Drug combination of quinoline derivative and anti-PD-1 monoclonal antibody

Abstract

Provided is a pharmaceutical combination of a quinoline derivative and a PD-1 monoclonal antibody, which comprises a tyrosine kinase inhibitor and an immune checkpoint inhibitor, wherein the tyrosine kinase inhibitor is a compound of formula I or a pharmaceutically acceptable salt thereof. The pharmaceutical combination has good anti-head, neck and chest tumor activity.

Description

Technical Field

[0001] This application belongs to the field of pharmaceutical technology and relates to combination therapies that can be used for anti-tumor treatment. Specifically, this application relates to a combination based on a quinoline derivative and a PD-1 monoclonal antibody and its use in anti-head, neck, and thoracic tumors. Background Art

[0002] Tyrosine kinases are a group of enzymes that catalyze the phosphorylation of tyrosine residues in proteins and play an important role in intracellular signal transduction. They are involved in the regulation, signal transmission, and development of normal cells and are also closely related to the proliferation, differentiation, migration, and apoptosis of tumor cells. Many receptor tyrosine kinases are associated with tumor formation and can be classified into epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), etc. according to the different structures of their extracellular regions.

[0003] Anlotinib is a quinoline derivative tyrosine kinase inhibitor that acts as a multi-target tyrosine kinase inhibitor (TKI) in influencing tumor angiogenesis and proliferation signal transduction. The main targets include: receptor tyrosine kinases vascular endothelial growth factor receptor (VEGFR) 1 to 3, epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR) 1 to 4, platelet-derived growth factor receptor (PDGFR) α and β, and stem cell factor receptor (SCFR) 7, 8, and 9. A phase 2 trial showed that anlotinib could improve progression-free survival and had potential benefits for overall survival (Han B, et al. Br J Cancer. 2018; 118(5): 654-661). A multi-center, double-blind, phase 3 randomized clinical trial showed that in Chinese patients, anlotinib led to prolonged overall survival and progression-free survival, and this finding indicated that anlotinib was well tolerated and was a potential third-line or further treatment for patients with advanced NSCLC (Han B, et al. JAMA Oncol. 2018 Nov; 4(11): 1569-1575).

[0004] Document WO2008112407 discloses a tyrosine kinase inhibitor 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl]cyclopropanamine of the quinoline derivative class and its preparation method in Example 24. Its structural formula is shown as Formula I:

[0005]

[0006] PD-1 (programmed death-1) is a key immune checkpoint receptor expressed by activated T and B lymphocytes and mediates immunosuppression. Its ligands include at least PD-L1 and PD-L2. PD-L1 (Programmed death-ligand 1), also known as CD274 or B7-H1, is a 40 kDa type I transmembrane protein encoded by the CD274 gene and is a ligand of PD-1. Both PD-L1 and PD-1 belong to the immunoglobulin superfamily and are composed of two extracellular Ig domains, namely the N-terminal V domain and the C-terminal constant domain. The binding interfaces of PD-L1 with programmed death receptor-1 (PD-1) and B7-1 (CD80) are on the IgV-like domain (Lin et al. (2008) PNAS 105: 3011-3016). PD-L1 contains a conserved short intracellular tail region (about 30 amino acids), and PD-1 contains two cytoplasmic tyrosine-based signaling motifs, namely immunoreceptor tyrosine-based inhibitory motif (ITIM) and immunoreceptor tyrosine-based switch motif (ITSM). After T cell stimulation, PD-1 recruits the tyrosine phosphatase SHP-2 to the ITSM motif in its cytoplasmic tail, resulting in dephosphorylation of effector molecules (such as CD3ζ, PKCθ, and ZAP70) involved in the CD3+ T cell signaling cascade (Freeman et al. (2000) J Exp Med 192: 1027-34; Latchman et al. (2001) Nat Immunol 2: 261-8; Carter et al. (2002) Eur J Immunol 32: 634-43). PD-L1 is widely distributed not only on leukocytes and non-hematopoietic cells in lymphoid and non-lymphoid tissues but also on various cancer cells, highly expressed on the surface of various tumor cells, and the malignancy and poor prognosis of tumors are closely related to the expression level of PD-L1. There is clinical data indicating that high tumor expression of PD-L1 is associated with increased tumor invasiveness and poor prognosis.The formation of the PD-1 / PD-L1 complex transmits inhibitory signals and negatively regulates T cell immune responses; it inhibits TCR-mediated T cell activation, cytokine production, and T cell proliferation (Fife et al. (2011) Nature Immunology 10: 1185-1193); induces exhaustion or anergy among antigen-specific T cells (Hofmeyer et al. (2011) Journal of Biomedicine and Biotechnology 2011: 1-9); promotes the differentiation of Th1 cells into Foxp3+ regulatory T cells (Armanath et al. (2011) Science TransMed 3: 1-13; Francisco et al. (2009) J. Exp. Med. 206: 3015-3029); and induces apoptosis of effector T cells. Disruption of the PD-L1 gene results in upregulated T cell responses and the generation of autoreactive T cells (Latchman et al. (2004) PNAS 101: 10691-10696). Blockade of PD-1 or PD-L1 antibodies leads to increased anti-tumor immunity (Iwai et al. (2002) PNAS 99: 12293-12297).

[0007] Chinese Patent Document CN106977602A discloses a PD-1 monoclonal antibody 14C12H1L1, which can effectively block the binding of PD1 and PD-L1 and shows good anti-tumor activity.

[0008] The biggest challenge encountered by predecessors in the process of tumor immunotherapy is the poor efficacy caused by tumor immune tolerance and escape. Therefore, it has important theoretical significance and application value to break the immune tolerance established by the body against tumor cells through the combined use of small molecule anti-tumor compounds and anti-PD-1 / PD-L1 antibodies. Summary of the Invention

[0009] The object of the present invention is to provide at least a drug combination comprising a tyrosine kinase inhibitor and a human PD-1 antibody, wherein the human PD-1 antibody comprises a light chain and a heavy chain, the light chain comprises light chain complementarity determining regions LCDR1, LCDR2, and LCDR3, the light chain complementarity determining regions are respectively composed of the amino acid sequences shown in SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3, and wherein the heavy chain comprises heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3, the heavy chain complementarity determining regions are respectively composed of the amino acid sequences shown in SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6.

[0010] In some embodiments, the tyrosine kinase inhibitor is a compound of Formula I or a pharmaceutically acceptable salt thereof. In some specific embodiments, the tyrosine kinase inhibitor is the hydrochloride salt of the compound of Formula I, namely anlotinib hydrochloride.

[0011] In some embodiments, the human PD-1 antibody comprises a light chain variable region having the amino acid sequence as shown in SEQ ID NO:7 and a heavy chain variable region as shown in SEQ ID NO:8.

[0012] In some embodiments, the human PD-1 antibody is 14C12H1L1.

[0013] In some embodiments, the compound of Formula I may exist in the form of a pharmaceutically acceptable salt or a pharmaceutically acceptable formulation thereof, preferably in the form of its hydrochloride salt.

[0014] In some specific embodiments, the compound is the hydrochloride salt of 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl]cyclopropanamine, namely anlotinib hydrochloride.

[0015] In some embodiments, the pharmaceutical combination comprises: a compound of Formula I or its hydrochloride salt (e.g., dihydrochloride); and the 14C12H1L1 monoclonal antibody or an antigen-binding fragment thereof.

[0016] The object of the present invention also lies in providing at least a use of a pharmaceutical combination for treating tumors, the pharmaceutical combination comprising a tyrosine kinase inhibitor and a human PD-1 antibody, the human PD-1 antibody comprising a light chain and a heavy chain, wherein the light chain comprises light chain complementarity determining regions LCDR1, LCDR2 and LCDR3, the light chain complementarity determining regions are respectively composed of the amino acid sequences shown in SEQ ID NO:1, SEQ ID NO:2 and SEQ ID NO:3, and wherein the heavy chain comprises heavy chain complementarity determining regions HCDR1, HCDR2 and HCDR3, the heavy chain complementarity determining regions are respectively composed of the amino acid sequences shown in SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6.

[0017] In some embodiments, the tyrosine kinase inhibitor is a compound of Formula I or its hydrochloride salt.

[0018] In some embodiments, the human PD-1 antibody comprises a light chain variable region having the amino acid sequence as shown in SEQ ID NO:7 and a heavy chain variable region as shown in SEQ ID NO:8. In some embodiments, the human PD-1 antibody is 14C12H1L1.

[0019] In some embodiments, the use of treating tumors is for treating head, neck, and thoracic tumors. In some embodiments, the head, neck, and thoracic tumors are advanced head, neck, and thoracic tumors. In some embodiments, the head, neck, and thoracic tumors have previously failed or been intolerant to at least one line of platinum-containing chemotherapy. In some embodiments, the head, neck, and thoracic tumors are histologically confirmed head, neck, and thoracic tumors that have failed standard treatment or for which there is no standard treatment method.

[0020] In some embodiments, the use of treating tumors is for treating recurrent / metastatic head and neck squamous cell carcinoma. In some embodiments, the primary sites of the recurrent / metastatic head and neck squamous cell carcinoma are the oral cavity, oropharynx, hypopharynx, or larynx.

[0021] In some embodiments, the use of treating tumors is for treating non-squamous cell carcinoma of the head and neck. In some embodiments, the non-squamous cell carcinoma of the head and neck is advanced / metastatic non-squamous cell carcinoma of the head and neck. In some other embodiments, the non-squamous cell carcinoma of the head and neck is histologically confirmed advanced / metastatic non-squamous cell carcinoma of the head and neck that has failed standard treatment or for which there is no standard treatment method.

[0022] In some embodiments, the use of treating tumors includes treating adenocarcinoma, adenoid cystic carcinoma, mucoepidermoid carcinoma, or lacrimal gland adenocarcinoma.

[0023] In some embodiments, the use of treating tumors is for treating thyroid cancer. In some embodiments, it is anaplastic thyroid cancer. In some other embodiments, it is histologically confirmed anaplastic thyroid cancer that has failed standard treatment or is untreated and inoperable.

[0024] In some embodiments, the use of treating tumors is for treating small cell lung cancer. In some embodiments, the small cell lung cancer is histologically confirmed small cell lung cancer that has failed only one platinum-containing chemotherapy regimen.

[0025] In some embodiments, the use of treating tumors is for treating non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is non-squamous non-small cell lung cancer. In some other embodiments, the non-small cell lung cancer is non-squamous non-small cell lung cancer, and the treatment population is patients in stages IIIB to IV as defined by the IASLC 8th Edition TNM staging system. In some embodiments, the non-small cell lung cancer is non-squamous non-small cell lung cancer that has failed standard treatment. In some embodiments, the non-small cell lung cancer is squamous non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is squamous non-small cell lung cancer, and the clinical stage is stage IIIB, IIIC, or IV (as defined by the IASLC 8th Edition TNM staging system). In some embodiments, the use of treating tumors is for treating non-small cell lung cancer that has failed at least one platinum-containing or non-platinum doublet chemotherapy regimen.

[0026] In some embodiments, the use of treating a tumor is for pleural mesothelioma. In some embodiments, the pleural mesothelioma is recurrent / metastatic pleural mesothelioma. In other embodiments, the pleural mesothelioma is histologically diagnosed recurrent / metastatic pleural mesothelioma that has failed at least one line of chemotherapy and is not surgically resectable or eligible for radical radiotherapy.

[0027] In some embodiments, the use of treating a tumor is for thymic carcinoma. In some embodiments, the thymic carcinoma is recurrent / metastatic thymic carcinoma. In other embodiments, the thymic carcinoma is histologically diagnosed recurrent / metastatic thymic carcinoma that has failed at least one line of chemotherapy and is not surgically resectable or eligible for radical radiotherapy.

[0028] The present invention also provides a method for treating a subject having a head, neck, and thoracic tumor, comprising administering to the subject a therapeutically effective amount of a tyrosine kinase inhibitor and a therapeutically effective amount of a human PD-1 antibody, wherein the human PD-1 antibody comprises a light chain and a heavy chain, wherein the light chain comprises light chain complementarity determining regions LCDR1, LCDR2, and LCDR3, the light chain complementarity determining regions consisting of the amino acid sequences set forth in SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3, respectively, and wherein the heavy chain comprises heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3, the heavy chain complementarity determining regions consisting of the amino acid sequences set forth in SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively. In some embodiments, the tyrosine kinase inhibitor is a compound of Formula I or a hydrochloride thereof. In some embodiments, the human PD-1 antibody comprises a light chain variable region having the amino acid sequence as set forth in SEQ ID NO:7 and a heavy chain variable region having the amino acid sequence as set forth in SEQ ID NO:8. In some embodiments, the human PD-1 antibody is 14C12H1L1.

[0029] The present invention also provides a combination therapy for treating a subject having a head, neck, and thoracic tumor, the method comprising administering to the subject a therapeutically effective amount of a tyrosine kinase inhibitor alone and a therapeutically effective amount of a human PD-1 antibody alone, wherein the human PD-1 antibody comprises a light chain and a heavy chain, wherein the light chain comprises light chain complementarity determining regions LCDR1, LCDR2, and LCDR3, the light chain complementarity determining regions consisting of the amino acid sequences set forth in SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3, respectively, and wherein the heavy chain comprises heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3, the heavy chain complementarity determining regions consisting of the amino acid sequences set forth in SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively.

