CN112915202B

CN112915202B - Pharmaceutical combination of quinoline derivative and PD-1 monoclonal antibody

Info

Publication number: CN112915202B
Application number: CN202011379288.XA
Authority: CN
Inventors: 王栋; 张喜全; 李百勇; 金小平; 王训强; 于鼎
Original assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd
Current assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd
Priority date: 2019-12-06
Filing date: 2020-11-30
Publication date: 2025-08-01
Anticipated expiration: 2040-11-30
Also published as: CN112915202A

Abstract

A pharmaceutical combination of a quinoline derivative and PD-1 mab is provided, comprising 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 medicine composition has good anti-head, neck and chest tumor activity.

Description

Pharmaceutical combination of quinoline derivative and PD-1 monoclonal antibody

Technical Field

The application belongs to the technical field of medicines, and relates to a combined therapy for resisting tumors. In particular, the application relates to a combination based on quinoline derivatives and PD-1 mab and its use in the treatment of head, neck and chest tumors.

Background

Tyrosine kinases are a group of enzymes that catalyze the phosphorylation of protein tyrosine residues, play an important role in intracellular signal transduction, and are involved in the regulation, signaling and development of normal cells, and are also closely related to proliferation, differentiation, migration and apoptosis of tumor cells. Many receptor tyrosine kinases are involved in 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) and the like according to the structure of their extracellular regions.

An Luoti Ni (Anlotinib) is a quinoline derivative tyrosine kinase inhibitor which plays a role in influencing tumor angiogenesis and proliferation signaling as a multi-target Tyrosine Kinase Inhibitor (TKI), and main targets include receptor tyrosine kinase Vascular Endothelial Growth Factor Receptors (VEGFR) 1 to 3, epidermal Growth Factor Receptors (EGFR), fibroblast Growth Factor Receptors (FGFR) 1 to 4, platelet-derived growth factor receptors (PDGFR) alpha and beta, and Stem Cell Factor Receptors (SCFR) 7, 8 and 9. A phase 2 trial showed that An Luoti Ni improved progression free survival and had the potential benefit of overall survival (Han B, et al Br J cancer.2018;118 (5): 654-661). A multicenter, double blind, 3-phase randomized clinical trial showed that An Luoti Ni resulted in prolonged overall and progression free survival in Chinese patients, which finding indicated that An Luoti Ni was well tolerated and was a potential three-wire or further treatment for patients with advanced NSCLC (Han B, et al JAMA Oncol.2018 Nov;4 (11): 1569-1575).

Document WO2008112407 discloses in example 24 a quinoline derivative tyrosine kinase inhibitor 1- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl ] oxy ] methyl ] cyclopropylamine and a process for its preparation, the structural formula of which is shown in formula I:

PD-1 (PD-1) is a key immune checkpoint receptor expressed by activated T-and B-lymphocytes and mediates immunosuppression, and its ligands include at least PD-L1 and PD-L2.PD-L1 (Programmed desath-ligand 1), also known as CD274 or B7-H1, is a type 1 transmembrane protein of 40kDa encoded by the CD274 gene, and is a ligand for PD-1. Both PD-L1 and PD-1 belong to the immunoglobulin superfamily and consist of two extracellular Ig domains, an N-terminal V domain and a C-terminal constant domain. the binding interface of PD-L1 to programmed death receptor-1 (PD-1) and B7-1 (CD 80) is on the IgV-like domain (Lin et al (2008) PNAS 105:3011-3016). PD-L1 contains a conserved short intracellular tail (about 30 amino acids) and PD-1 contains two cytoplasmic tyrosine-based signal motifs, an immunoreceptor tyrosine-based inhibitory motif (ITIM) and an immunoreceptor tyrosine-based switching motif (ITSM). Following T cell stimulation, PD-1 recruits tyrosine phosphatase SHP-2 to its ITSM motif within the cytoplasmic tail, resulting in dephosphorylation of effector molecules involved in the CD3+ T cell signaling cascade, such as CD3ζ, PKCθ and ZAP70 (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 white blood cells and non-hematopoietic cells in lymphoid and non-lymphoid tissues, but also on various cancer cells, is highly expressed on the surfaces of various tumor cells, and the malignancy and poor prognosis of tumors are closely related to the expression level of PD-L1. There are clinical data showing 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 an inhibitory signal and down regulates T cell immune responses, which inhibits TCR-mediated T cell activation, Cytokine production and T cell proliferation (Fife et al (2011) Nature Immunology 10:1185-1193), induction of failure or anergy among cognate antigen-specific T cells (Hofmeyer et al (2011) Journal of Biomedicine and Biotechnology 2011:1-9), promotion of Th1 cell differentiation 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 induction of apoptosis of effector T cells. Disruption of the PD-L1 gene results in an upregulated T cell response and production of autoreactive T cells (Latchman et al (2004) PNAS 101:10691-10696). Antibody blockade of PD-1 or PD-L1 results in increased anti-tumor immunity (Iwai et al (2002) PNAS 99:12293-12297).

Chinese patent document CN106977602A discloses a PD-1 monoclonal antibody 14C12H1L1, which can very effectively block the combination of PD1 and PD-L1 and shows better anti-tumor activity.

The biggest challenge encountered by predecessors during tumor immunotherapy is poor efficacy due to tumor immune tolerance and escape. Therefore, the combined use of the small-molecule anti-tumor compound and the anti-PD-1/PD-L1 antibody is used for breaking the immune tolerance of the organism to tumor cells, and has important theoretical significance and application value.

Disclosure of Invention

It is at least an object of the present invention to provide a pharmaceutical combination comprising a tyrosine kinase inhibitor and 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 consisting of the amino acid sequences shown in 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 consisting of the amino acid sequences shown 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 pharmaceutically acceptable salt thereof, and in some specific embodiments, the tyrosine kinase inhibitor is the hydrochloride salt of the compound of formula I, i.e., an Luoti ni.

