling pathway KRAS, NRAS, BRAF, PIK3CA, AKT1, PTEN, TP53, and EGFR, as well as VEGFR-2 (vascular endothelial growth factor receptor-2), COX-2 (cyclooxygenase-2), HER2 gene, CMET, FBXW7, CCND1, FGFR1 (fibroblast growth factor receptor 1), PTCH1 (parathyroid hormone-related protein receptor 1), RB 1.

Examples of small-molecule targeted antitumor agents include, but are not limited to, Gefitinib (Gefitinib), Erlotinib (Erlotinib), Lapatinib (Lapatinib), Sunitinib (Sunitinib), endostatin (Endostar), Celecoxib (Celecoxib), Aspirin (asperin), Rapamycin (Rapamycin), Imatinib (Imatinib), Tipifarnib, frataxinol (Flavopiridol), Apatinib (Apatinib), Aflibercept (Aflibercept), Afatinib (Afatinib), Crizotinib (Crizotinib), tratinib (Ceritinib), Vemurafenib (Vemurafenib), Dabrafenib (dabrafrafrafenib), cabbozantinib (cabozatinib), dactinotinib (Daritinib), valtinib (nilotinib), valcaninib (valcaninib), Sorafenib (valcaninib), Sorafenib (Sorafenib), Sorafenib (valcaninib), Sorafenib (valcanib), Sorafenib (valcaninib), Sorafenib (valcanib), valcaninib (valcanib), Sorafenib (valcaninib), Sorafenib (valcanib), valcanib (valcaninib (valcanib), valcaninib (valcaninib), valcanib), valcaninib (valcanib), val, The drug composition may be any one of the group consisting of imatinib (Olmutinib), Wolintinib (Savoltinib), Fuquintinib (Fruquintinib), Entrictinib (Entretinib), Dasatinib (Dasatinib), Ensartinib (Ensartinib), Lenvatinib (Lenvatinib), itacinib, Pyrutinib (Pyrotinib), Bimetinib (Binimetinib), Iratinib (Erdatinib), Asertinib (Axinib), Neratinib (Neratinib), Cobimitinib (Cobimetinib), Acalatinib, Famitatinib (Famitiniib), Maratinib (Masitinib), Ibutinib (Ibrutinib), Rociltinib, Nectitinib (Nominatinib), Nectinib (Nominanib), Nominanib (Vectinib), Nominanib (Nominanib), Nominanib (Nominandib (Nominanib), Nominanib (Nominanib), Nominanib (Nominanib), Nominandib (Nominanib (Nominandib), No, ALT-803, Palbociclib, Famitinib L-Malate, LTT-462, BLU-667, Ningetinib, Poziotinib, DS-1205c, Capivasertib, SH-1028, metformin, Sericib, OSE-2101, APL-101, Berzosertib, Idelalisib, Lerociclib, Ceralartib, PLB-1003, Tomivorib, AST-2818, SKLB-1028, D-0316, LY-3023414, Allitinib, TX-849, AP-788, AZD-4205, Lifrafenib, Vactosertib, Mivebresib, Napabuitinib, Sitravatinib, TAS-114, Silibribesib, Ricitenbic-3290254, Ricertib-497, Germinib-4596, Mas-087, Masl-1027, Galilenib-3, Germinib-369, Galilex-3, Germinib-369, Mas-369, Germinib-3, Germinib-3, Germinib-3, Germinib-3, Germinib-3, Germinib, Ge, 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, Olaparib, Veliparib, Talazoparib Tosylate, DV-281, Siremaddin, Telaglenastat, MP-0250, GLG-801, ABTL-0812, Bortezomib, Panobinostat (Panobinostat), Tucidinostat, Vorinostat, Resminostat, Epacinostat, Tazemetostat, Endostat, Moceostat, Quisinostat, LCL-001, KML-161, or a plurality thereof.