[0030] The present invention also provides a method for treating a subject suffering from cancer or a tumor, wherein the cancer or tumor is a head, neck, or thoracic tumor, and the method comprises: (i) measuring the levels of PD-1 and / or PD-L1 in a sample of the subject, wherein the subject is PD-1 and / or PD-L1 positive, and (ii) administering to the subject a therapeutically effective amount of an anti-PD-1 and / or PD-L1 antibody or an antigen-binding portion thereof.

[0031] The present invention also provides a method for treating a subject suffering from cancer or a tumor. In certain embodiments, the subject is a patient diagnosed with a head, neck, or thoracic tumor, such as a patient diagnosed with head and neck squamous cell carcinoma, or a patient with non-squamous head and neck cancer, or a patient with thyroid cancer, or a patient with small cell lung cancer, or a patient with non-small cell lung cancer, or a patient with non-squamous non-small cell lung cancer, or a patient with squamous non-small cell lung cancer, or a patient with pleural mesothelioma, or a patient with thymic carcinoma.

[0032] In some embodiments of the present invention, the head, neck, or thoracic tumor is an advanced head, neck, or thoracic tumor. In some embodiments, the head, neck, or thoracic tumor has previously failed or been intolerant to at least one line of platinum-containing chemotherapy treatment. In some embodiments, the head, neck, or thoracic tumor is a histologically confirmed head, neck, or thoracic tumor that has failed standard treatment or for which there is no standard treatment method.

[0033] In some embodiments, the head, neck, or thoracic tumor is recurrent / metastatic head and neck squamous cell carcinoma, and in some embodiments, the primary site of the recurrent / metastatic head and neck squamous cell carcinoma is the oral cavity, oropharynx, hypopharynx, or larynx.

[0034] In some embodiments, the head, neck, or thoracic tumor is non-squamous head and neck cancer, and in some embodiments, the non-squamous head and neck cancer is advanced / metastatic non-squamous head and neck cancer, and in some embodiments, the non-squamous head and neck cancer is a histologically confirmed advanced / metastatic non-squamous head and neck cancer that has failed standard treatment or for which there is no standard treatment method.

[0035] In some embodiments, the head, neck, or thoracic tumor includes adenocarcinoma, adenoid cystic carcinoma, mucoepidermoid carcinoma, or lacrimal gland carcinoma.

[0036] In some embodiments, the head, neck, or thoracic tumor is anaplastic thyroid cancer, and in some embodiments, the thyroid cancer is anaplastic thyroid cancer, and in some other embodiments, the thyroid cancer is a histologically confirmed anaplastic thyroid cancer that has failed standard treatment or has not been treated and is inoperable.

[0037] In some embodiments, the head, neck, or thoracic tumor is small cell lung cancer, and in some embodiments, the small cell lung cancer is a histologically confirmed small cell lung cancer that has failed only one platinum-containing chemotherapy regimen.

[0038] In some embodiments, the head, neck, and chest tumor is non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is non-squamous non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is non-squamous non-small cell lung cancer, and the treatment subject is patients in stages IIIB-IV as defined by the IASLC 8th Edition TNM staging system. In some embodiments, the non-small cell lung cancer is non-squamous non-small cell lung cancer that has failed standard treatment. In some embodiments, the non-small cell lung cancer is squamous non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is squamous non-small cell lung cancer, and the clinical stage is stage IIIB, IIIC, or IV (as defined by the IASLC 8th Edition TNM staging system). In some embodiments, the head, neck, and chest tumor is non-small cell lung cancer that has failed treatment with at least one platinum- or non-platinum-based doublet chemotherapy regimen.

[0039] In some embodiments, the head, neck, and chest tumor is pleural mesothelioma. In some embodiments, the pleural mesothelioma is recurrent / metastatic pleural mesothelioma. In some embodiments, the pleural mesothelioma is histologically confirmed recurrent / metastatic pleural mesothelioma that has failed at least one line of chemotherapy and is not surgically resectable or amenable to radical radiotherapy.

[0040] In some embodiments, the head, neck, and chest tumor is thymic carcinoma. In some embodiments, the thymic carcinoma is recurrent / metastatic thymic carcinoma. In some embodiments, the thymic carcinoma is histologically confirmed recurrent / metastatic thymic carcinoma that has failed at least one line of chemotherapy and is not surgically resectable or amenable to radical radiotherapy.

[0041] In some embodiments, the subject has previously received surgery, chemotherapy, and / or radiotherapy. In some specific embodiments, the subject experiences disease progression after achieving a complete remission following surgery, chemotherapy, and / or radiotherapy. In some specific embodiments, the subject does not achieve a complete remission or a partial remission after surgery, chemotherapy, and / or radiotherapy.

[0042] In some embodiments, the subject has not previously received systemic chemotherapy. In some embodiments, the subject has previously received surgical treatment, radiotherapy, induction chemotherapy, and / or adjuvant chemotherapy, or the subject receives concurrent chemotherapy. In some specific embodiments, the subject has not previously received systemic chemotherapy, but has received surgical treatment, radiotherapy, induction chemotherapy, and / or adjuvant chemotherapy or will receive concurrent chemotherapy. In some specific embodiments, after surgical treatment, radiotherapy, induction chemotherapy, concurrent chemotherapy, and / or adjuvant chemotherapy, the subject experiences disease progression again after achieving a complete remission. In some specific embodiments, after surgical treatment, radiotherapy, induction chemotherapy, concurrent chemotherapy, and / or adjuvant chemotherapy, the subject fails to achieve a complete remission or a partial remission. In some specific embodiments, after surgical treatment, radiotherapy, induction chemotherapy, concurrent chemotherapy, and / or adjuvant chemotherapy, the cancer metastasizes.

[0043] In some embodiments, the drug combination is a fixed combination. In some embodiments, the fixed combination is in the form of a solid pharmaceutical composition or a liquid pharmaceutical composition.

[0044] In some embodiments, the drug combination is a non-fixed combination. In some embodiments, the human PD-1 antibody and the compound of Formula I in the non-fixed combination are each in the form of a pharmaceutical composition.

[0045] The object of the present application also at least lies in providing a drug pack which separately contains single-packaged pharmaceutical compositions in separate containers, wherein, a pharmaceutical composition containing a compound of Formula I or a pharmaceutically acceptable salt thereof is contained in one container, and a pharmaceutical composition containing a human PD-1 antibody is contained in a second container.

[0046] In some embodiments of the present application, the pharmaceutical composition contains a compound of Formula I in an amount of 6 to 168 mg. In some embodiments, the pharmaceutical composition contains a compound of Formula I in an amount selected from 6 mg, 8 mg, 10 mg, 12 mg, 15 mg, 20 mg, 30 mg, 50 mg, 56 mg, 70 mg, 8 mg, 112 mg, 140 mg, 168 mg, or a range formed by any of the above values. In some embodiments, the pharmaceutical composition contains a compound of Formula I in an amount of 10 mg to 12 mg. In some embodiments, the pharmaceutical composition contains a compound of Formula I in an amount of 10 mg. In some embodiments, the pharmaceutical composition contains a compound of Formula I in an amount of 12 mg.

[0047] In some embodiments, the human PD-1 antibody is administered in one or more unitary doses effective to treat the cancer. In some specific embodiments, the unitary dose ranges from about 10 mg to about 1000 mg of the human PD-1 antibody. In some specific embodiments, the unitary dose is selected from about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg of the human PD-1 antibody. In some specific embodiments, the unitary dose is selected from about 200 mg of the human PD-1 antibody.

[0048] In some embodiments, the administration treatment of the human PD-1 antibody is cycled every 2 weeks (14 days) or every 3 weeks (21 days), and preferably the human PD-1 antibody is intravenously administered on the first day (D1) of each cycle. That is, the anti-PD-1 antibody is administered at a frequency of once every two weeks (q2w) or once every three weeks (q3w).

[0049] The present application also aims to provide a unit dosage form, wherein the unit dosage form comprises: a compound component, 6-12 mg of a compound of formula I or its hydrochloride; and an antibody component, 50-350 mg of a human PD-1 antibody or its antigen-binding fragment; wherein the compound component and the antibody component are separately packaged.

[0050] In some embodiments, the unit dosage form comprises: a compound component, 8 mg, 10 mg or 12 mg of a compound of formula I or its hydrochloride; and an antibody component, 100 mg or 200 mg of a human PD-1 antibody or its antigen-binding fragment; wherein the compound component and the antibody component are separately packaged.

[0051] The present application also aims to provide a method for preventing or treating cancer or tumor, wherein one or more portions of the above-mentioned unit dosage form are administered to a subject in need. Preferably, the compound component and the antibody component in the unit dosage form are administered separately. Preferably, the cancer or tumor is a head, neck or thoracic tumor.

[0052] In some embodiments of the present application, anlotinib is administered in combination with 14C12H1L1, with a treatment cycle of every 21 days, and the drug is administered in the following manner: anlotinib 10 mg / time or 12 mg / time, 14C12H1L1 is administered daily from D1 to D14, once every 3 weeks, 200 mg / time.

[0053] In some embodiments of the present application, anlotinib is administered in combination with 14C12H1L1. The administration method of anlotinib hydrochloride capsules is: once a day, 12 mg or 10 mg each time. Oral administration is continued for 2 weeks and then stopped for 1 week, that is, 3 weeks (21 days) is a treatment cycle. If a dose is missed during the medication period, and it is confirmed that the time until the next dose is less than 12 hours, do not take a supplementary dose. The administration method of 14C12H1L1 injection is: once every 3 weeks, 200 mg each time, by intravenous infusion. The infusion time is 60 ± 10 min.

[0054] The results show that the drug combination of anlotinib and 14C12H1L1 in the present application has unexpected effects in preventing or treating head, neck and chest tumors. In multiple clinical applications, it can either inhibit the growth of tumor lesions or reduce the tumor volume. Surprisingly, the experimental results show that the drug combination of anlotinib hydrochloride and 14C12H1L1 can have an obvious synergistic effect and break the immune tolerance of the body established against tumor cells.

[0055] The drug combination of the present invention shows better efficacy than existing therapies in patients with squamous non-small cell lung cancer who have relapsed or metastasized after surgery and / or chemotherapy, and the chemotherapy is, for example, docetaxel combined with lobaplatin treatment.

[0056] The drug combination of the present invention shows better efficacy than existing therapies in patients with non-squamous non-small cell lung cancer who have relapsed or metastasized after chemotherapy, and the chemotherapy is, for example, pemetrexed combined with carboplatin, pemetrexed + nedaplatin, or paclitaxel + nedaplatin treatment.

[0057] The drug combination of the present invention shows better efficacy than existing therapies in patients with small cell lung cancer who have relapsed or metastasized after chemotherapy, and the chemotherapy is, for example, cisplatin combined with etoposide, pemetrexed combined with nedaplatin, or paclitaxel combined with nedaplatin treatment.

[0058] The drug combination of the present invention shows better efficacy than existing therapies in patients with lacrimal gland adenoid cystic carcinoma who have relapsed or metastasized after surgery and / or chemotherapy.

[0059] The drug combination of the present invention shows better efficacy than existing therapies in patients with head and neck squamous cell carcinoma who have relapsed or metastasized after chemotherapy, and the chemotherapy is, for example, paclitaxel combined with cisplatin treatment, or paclitaxel combined with nedaplatin treatment.

[0060] The drug combination of the present invention shows better efficacy than existing therapies in patients with lung cancer who have developed brain metastases or multiple metastases after surgery and / or chemotherapy, and the chemotherapy is, for example, etoposide combined with cisplatin treatment, and the multiple metastases are lymph node metastases, liver metastases, spleen metastases and / or brain metastases.

[0061] The drug combination of the present invention shows better efficacy than existing therapies in patients with thyroid cancer with lymph node metastasis after surgery and / or chemotherapy, and the lymph node metastasis is multiple lymph node metastasis.

[0062] The drug combination of the present invention shows better efficacy than existing therapies in patients with anaplastic thyroid cancer with multiple lymph node metastasis after surgery, and the lymph node metastasis is multiple lymph node metastasis.

[0063] The drug combination of the present invention shows better efficacy than existing therapies in patients with non-squamous non-small cell lung cancer with recurrence or metastasis after chemotherapy, and the chemotherapy is, for example, pemetrexed combined with carboplatin treatment.

[0064] The drug combination of the present invention shows better efficacy than existing therapies in patients with maxillary sinus malignant tumor who are not suitable for surgical treatment, and the maxillary sinus malignant tumor is squamous cell carcinoma.

[0065] Anlotinib

[0066] As used in the present application, the chemical name of the anlotinib (i.e., the compound of formula I) is 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl]cyclopropanamine, and it has the following structural formula:

[0067]

[0068] As used in the present application, the anlotinib includes its non-salt form (for example, free acid or free base), and also includes its pharmaceutically acceptable salts, and both the non-salt form and the salts are included in the protection scope of the present application. For example, the pharmaceutically acceptable salt of the anlotinib can be hydrochloride or dihydrochloride. The dose of anlotinib or its salt involved in the present application, unless otherwise specified, is calculated based on anlotinib free base.