In some embodiments, the human PD-1 antibody comprises a light chain variable region having an amino acid sequence as set forth in SEQ ID NO. 7 and a heavy chain variable region as set forth in SEQ ID NO. 8.

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

In some embodiments, the compound of formula I may be present in a pharmaceutically acceptable salt or a pharmaceutically acceptable formulation thereof, preferably in the form of its hydrochloride salt.

In some 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 ] cyclopropylamine, i.e., an Luoti nii hydrochloride.

In some embodiments, the pharmaceutical combination comprises a compound of formula I or a hydrochloride salt thereof (e.g., a dihydrochloride salt), and a 14C12H1L1 mab or antigen-binding fragment thereof.

It is at least an object of the present invention to provide a pharmaceutical 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, 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 shown 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 shown in SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6, respectively, for use in the treatment of tumors.

In some embodiments, the tyrosine kinase inhibitor is a compound of formula I or a hydrochloride salt thereof.

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

In some embodiments, the use of the treatment tumor is the treatment of head and neck chest tumors. In some embodiments, the head, neck and chest tumor is an advanced head, neck and chest tumor. In some embodiments, the head, neck and chest tumor has failed or is intolerant of at least one line of platinum-containing chemotherapy treatment. In some embodiments, the head, neck and chest tumor is a histologically confirmed standard of treatment failure or no standard of treatment.

In some embodiments, the use of the treatment tumor is to treat recurrent/metastatic head and neck squamous cell carcinoma, in some embodiments, the primary site of the recurrent/metastatic head and neck squamous cell carcinoma is the oral cavity, oropharynx, hypopharynx, or larynx.

In some embodiments, the use of the treatment of a tumor is the treatment of head and neck non-squamous carcinoma. In some embodiments, the head and neck non-squamous carcinoma is advanced/metastatic head and neck non-squamous carcinoma, and in other embodiments, the head and neck non-squamous carcinoma is advanced/metastatic head and neck non-squamous carcinoma that has failed a histologically-confirmed standard of treatment or is devoid of standard treatment.

In some embodiments, the use of treating a tumor comprises for treating adenocarcinoma, adenoid cystic carcinoma, mucoepidermoid carcinoma, or lacrimal adenocarcinoma.

In some embodiments, the use of the treatment of a tumor is the treatment of thyroid cancer. In some embodiments, the thyroid cancer is thyroid undifferentiated carcinoma, in other embodiments, the histologically confirmed standard treatment fails or untreated, non-surgically resectable thyroid undifferentiated carcinoma.

In some embodiments, the use of treating a tumor is treating small cell lung cancer. In some embodiments, the small cell lung cancer is a histologically confirmed small cell lung cancer that has failed to receive treatment with only one platinum-containing chemotherapeutic regimen.

In some embodiments, the use of treating a tumor is treating non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is non-squamous non-small cell lung cancer. In other embodiments, the non-small cell lung cancer is non-squamous non-small cell lung cancer and the subject is stage IIIB-IV patients defined according to IASLC version 8 TNM staging system. In some embodiments, the non-small cell lung cancer is non-squamous non-small cell lung cancer that 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 version 8 TNM staging system). In some embodiments, the tumor-treating use is for treating non-small cell lung cancer that fails to receive treatment with at least one platinum-containing or non-platinum dual drug chemotherapy regimen.

In some embodiments, the use for treating a tumor is pleural mesothelioma. In some embodiments, the pleural mesothelioma is a recurrent/metastatic pleural mesothelioma, in other embodiments, the pleural mesothelioma is a recurrent/metastatic pleural mesothelioma that has been histologically diagnosed, failed at least to receive first-line chemotherapy, and is not surgically resectable or subjected to radical radiation therapy.

In some embodiments, the use for treating a tumor is thymus cancer. In some embodiments, the thymus cancer is recurrent/metastatic thymus cancer, and in other embodiments, the thymus cancer is recurrent/metastatic thymus cancer that has been histologically diagnosed, failed at least one line of chemotherapy, and is not surgically resectable or undergoing radical radiation therapy.

The invention also provides a method for treating a subject having a head and neck chest 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, 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 consisting of the amino acid sequences shown 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 consisting of the amino acid sequences shown 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 salt thereof. In some embodiments, the human PD-1 antibody comprises a light chain variable region having an amino acid sequence as set forth in SEQ ID NO. 7 and a heavy chain variable region as set forth in SEQ ID NO. 8. In some embodiments, the human PD-1 antibody is 14C12H1L1.

The invention also provides a combination therapy for treating a subject having a head and neck chest tumor, the method comprising separately administering to the subject a therapeutically effective amount of a tyrosine kinase inhibitor and separately administering a therapeutically effective amount of 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 consisting of the amino acid sequences shown 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 consisting of the amino acid sequences shown in SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6, respectively.

The invention also provides a method of treating a subject having cancer or a tumor that is a head, neck and chest tumor, the method comprising (i) measuring PD-1 and/or PD-L1 levels 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 antigen-binding portion thereof.

The invention also provides a method for treating a subject having cancer or a tumor. In certain embodiments, the subject is a patient diagnosed with a tumor of the head and neck chest, such as a patient diagnosed with squamous cell carcinoma of the head and neck, or a patient with non-squamous cell carcinoma of the head and neck, or a patient with thyroid cancer, or a patient with small cell lung cancer, or non-squamous cell lung cancer, or a patient with squamous non-small cell lung cancer, or a patient with pleural mesothelioma, or a patient with thymus cancer.

In some aspects of the invention, the head, neck and chest tumor is an advanced head, neck and chest tumor. In some embodiments, the head, neck and chest tumor has failed or is intolerant of at least one line of platinum-containing chemotherapy treatment. In some embodiments, the head, neck and chest tumor is a histologically confirmed standard of treatment failure or no standard of treatment.