In some embodiments, the small molecule targeted anti-tumor drug is one or more of gefitinib, erlotinib, lapatinib, sunitinib, sorafenib, endostatin, celecoxib, aspirin, rapamycin, imatinib, Tipifarnib, frataxin.

In some embodiments, the second therapeutic agent is a macromolecular antibody drug. 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), Carelizumab (Camrelizumab), tirelinumab (BGB-A317), Jennuzumab (GB226), Rilizumab (LZM009), HLX-10, BAT-1306, AK103(HX008), AK104 (Kangfang), CS1003, SCT-I10A, F520, SG001, and GLS-010.

In some embodiments, the anti-PD-L1 antibody may be selected from any one or more of Abelmizumab (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 (Trastuzmab), trastuzumab-Emtansine (TDM1), Cetuximab (Cotuximab), Nimotuzumab (Nimotuzumab), Panitumumab (Panitumumab), Matuzumab (Matuzumab), Rituzumab (Netuzumab), Dinutuzumab, Rituximab (Rituximab), Titumumab (Ibritumomab), Oatumumab (Ofatumumab), Obinutuzumab (Alemtuzumab), darunavizumab

(Daratumumab), Gemtuzumab Ozogamicin (Gemtuzumab), Epotuzumab (Elotuzumab), Bentuximab (Brentuximab), Oxytuzumab (Inotuzumab Ozogamicin), and Bonatuzumab (Blinatumumab).

In some specific embodiments, the antibody drug is one or more of trastuzumab, 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, sirolimus (Temsirolimus), everolimus (everolimus), Temsirolimus (Temsirolimus), ridaforolimus (ridaforolimus), Temsirolimus; preferably sirolimus (temsirolimus) and everolimus (everolimus).

In some embodiments, the second therapeutic agent is irinotecan.

In some embodiments, the second therapeutic agent is one or more of a taxane and a platinum complex. In some embodiments, the second therapeutic agent is one or more of paclitaxel liposomes and a platinum complex. In some embodiments, the second therapeutic agent is one or more of a taxane and nedaplatin. In some embodiments, the second therapeutic agent is one or both of paclitaxel liposome and nedaplatin.

In some embodiments, the second therapeutic agent is one or both of paclitaxel and carboplatin.

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

In some embodiments, the second therapeutic agent is capecitabine.

In some embodiments, the second therapeutic agent is one, two or three of epirubicin, cisplatin, and fluorouracil, specifically an EDF regimen or an ECF regimen.

In some embodiments, the second therapeutic agent is cisplatin and fluorouracil, in particular the DF regimen.

In some embodiments, the second therapeutic agent is a DF in combination with a radiation therapy regimen.

In some embodiments, the second therapeutic agent is one, two, three, or four of cisplatin, methotrexate, and calcium tetrahydrofolate, specifically a DM regimen.

In some embodiments, the second therapeutic agent is one, two, three, or four of cisplatin, carboplatin, fluorouracil, and interferon, specifically a dual platinum biologic chemotherapeutic regimen.

In some embodiments, the second therapeutic agent is one, two or three of paclitaxel, cisplatin, and etoposide, specifically a TPE regimen.

In some embodiments, the second therapeutic agent is one, two or three of cisplatin, fluorouracil, vinblastine, in particular a DFV combination radiotherapy regimen.

In some embodiments, the second therapeutic agent is one, two or three of cisplatin, fluorouracil and paclitaxel, specifically a DFT regimen.

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, not sequentially.

Further, the combination drug for esophageal cancer is a preparation suitable for any administration mode of oral administration, parenteral administration, intraperitoneal administration, intravenous administration, intra-arterial administration, transdermal administration, sublingual administration, intramuscular administration, rectal administration, transbuccal administration, intranasal administration, inhalation administration, vaginal administration, intraocular administration, topical administration, subcutaneous administration, intralipid administration, intra-articular administration, intraperitoneal administration 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 an EDF protocol. The method comprises the following steps: epirubicin 50mg/m²Day 1, intravenous drip, cisplatin 60mg/m²Intravenous injection on day 1, fluorouracil 200mg/m²Continuously dripping for 21 days; 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 employed in combination with a DF regimen. The method comprises the following steps: cisplatin 20mg/m²Intravenous drip on day 1-5, fluorouracil 750mg/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 28 days.