[0069] 14C12H1L1

[0070] As used in the present application, 14C12H1L1 is an anti-PD-1 monoclonal antibody, and its sequence and structure can be found in the literature (CN106977602A). In the 14C12H1L1 monoclonal antibody, LCDR1 contains the sequence QDINTY (SEQ ID NO:1), LCDR2 contains the sequence RAN (SEQ ID NO:2), LCDR3 contains the sequence LQYDEFPLT (SEQ ID NO:3), HCDR1 contains the sequence GFAFSSYD (SEQ ID NO:4), HCDR2 contains the sequence ISGGGRYT (SEQ ID NO:5), and HCDR3 contains the sequence ANRYGEAWFAY (SEQ ID NO:6).

[0071] The amino acid sequence of its light chain variable region is as follows:

[0072] DIQMTQSPSSMSASVGDRVTFTCRASQDINTYLSWFQQKPGKSPKTLIYRANRLVSGVPSRFSGSGSGQDYTLTISSLQPEDMATYYCLQYDEFPLTFGAGTKLELK (SEQ ID NO:7).

[0073] The amino acid sequence of its heavy chain variable region is as follows:

[0074] EVQLVESGGGLVQPGGSLRLSCAASGFAFSSYDMSWVRQAPGKGLDWVATISGGGRYTYYPDSVKGRFTISRDNSKNNLYLQMNSLRAEDTALYYCANRYGEAWFAYWGQGTLVTVSS (SEQ ID NO:8).

[0075] Definitions and explanations

[0076] Unless otherwise specified, the following terms used in the present application have the following meanings. A particular term should not be considered indefinite or unclear without a special definition, but should be understood according to the ordinary meaning in the art. When a trade name appears in the present application, it is intended to refer to its corresponding product, composition or its active ingredient.

[0077] As used herein, the term "antibody" refers to an antigen-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 thereof 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 can be of the IgG1, IgG2, IgG3, or IgG4 isotype.

[0078] The term "isotype" refers to the class of antibody encoded by the heavy-chain constant region gene. 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 of the present application can be derived from any species, including but not limited to mice, rats, rabbits, primates, camels, and humans. The PD-1 / PD-L1 antibodies and fragments thereof can be chimeric antibodies, humanized antibodies, or fully human antibodies.

[0079] The term "humanized antibody" 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 human immunoglobulin sequences. A humanized antibody may contain substitutions in the framework region such that the framework may not be an exact copy of the expressed human immunoglobulin or germline gene sequence.

[0080] "Isolated antibody" means an antibody that is substantially free of other antibodies having different antigen specificities (e.g., an isolated antibody that specifically binds PD-1 / PD-L1 is substantially free of antibodies that specifically bind antigens other than PD-1 / PD-L1). However, an isolated antibody that specifically binds PD-1 / PD-L1 may have cross-reactivity with other antigens, such as PD-1 / PD-L1 molecules from different species. In addition, an isolated antibody may be substantially free of other cellular materials and / or chemicals.

[0081] The "antigen-binding portion" (also referred to as "antigen-binding fragment") of an antibody means one or more fragments of the antibody that retain the ability to specifically bind the antigen bound by the intact antibody.

[0082] As used herein, the term "derived," when used in reference to a molecule or polypeptide relative to a reference antibody or other binding protein, means a molecule or polypeptide that is capable of specifically binding the same epitope as the reference antibody or other binding protein.

[0083] As used herein, the term "EC50" refers to the effective concentration, the 50% maximal response of an antibody. As used herein, the term "IC50" refers to the inhibitory concentration, the 50% maximal response of an antibody. Both EC50 and IC50 can be measured by ELISA or FACS analysis or any other method known in the art.

[0084] The term "treatment" generally refers to an operation to obtain the desired pharmacological and / or physiological effect. This effect can be prophylactic according to completely or partially preventing a disease or its symptoms; and / or can be therapeutic according to partially or completely stabilizing or curing a disease and / or the side effects caused by the disease. "Treatment" as used herein covers any treatment of a patient's disease, including: (a) preventing the occurrence of a disease or symptom in a patient who is susceptible to the disease or symptom but has not been diagnosed with the disease; (b) inhibiting the symptoms of a disease, i.e., preventing its development; or (c) alleviating the symptoms of a disease, i.e., causing the disease or symptom to regress.

[0085] As used herein, the term "systemic treatment" refers to a treatment in which a pharmaceutical substance is delivered through the bloodstream to reach and affect cells throughout the body.

[0086] As used herein, the term "systemic chemotherapy" refers to systemic chemotherapy that does not include chemotherapy for locally advanced disease as part of a multimodal treatment, where chemotherapy for locally advanced disease includes induction chemotherapy, chemotherapy concurrent with radiotherapy, and adjuvant chemotherapy.

[0087] As used herein, the term "subject" refers to a mammal, such as a rodent, feline, canine, and primate. Preferably, the subject according to the present application is a human.

[0088] "Administering" means physically introducing to a subject a composition comprising a therapeutic agent using any of a variety of methods and delivery systems known to those of skill in the art. Routes of administration of immune checkpoint inhibitors (e.g., anti-PD-1 antibodies or anti-PD-L1 antibodies) include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal, or other parenteral routes of administration, such as by injection or infusion. As used herein, the phrase "parenteral administration" refers to a mode of administration other than enteral and topical administration, usually by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratracheal, subcutaneous, subepidermal, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injection and infusion, and in vivo electroporation. In certain embodiments, the immune checkpoint inhibitor (e.g., anti-PD-1 antibody or anti-PD-L1 antibody) is administered by a non-parenteral route, and in certain embodiments, orally. Other non-parenteral routes include topical, epidermal, or mucosal routes of administration, such as, intranasally, vaginally, rectally, sublingually, or topically. Administration can also be carried out, for example, once, multiple times, and / or over one or more extended time periods.

[0089] As used herein, "adverse event" (AE) is any adverse and usually unintended or undesired sign (including abnormal laboratory findings), symptom, or disease associated with the application of a medical treatment. For example, an adverse event can be associated with the activation of the immune system or the expansion of immune system cells (e.g., T cells) in response to a treatment. A medical treatment can have one or more associated AEs, and each AE can have the same or different severity levels. A reference to a method that "modifies an adverse event" refers to a treatment regimen that reduces the incidence and / or severity of one or more AEs associated with the application of different treatment regimens.

[0090] As used herein, "dosing interval" refers to the amount of time elapsed between multiple doses of a formulation disclosed herein administered to a subject. Thus, the dosing interval can be indicated as a range.

[0091] As used herein, the term "dosing frequency" represents the frequency of administration of doses of a formulation disclosed herein over a given time. The dosing frequency can be indicated as the number of administrations per given time, e.g., once a week or once every two weeks.

[0092] The application of the term "flat dose" refers to a dose administered to a patient without regard to the patient's weight or body surface area (BSA). Thus, a flat dose is specified as an absolute amount of a pharmaceutical agent (e.g., an anti-PD-1 antibody), rather than as a mg / kg dose. For example, a 60 kg person and a 100 kg person will receive the same dose of an antibody (e.g., 240 mg of an anti-PD-1 antibody).

[0093] The application of the term "fixed dose" to the compositions of the present application means that two or more different antibodies in a single composition are present in the composition at a specific (fixed) ratio to each other. In certain embodiments, the fixed dose is based on the weight of the antibody (e.g., mg). In certain embodiments, the fixed dose is based on the concentration of the antibody (e.g., mg / ml). In certain embodiments, the ratio of mg of the first antibody:mg of the second antibody is at least about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:15, about 1:20, about 1:30, about 1:40, about 1:50, about 1:60, about 1:70, about 1:80, about 1:90, about 1:100, about 1:120, about 1:140, about 1:160, about 1:180, about 1:200, about 200:1, about 180:1, about 160:1, about 140:1, about 120:1, about 100:1, about 90:1, about 80:1, about 70:1, about 60:1, about 50:1, about 40:1, about 30:1, about 20:1, about 15:1, about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1 or about 2:1. For example, a 3:1 ratio of the first antibody to the second antibody can mean that a vial can contain about 240 mg of the first antibody and 80 mg of the second antibody, or about 3 mg / ml of the first antibody and 1 mg / ml of the second antibody.

[0094] The term "weight-based dose" as referred to herein means a dose administered to a patient that is calculated based on the weight of the patient. For example, when a patient with a body weight of 60 kg requires 3 mg / kg of an anti-PD-1 antibody and 1 mg / kg of an anti-CTLA-4 antibody, one can withdraw an appropriate amount of the anti-PD-1 antibody (i.e., 180 mg) and the anti-CTLA-4 antibody (i.e., 60 mg) at one time from a fixed-dose formulation with a 3:1 ratio of the anti-PD-1 antibody to the anti-CTLA-4 antibody.

[0095] The term "immunotherapy" refers to treating a subject suffering from a disease or at risk of infection or disease recurrence by a method that includes inducing, enhancing, suppressing, or otherwise altering the immune response. "Treatment" or "therapy" of a subject refers to any type of intervention or process performed on the subject, or the administration of an active agent to the subject, with the aim of reversing, alleviating, improving, suppressing, slowing down, or preventing the onset, progression, development, severity, or recurrence of symptoms, complications, or diseases, or biochemical indicators related to the disease.

[0096] As used herein, "PD1 / PD-L1 positive" can be used interchangeably with "at least about 1% PD-1 / PD-L1 expression". In one embodiment, PD-1 / PD-L1 expression can be used by any method known in the art. In another embodiment, PD-1 / PD-L1 expression is measured by automated IHC. In certain embodiments, "PD-1 / PD-L1 positive" means the presence of at least 100 cells expressing PD-1 / PD-L1 on the cell surface.

[0097] "Programmed death receptor-1 (PD-1)" refers to an immunosuppressive receptor belonging to the CD28 family. PD-1 is mainly expressed on previously activated T cells in vivo and binds two ligands, PD-L1 and PD-L2. The term "PD-1" as used herein includes human PD-1 (hPD-1), variants of hPD-1, allotypes, and species homologs, as well as analogs having at least one common epitope with hPD-1.

[0098] "Programmed death ligand-1 (PD-L1)" is one of two cell surface glycoprotein ligands for PD-1 (the other being PD-L2), which downregulates T cell activation and cytokine secretion upon binding to PD-1.

[0099] "Subject" includes any human or non-human animal. The term "non-human animal" includes, but is not limited to, vertebrates such as non-human primates, sheep, dogs, and rodents such as mice, rats, and guinea pigs. In certain embodiments, the subject is a human. The terms "subject", "test subject", and "patient" may be used interchangeably in certain contexts herein.

[0100] A "therapeutically effective amount" or "therapeutically effective dose" of a drug or therapeutic agent is any amount of the drug that, when used alone or in combination with another therapeutic agent, protects a subject from the onset of a disease or promotes the regression of a disease, as evidenced by a decrease in the severity of the disease symptoms, an increase in the frequency and duration of the disease-free symptom phase, or the prevention of damage or disability caused by the disease. The ability of a therapeutic agent to promote disease regression can be evaluated using a variety of methods known to skilled practitioners, such as in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by measuring the activity of the agent in in vitro assays.

[0101] As used herein, a "sub-therapeutic dose" refers to a dose of a therapeutic compound (e.g., an antibody) that is lower than the commonly used or typical dose of the therapeutic compound when administered alone for the treatment of a proliferative disease (e.g., cancer).

[0102] As an example, an "anticancer drug" promotes cancer regression in a subject or prevents further tumor growth. In certain embodiments, a therapeutically effective amount of the drug promotes cancer regression to the point of eliminating the cancer. "Promoting cancer regression" means administering an effective amount of the drug, either alone or in combination with an anti-tumor agent, that results in a decrease in tumor growth or size, necrosis of the tumor, a reduction in the severity of at least one disease symptom, an increase in the frequency and duration of the disease symptom-free phase, or prevention of damage or disability caused by the affliction of the disease. In addition, the terms "effective" and "efficacy" with respect to treatment include pharmacological efficacy and physiological safety. Pharmacological efficacy represents the ability of the drug to promote cancer regression in a patient. Physiological safety represents the level of toxicity or other adverse physiological effects (adverse reactions) at the cellular, organ, and / or organism level caused by the administration of the drug.

[0103] As an example for treating a tumor, a therapeutically effective amount of an anticancer drug can inhibit cell growth 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% relative to an untreated subject, or, in certain embodiments, relative to a patient treated with standard of care therapy. In other embodiments of the present application, tumor regression can be observed and persist for a period of at least about 20 days, at least about 40 days, or at least about 60 days. Despite these ultimate measures of treatment efficacy, the evaluation of immunotherapeutic drugs must also consider "immune-related" response patterns.

[0104] An "immune-related" response pattern refers to a clinical response pattern frequently observed in cancer patients treated with an immunotherapeutic agent that exerts an anti-tumor effect by inducing a cancer-specific immune response or by altering the innate immune process. This response pattern is characterized by a beneficial treatment effect following an initial increase in tumor burden or the appearance of new lesions, which would be classified as disease progression and synonymous with drug failure in the evaluation of traditional chemotherapeutic agents. Thus, the proper evaluation of immunotherapeutic agents may require long-term monitoring of the effects of these agents on the target disease.