In some embodiments, the head and neck chest tumor is an anti-recurrent/metastatic head and neck squamous cell carcinoma, in some embodiments, the primary site of the recurrent/metastatic head and neck squamous cell carcinoma is the oral cavity, oropharynx, hypopharynx, or larynx.

In some embodiments, the head and neck chest tumor is a head and neck non-squamous carcinoma, in some embodiments, the head and neck non-squamous carcinoma is an advanced/metastatic head and neck non-squamous carcinoma that has failed histologically-confirmed standard of treatment or is devoid of standard of treatment.

In some embodiments, the head, neck, chest tumor comprises adenocarcinoma, adenoid cystic carcinoma, mucoepidermoid carcinoma, or lacrimal carcinoma.

In some embodiments, the head and neck chest tumor is an anti-thyroid cancer, in some embodiments, the thyroid cancer is a thyroid undifferentiated carcinoma, in other embodiments, the thyroid cancer is a histologically confirmed standard treatment failure or untreated, non-surgically resectable thyroid undifferentiated carcinoma.

In some embodiments, the head and neck chest tumor is small cell lung cancer, and in some embodiments, the small cell lung cancer is histologically confirmed, and is small cell lung cancer that has failed treatment with only one platinum-containing chemotherapy regimen.

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 cancer non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is non-squamous carcinoma non-small cell lung cancer and the treatment is stage IIIB-IV patients defined according to IASLC version 8 TNM staging system. In some embodiments, the non-small cell lung cancer is non-squamous carcinoma non-small cell lung cancer that failed standard treatment. In some aspects, the non-small cell lung cancer is squamous carcinoma non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is squamous carcinoma non-small cell lung cancer and the clinical stage is stage IIIB, IIIC or IV (as defined by the iasc version 8 TNM staging system). In some embodiments, the head, neck and chest tumor is non-small cell lung cancer that fails to receive treatment with at least one platinum-containing or non-platinum dual drug chemotherapy regimen.

In some embodiments, the head, neck and chest tumor is a pleural mesothelioma. In some embodiments, the pleural mesothelioma is a recurrent/metastatic pleural mesothelioma. In some embodiments, the pleural mesothelioma is a histologically confirmed diagnosis of recurrent/metastatic pleural mesothelioma that has failed at least one-line chemotherapy and is not surgically resectable or undergoing radical radiation therapy.

In some embodiments, the head, neck and chest tumor is thymus cancer. In some embodiments, the thymus cancer is recurrent/metastatic thymus cancer. In some embodiments, the thymus cancer is a histologically confirmed diagnosis of recurrent/metastatic thymus cancer that has failed at least one-line chemotherapy and is not surgically resectable or undergoing radical radiation therapy.

In some embodiments, the subject has previously received surgery, chemotherapy, and/or radiation therapy. In some embodiments, the subject is fully relieved after surgery, chemotherapy, and/or radiation therapy and the disease progression is again followed. In some embodiments, the subject fails to completely or partially alleviate following surgery, chemotherapy, and/or radiation therapy.

In some embodiments, the subject has not previously received systemic chemotherapy. In some embodiments, the subject has previously received surgical treatment, radiation treatment, induction chemotherapy, and/or adjuvant chemotherapy, or the subject receives concurrent chemotherapy. In some embodiments, the subject has not previously received systemic chemotherapy, but has received surgical treatment, radiation treatment, induction chemotherapy, and/or adjuvant chemotherapy or will receive concurrent chemotherapy. In some embodiments, the subject is treated with surgery, radiation, induced chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy to obtain complete remission before disease progression. In some embodiments, the subject fails to completely or partially alleviate following surgical treatment, radiation treatment, induction chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy. In some embodiments, the subject undergoes metastasis following surgical treatment, radiation treatment, induction of chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy.

In some embodiments, the pharmaceutical 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.

In some embodiments, the pharmaceutical 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.

It is also at least an object of the present application to provide a pharmaceutical pack comprising the single packaged pharmaceutical compositions in separate containers, wherein the pharmaceutical composition comprising the compound of formula I or a pharmaceutically acceptable salt thereof is contained in one container and the pharmaceutical composition comprising the human PD-1 antibody is contained in a second container.

In some embodiments of the application, the pharmaceutical composition comprises the compound of formula I in an amount of 6 to 168 mg. In some embodiments, the pharmaceutical composition comprises a compound of formula I in an amount selected from 6mg, 8mg, 10mg, 12mg, 15mg, 20mg, 30mg, 50mg, 56mg, 70mg, 84mg, 112mg, 140mg, 168mg, or any range formed by any of the foregoing. In some embodiments, the pharmaceutical composition comprises 10mg to 12mg of the compound of formula I. In some embodiments, the pharmaceutical composition comprises the compound of formula I in an amount of 10 mg. In some embodiments, the pharmaceutical composition comprises a compound of formula I in an amount of 12 mg.

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

In some embodiments, the treatment for administration of the human PD-1 antibody is for a period of 2 weeks (14 days) or 3 weeks (21 days), preferably the human PD-1 antibody is administered intravenously on the first day (D1) of each period. That is, the anti-PD-1 antibody is administered at a frequency of once every two weeks (q 2 w) or once every three weeks (q 3 w).

The application also provides a unit preparation, which comprises a compound component, 6-12 mg of a compound of formula I or hydrochloride thereof and an antibody component, 50-350 mg of a human PD-1 antibody or antigen binding fragment thereof, wherein the compound component and the antibody component are respectively and independently packaged.

In some embodiments, the unit formulation comprises a compound component, 8mg, 10mg, or 12mg of a compound of formula I or a hydrochloride salt thereof, and an antibody component, 100mg or 200mg of a human PD-1 antibody or an antigen-binding fragment thereof, wherein the compound component and the antibody component are packaged separately.