In certain particular embodiments, compound I or a pharmaceutically acceptable salt thereof is used in combination with a DF in combination with a radiation therapy regimen. The method comprises the following steps: cisplatin 20mg/m²Intravenous drip on day 1-5, fluorouracil 750mg/m²Intravenous drip is carried out on days 1-5; radiotherapy 5000CGY is synchronous with chemotherapy; 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 28 days.

In certain particular embodiments, compound I or a pharmaceutically acceptable salt thereof is used in combination with a DM regimen. The method comprises the following steps: cisplatin 20mg/m²Intravenous injection on day 1-5, methotrexate 200mg/m²Intravenous drip on days 2 and 15; calcium tetrahydrofolate 15mg, intramuscular injection on days 2 and 15. 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 28 days.

In certain particular embodiments, compound I or a pharmaceutically acceptable salt thereof is used in combination with a dual platinum biotherapeutic regimen. The method comprises the following steps: cis-platinum 25mg/m²Intravenous injection on day 2-4, carboplatin 250mg/m²Day 1, intravenous drip, fluorouracil 500mg/m²Intravenous drip on day 1-4, and subcutaneous injection of interferon 30 ten thousand on day 1-28; 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 28 days.

In certain particular embodiments, compound I or a pharmaceutically acceptable salt thereof is used in combination with the UT regimen. The method comprises the following steps: cis-platinum (DDP)50mg/m²Day 1, intravenous injection; paclitaxel 90mg/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 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 a TPE regimen. The method comprises the following steps: paclitaxel 150mg/m²1, 4 days of intravenous drip, cisplatin 15mg/m²Etoposide 50mg/m on days 1 and 4 of intravenous injection²Intravenous drip on days 1 and 4, and rest for one week after three weeks; 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 specific embodiments, compound I or a pharmaceutically acceptable salt thereof is used in combination with a DFV combination radiation therapy regimen. The method comprises the following steps: cisplatin 20mg/m²Intravenous injection on days 1-5 and 17-21, fluorouracil 300mg/m²1-21 days of intravenous drip, 1mg/m of vinblastine²The combination compound I or the pharmaceutically acceptable salt thereof can be selected from but not limited to oral administration with a dose of 3-30 mg once or more times per day, and the continuous administration is stopped for 5 days and 2 days after intravenous drip on days 1-4, 17-20 and 21 days of radiotherapy completion of radiotherapy of 37.5 or 45GY (total amount); one cycle of 21 days.

In certain particular embodiments, compound I or a pharmaceutically acceptable salt thereof is used in combination with the DFT protocol. The method comprises the following steps: cisplatin 20mg/m²Intravenous injection on day 1-5, fluorouracil 750mg/m²Dripping on day 1-5,taxol 175mg/m²Day 1, intravenous drip, 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 28 days.

In some embodiments, a kit of pharmaceutical compositions for treating esophageal 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 esophageal cancer is also provided, which comprises (a) a first pharmaceutical composition comprising a macromolecular antibody 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 esophageal 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.

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 the medicament, especially the chemotherapeutic medicament, on the esophageal cancer, enhance the curative effect and reduce the dosage of the chemotherapeutic medicament, thereby reducing the side effect. The invention provides a new idea for the treatment of esophageal cancer, in particular to the second-line treatment of esophageal cancer which fails to be treated by 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: the subject (a) inhibits the symptoms of the disease, i.e., prevents 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.