[0105] A therapeutically effective amount of a drug includes a "preventive effective amount", which is any amount of the drug that inhibits the occurrence or recurrence of cancer when administered alone or in combination with an anti-tumor agent to a subject at risk of developing cancer (e.g., a subject with a pre-malignant condition) or a subject at risk of cancer recurrence. In certain embodiments, the preventive effective amount completely prevents the occurrence or recurrence of cancer. "Inhibiting" the occurrence or recurrence of cancer means reducing the likelihood of the occurrence or recurrence of cancer, or completely preventing the occurrence or recurrence of cancer.

[0106] "Recurrent" cancer is cancer that regenerates at the initial site or at a distant site after responding to initial treatment (e.g., surgery). "Local recurrent" cancer is cancer that appears at the same location as the previously treated cancer after treatment.

[0107] "Unresectable" cancer cannot be removed by surgery.

[0108] "Metastatic" cancer refers to cancer that spreads from one part of the body (e.g., the lungs) to another part of the body.

[0109] The use of alternatives (e.g., "or") should be understood to mean any one, two, or any combination of the alternatives. The indefinite article "a" or "an" as used herein should be understood to mean "one or more / one or more kinds" of any listed or enumerated component.

[0110] The terms "about", "approximately", or "substantially comprise" mean a value or a composition within an acceptable error range of a specific value or composition determined by a person of ordinary skill in the art, which will depend in part on how the value or composition is measured or determined, i.e., the limitations of the measurement system. For example, "about", "approximately", or "substantially comprise" may mean within 1 or more standard deviations in accordance with the practice in the art. Alternatively, "about" or "substantially comprise" may mean a range that differs from the parameter or numerical value being modified by at most 10% or 20% (i.e., ±10% or ±20%). For example, about 3 mg may include any number between 2.7 mg and 3.3 mg (for 10%) or between 2.4 mg and 3.6 mg (for 20%). In addition, especially with respect to biological systems or processes, the term may mean up to an order of magnitude or up to 5 times the numerical value. When a specific value or composition is provided in the present application and the claims, unless otherwise stated, the meaning of "about" or "substantially comprise" should be assumed to be within the acceptable error range of that specific value or composition.

[0111] As used herein, the terms "about once a week", "about once every two weeks", or any other similar dosing interval term refers to an approximation. "About once a week" can include every 7 days ± 1 day, i.e., every 6 days to every 8 days. "About once every two weeks" can include every 14 days ± 3 days, i.e., every 11 days to every 17 days. Similar approximations apply to, for example, about once every 3 weeks, about once every 4 weeks, about once every 5 weeks, about once every 6 weeks, and about once every 12 weeks. In certain embodiments, a dosing interval of about once every 6 weeks or about once every 12 weeks means that the first dose can be administered on any day of the first week, and then the second dose can be administered on any day of the sixth or twelfth week, respectively. In other embodiments, a dosing interval of about once every 6 weeks or about once every 12 weeks means that the first dose is administered on a specific day of the first week (e.g., Monday), and then the second dose is administered on the same day (i.e., Monday) of the sixth or twelfth week, respectively. Similar principles apply to phrases including, but not limited to, "about once every 2 weeks", "about once a month", etc.

[0112] As described herein, any concentration range, percentage range, ratio range, or integer range should be understood to include any integer value within the recited range, and when appropriate, include its fractions (such as tenths and hundredths of an integer), unless otherwise indicated.

[0113] Unless otherwise specified, "about" or "approximately" in this application means fluctuating within ±5% of the given specific numerical range, preferably within ±2%, and more preferably within ±1%. For example, a pH of about 5.5 means a pH of 5.5 ± 5%, preferably a pH of 5.5 ± 2%, and more preferably a pH of 5.5 ± 1%.

[0114] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0115] The term "pharmaceutically acceptable salt" includes salts formed by basic radicals and free acids or acid radicals and free bases, such as hydrochloride, hydrobromide, nitrate, sulfate, phosphate, formate, acetate, trifluoroacetate, fumarate, oxalate, maleate, citrate, succinate, mesylate, benzenesulfonate or p-toluenesulfonate, preferably hydrochloride, hydrobromide, sulfate, formate, acetate, trifluoroacetate, fumarate, maleate, mesylate, p-toluenesulfonate, sodium salt, potassium salt, ammonium salt, amino acid salt, etc. In the present application, when forming a pharmaceutically acceptable salt, the molar ratio of the free acid to the basic radical 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 radical 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.

[0116] The term "fixed combination" means that the active components (such as anti-PD-1 antibody or compound of formula 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.

[0117] The term "non-fixed combination" means that two or more active components are administered to a subject simultaneously, in parallel or sequentially without a specific time limit as independent entities (such as pharmaceutical compositions, formulations), wherein the active ingredients administered to the subject reach a therapeutically effective amount level. Examples of non-fixed combinations that can be cited are cocktail therapies, such as administering 3 or more active components. In a non-fixed combination, each of the active components can be packaged, sold or administered as a completely independent pharmaceutical composition. The "non-fixed combination" also includes the combined use between "fixed combinations", or between "fixed combinations" and independent entities of any one or more active components.

[0118] As used herein, "co-administration" or "combined use" means that two or more active substances can be administered to a subject together in a mixture, simultaneously as a single formulation or sequentially in any order as a single formulation.

[0119] The term "pharmaceutical composition" refers to a mixture composed of one or more active ingredients (such as anti-PD-1 antibody or compound of formula I) of the present application or their pharmaceutical combinations and pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compounds or their pharmaceutical combinations of the present application to a subject.

[0120] The term "synergistic effect" refers to the effect (such as inhibiting the growth of colon cancer or alleviating the symptoms of colon cancer) produced by two or more components (such as an anti-PD-1 antibody or a compound of formula I) being greater than the simple addition of the effects of the components when administered alone.

[0121] Route of administration

[0122] The following does not limit the mode of administration of the pharmaceutical combination of the present application.

[0123] The components in the pharmaceutical combination of the present application can be formulated separately or some or all of them can be formulated together. In one embodiment, the pharmaceutical combination of the present application can be formulated into a pharmaceutical composition suitable for single or multiple administrations.

[0124] The components in the pharmaceutical combination of the present application can be administered separately or some or all of them can be administered together. The components in the pharmaceutical combination of the present application can be administered substantially non-simultaneously or some or all of them can be administered substantially simultaneously.

[0125] The components in the pharmaceutical combination of the present application can be administered independently or some or all of them can be administered together by various suitable routes, including but not limited to oral or parenteral (by intravenous, intramuscular, topical or subcutaneous routes). In some embodiments, the components of the pharmaceutical combination of the present application can be administered independently or some or all of them can be administered together orally or by injection, such as intravenous injection or intraperitoneal injection.

[0126] The components in the pharmaceutical combination of the present application can be independently or some or all of them can be together suitable dosage forms, including but not limited to tablets, lozenges, pills, capsules (such as hard capsules, soft capsules, enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersants and dosage forms of sustained-release preparations for oral or non-oral administration.

[0127] The components in the pharmaceutical combination of the present application can independently or some or all of them can be together contain a pharmaceutically acceptable carrier and / or excipient.

[0128] The pharmaceutical combination of the present application may further contain an additional therapeutic agent. In one embodiment, the additional therapeutic agent can be a cancer therapeutic agent known in the art.

[0129] The present application further includes the following:

[0130] 1. A pharmaceutical combination, comprising:

[0131] a) A human PD-1 antibody, said human PD-1 antibody comprising a light chain and a heavy chain, wherein said light chain comprises light chain complementarity determining regions LCDR1, LCDR2 and LCDR3, said light chain complementarity determining regions being composed of the amino acid sequences shown by SEQ ID NO:1, SEQ ID NO:2 and SEQ ID NO:3 respectively, and wherein said heavy chain comprises heavy chain complementarity determining regions HCDR1, HCDR2 and HCDR3, said heavy chain complementarity determining regions being composed of the amino acid sequences shown by SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6 respectively, and

[0132] b) A tyrosine kinase inhibitor, wherein said tyrosine kinase inhibitor is a compound of formula I or a pharmaceutically acceptable salt thereof,

[0133]

[0134] 2. The pharmaceutical combination according to item 1, wherein the pharmaceutically acceptable salt of the compound of formula I is the hydrochloride salt of 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl]cyclopropanamine, preferably the dihydrochloride salt.

[0135] 3. The pharmaceutical combination according to any one of the foregoing, wherein said human PD-1 antibody comprises a light chain variable region having the amino acid sequence as shown by SEQ ID NO:7 and a heavy chain variable region as shown by SEQ ID NO:8.

[0136] 4. The pharmaceutical combination according to any one of the foregoing, wherein said human PD-1 antibody is 14C12H1L1.

[0137] 5. The pharmaceutical combination according to any one of the foregoing, said pharmaceutical combination being a non-fixed combination.

[0138] 6. The pharmaceutical combination according to any one of the foregoing, wherein the human PD-1 antibody and the compound of formula I or a pharmaceutically acceptable salt thereof in said non-fixed combination are each in the form of a pharmaceutical composition.

[0139] 7. Use of the pharmaceutical combination according to any one of the foregoing in the treatment or prevention of head, neck and chest tumors.

[0140] 8. The use according to any one of the foregoing, said pharmaceutical combination being used for the treatment of advanced head, neck and chest tumors.

[0141] 9. The use according to any one of the foregoing, said pharmaceutical combination being used for the treatment of advanced head, neck and chest tumors and having received at least one line of platinum-containing regimen systemic chemotherapy.

[0142] 10. Use according to any one of the above, wherein the pharmaceutical combination is used for treating squamous cell carcinoma of the head and neck, non-squamous carcinoma of the head and neck, adenocarcinoma, adenoid cystic carcinoma, mucoepidermoid carcinoma, squamous cell carcinoma, lacrimal gland adenocarcinoma, thyroid carcinoma, small cell lung cancer, non-small cell lung cancer, pleural mesothelioma or thymic carcinoma.

[0143] 11. Use according to any one of the above, wherein the pharmaceutical combination is used for treating recurrent / metastatic squamous cell carcinoma of the head and neck, advanced / metastatic non-squamous carcinoma of the head and neck, anaplastic thyroid carcinoma, small cell lung cancer with failure of platinum-containing chemotherapy regimens, non-squamous non-small cell lung cancer, squamous non-small cell lung cancer, recurrent / metastatic pleural mesothelioma or recurrent / metastatic thymic carcinoma.

[0144] 12. Use according to any one of the above, wherein the unified administration dose of the hydrochloride salt of the compound of formula I in the pharmaceutical combination is about 10 mg / time or 12 mg / time, and the unified administration dose of 14C12H1L1 is about 200 mg / time.

[0145] 13. Use according to any one of the above, wherein the hydrochloride salt of the compound of formula I in the pharmaceutical combination is administered once a day, 12 mg or 10 mg each time, orally for 2 consecutive weeks and then stopped for 1 week, and the 14C12H1L1 injection is administered once every 3 weeks, 200 mg / time.

[0146] 14. A product comprising a container containing a fixed dose of the hydrochloride salt of the compound of formula I and the 14C12H1L1 antibody, wherein the fixed dose of the hydrochloride salt of the compound of formula I is selected from about 8 mg, about 10 mg and about 12 mg, and the fixed dose of the 14C12H1L1 antibody is selected from about 100 mg and about 200 mg. Detailed Embodiments

[0147] The present application will be further described below in conjunction with specific embodiments. However, these embodiments in the present application are only used for illustration and do not limit the scope of the present application. Similarly, the present application is not limited to any specific preferred implementation described herein. Those skilled in the art should understand that equivalent replacements or corresponding improvements made to the technical features of the present application still fall within the protection scope of the present application. Unless otherwise specified, the reagents used in the following examples are all commercially available products, and the preparation of solutions can adopt conventional techniques in the art.

[0148] Table 1 Abbreviation Table

[0149]

[0150]

[0151] "Failure of platinum-containing chemotherapy regimens" means disease progression or intolerable toxic side effects during or after receiving first-line chemotherapy or chemoradiotherapy with platinum-containing regimens.

[0152] "Non-small cell lung cancer that has failed standard treatment" refers to non-small cell lung cancer in which "patients with sensitive EGFR gene mutations need to have failed treatment with at least one EGFR-TKI inhibitor; or, if patients have the EGFR-T790M mutation, they need to have failed treatment with third-generation EGFR inhibitors; or, ALK gene rearrangement positive: failed treatment with ALK inhibitors; or, if the patient has only received crizotinib treatment, then failed treatment with one other ALK inhibitor; or, ROS1 gene rearrangement positive: failed treatment with ROS1 inhibitors; or, other gene mutations positive or driver gene negative: previously failed treatment with at least one platinum-based doublet chemotherapy regimen".

[0153] "Non-small cell lung cancer that has failed platinum-containing or non-platinum doublet chemotherapy regimens" refers to disease progression or intolerable toxic side effects during or after first-line chemotherapy treatment (including during maintenance chemotherapy), with imaging evidence of disease progression. "Recurrent / metastatic pleural mesothelioma and thymic carcinoma that have failed at least first-line chemotherapy and are not surgically resectable or amenable to radical radiotherapy" refers to disease progression or intolerable toxic side effects during or after first-line systemic chemotherapy (which may include platinum-based or taxane-based regimens), with imaging evidence of disease progression.