It is also an object of the present application to provide a method for preventing or treating cancer or tumor, wherein one or more of the above unit preparations are administered to a subject in need thereof. Preferably, the compound component and the antibody component of the unit formulation are each administered separately. Preferably, the cancer or tumor is a head, neck and chest tumor.

In some embodiments of the application An Luoti Ni is administered in combination with 14C12H1L1, for a treatment period of 21 days, at 10 mg/time or 12 mg/time An Luoti Ni, and D1-D14 is administered 14C12H1L1 daily, once every 3 weeks, at 200 mg/time.

In some embodiments of the application An Luoti Ni is administered in combination with 14C12H1L1, and An Luoti Ni is administered in capsules of 12mg or 10mg each time, 1 time a day. The oral administration is continued for 2 weeks and stopped for 1 week, i.e. 3 weeks (21 days) is a treatment period. If the medicine taking period is missed, the time from the next medicine taking period is confirmed to be shorter than 12 hours, and the medicine is not taken again. The administration mode of the 14C12H1L1 injection is that the injection is administered 1 time every 3 weeks, 200 mg/time and intravenous infusion. The infusion time is 60+/-10 min.

The result shows that the An Luoti-Ni combined 14C12H1L1 pharmaceutical composition has unexpected effect in preventing or treating head, neck and chest tumors, and shows that the tumor focus growth is inhibited or the tumor volume is reduced in a plurality of clinical applications. The experimental result surprisingly shows that the drug of the An Luoti-Ni hydrochloride combined with the 14C12H1L1 can have obvious synergistic effect, and breaks through the immune tolerance of the organism to tumor cells.

The pharmaceutical combination of the present invention shows superior efficacy over existing therapies in patients with squamous non-small cell lung cancer that recur or metastasize after surgery and/or chemotherapy, such as docetaxel in combination with lobaplatin.

The pharmaceutical combination of the present invention shows superior efficacy over existing therapies in non-squamous non-small cell lung cancer patients who relapse or metastasize after chemotherapy, such as pemetrexed in combination with carboplatin, pemetrexed + nedaplatin, or paclitaxel + nedaplatin treatment.

The pharmaceutical combination of the present invention shows superior efficacy over existing therapies in patients with small cell lung cancer that recur or metastasize after chemotherapy, such as cisplatin in combination with etoposide, pemetrexed in combination with nedaplatin, or paclitaxel in combination with nedaplatin.

The pharmaceutical combination of the present invention shows superior efficacy in patients with lacrimal adenoid cystic carcinoma undergoing postoperative and/or chemotherapy recurrence or metastasis compared to existing therapies.

The pharmaceutical combination of the invention shows superior efficacy compared to existing therapies in patients with recurrent or metastatic head and neck squamous cell carcinoma after chemotherapy, such as paclitaxel in combination with cisplatin or paclitaxel in combination with nedaplatin.

The pharmaceutical combination of the invention shows superior efficacy compared to existing therapies in lung cancer patients with brain metastasis or multiple metastasis following surgery and/or chemotherapy, such as etoposide in combination with cisplatin treatment, the multiple metastasis being lymph node metastasis, liver metastasis, spleen metastasis and/or brain metastasis.

The pharmaceutical combination of the present invention shows superior efficacy compared to existing therapies in thyroid cancer patients suffering from lymph node metastasis after surgery and/or chemotherapy, which is multiple lymph node metastasis.

The pharmaceutical combination of the present invention shows superior efficacy compared to existing therapies in patients with anaplastic thyroid cancer who undergo multiple lymph node metastasis after surgery, which is multiple lymph node metastasis.

The pharmaceutical combination of the present invention shows superior efficacy over existing therapies in non-squamous non-small cell lung cancer patients who relapse or metastasize after chemotherapy, such as pemetrexed in combination with carboplatin.

The pharmaceutical combination of the present invention shows superior efficacy over existing therapies in patients with a maxillary Dou Exing tumor unsuitable for surgical treatment, which maxillary Dou Exing tumor is squamous carcinoma.

An Luoti Ni

As used herein, the chemical name of An Luoti ni (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 ] cyclopropylamine having the structural formula:

As used herein, an Luoti n includes both its non-salt form (e.g., free acid or free base) and its pharmaceutically acceptable salt, which are within the scope of the present application. For example, the pharmaceutically acceptable salt of An Luoti n may be the hydrochloride or dihydrochloride salt. The dosages of An Luoti ni or salts thereof referred to in this application are calculated on the basis of An Luoti ni free base unless otherwise indicated.

14C12H1L1

As used herein, 14C12H1L1 is an anti-PD-1 monoclonal antibody, the sequence and structure of which can be found in the literature (CN 106977602 a). In the 14C12H1L1 monoclonal antibody, LCDR1 comprises sequence QDINTY (SEQ ID NO: 1), LCDR2 comprises sequence RAN (SEQ ID NO: 2), LCDR3 comprises sequence LQYDEFPLT (SEQ ID NO: 3), HCDR1 comprises sequence GFAFSSYD (SEQ ID NO: 4), HCDR2 comprises sequence ISGGGRYT (SEQ ID NO: 5), and HCDR3 comprises sequence ANRYGEAWFAY (SEQ ID NO: 6).

The amino acid sequence of the light chain variable region is as follows:

DIQMTQSPSSMSASVGDRVTFTCRASQDINTYLSWFQQKPGKSPKTLIYRANRLVSGVPSRFSGSGSGQDYTLTISSLQPEDMATYYCLQYDEFPLTFGAGTKLELK(SEQ ID NO:7).