As used herein, the term "subject" means a mammal, such as a rodent, feline, canine, and primate. Preferably, the subject according to the present application is a human. The terms "subject", "patient" and "patient" are used interchangeably herein.

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.

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 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 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/pyroxene),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.

The term "neoadjuvant therapy" as used herein refers to systemic therapy prior to local treatment (surgery) to reduce the mass to the descending stage, increase the rate of resection of R0 and kill the invisible metastatic cells early, facilitating subsequent treatment.

The term "resection rate of R0" as used herein refers to the rate of complete tumor resection. Resection integrity should be assessed after surgical treatment, R0 is complete resection of the tumor, margin negative; r1 is incomplete in tumor excision and positive under the lens at the edge; r2 is incomplete excision and is visually positive at the edge.

"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 examples of the present application, the rate of disease control in clinical trials is above 50%, preferably above about 60%, further preferably above about 70%, more preferably above about 80%, especially above 90% in human patients with esophageal cancer.

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.

Example 1

Patients with histologically or cytologically confirmed esophageal squamous carcinoma who are locally advanced and unresectable, locally recurrent or with distant metastasis; the conventional block randomization method is adopted to divide the group A and the group B, and respectively combine the irinotecan and the irinotecan, and the specific administration scheme is as follows:

group a (experimental group):

arotinib hydrochloride in combination with irinotecan: the capsule of Arotinib hydrochloride 12mg (specification: 12 mg/capsule) is administered daily on an empty stomach, and is continuously administered orally for 2 weeks for 1 week, and irinotecan 65mg/m²D1, d8 intravenous drip. 3 weeks is a treatment cycle until disease Progression (PD) or intolerance of toxicity.

Group B (control group):

irinotecan 65mg/m²D1, d8 intravenous drip. 3 weeks is a treatment cycle until disease Progression (PD) or intolerance of toxicity.

The general condition of the patients is described in table 1.

TABLE 1

Description of the general condition of a patient		Test set (n ═ 22)	Control group (n ═ 21)
				Age (year of old)	Mean±SD	61.45±10.41	59.05±7.66
Sex	For male	17	13
					Woman	5	8
ECOG	0	9	11
					1	13	10
Distant organ metastasis	Is free of	13	17
					Is provided with	9	4
Associated with a disease	Is free of	15	14
					Is provided with	7	7
History of surgery	Is free of	8	8
					Is provided with	14	13
History of radiotherapy	Is free of	12	15
					Is provided with	10	6
History of other anti-tumor treatments	Is free of	22	21
					Is provided with	0	0

The observed efficacy indices include Progression Free Survival (PFS), Disease Control Rate (DCR), objective remission rate (ORR, including the ratio of Complete Remission (CR) and Partial Remission (PR)), Overall Survival (OS), quality of life (QoL), safety indices.

In the evaluated data, median progression free survival (mPFS) was 112 days for the test group patients and 66 days for the control group patients (logrank test: P ═ 0.025). The prolonged median progression free survival (mPFS) for the patients in the test group was 56 days, significantly different relative to the control group.

The result of the curative effect analysis is as follows:

the study shows that for esophageal cancer patients, the median progression-free survival time of the irinotecan combined with anirtinib in the treatment scheme is remarkably prolonged compared with that of the single treatment scheme, the Disease Control Rate (DCR) is improved, and the clinical benefit is realized.

Example 2

The patients with esophageal squamous carcinoma with local recurrence proved by pathological histological and/or cytological examination are combined with radiotherapy and nilotinib, and the specific administration is as follows:

radiotherapy: 59.4Gy/1.8Gy/33 Fx; anrotinib hydrochloride capsules: 12mg of pod 1-14 was administered on days 1 to 14 per cycle, with 1 treatment cycle every 3 weeks.

The observed efficacy indices include Objective Remission Rate (ORR), treatment-related toxicity, Local Control Rate (LCR), Distant Metastasis Rate (DMR), disease-free progression survival (PFS), Overall Survival (OS).