[0154] "14C12H1L1 injection" refers to a medical preparation for injection containing the 14C12H1L1 monoclonal antibody, which is usually administered to patients via intravenous infusion. In specific embodiments, the expression "14C12H1L1 injection, 200 mg / time" can be understood in the usual manner in the art as a liquid medical preparation for injection containing 200 mg of the 14C12H1L1 monoclonal antibody administered to the patient each time.

[0155] Example 1 Clinical Research Protocol - Research Criteria and Endpoints

[0156] 1.1 Inclusion and Exclusion Criteria

[0157] Inclusion Criteria: Patients who meet the following inclusion items can be enrolled in this trial

[0158] 1) Meet all the conditions of any of the following cohorts:

[0159] Cohort 1:

[0160] a) Patients with histologically confirmed recurrent / metastatic head and neck squamous cell carcinoma, with the primary site being the oral cavity, oropharynx, hypopharynx, or larynx;

[0161] b) Have failed or been intolerant to at least one prior line of platinum-containing chemotherapy. For patients who have received neoadjuvant chemotherapy, concurrent chemoradiotherapy, or adjuvant chemotherapy, if recurrence / metastasis occurs within 6 months after the end of the last treatment, then that treatment regimen counts as a first-line treatment regimen.

[0162] Cohort 2:

[0163] Patients with histologically confirmed advanced / metastatic non-squamous head and neck cancer who have failed standard treatment or for whom there is no standard treatment method (such as adenocarcinoma, adenoid cystic carcinoma, mucoepidermoid carcinoma, and lacrimal gland adenocarcinoma, etc.).

[0164] Cohort 3:

[0165] Patients with histologically confirmed anaplastic thyroid cancer that has failed standard treatment or is untreated, and is inoperable, and the patient is expected to survive for more than 2 months.

[0166] Cohort 4:

[0167] Patients with histologically confirmed small cell lung cancer who have failed only one platinum-containing chemotherapy regimen;

[0168] Definition of treatment failure: Disease progression or intolerable toxic side effects during or after receiving first-line chemotherapy or chemoradiotherapy with a platinum-containing regimen.

[0169] Cohort 5:

[0170] a) Patients with histologically confirmed non-squamous non-small cell lung cancer and stage IIIB-IV according to the IASLC 8th edition TNM staging system;

[0171] b) Have failed standard treatment, defined as follows:

[0172] · Positive for sensitive EGFR gene mutations: Require failure of at least one EGFR-TKI inhibitor treatment; for patients with EGFR-T790M mutations, they need to have failed treatment with a third-generation EGFR inhibitor before being eligible;

[0173] · Positive for ALK gene rearrangement: Must have failed treatment with an ALK inhibitor; if the patient has only received crizotinib treatment, then they need to have failed treatment with another ALK inhibitor;

[0174] · Positive for ROS1 gene rearrangement: Must have failed treatment with a ROS1 inhibitor;

[0175] · Positive for other gene mutations or negative for driver genes: Have failed at least one platinum-based doublet chemotherapy regimen.

[0176] Cohort 6:

[0177] a) Histologically confirmed squamous non-small cell lung cancer, with clinical stage IIIB, IIIC or IV (according to the 8th edition of the TNM staging system for lung cancer by the International Association for the Study of Lung Cancer and the American Joint Committee on Cancer Classification). Enrollment of mixed carcinomas with a major histological component of squamous cell carcinoma is allowed;

[0178] b) Treatment failure after at least one platinum-based or non-platinum-based doublet chemotherapy regimen.

[0179] Definition of treatment failure: Disease progression or intolerable toxic side effects during or after first-line chemotherapy (including during maintenance chemotherapy), and there must be imaging evidence of disease progression. For adjuvant treatment (chemotherapy or chemoradiotherapy), if disease progression occurs during or within 6 months after treatment, it should be counted as a first-line treatment regimen.

[0180] Cohort Seven:

[0181] Patients with histologically confirmed recurrent / metastatic pleural mesothelioma or thymic carcinoma who have failed at least one line of chemotherapy and are not surgically resectable or eligible for radical radiotherapy;

[0182] Definition of treatment failure: Disease progression or intolerable toxic side effects during or after first-line systemic chemotherapy (which may include platinum-based or taxane-based regimens), and there must be imaging evidence of disease progression. For neoadjuvant / adjuvant treatment (chemotherapy or chemoradiotherapy), if disease progression occurs during or within 6 months after treatment, it should be counted as a first-line treatment regimen.

[0183] 2) At least 18 years old; ECOG performance status: 0 - 1; Estimated survival of more than 3 months (excluding anaplastic thyroid carcinoma);

[0184] 3) Presence of measurable lesions defined by RECIST 1.1 criteria. A previously irradiated lesion can be considered a measurable lesion only if there is a clear progression after radiotherapy and the previously irradiated lesion is not the only lesion.

[0185] 4) Agree to provide previously archived tumor tissue samples (tissue samples within 2 years before enrollment) or freshly obtained samples. The specimens need to meet the requirement that after formalin fixation and paraffin embedding (FFPE), 10 sections of 4 - 6 μm thickness can be cut from the tumor tissue block for staining and testing. Specimens obtained by fine needle aspiration biopsy, cell smears from pleural effusion drainage and centrifugation, bone lesions without soft tissue components or decalcified bone tumor specimens, and tissue obtained by drill biopsy are not acceptable for biomarker testing. If there are no archived tumor tissue samples within 2 years or the number of sections is less than 10, enrollment can be considered after discussion and approval by the sponsor;

[0186] 5) Normal function of major organs.

[0187] 6) The patient voluntarily joined this study, signed the informed consent form, and had good compliance.

[0188] Exclusion criteria: Subjects who meet any of the following criteria will not be included in this study.

[0189] 1) Those who have previously received local radiotherapy can be included if they meet the following conditions: More than 4 weeks (more than 2 weeks for brain radiotherapy) have passed since the end of radiotherapy until the start of the study treatment; and the target lesions selected for this study are not within the radiotherapy area; or the target lesions are within the radiotherapy area, but have been confirmed to have progressed.

[0190] 2) Brain metastases with symptoms or with symptom control time less than 2 months.

[0191] 3) Patients who have had other malignancies in the past 5 years (except for cured basal cell carcinoma of the skin and carcinoma in situ of the cervix).

[0192] 4) Those with multiple factors affecting oral medications (such as inability to swallow, after gastrointestinal resection, chronic diarrhea, and intestinal obstruction, etc.).

[0193] 5) Imaging (CT or MRI) shows that the tumor invades large blood vessels or has an unclear boundary with blood vessels.

[0194] 6) Received major surgical treatment, incisional biopsy, or obvious traumatic injury within 28 days before the first dose.

[0195] 7) Experienced arterial / venous thromboembolic events within 6 months before the first dose, such as cerebrovascular accident (including transient ischemic attack), deep vein thrombosis, and pulmonary embolism.

[0196] 8) Those with a history of abuse of psychotropic drugs and unable to quit or with mental disorders.

[0197] 9) Participated in other clinical trials within four weeks.

[0198] 10) According to the judgment of the researcher, those with concomitant diseases that seriously endanger the safety of the patient or affect the patient's completion of the study.

[0199] 1.2 Withdrawal criteria

[0200] 1) Disease progression occurred, and the researcher judged that the subject could not benefit from continued treatment.

[0201] 2) Adverse events occurred and could not be tolerated or relieved.

[0202] 3) Subjects who had serious adverse events and were not suitable to continue participating in the study.

[0203] 4) Seriously deviated from or violated the protocol and had an impact on the evaluation of drug safety or effectiveness.

[0204] 5) The subject withdraws the informed consent;

[0205] 6) Those who cannot continue to complete the follow-up on time for various reasons.

[0206] 1.3 Study endpoints

[0207] The first stage: Safety lead-in period

[0208] Primary endpoint:

[0209] The safety and tolerance in the first cycle

[0210] Secondary endpoints:

[0211] Objective response rate (ORR), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), etc.

[0212] The second stage: Formal trial

[0213] Primary endpoint

[0214] Objective response rate (ORR)

[0215] Secondary endpoints

[0216] Disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS)

[0217] etc.

[0218] The incidence and severity of adverse events (AE) and serious adverse events (SAE), as well as abnormal laboratory test indicators.

[0219] Example 2. Clinical trial design

[0220] A single-arm, open-label, multi-cohort, multi-center Phase II clinical trial is adopted.

[0221] 2.1 Sample size

[0222] This study has a total of 7 cohorts, and 10 - 20 cases are included in each cohort (adjusted according to the specific trial results).

[0223] 2.2 Imaging assessment design

[0224] The primary efficacy endpoint of this study is ORR, and the results evaluated by the researchers at each research center are adopted. An independent imaging group is additionally set up in this study to conduct a review of the imaging efficacy assessment.

[0225] 2.3 Drug administration plan design

[0226] The drug administration objects are each patient recruited in Cohort 1 to Cohort 7 in Example 1.

[0227] The study is divided into two phases:

[0228] The first phase is a single-arm study, which is a safety lead-in period. Patients will receive anlotinib combined with 14C12H1L1 monoclonal antibody. Each treatment cycle is 21 days. After collecting safety information to determine the RP2D of anlotinib combined with 14C12H1L1 in patients with advanced head, neck and thoracic tumors, a formal trial will be conducted. The lead-in period includes the following two dose groups:

[0229] Dose group A: Anlotinib 10 mg, D1 - D14 + 14C12H1L1 once every 3 weeks, 200 mg / time

[0230] Dose group B: Anlotinib 12 mg, D1 - D14 + 14C12H1L1 once every 3 weeks, 200 mg / time

[0231] Each dose group plans to enroll 3 - 6 patients to observe the safety of the combined medication. Based on the safety data of large-sample clinical studies of anlotinib capsules in the past, dose exploration will start from the dosing regimen of dose group A in the lead-in period (if the 3 - 6 patients enrolled in dose group A have good tolerance in the first cycle, 3 - 6 patients in dose group B will be explored). After the lead-in trial, the main investigator and the sponsor will discuss and determine the RP2D of anlotinib combined with 14C12H1L1 in patients with advanced head, neck and thoracic tumors.

[0232] The second phase is a formal trial. Patients will receive anlotinib combined with 14C12H1L1 treatment:

[0233] Anlotinib Hydrochloride Capsules:

[0234] Once daily (it is recommended to take on an empty stomach within ±60 minutes before or after the start of the infusion of 14C12H1L1 injection), 12 mg each time (the final dose is determined by the safety lead-in period, tentatively 12 mg). Take orally continuously for 2 weeks and then stop for 1 week, that is, 3 weeks (21 days) is a treatment cycle. If a dose is missed during the medication period, and it is confirmed that the time until the next dose is less than 12 hours, do not make up the missed dose.

[0235] 14C12H1L1 Injection:

[0236] Administered once every 3 weeks, 200 mg / time, by intravenous infusion. The infusion time is 60 ± 10 minutes.

[0237] Medication cycle:

[0238] Each treatment cycle is 21 days. During the medication period, other anti-tumor treatments cannot be carried out; patients with disease control (CR + PR + SD) and tolerable adverse reactions continue to take the medication until disease progression or intolerance.

[0239] The efficacy is evaluated every two cycles. Patients with disease control (CR+PR+SD) and tolerable adverse reactions can continue taking the medication until the study ends when they lose clinical benefit, the toxicity becomes intolerable, the efficacy evaluation is PD, or the investigator deems it inappropriate to continue taking the medication.

[0240] Dose adjustment of Anlotinib Hydrochloride Capsules:

[0241] During the study, the dose of Anlotinib Hydrochloride can be down-regulated due to drug-related adverse events (down-regulated in sequence from 12 mg to 10 mg to 8 mg, and cross-dose adjustment is not allowed). Patients who cannot tolerate the 8 mg dose level need to terminate the study. For patients with Anlotinib Hydrochloride Capsules whose doses have been down-regulated to 10 mg or 8 mg, after taking the medication for a period of time, if the investigator determines that there may be disease progression and the patient's safety is stable, the dose can be up-regulated once. Each patient can only have one dose up-regulation at most, and cross-dose group adjustment is not allowed.

[0242] The dose of 14C12H1L1 Injection is fixed, and there is no dose-down regulation plan.

[0243] 2.4 Method of combined administration

[0244] 14C12H1L1 Injection:

[0245] 200 mg is diluted to 100 mL with normal saline, and the infusion time is 60±10 min. It is administered once every 21 days. The infusion time starts from the start of the infusion of 14C12H1L1 and ends when the infusion of 14C12H1L1 ends and the normal saline flushing ends (it is recommended to flush the tube with 20 mL of normal saline). For subjects who cannot tolerate a 60-min infusion, the infusion time can be extended to a maximum of 120 minutes (±15 minutes).