The amino acid sequence of the heavy chain variable region is as follows:

EVQLVESGGGLVQPGGSLRLSCAASGFAFSSYDMSWVRQAPGKGLDWVATISGGGRYTYYPDSVKGRFTISRDNSKNNLYLQMNSLRAEDTALYYCANRYGEAWFAYWGQGTLVTVSS(SEQ ID NO:8).

definition and description

The following terms used in the present application have the following meanings unless otherwise indicated. A particular term, unless otherwise defined, shall not be construed as being ambiguous or otherwise unclear, but shall be construed in accordance with the ordinary meaning in the art. When trade names are present in the present application, it is intended to refer to their corresponding commercial products, compositions or active ingredients thereof.

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 may be whole antibodies or any fragment thereof. Thus, antibodies and fragments thereof of the 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 may also include recombinant polypeptides, fusion proteins, and bispecific antibodies. The anti-PD-L1 antibodies and fragments thereof disclosed herein may be of the IgG1, igG2, igG3 or IgG4 isotype.

The term "isotype" refers to the type 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 may be derived from any species including, but not limited to, mice, rats, rabbits, primates, llamas, and humans. The PD-1/PD-L1 antibodies and fragments thereof may be chimeric, humanized or fully human antibodies.

The term "humanized antibody" refers to antibodies in which the antigen binding site is derived from a non-human species and the variable region framework is derived from a human immunoglobulin sequence. Humanized antibodies may comprise substitutions in the framework regions such that the framework may not be an exact copy of the expressed human immunoglobulin or germline gene sequence.

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

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

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 capable of specifically binding the same epitope as the reference antibody or other binding protein.

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

The term "treatment" generally refers to an operation to obtain a desired pharmacological and/or physiological effect. The effect may be prophylactic according to the complete or partial prevention of the disease or symptoms thereof, and/or may be therapeutic according to the partial or complete stabilization or cure of the disease and/or side effects due to the disease. As used herein, "treatment" encompasses any treatment of a disease in a patient, including (a) preventing a disease or condition that is susceptible to infection but has not yet been diagnosed in a patient suffering from the disease or condition, (b) inhibiting the symptoms of the disease, i.e., preventing its progression, or (c) alleviating the symptoms of the disease, i.e., causing regression of the disease or condition.

As used herein, the term "systemic treatment" refers to the treatment of drug substances delivered through the blood stream to reach and affect systemic cells.

As used herein, the term "systemic chemotherapy" refers to systemic chemotherapy that does not include chemotherapy for locally advanced disease as a link to multi-mode treatment, where chemotherapy for locally advanced disease includes induction chemotherapy, radiotherapy-concurrent chemotherapy, and adjuvant chemotherapy.

As used herein, the term "subject" refers to mammals, such as rodents, felines, canines, and primates. Preferably, the subject according to the application is a human.

"Administering" means physically introducing a composition comprising a therapeutic agent into a subject 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. The phrase "parenteral administration" as used herein refers to modes of administration other than enteral and topical administration, typically by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion, and in vivo electroporation. In certain embodiments, the immune checkpoint inhibitor (e.g., an anti-PD-1 antibody or an anti-PD-L1 antibody) is administered by a non-parenteral route, in certain embodiments, orally. Other non-parenteral routes include topical, epidermal or mucosal routes of administration, e.g., intranasally, vaginally, rectally, sublingually or topically. Administration may also be performed, for example, one, multiple times, and/or over one or more extended periods of time.

As used herein, an "adverse event" (AE) is any adverse and often unintended or undesirable sign (including abnormal laboratory findings), symptom, or disease associated with the application of medical treatment. For example, an adverse event may be associated with activation of the immune system or expansion of immune system cells (e.g., T cells) in response to treatment. Medical treatments may have one or more associated AEs, and each AE may have the same or different severity levels. References to methods capable of "altering adverse events" refer to treatment regimens that reduce the incidence and/or severity of one or more AEs associated with the application of different treatment regimens.

As used herein, "dosing interval" refers to the amount of time that elapses between multiple doses of the formulation disclosed herein administered to a subject. The dosing interval may thus be indicated as a range.

The term "frequency of administration" as used herein means the frequency of the dosage administered of the formulations disclosed herein in a given time. The dosing frequency may be indicated as the number of doses per given time, e.g. 1 time per week or 1 time per 2 weeks.

The use of the term "flat dose" refers to the dose administered to a patient irrespective of the weight or Body Surface Area (BSA) of the patient. The unified dose is therefore specified as an absolute amount of agent (e.g., anti-PD-1 antibody) rather than as a mg/kg dose. For example, 60kg of humans and 100kg of humans will receive the same dose of antibody (e.g., 240mg of anti-PD-1 antibody).

The use of the term "fixed dose" in relation to the compositions of the application means that two or more different antibodies in a single composition are present in a specific (fixed) ratio to each other in the composition. 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 the mg first antibody to the mg 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 7:1, about 1:1, about 1:1:1, about 5:1, about 1:1 or about 1:2:1. For example, a 3:1 ratio of primary antibody to secondary antibody may mean that about 240mg primary antibody and 80mg secondary antibody, or about 3mg primary antibody and 1mg secondary antibody may be contained in a bottle.

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

The term "immunotherapy" refers to the treatment of a subject suffering from a disease or at risk of infection or suffering from recurrence of a disease by a method that includes inducing, enhancing, suppressing or otherwise altering an immune response. "treatment" or "therapy" of a subject refers to any type of intervention or procedure performed on the subject, or administration of an active agent to the subject, with the purpose of reversing, alleviating, ameliorating, inhibiting, slowing or preventing the onset, progression, development, severity or recurrence of a symptom, complication or disorder, or a biochemical indicator associated with a disease.

As used herein, "PD1/PD-L1 positive" may be used interchangeably with "at least about 1% PD-1/PD-L1 expression". In one embodiment, PD-1/PD-L1 expression may 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 that there are at least 100 cells expressing PD-1/PD-L1 on the cell surface.