This study showed that for esophageal cancer patients, the treatment regimen of amitriptib in combination with radiotherapy is clinically beneficial.

Example 3

The potential resectable esophageal squamous cell carcinoma in the IIB-IVA stage diagnosed by histopathology or cytology has at least one patient with a treated measurable focus (the length and diameter of the helical CT scan is more than or equal to 10mm and meets the requirements of RESCIST version 1.1 standard), and the ambertinib, the paclitaxel liposome and the nedaplatin are jointly administered to carry out preoperative new adjuvant therapy, and the specific administration scheme is as follows:

anrotinib hydrochloride capsules: taking before breakfast on empty stomach 1 time daily, 1 granule (12mg) each time, continuously taking for 2 weeks, 1 cycle every 3 weeks, 2 cycles before operation, 4-6 cycles after operation, and maintaining the Arotinib therapy until the progression;

paclitaxel liposome: 175mg/m²Intravenous drip on day 1 of each cycle, 1 cycle every 3 weeks, 2 cycles before surgery and 4-6 cycles after surgery;

nedaplatin: 80mg/m²Intravenous drip on day 1 of each cycle, 1 cycle every 3 weeks, 2 cycles before surgery and 4-6 cycles after surgery.

The observed efficacy indices include Objective Remission Rate (ORR), Progression Free Survival (PFS), R0 resection rate (complete tumor resection rate), complete pathological remission rate, quality of life (QoL), safety indices.

This study showed that for esophageal cancer patients, there is clinical benefit in the combined paclitaxel liposome and nedaplatin treatment regimen of erlotinib.

Claims

1. The application of the compound I or the pharmaceutically acceptable salt thereof and a second therapeutic agent in the preparation of medicines for treating esophageal cancer, wherein the second therapeutic agent is one or more of chemotherapeutic medicines and/or small molecule targeted antitumor medicines and/or immunotherapy medicines and/or macromolecular antibody medicines,

2. use according to claim 1, wherein the esophageal cancer is esophageal squamous carcinoma and/or esophageal adenocarcinoma and/or undifferentiated esophageal cancer; alternatively, the esophageal cancer is latent esophageal cancer, erosive esophageal cancer, plaque-type esophageal cancer, papillary esophageal cancer, medullary esophageal cancer, mushroom-type esophageal cancer, ulcer-type esophageal cancer, narrowed esophageal cancer, intracavity-type esophageal cancer, and/or indeterminate esophageal cancer.

3. Use according to any one of claims 1-2, wherein the esophageal cancer is primary and/or secondary esophageal cancer and/or esophageal cancer with failed prior therapy and/or advanced esophageal cancer and/or metastatic esophageal cancer, preferably the esophageal cancer is esophageal cancer with failed surgical and/or radiotherapeutic and/or chemotherapeutic drug therapy, more preferably the esophageal cancer is esophageal cancer with failed therapy with taxane antineoplastic agents, vinblastine antineoplastic agents, platinum complexes and/or pyrimidine antagonists.

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, 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 compound is one or more of etoposide, teniposide and epipodophyllotoxin glucopyranoside;

the chemotherapeutic drug further comprises one or more of bleomycin, pingyangmycin, pelomomycin, mitomycin, actinomycin D (dactinomycin), dacarbazine, eribulin, lycium barbarum polysaccharide, methotrexate, thioguanine, pemetrexed, bendamustine temozolomide, Sapacitabine, plinabulin, trooshusuo, 153Sm-EDTMP, tegafur, and encequidar.