[0246] Anlotinib Hydrochloride Capsules:

[0247] Once a day (fasting oral administration before breakfast), 1 capsule (12 mg) each time (the final dose is determined by the safety lead-in period, tentatively 12 mg). It is recommended to take it on an empty stomach within ±60 min of the start of the infusion of 14C12H1L1 Injection. Take orally continuously for 2 weeks and then stop for 1 week, that is, 3 weeks (21 days) is one treatment cycle. Under normal circumstances, it is recommended to take it at a fixed time every day. On the day of blood collection or safety inspection, take the medicine after blood collection. If a dose is missed during the medication period, and it is confirmed that the time until the next dose is less than 12 hours, do not take a supplementary dose.

[0248] Medication cycle:

[0249] Each 21 days is one treatment cycle. Other anti-tumor treatments cannot be carried out during the medication period; patients with disease control (CR+PR+SD) and tolerable adverse reactions continue to take the medication until the disease progresses or they cannot tolerate it.

[0250] The subjects to be administered drugs are all the patients recruited in Cohorts 1 to 7 in Example 1.

[0251] 2.5 Delayed drug administration and dose adjustment

[0252] If an adverse event caused by the injection containing 14C12H1L1 monoclonal antibody results in delayed drug use and the drug use cannot be resumed after more than 12 weeks, the treatment with the injection containing 14C12H1L1 should be permanently terminated. For the treatment suggestions for adverse events caused by the 14C12H1L1 injection, please refer to "Treatment Suggestions for Immune-Related Adverse Events Caused by Immune Checkpoint Inhibitor Therapy". The 14C12H1L1 injection allows delayed drug use without dose adjustment.

[0253] During the medication period (1 to 14 days) of each cycle of anlotinib hydrochloride capsules, if an adverse reaction related to anlotinib occurs and delayed drug administration is required, the maximum delay time cannot exceed 5 days. If the drug cannot be continued after more than 5 days, the remaining anlotinib in this cycle will no longer be used. When starting the next cycle of drug use, if delayed drug use can continue due to adverse reactions, the maximum delay time cannot exceed 2 weeks. Patients who still cannot take anlotinib (including reducing the dose) after more than 2 weeks need to permanently discontinue anlotinib (except for events not caused by safety reasons). During this study, if necessary, anlotinib hydrochloride capsules can be delayed in drug use or the dose can be adjusted.

[0254] During the study, when an adverse event related to anlotinib occurs, dose reduction is allowed: 12 mg → 10 mg and 10 mg → 8 mg. At the 8 mg level, if the drug still cannot be tolerated, drug use should be terminated. After dose reduction for a period of time, considering the possible progression of the disease and controllable safety, it is allowed to increase the dose to the original level starting from the next cycle.

[0255] 2.6 Disease progression and efficacy evaluation

[0256] During the clinical use of drugs similar to the 14C12H1L1 injection, there is pseudo-progression in the subjects. The efficacy evaluation criteria for this study are based on RECIST 1.1 (Response Evaluation Criteria in Solid Tumors). At the same time, the iRECIST standard (Evaluation Criteria Related to Tumor Immunotherapy) is used to confirm the efficacy. That is, for subjects determined to have disease progression (PD) according to the RECIST 1.1 standard, further confirmation is carried out according to the iRECIST standard to decide whether to further observe drug use.

[0257] Starting from the first day of the first cycle, the efficacy is evaluated every two cycles until the subject has radiologically confirmed disease progression. This evaluation will not change the evaluation frequency due to the subject's treatment delay or interruption. If the subject terminates the study treatment for reasons other than disease progression, they still need to continue to receive the above-mentioned frequency of tumor imaging evaluation until the subject starts a new anti-tumor treatment, or radiological evidence of disease progression, or the subject withdraws voluntarily, or the subject dies, whichever occurs first.

[0258] The imaging evaluation method of the tumor can use CT or MRI, but the evaluation method, machine, and technical parameters should be consistent throughout the study; if there are no contraindications, contrast agents should be used. If a tumor evaluation has been performed within 14 days before the first dose and the same method is used in the same hospital, it can be used as the baseline tumor evaluation. The baseline tumor evaluation should include CT or MRI of the chest, abdomen, and pelvis. A plain scan + enhanced / contrast-enhanced MRI of the brain should be performed during the screening period. Imaging examinations should be performed on all suspicious lesion sites. For patients with bone metastases, bone scans should be used to follow up the lesions. For patients with bone metastases, if there is no aggravation of clinical symptoms, there is no need to recheck during each tumor evaluation. If there is aggravation of clinical symptoms, recheck should be performed in a timely manner. For cases suspected of disease progression before the start of the planned next evaluation, an unplanned tumor evaluation should be performed. During the trial, only imaging examinations of the lesion sites are performed. If there are suspicious sites during the period, corresponding site imaging can be added for examination.

[0259] Example 3. Collection of biological samples

[0260] 3.1 Detection of serum anti-14C12H1L1 antibody (ADA)

[0261] The time points for immunogenicity monitoring are based on the administration time of the 14C12H1L1 injection; when the administration of 14C12H1L1 is delayed, the immunogenicity blood sampling is correspondingly delayed. If the ADA of the subject is detected to be positive, then neutralizing antibodies are additionally detected.

[0262] Samples are collected before dosing (-60 min) at cycles 1, 2, 4, 8 and every 6 cycles thereafter. At the same time, samples are collected 30 min (±5 min) after the end of the infusion in cycles 1 and 8 and 30 days (±7 days), 90 days (±7 days) after the last dose. Each time, 5 mL of venous blood is collected and placed in a blood collection tube containing clot activator and separating gel. After standing at room temperature for 30 min and natural coagulation, it is centrifuged at 3000 g for 10 min and evenly divided into 4 cryotubes (3 for detection and 1 for backup, with each detection tube containing no less than 0.5 mL). The serum is taken, labeled, and stored in a refrigerator at -40 to -80 °C for detecting immunogenicity and the blood drug concentration of 14C12H1L1.

[0263] During the trial, if an unexpected immune-related adverse event occurs, an additional blood sample collection is required in a timely manner after the adverse event is confirmed to detect immunogenicity and the blood drug concentration of 14C12H1L1. However, if the time since the most recent blood sample collection is less than 24 hours, the collection can be omitted.

[0264] Note: According to the ADA results, neutralizing antibodies will be measured if necessary in the follow-up.

[0265] 3.2 Biomarker determination

[0266] To participate in this study, tumor tissue specimens need to be provided for biomarker research, including PD-L1 expression, mismatch repair / microsatellite instability (MMR / MSI) detection, etc.

[0267] For the samples for biomarker detection, fresh biopsy tissue samples within 1 month before enrollment are preferred. When taking fresh tissue samples, percutaneous puncture is performed with 1 or more needles. 10 mL of blood samples from the subjects are collected before enrollment (within 7 days before taking the medicine) and at the end of the study (±3 days) for detecting the bTMB level, etc.

[0268] Example 4. Efficacy and safety evaluation

[0269] 4.1. Analysis of the primary efficacy index

[0270] 4.1.1. Objective response rate (ORR):

[0271] Calculate the ratio of the number of objective response cases (PR + CR) in each group to the total number of cases in each group and the 95% CI. The 95% CI of ORR is calculated based on the exact binomial method of the F distribution.

[0272] 4.1.2. Analysis of secondary efficacy indexes

[0273] 4.1.2.1. Progression-free survival (PFS)

[0274] The Kaplan-Meier method is used to estimate the median PFS and draw a survival curve.

[0275] 4.1.2.2. Overall survival (OS)

[0276] The Kaplan-Meier method is used to estimate the median OS and draw a survival curve.

[0277] 4.1.2.3. Duration of response (DOR)

[0278] The Kaplan-Meier method is used to estimate the median PFS and its 95% CI and draw a survival curve.

[0279] 4.1.2.4. Disease Control Rate (DCR):

[0280] Calculate the ratio and 95% CI of the number of disease control cases (CR + PR + SD) to the total number of cases. The 95% CI of DCR is calculated based on the exact binomial method of the F distribution.

[0281] 4.2. Safety Evaluation

[0282] 4.2.1. Drug Exposure and Compliance

[0283] Describe the drug exposure using mean, standard deviation, maximum value, minimum value, and median.

[0284] Summarize the situation of subjects exposed to the study drug treatment, the number of cycles completed by patients, the dose adjustment during treatment, the cumulative number of dose adjustment times during treatment, etc.

[0285] Statistically describe the treatment time of the study drug during the treatment period, the total dose of the study drug taken, the daily average dose, and the dose compliance of the study drug.

[0286] The dose compliance of the study drug will be calculated based on the total actual dose of the study drug taken per day recorded in the eCRF and the total dose of the study drug specified in the protocol.

[0287] One-way ANOVA is used for the comparison of the treatment time of each study drug, the total dose of the study drug taken, the daily average dose, and the dose compliance of the study drug. The chi-square test or Fisher's exact probability method is used for the comparison of compliance classifications.

[0288] 4.2.2. Adverse Events

[0289] Summarize the number of cases, the number of events, and the incidence of adverse events, adverse events before the first dose, adverse events during treatment, unexpected adverse events during treatment, important adverse events during treatment, adverse events of special concern during treatment, adverse events of grade 3 and above during treatment, serious adverse events during treatment, adverse events related to the study drug during treatment, SAEs related to the study drug during treatment, adverse events that lead to dose adjustment, permanent treatment discontinuation, trial termination, and patient death during treatment, and summarize them according to SOC and PT classifications.

[0290] Summarize the adverse events and drug-related adverse events with an incidence of ≥ 5% during treatment according to PT classification.

[0291] Summarize the drug-related adverse events with CTC AE grade 3 or 4 during treatment according to PT classification.

[0292] Summarize the adverse events and drug-related adverse events with an incidence of ≥ 10% during treatment according to PT classification.

[0293] Median time to first occurrence of adverse events of special interest.

[0294] 4.2.3. Vital signs

[0295] The mean ± standard deviation, maximum value, minimum value, and median were used to describe the measurement values and changes before and after treatment.

[0296] 4.2.4. Laboratory test indicators

[0297] Table 2 Inspection items

[0298]

[0299] Blood routine, blood biochemistry, thyroid function, coagulation function, amylase, and lipase values before and after treatment were expressed as mean ± standard deviation, maximum, minimum, and median. Paired t-tests were used for intra-group comparisons. Cross-classification tables were used to describe changes in normal and abnormal values before and after treatment.

[0300] Urinalysis: Use a cross-classification table to describe the normal and abnormal changes before and after treatment.

[0301] Stool routine: Use a cross-classification table to describe the normal and abnormal changes before and after treatment.

[0302] The proportion of subjects with abnormal changes described as "abnormal and clinically significant", where the clinical significance of the abnormality was determined by the investigator.

[0303] 4.2.5. Electrocardiogram

[0304] Electrocardiogram: Based on the normal and abnormal judgment of the researchers, describe the changes in normal and abnormal conditions before and after treatment.

[0305] Heart rate, PR interval, QRS interval, QT interval, and QTc values before and after drug administration are presented as mean ± standard deviation, maximum, minimum, and median values. Overall electrocardiographic assessment results are presented using a cross-classification table to describe normal and abnormal changes before and after drug administration. The proportion of subjects with abnormal changes who had "clinically significant abnormalities" is described, with the investigator's judgment as to whether the abnormalities were clinically significant. A list of abnormalities after drug administration is presented in a table.

[0306] 4.2.6. Physical examination

[0307] Describe normal and abnormal changes before and after treatment.

[0308] Example 5. Clinical application

[0309] 1. Patient: E09002 - Head and neck squamous cell carcinoma

[0310] A 56-year-old male. On May 29, 2020, the postoperative pathological diagnosis was: squamous epithelial severe dysplasia with carcinogenesis. CT on May 20, 2020 showed changes after right lower lobe lung cancer surgery, and increased soft tissue in the right hilar region, indicating disease progression. The patient's previous chemotherapy history: From October 9, 2019 to December 17, 2019, docetaxel for injection 120 mg + lobaplatin injection 50 mg, chemotherapy for 3 cycles, and the efficacy evaluation was SD. On February 20, 2020, docetaxel for injection 100 mg + lobaplatin 40 mg was started for 1 cycle of chemotherapy. CT on May 20, 2020 indicated progression.

[0311] On June 13, 2020, oral administration of anlotinib hydrochloride capsules 12 mg once a day was started, taken continuously for 2 weeks and then stopped for 1 week, for 14C12H1L1200 mg treatment, with each 3-week period as a dosing cycle. The patient had good overall tolerance during the medication period and could continue the medication.