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

"Programmed death ligand-1 (PD-L1)" is one of two cell surface glycoprotein ligands (the other is PD-L2) directed against PD-1, which down-regulates T cell activation and cytokine secretion upon binding to PD-1.

"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," "subject," and "patient" are used interchangeably in certain contexts herein.

A "therapeutically effective amount" or "therapeutically effective dose" of a drug or therapeutic agent is any amount of drug that, when used alone or in combination with another therapeutic agent, protects a subject from onset of a disease or promotes regression of a disease as evidenced by a decrease in severity of disease symptoms, an increase in frequency and duration of disease-free symptom stages, or prevention of injury or disability caused by affliction of the disease. The ability of a therapeutic agent to promote disease regression can be assessed using a variety of methods known to the skilled practitioner, such as in human subjects during clinical trials, in animal model systems that predict efficacy for humans, or by assaying the activity of the agent in an in vitro assay.

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

As an example, an "anticancer agent" promotes cancer regression or prevents further tumor growth in a subject. In certain embodiments, a therapeutically effective amount of the drug promotes regression of the cancer to the point of elimination of the cancer. By "promoting cancer regression" is meant administration of an effective amount of the drug, alone or in combination with an anti-neoplastic agent, resulting in a reduction 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 disease-free symptom stages, or prevention of injury or disability caused by affliction of the disease. Furthermore, the terms "effective" and "effectiveness" in relation to treatment include pharmacological effectiveness and physiological safety. Pharmacological effectiveness refers to the ability of a drug to promote regression of cancer in a patient. Physiological safety means the level of toxicity or other adverse physiological effects (adverse effects) at the cellular, organ and/or organism level caused by drug administration.

As an example for treating a tumor, a therapeutically effective amount of an anti-cancer agent 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 application, tumor regression may be observed for a period of at least about 20 days, at least about 40 days, or at least about 60 days. Despite these final measures of therapeutic effectiveness, the evaluation of immunotherapeutic drugs must also take into account "immune-related" response patterns.

An "immune-related" response pattern refers to a clinical response pattern often observed in cancer patients treated with immunotherapeutic agents that produce 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 therapeutic effect after an initial increase in tumor burden or the appearance of new lesions, which will be classified as disease progression in the evaluation of traditional chemotherapeutic agents and will be synonymous with drug failure. Thus, proper evaluation of immunotherapeutic agents may require long-term monitoring of the effect of these agents on target disease.

A therapeutically effective amount of a drug includes a "prophylactically effective amount," which is any amount of drug that inhibits the occurrence or recurrence of cancer when administered alone or in combination with an antineoplastic agent to a subject at risk of developing cancer (e.g., a subject with a premalignant condition) or a subject at risk of recurrence of cancer. In certain embodiments, a prophylactically effective amount completely prevents the occurrence or recurrence of cancer. "inhibiting" the occurrence or recurrence of cancer refers to reducing the likelihood of occurrence or recurrence of cancer, or preventing the occurrence or recurrence of cancer altogether.

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

"Unresectable" cancers are not removed by surgery.

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

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

The terms "about," "approximately" or "substantially comprise" mean a value or composition that is within an acceptable error range for the particular value or composition as determined by one of ordinary skill in the art, which will depend in part on how the value or composition is measured or measured, i.e., the limitations of the measurement system. For example, "about," "about," or "substantially comprising" may mean within 1 or more than 1 standard deviation per practice in the art. Alternatively, "about" or "substantially comprising" may refer to a range that differs by at most 10% or 20% (i.e., ±10% or ±20%) from the parameter or value modified thereby. For example, about 3mg may include any number between 2.7mg to 3.3mg (for 10%) or between 2.4mg to 3.6mg (for 20%). Furthermore, in particular with respect to biological systems or processes, the term may refer to up to an order of magnitude or up to 5 times the value. When a particular value or composition is provided in the application and claims, unless otherwise indicated, the meaning of "about" or "consisting essentially of" should be assumed to be within an acceptable error range for that particular value or composition.

The terms "about once a week", "about once every two weeks" or any other similar dosing interval terms as used herein refer to approximations. "about once a week" may include every 7 days + -1 day, i.e., every 6 days to every 8 days. "about once every two weeks" may include every 14 days + -3 days, i.e., every 11 days to every 17 days. Similar approximations apply, 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, an dosing interval of about once every 6 weeks or about once every 12 weeks means that the first dose may be administered on any day of the first week and then the second dose may 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 refers to the administration of a first dose on a particular day of the first week (e.g., monday) and then a second dose on the same day of the sixth or twelfth week (i.e., monday), respectively. Similar principles apply to phrases that include, but are not limited to, "about 1 every 2 weeks", "about 1 every month", and the like.

As described herein, any concentration range, percentage range, ratio range, or integer range should be understood to include the values of any integer within the recited range, and fractions thereof (such as tenths and hundredths of integers) as appropriate, unless otherwise indicated.

Unless specifically stated otherwise, "about" or "approximately" in the present application means that the fluctuation is within + -5%, preferably within + -2%, and more preferably within + -1% of the specified numerical range given. For example, a pH of about 5.5 means a pH of 5.5.+ -. 5%, preferably a pH of 5.5.+ -. 2%, more preferably a pH of 5.5.+ -. 1%.

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

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

The term "fixed combination" refers to the simultaneous administration of the active ingredients (e.g., an anti-PD-1 antibody or a compound of formula I) to a subject in a fixed total dose or dose ratio, or in the form of a single entity, pharmaceutical composition, or formulation.