5. The use of any one of claims 1-3, wherein the small molecule targeted antineoplastic agent is gefitinib, erlotinib, lapatinib, sunitinib, sorafenib, endostatin, celecoxib, aspirin, rapamycin, imatinib, Tipifarnib, fraxidil, apatinib, aflibercept, afatinib, crizotinib, ceritinib, rofenib, dabrafenib, cabozitinib, dacomitinib, oxitinib, erlotinib, brigatinib, lorartinib, trametinib, erlotinib, vandetanib, seretinib, tematinib, orlitinib, erlotinib, vandetatinib, tematinib, voritinib, emtinib, dasatinib, emtinib, getinib, lenvatinib, itatinib, itatininib, itatinib, erlotinib, amitinib, erlotinib, amitinib, ami, Masitinib, ibrutinib, Rociletinib, lenalidomide, nilotinib, bosutinib, secatinib, pazopanib, trabectedin, regorafenib, furoquintinib, cediranib, bortezomib, carfilzomib, isozamide, LOXO-292, Vorolanib, Bemcentinib, caplatinib, Entretinib, TAK-931, ALT-803, Palbociclib, Famitiniib L-Malatee, LTT-462, BLU-667, Ningetinib, Poziotinib, DS-1205, Capivastib, SH-1028, metformin, Seliciclib, OSE-2101, APL-101, Berzoserib, elisib, Leracilcicificiclib, Leracirtirtinib 1003, PLisnib 1003-1028, PLisb-1028, LKC-848, Valticobertib, Valticib-848, Valticobrevib-1028-848, Valticobertib, Valticib-358, Valticobrevib, Valticib-358, Valciib-32223, Valcebratib-103, Valcebratib-III, Valcebratib, Valceib-7, Valceib-III, L-III, L-III, L, TAS-0728, Masitinib, Tepotitinib, HS-10296, AZD-4547, Merestinib, Olappted Pegol, Galunertib, 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, Copaliparib, Niraparib, Olaparib, Veliparib, Vetapertib, Talazaripid, Talazarist, Talazatib, Tatactolastin-281, Tatactolastin-161, Tatactolastin-08150, Tascal-081, Tascal-081, Tatazost-081, Tacrospovidone, Tacrose, Tacrospovidone-281, Tacrospovidone, Tacrose-50, Tacrospovidone-081, Tacrospovidone, Tacrose, Tacrospovidone, Tacrose, Tacros.

6. 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, sirolimus, everolimus, temsirolimus, despholimus, temsirolimus.

7. 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, oxizumab ozotan, bornaluzumab, zanolizumab, palivizumab, tefrazezumab, certolizumab, charilumab, charilex strain mab, gravelizumab, HLX-10, eujelizumab-1306, AK103, AK104, CS1003, SCT-I10A, SG 520, avelizumab, or an, Durvalumab, KL-A167, SHR-1316, BGB-333, JS003, STI-A1014, KN035, MSB2311, HLX-20, CS-1001, ipilimumab, tiximumab, AGEN-1884, BMS-986249, BMS-986218, AK-104, IBI 310.

8. The use of any one of claims 1-5, wherein the second therapeutic agent is one or both of doxorubicin and cisplatin;

alternatively, the second therapeutic agent is irinotecan;

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

alternatively, the second therapeutic agent is capecitabine;

or, the second therapeutic agent is one, two or three of epirubicin, cisplatin and fluorouracil;

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

or, the second therapeutic agent is one, two or three of cisplatin, methotrexate and calcium tetrahydrofolate;

alternatively, the second therapeutic agent is one, two, three or four of cisplatin, carboplatin, fluorouracil and interferon;

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

alternatively, the second therapeutic agent is one, two or three of paclitaxel, cisplatin and etoposide;

or the second therapeutic agent is one, two or three of cisplatin, fluorouracil and vinblastine;

alternatively, the second therapeutic agent is one, two or three of cisplatin, fluorouracil and paclitaxel.

9. The use according to any one of claims 1 to 6, wherein the daily dose for the administration of quinoline compound I or a pharmaceutically acceptable salt thereof is from 3 mg to 30mg, preferably from 5mg to 20mg, 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 6, wherein the quinoline compound I or the pharmaceutically acceptable salt thereof is administered in a manner that is separated by 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.