[0312] Screening period: Target lesion: 33.1 mm; Non-target lesions: Multiple lymph nodes in the pulmonary artery window

[0313] After the second cycle of dosing: Target lesion: 22.4 mm (PR); Non-target lesions: Non-CR / Non-PD

[0314] After the fourth cycle of dosing: Target lesion: 22 mm (PR); Non-target lesions: Non-CR / Non-PD

[0315] After the sixth cycle of dosing: Target lesion: <10 mm (CR); Non-target lesions: Non-CR / Non-PD

[0316] 2. Patient: E02003 / S02005 - Lacrimal gland adenocarcinoma / adenoid cystic carcinoma

[0317] Previous medical history: A 27-year-old male. In July 2007, a mass resection surgery was performed on the left orbital mass. Postoperative pathology showed left lacrimal gland adenoid cystic carcinoma. No relevant treatment was carried out after the operation. In 2011, the left orbital mass was found again and surgical treatment was performed. Postoperative pathology showed adenoid cystic carcinoma. Particle implantation treatment was performed after the operation (details unknown). CT reexamination in September 2018: The soft tissue nodule shadow in the left orbit near the lateral wall increased. In September 2018, left orbital mass resection was performed again. Postoperative pathology showed adenoid cystic carcinoma. Two cycles of AP regimen chemotherapy and particle implantation treatment were performed after the operation (details unknown). In September 2019, a mass could be felt on the outside of the left mandible. Percutaneous biopsy showed tumor cells, suspected low-grade malignant epithelial tumor. MRI reexamination in October 2019 showed abnormal changes in the left orbit, the orbital mass involved the temporal fossa and the temporal pole intracranially; the bilateral inferior alveolar nerves were thickened and significantly enhanced, and the left mass spread along the nerve, considering recurrence. On November 18, 2019, an extended resection of the left mandibular mass was performed. Postoperative pathology showed adenoid cystic carcinoma. From December 16, 2019 to January 23, 2020, postoperative radiotherapy was performed.

[0318] Pathological report: Adenoid cystic carcinoma

[0319] Dosage: Anlotinib hydrochloride: 12 mg, 14C12H1L1: 200 mg

[0320] Efficacy evaluation:

[0321] Screening period: Target lesion: 25 mm; Non-target lesion: Mediastinal lymph nodes

[0322] After the second cycle of drug administration: Target lesion: 19 mm; Non-target lesion: Non-CR / Non-PD

[0323] 3. Patient: E10007 - Head and neck squamous cell carcinoma

[0324] Medical history: On February 20, 2020, the patient underwent oropharyngeal CT and MRI, which showed: a mass in the right oropharynx. The pathological section showed that poorly differentiated carcinoma infiltration was seen in the sentinel fibers and skeletal muscles, and immunohistochemistry indicated squamous cell carcinoma. Subsequently, on March 11, 2020, April 2, 2020, April 22, 2020, May 13, 2020, and June 3, 2020, the patient was given TP regimen chemotherapy, and antiemetic, fluid replacement and other symptomatic supportive treatments were given during chemotherapy. The tumor control was not good after chemotherapy. Subsequently, anlotinib combined with 14C12H1L1 was given for treatment.

[0325] Dosage: Anlotinib hydrochloride: 12 mg, 14C12H1L1: 200 mg

[0326] The overall tolerance was good during the medication period, and the medication can be continued.

[0327] Efficacy evaluation:

[0328] Screening period: Target lesion: A cystic-solid mass of 30 mm in the left submandibular area; Non-target lesion: Multiple cystic-solid masses in the left submandibular area

[0329] After the second cycle of drug administration: Target lesion: 28 mm; Non-target lesion: Non-CR / Non-PD

[0330] After the fourth cycle of drug administration: Target lesion: 28 mm; Non-target lesion: Non-CR / Non-PD

[0331] After the sixth cycle of drug administration: Target lesion: 28 mm; Non-target lesion: Non-CR / Non-PD

[0332] 4. Patient: S07007 / E07005 - Head and neck squamous cell carcinoma

[0333] Past medical history: A 51-year-old male. Pathological examination on January 28, 2019 showed: (biopsy of the mass in the floor of the mouth and ventral surface of the tongue) moderately atypical hyperplasia of squamous epithelium. On February 1, 2019, the histological report showed: (left ventral surface of the tongue) superficial well-differentiated squamous cell carcinoma in the epithelium. The histological report on February 22, 2019 showed: (primary tongue lesion) well-moderately differentiated squamous cell carcinoma, P16-. The patient's CT report on March 20, 2020 showed: The mass in the area near the hilum of the right upper lung was larger than before, and there was obstructive atelectasis in the right upper lung. The enlarged mediastinal lymph nodes were slightly larger than before. The efficacy evaluation was: PD. From March 31, 2020 to April 23, 2020, albumin-bound paclitaxel 395 mg + nedaplatin 120 mg were administered for 2 cycles. The patient's CT report on May 28, 2020 showed: Some of the mediastinal lymph nodes were larger than before. Efficacy evaluation: PD.

[0334] On June 10, 2020, C1D1 administration was carried out. Start taking 12 mg of anlotinib hydrochloride capsules on an empty stomach once a day, stop for one week after two consecutive weeks, and three consecutive weeks is one cycle. 14C12H1L1 is administered once per cycle. The patient had good overall tolerance during the medication period and could continue the medication.

[0335] Dosage: ALTN: 12 mg, 14C12H1L1: 200 mg;

[0336] Efficacy evaluation:

[0337] Screening period: Target lesions: 65 mm (right upper lung nodule + mediastinal lymph nodes);

[0338] Non-target lesions: Mediastinal lymph nodes.

[0339] After the second cycle of administration: Target lesions: SD (52 mm); Non-target lesions: non-CR / non-PD.

[0340] After the fourth cycle of administration: Target lesions: PR (40 mm); Non-target lesions: non-CR / non-PD.

[0341] After the sixth cycle of administration: Target lesions: PR (40 mm); Non-target lesions: non-CR / non-PD.

[0342] 5. Patient: S07002 / E07002 - Non-small cell lung cancer

[0343] Past medical history: A 61-year-old male. Pathological examination on October 23, 2019 showed: (right lung mass puncture) poorly differentiated non-small cell carcinoma. Supplementary immunohistochemical report showed: (right lung mass puncture) HE combined with immunohistochemistry was consistent with poorly differentiated adenocarcinoma. Gene detection showed that EGFR, ALK, and ROS1 were all negative. From November 3, 2019 to January 12, 2020, pemetrexed 750 mg + carboplatin 500 mg was used for 4 cycles. The patient's CT report on April 22, 2020 showed: The mass in the upper lobe of the right lung was smaller than before; a new nodule in the lower right lung, with a high possibility of metastatic tumor. The soft tissue nodules and masses in the right cardiophrenic angle area were larger than before, and the right chest wall was invaded. The efficacy evaluation was: PD.

[0344] On May 9, 2020, C1D1 administration was carried out, and 10 mg of anlotinib hydrochloride capsules were taken once a day on an empty stomach, stopped for one week after two consecutive weeks, and three consecutive weeks were a cycle. 14C12H1L1 was administered once per cycle. The patient had good overall tolerance during the medication period and could continue the medication.

[0345] Medication dose: Anlotinib hydrochloride: 10 mg, 14C12H1L1: 200 mg;

[0346] Efficacy evaluation:

[0347] Screening period: Target lesions: 135 mm (right anterior chest wall + right cardiophrenic angle + anterior segment of the upper right lung);

[0348] Non-target lesions: None.

[0349] After the second cycle of administration: Target lesions: SD (101 mm); Non-target lesions: NA.

[0350] After the fourth cycle of administration: Target lesions: PR (72 mm); Non-target lesions: NA.

[0351] After the sixth cycle of administration: Target lesions: PR (72 mm); Non-target lesions: NA.

[0352] After the eighth cycle of administration: Target lesions: PR (69 mm); Non-target lesions: NA.

[0353] 6. Patient: E10002 - Head and Neck Thoracic Tumor

[0354] Male, 60 years old, medical history: The patient underwent a head MR in January 2020: brain metastases; CT showed: 1. Soft tissue density shadow beside the hilum of the left upper lobe of the lung, considering pulmonary malignant tumor, central lung cancer with distal atelectasis, multiple metastases in the liver and spleen, multiple lymph node metastases in the mediastinum, neck, porta hepatis and beside the pancreatic head; 2. Centrilobular emphysema: multiple small nodules in both lungs; 3. Enlarged cardiac silhouette, atherosclerosis of the aorta and coronary arteries; 4. Small accessory spleen, left renal cyst; Five cycles of EP regimen chemotherapy were performed on February 6, 2020, March 4, 2020, March 30, 2020, April 24, 2020, and May 14, 2020. At the same time, antiemetic and symptomatic treatments were given. The overall tolerance was good during the medication period, and the medication could be continued.

[0355] Dosage: Anlotinib Hydrochloride: 12 mg po, 14C12H1L1: 200 mg

[0356] Efficacy evaluation:

[0357] Screening period

[0358] Target lesions: Lymph node metastasis in the left submandibular area: 58 mm; Solid mass in the left upper lobe of the lung near the hilum: 42 mm, Lymph node metastasis in the porta hepatis: 57 mm, Solid nodule in the spleen: 27 mm

[0359] Non-target lesions: Bilateral cervical lymph node enlargement; Left axillary lymph node enlargement; Multiple lymph nodes around the celiac trunk on the lesser curvature of the gastric body; Solid nodule in the left lower lobe of the lung near the hilum; Multiple brain metastases in both cerebral and cerebellar hemispheres

[0360] After the second cycle of administration: Target lesions: Lymph node metastasis in the left submandibular area: 34 mm; Solid mass in the left upper lobe of the lung near the hilum: 42 mm, Lymph node metastasis in the porta hepatis: 36 mm, Solid nodule in the spleen: 18 mm; Non-target lesions: Non-CR / Non-PD

[0361] After the fourth cycle of administration: Target lesions: Lymph node metastasis in the left submandibular area: 24 mm; Solid mass in the left upper lobe of the lung near the hilum: 43 mm, Lymph node metastasis in the porta hepatis: 34 mm, Solid nodule in the spleen: 17 mm; Non-target lesions: Non-CR / Non-PD

[0362] After the sixth cycle of administration: Target lesions: Lymph node metastasis in the left submandibular area: 24 mm; Solid mass in the left upper lobe of the lung near the hilum: 43 mm, Lymph node metastasis in the porta hepatis: 32 mm, Solid nodule in the spleen: 16 mm; Non-target lesions: Non-CR / Non-PD

[0363] 7. Patient: S07018 / E07012 - Thyroid cancer

[0364] Past medical history: A 31-year-old female. Pathological examination on July 23, 2020 showed: (bilateral thyroid 6 / 7 regions, mediastinal lymph nodes) (near the left lobe of the thyroid isthmus) malignant tumor, considered undifferentiated carcinoma, and cancer metastasis was seen in the mediastinal lymph nodes. Bilateral thyroid lobectomy and neck lymph node dissection of VI and VII regions were performed on July 21, 2020. CT of the patient on August 5, 2020 showed: postoperative changes after thyroid cancer, soft tissue mass in the left anterior superior mediastinum, considering the possibility of metastatic tumor and esophageal invasion. Efficacy evaluation: PD.

[0365] On August 18, 2020, C1D1 administration was carried out. Start taking 12 mg of anlotinib hydrochloride capsules once a day on an empty stomach, stop for one week after two consecutive weeks, and three consecutive weeks is one cycle. 14C12H1L1 is administered once per cycle. On October 19, 2020, a C3D21 cycle follow-up was performed. Due to the occurrence of grade III AE of hypertension, the dose of anlotinib hydrochloride capsules was reduced to 10 mg for taking. The patient had good overall tolerance during the medication period and could continue the medication.

[0366] Medication dose: C1D1 - C3D21 anlotinib hydrochloride: 12 mg, 14C12H1L1: 200 mg;

[0367] Medication dose: C4D1 - present anlotinib hydrochloride: 10 mg, 14C12H1L1: 200 mg;

[0368] Efficacy evaluation:

[0369] Screening period: Target lesion: 43 mm (left anterior superior mediastinum);

[0370] Non-target lesions: Lymph nodes between blood vessels in the right anterior superior mediastinum

[0371] After the second cycle of administration: Target lesion: PR (22 mm); Non-target lesions: Non-CR / Non-PD.

[0372] After the fourth cycle of administration: Target lesion: PR (16 mm); Non-target lesions: Non-CR / Non-PD.

[0373] 8. Patient: E08001 / S08001 - Thyroid cancer

[0374] Pathological report: Anaplastic thyroid cancer

[0375] Medication dose: Anlotinib hydrochloride: 12 mg, 14C12H1L1: 200 mg

[0376] Efficacy evaluation:

[0377] A 66-year-old female. On June 21, 2013, the postoperative pathological diagnosis was anaplastic thyroid cancer. Total thyroidectomy was performed on June 21, 2013. Right cervical lymph node dissection (Group III) was performed on February 15, 2019. Right radical neck dissection was performed on June 11, 2020. On July 1, 2020, PET-CT showed multiple enlarged lymph nodes in the neck, considered malignant, and no other obvious malignant lesions were found. From July 29 to August 18, 2020, enhanced chest, abdomen and pelvis CT showed: changes after total thyroidectomy, roughly the same as before; newly seen changes after right neck surgery, pneumothorax in the surgical area, multiple subcutaneous exudates in the surgical area, and increased tissue density in the surgical area; multiple subpleural nodules in both lungs, with little change compared with before. Enhanced MRI of the neck soft tissue: multiple mass shadows in the right neck, considered multiple lymph node metastases, some of the original lesions disappeared after surgery, some lesions enlarged compared with before, and multiple new lesions were seen. From August 12, 2020, the first course of 14C12H1L1 combined with anlotinib was given, with a dosing cycle every 3 weeks.