The term "non-fixed combination" refers to the simultaneous, concurrent or sequential administration of two or more active ingredients as separate entities (e.g., pharmaceutical compositions, formulations) to a subject, wherein the administration of the active ingredients to the subject achieves a therapeutically effective amount level, without specific time limitations. An example of a non-fixed combination is a cocktail therapy, e.g., administration of 3 or more active ingredients. In a non-fixed combination, the individual active ingredients may be packaged, marketed or administered as a fully independent pharmaceutical composition. The term "non-immobilized combination" also includes the use of "immobilized combinations" between, or in combination with, separate entities of any one or more of the active ingredients.

As used herein, "combined" or "combined" 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.

The term "pharmaceutical composition" refers to a mixture of one or more of the active ingredients of the present application (e.g. an anti-PD-1 antibody or a compound of formula I) or a pharmaceutical combination thereof, and pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate administration of the compound of the application or a pharmaceutical combination thereof to a subject.

The term "synergistic effect" refers to a simple addition of two or more components (e.g., an anti-PD-1 antibody or a compound of formula I) that produces an effect (e.g., inhibition of colon cancer growth, or alleviation of symptoms of colon cancer) that is greater than the effect of the components administered alone.

Mode of administration

The following is not intended to limit the manner of administration of the pharmaceutical combination of the application.

The components of the pharmaceutical combination of the present application may be formulated separately each, or some or all of them may be co-formulated. In one embodiment, the pharmaceutical combination of the application may be formulated into a pharmaceutical composition suitable for single or multiple administration.

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

The components of the pharmaceutical combination of the present application may each be administered independently, or some or all of them together, in a suitable variety of ways, including, but not limited to, orally or parenterally (via intravenous, intramuscular, topical or subcutaneous routes). In some embodiments, the components of the pharmaceutical combination of the present application may each be administered orally or by injection, e.g., intravenously or intraperitoneally, independently, or in combination with some or all of them.

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

The components of the pharmaceutical combination of the present application may each independently, or some or all of them together comprise a pharmaceutically acceptable carrier and/or excipient.

The pharmaceutical combinations of the application may also comprise additional therapeutic agents. In one embodiment, the additional therapeutic agent may be a cancer therapeutic agent known in the art.

The application also includes the following:

1. a pharmaceutical combination comprising:

a) A 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 consisting of the amino acid sequences shown 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 shown in SEQ ID No. 4, SEQ ID No. 5, and SEQ ID No. 6, respectively, and

B) A tyrosine kinase inhibitor, wherein the tyrosine kinase inhibitor is a compound of formula I or a pharmaceutically acceptable salt thereof,

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

3. The pharmaceutical combination of any one of the preceding claims, wherein the human PD-1 antibody comprises a light chain variable region as set forth in SEQ ID No. 7 and a heavy chain variable region as set forth in SEQ ID No. 8.

4. The pharmaceutical combination of any one of the preceding claims, wherein the human PD-1 antibody is 14C12H1L1.

5. A pharmaceutical combination according to any one of the preceding claims, which is a non-fixed combination.

6. The pharmaceutical combination of any one of the preceding claims, wherein the human PD-1 antibody and the compound of formula I or a pharmaceutically acceptable salt thereof in the non-fixed combination are each in the form of a pharmaceutical composition.

7. Use of a pharmaceutical combination according to any one of the preceding claims for the treatment or prophylaxis of head and neck chest tumours.

8. The use of any of the preceding claims, the pharmaceutical combination being for the treatment of advanced head, neck and chest tumors.

9. The use of any of the preceding claims, the pharmaceutical combination being for the treatment of advanced head and neck chest tumors and having received at least first line platinum-containing regimen systemic chemotherapy.

10. The use of any one of the preceding claims, the pharmaceutical combination being for the treatment of head and neck squamous cell carcinoma, head and neck non-squamous carcinoma, adenocarcinoma, adenoid cystic carcinoma, myxoepidermoid carcinoma, squamous carcinoma, lacrimal carcinoma, thyroid carcinoma, small cell lung carcinoma, non-small cell lung carcinoma, pleural mesothelioma or thymus carcinoma.

11. The use of any of the foregoing, the pharmaceutical combination for the treatment of recurrent/metastatic head and neck squamous cell carcinoma, advanced/metastatic head and neck non-squamous carcinoma, thyroid undifferentiated carcinoma, small-cell lung cancer failing a platinum-containing chemotherapy regimen, non-squamous carcinoma non-small-cell lung cancer, recurrent/metastatic pleural mesothelioma, or recurrent/metastatic thymus cancer.

12. The use of any of the preceding claims, wherein the pharmaceutical combination is administered at a unified dosage of the hydrochloride salt of the compound of formula I of about 10 mg/time or 12 mg/time, and 14C12H1L1 is administered at a unified dosage of about 200 mg/time.

13. The use according to any of the preceding claims, wherein the pharmaceutical composition is administered 1 time daily with 12mg or 10mg each time, 2 consecutive weeks for 1 week, and the 14C12H1L1 injection is administered 1 time every 3 weeks with 200 mg/time.

14. A preparation comprising a container containing a fixed dose of a compound of formula I hydrochloride and a 14C12H1L1 antibody, wherein the fixed dose of the compound of formula I hydrochloride is selected from the group consisting of about 8mg, about 10mg, and about 12mg, and the fixed dose of 14C12H1L1 antibody is selected from the group consisting of about 100mg and about 200mg.

Detailed Description

The application will be further described with reference to specific examples, which are, however, only intended to illustrate and not limit the scope of the application. Also, the application is not limited to any particular preferred embodiment described herein. It should be understood by those skilled in the art that equivalent substitutions and corresponding modifications to the technical features of the present application are still within the scope of the present application. The reagents used in the examples below are commercially available products, and the solutions may be formulated using techniques conventional in the art, unless otherwise specified.

Table 1 abbreviation Table

By "failure of treatment with a platinum-containing chemotherapeutic regimen" is meant intolerance of disease progression or toxic side effects during or after treatment with a platinum-containing regimen of first-line or radiotherapy.