[0378] The CT results are as follows:

[0379] Screening period: Target lesion: 61.9 mm; Non-target lesion: lymph node

[0380] After the second cycle of drug administration: Target lesion: 18.0 mm; Non-target lesion: present

[0381] After the fourth cycle of drug administration: Target lesion: 15.5 mm; Non-target lesion: present

[0382] 9. Patient: E11002 / S11003 - adenocarcinoma

[0383] Past medical history: A 69-year-old female. On April 27, 2018, radical resection of the right upper lobe of the lung under thoracoscopy was performed under general anesthesia with tracheal intubation. Four cycles of chemotherapy (paclitaxel + nedaplatin) were performed on June 13, 2018, July 18, 2018, September 3, 2018, and October 15, 2018 respectively; Three cycles of chemotherapy (pemetrexed + nedaplatin) were performed on December 18, 2019, January 11, 2020, and February 22, 2018. Chest CT on August 5, 2020 showed: multiple thickenings of the right pleura and multiple soft tissue density nodules, the largest with a long diameter of about 0.9 cm, suggesting pleural metastasis. It indicated disease progression.

[0384] On August 17, 2020, C1D1 administration began. Anlotinib hydrochloride capsules were orally administered once a day, 12 mg each time, for two consecutive weeks followed by a one-week break. 14C12H1L1 was administered once every three weeks by intravenous infusion, and the infusion time was 60 ± 10 minutes. Each 21-day period was considered a cycle until disease progression or intolerance. On September 22, 2020, due to grade III hand-foot syndrome, the anlotinib dose in the third cycle was 10 mg. On October 13, 2020, due to grade III oral pain, the administration of anlotinib in the fourth cycle was delayed by one cycle. On November 11, 2020, the subject recovered to < grade 2, and the anlotinib dose was reduced to 8 mg and administration continued.

[0385] Pathological report: Adenocarcinoma of the puncture tissue of the "right lung" on April 18, 2018.

[0386] Dosage: C1D1 - C2D21: Anlotinib hydrochloride: 12 mg, 14C12H1L1: 200 mg

[0387] Dosage: C3D1 - C3D21: Anlotinib hydrochloride: 10 mg, 14C12H1L1: 200 mg

[0388] C4D1 - C4D21: 14C12H1L1: 200 mg

[0389] C5D1 - C5D21: Anlotinib hydrochloride: 8 mg, 14C12H1L1: 200 mg

[0390] Efficacy evaluation: PR in the second cycle, SD in the fourth cycle

[0391] Screening period: Target lesion: 13.9 mm; Non-target lesions: Nodules near the diaphragmatic surface in the lower right lung field, multiple nodules in the right pleura

[0392] After administration in the 2nd cycle: Target lesion: 8 mm; Non-target lesions: Non-CR / Non-PD

[0393] After administration in the 4th cycle: Target lesion: 11.6 mm; Non-target lesions: Non-CR / Non-PD

[0394] 10. Patient: E11003 / S11006 - Squamous cell carcinoma

[0395] Past medical history: Pathological diagnosis of squamous cell carcinoma on February 5, 2020. Chest CT on August 19, 2020 showed: Irregular soft tissue shadow beside the bronchial opening in the right lower pulmonary hilar region, stenosis of the dorsal segment and posterior basal segment bronchi of the lower lobe, the soft tissue shadow enlarged compared with before, multiple new solid nodules appeared in both lungs, mostly considered metastatic tumors, increased and enlarged compared with before, multiple lymph node enlargements in the left supraclavicular fossa, mediastinum, bilateral pulmonary hila, and hepatogastric ligament region, some accompanied by necrosis, increased and enlarged compared with before. It indicated disease progression.

[0396] Starting from September 10, 2020, oral administration of Anlotinib Hydrochloride Capsules was carried out once a day, 12 mg each time, for two consecutive weeks followed by a one-week break. 14C12H1L1 was administered once every three weeks by intravenous infusion, and the infusion time was 60 ± 10 minutes. Each 21-day period was considered a cycle. The patient tolerated the medication well during the treatment and could continue the administration.

[0397] Pathological report: <Right lower lung fibrobronchoscope biopsy> Squamous cell carcinoma

[0398] Dosage: Anlotinib Hydrochloride: 12 mg, 14C12H1L1: 200 mg

[0399] Efficacy evaluation: SD

[0400] Screening period: Target lesion: 101.7 mm; Non-target lesion: Left hilar lymph nodes

[0401] After the second cycle of administration: Target lesion: 89.5 mm; Non-target lesion: Non-CR / Non-PD

[0402] 11. Patient: E09003 - Small cell carcinoma

[0403] A 68-year-old male. On March 5, 2019, the postoperative pathological diagnosis was small cell carcinoma. On March 30, 2020, CT showed that the large patchy area in the left lower lobe of the lung was slightly more limited than before, and the enlarged lymph nodes beside the aortic arch were slightly larger than before, indicating disease progression. The patient's previous chemotherapy history: From March 8, 2019, to July 19, 2019, cisplatin 30 mg + etoposide 0.1 g were used for chemotherapy for 5 cycles. From September 2, 2019, to September 6, 2019, cisplatin 20 mg + etoposide 0.1 g were used for chemotherapy for 1 cycle. From November 4, 2019, to December 23, 2019, radiotherapy was performed. CT on March 30, 2020, indicated progression.

[0404] On July 8, 2020, oral administration of Anlotinib Hydrochloride Capsules 12 mg once a day was started for 2 weeks followed by a 1-week break, and 14C12H1L1 200 mg was used for treatment. Each 3-week period was considered a dosing cycle. The patient is currently in the C6 cycle follow-up, and the overall tolerance during the medication is good, and the medication can be continued.

[0405] Screening period: Target lesion: 56.9 mm; Non-target lesion: Soft tissue shadow in the left hilum of the lung

[0406] After the second cycle of administration: Target lesion: 25.5 mm PR; Non-target lesion: Non-CR / Non-PD

[0407] After the fourth cycle of administration: Target lesion: 16.9 mm PR; Non-target lesion: Non-CR / Non-PD

[0408] 12. Patient: E10001 - Head, Neck and Thoracic Tumor

[0409] A 52-year-old male with left nasal congestion and left palatal swelling, and facial skin numbness was admitted on May 18, 2020 with the diagnosis of "nature of left maxillary sinus mass to be determined". The puncture pathology on May 27, 2020 showed myoepithelial carcinoma. The initial diagnosis was malignant tumor of the maxillary sinus. Since it was difficult to perform surgery due to the location of the tumor and there was no standard treatment plan, he was considered to participate in a clinical study and was enrolled on June 12, 2020.

[0410] Dosage: Anlotinib hydrochloride: 12 mg and 14C12H1L1: 200 mg were started on June 12, 2020. This patient is currently in the C8 cycle of medication. The overall tolerance during medication is good and the medication can be continued.

[0411] Efficacy evaluation:

[0412] Screening period:

[0413] Target lesion: A solid mass of 71 mm in the right upper jaw;

[0414] Non-target lesions: Multiple lymph nodes in the bilateral neck spaces

[0415] After the second cycle of drug administration: Target lesion: 51 mm; Non-target lesions: Non-CR / Non-PD

[0416] After the fourth cycle of drug administration: Target lesion: 50 mm; Non-target lesions: Non-CR / Non-PD

[0417] After the sixth cycle of drug administration: Target lesion: 52 mm; Non-target lesions: Non-CR / Non-PD

[0418] According to the content disclosed in the present application, although the compositions and methods of the present application are described according to preferred embodiments, those skilled in the art can make changes to the compositions and / or methods described herein and the steps or the order of the steps of the methods without departing from the concept, spirit and scope of the present application.

[0419] The disclosure of all the documents cited herein is incorporated herein by reference to the extent that they provide exemplary, procedural and other details to supplement the content described herein. Sequence Listing <110> Chia Tai Tianqing Pharmaceutical Group Co., Ltd. <120> Drug combination of quinoline derivatives and PD-1 monoclonal antibody <130> November 27, 2020 <160> 8 <170> SIPOSequenceListing 1.0 <210> 1 <211> 6 <212> PRT <213> Synthetic sequence <400> 1 Gln Asp Ile Asn Thr Tyr 1 5 <210> 2 <211> 3 <212> PRT <213> Synthetic sequence <400> 2 Arg Ala Asn 1 <210> 3 <211> 9 <212> PRT <213> Synthetic sequence <400> 3 Leu Gln Tyr Asp Glu Phe Pro Leu Thr 1 5 <210> 4 <211> 8 <212> PRT <213> Synthetic sequence <400> 4 Gly Phe Ala Phe Ser Ser Tyr Asp 1 5 <210> 5 <211> 8 <212> PRT <213> Synthetic sequence <400> 5 Ile Ser Gly Gly Gly Arg Tyr Thr 1 5 <210> 6 <211> 11 <212> PRT <213> Synthetic sequence <z400> 6 Ala Asn Arg Tyr Gly Glu Ala Trp Phe Ala Tyr 1 5 10 <210> 7 <211> 107 <212> PRT <213> Synthetic sequence <400> 7 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Met Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Phe Thr Cys Arg Ala Ser Gln Asp Ile Asn Thr Tyr 20 25 30 Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ser Pro Lys Thr Leu Ile 35 40 45 Tyr Arg Ala Asn Arg Leu Val Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Gln Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Met Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Glu Phe Pro Leu 85 90 95 Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105 <210> 8 <211> 118 <212> PRT <213> Synthetic sequence <400> 8 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Ser Ser Tyr 20 25 30 Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Asp Trp Val 35 40 45 Ala Thr Ile Ser Gly Gly Gly Arg Tyr Thr Tyr Tyr Pro Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Asn Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Asn Arg Tyr Gly Glu Ala Trp Phe Ala Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115

Claims

1. Use of a human PD-1 antibody and a tyrosine kinase inhibitor in the preparation of a medicament for treating head and neck squamous cell carcinoma, Among them, wherein the human PD-1 antibody comprises a light chain and a heavy chain, the light chain comprises light chain complementarity determining regions LCDR1, LCDR2 and LCDR3 having amino acid sequences shown in SEQ ID NO:1, SEQ ID NO:2 and SEQ ID NO:3 respectively, and the heavy chain comprises heavy chain complementarity determining regions HCDR1, HCDR2 and HCDR3 having amino acid sequences shown in SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6 respectively, wherein the tyrosine kinase inhibitor is a compound of formula I or a pharmaceutically acceptable salt thereof, 2. The use according to claim 1, wherein the pharmaceutically acceptable salt of the compound of formula I is the hydrochloride salt of 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl]cyclopropanamine.

3. The use according to claim 1, wherein the pharmaceutically acceptable salt of the compound of formula I is the dihydrochloride salt of 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl]cyclopropanamine.

4. The use according to claim 1, wherein the human PD-1 antibody comprises a light chain variable region having an amino acid sequence shown in SEQ ID NO:7 and a heavy chain variable region having an amino acid sequence shown in SEQ ID NO:

8.

5. The use according to claim 1, wherein the human PD-1 antibody is 14C12H1L1.

6. Use of a human PD-1 antibody in the preparation of a medicament for treating head and neck squamous cell carcinoma in combination with a tyrosine kinase inhibitor, Among them, wherein the human PD-1 antibody comprises a light chain and a heavy chain, the light chain comprises light chain complementarity determining regions LCDR1, LCDR2 and LCDR3 having amino acid sequences shown in SEQ ID NO:1, SEQ ID NO:2 and SEQ ID NO:3 respectively, and the heavy chain comprises heavy chain complementarity determining regions HCDR1, HCDR2 and HCDR3 having amino acid sequences shown in SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6 respectively, wherein the tyrosine kinase inhibitor is a compound of formula I or a pharmaceutically acceptable salt thereof, 7. The use according to claim 6, wherein the pharmaceutically acceptable salt of the compound of formula I is the hydrochloride salt of 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl]cyclopropanamine.

8. The use according to claim 6, wherein the pharmaceutically acceptable salt of the compound of formula I is the dihydrochloride salt of 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl]cyclopropanamine.

9. The use according to claim 6, wherein the human PD-1 antibody comprises a light chain variable region having the amino acid sequence as shown in SEQ ID NO:7 and a heavy chain variable region as shown in SEQ ID NO:

8.

10. The use according to claim 6, wherein the human PD-1 antibody is 14C12H1L1.

11. The use according to any one of claims 1-10, wherein the human PD-1 antibody and the compound of formula I or a pharmaceutically acceptable salt thereof are each in the form of a pharmaceutical composition.

12. The use according to any one of claims 1-10, wherein the head and neck squamous cell carcinoma is recurrent / metastatic head and neck squamous cell carcinoma.

13. The use according to any one of claims 1-10, wherein the human PD-1 antibody is administered at a frequency of once every 2 weeks or once every 3 weeks.

14. The use according to any one of claims 1-10, wherein the human PD-1 antibody is administered in one or more uniform doses selected from 200 mg.

15. The use according to claim 5 or 10, wherein The hydrochloride salt of the compound of formula I is administered once daily, 12 mg or 10 mg each time, orally for 2 consecutive weeks followed by a 1-week break, and 14C12H1L1 is administered once every 3 weeks, 200 mg each time.

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