The term "standard-failed non-small cell lung cancer" refers to non-small cell lung cancer in which "EGFR gene-sensitive mutations are positive for treatment with at least one EGFR-TKI inhibitor," or, if EGFR-T790M mutation is present, patients are required to receive a third generation EGFR inhibitor treatment failure, or, ALK gene rearrangement is positive for treatment with an ALK inhibitor, or, if patients are only treated with crizotinib, then with one other ALK inhibitor, or, ROS1 gene rearrangement is positive for treatment with an ROS1 inhibitor, or, the remaining genes are variant positive or driving gene negative for non-small cell lung cancer that was previously treated with at least one platinum-containing dual drug chemotherapy regimen.

By "non-small cell lung cancer that fails to undergo treatment with a platinum or non-platinum containing dual drug chemotherapy regimen" is meant that the disease progression or toxic side effects are intolerable during or after receiving first line chemotherapy treatment (including during maintenance chemotherapy), with imaging evidence that the disease progression. "recurrent/metastatic pleural mesothelioma that has failed at least first-line chemotherapy and is not surgically resectable or undergoing radical radiation therapy," means that disease progression or toxic side effects are intolerable during or after treatment with first-line systemic chemotherapy (which may include platinum-based or taxus-based), with imaging evidence that disease progression is warranted.

"14C12H1L1 injecta" refers to a medical formulation for injection containing a 14C12H1L1 monoclonal antibody, which is typically administered to a patient by the intravenous infusion route. In particular embodiments, the expression "14C12H1L1 injecta, 200 mg/time" can be understood in the manner usual in the art as a liquid injectable medical formulation containing 200mg of 14C12H1L1 monoclonal antibody per administration to a patient.

Example one clinical study protocol-study criteria and endpoint

1.1 Inclusion exclusion criteria

The inclusion criteria are that the user who meets the following inclusion items can enter the group test

1) All conditions of any one of the following queues are met:

Queue one:

a) Recurrent/metastatic head and neck squamous cell carcinoma patient with histologically confirmed diagnosis, wherein the primary part is oral cavity, oropharynx, hypopharynx or larynx;

b) At least one line of platinum-containing chemotherapy has been previously either failed or intolerant. For patients who have received neoadjuvant chemotherapy, concurrent radiotherapy or adjuvant chemotherapy in the past, if recurrence/metastasis occurs within 6 months from the end of the last treatment, the treatment regimen is counted as a first-line treatment regimen.

Queue two:

Advanced/metastatic head-neck non-squamous carcinoma patients (e.g., adenocarcinoma, adenoid cystic carcinoma, mucoepidermoid carcinoma, lacrimal carcinoma, etc.) who have failed histologically-confirmed standard therapy or who have no standard treatment.

And a third queue:

Patients with histologically confirmed standard treatment failure or untreated, non-surgically resectable thyroid undifferentiated carcinoma, and patients are expected to survive for longer than 2 months.

Queue four:

patients who have been histologically confirmed to receive only one platinum-containing chemotherapy regimen for treatment of failed small cell lung cancer;

Treatment failure is defined as intolerance of disease progression or toxic side effects during or after treatment with platinum-containing regimens of first-line or radiotherapy.

Queue five:

a) The patient is histologically diagnosed to be non-squamous carcinoma non-small cell lung cancer and IIIB to IV stage according to the definition of IASLC 8 th edition TNM staging system;

b) Failure to undergo standard treatment is defined as follows:

EGFR gene sensitive mutation positive by treatment failure with at least one EGFR-TKI inhibitor, and optional if patients with EGFR-T790M mutation are subject to treatment failure with three generations of EGFR inhibitors;

ALK gene rearrangement positive, namely failure to treat by ALK inhibitor, wherein if a patient is only treated by the prochloraz, the patient is required to be treated by other ALK inhibitor again;

ROS1 gene rearrangement positive, failure to undergo ROS1 inhibitor treatment;

The remaining genes were mutation positive or driving gene negative, failed to be treated by previous treatment with at least one platinum-containing dual drug chemotherapy regimen.

Queue six:

a) The histologically confirmed diagnosis is squamous non-small cell lung cancer, and stage IIIB, IIIC or IV (according to International Association of Lung cancer research and United states Joint Commission on cancer Lung cancer TNM staging System 8). Mixed cancers that allow the major tissue component of the group to be squamous carcinoma;

b) Treatment failed with at least one platinum or non-platinum containing dual drug chemotherapy regimen.

Treatment failure is defined as intolerance of disease progression or toxic side effects during or after treatment (including maintenance of chemotherapy) with first line chemotherapy, and imaging evidence must be provided to demonstrate disease progression. For adjuvant therapy (chemotherapy or radiotherapy), if disease progression occurs during treatment or within 6 months after cessation of treatment, it should be counted as a first line treatment regimen.

Queue seven:

Patients with histologically confirmed diagnosis, at least with recurrent/metastatic pleural mesothelioma who failed first-line chemotherapy and were not surgically resectable or undergoing radical radiotherapy;

Treatment failure is defined as intolerance of disease progression or toxic side effects during or after treatment with first-line systemic chemotherapy (which may include platinum or taxa based), for which imaging evidence is necessary. For neoadjuvant/adjuvant therapy (chemotherapy or radiotherapy), if disease progression occurs during the course of treatment or within 6 months after cessation of treatment, it should be counted as a first line treatment regimen.

2) Years old 18 years old, ECOG physical condition of 0-1 minute, expected survival period exceeding 3 months (excluding thyroid undifferentiated carcinoma);

3) The focus can be considered as a measurable focus only when the measurable focus defined by RECIST 1.1 standard exists, the former irradiation focus has definite progress after radiotherapy and the former irradiation focus is not the only focus;

4) The provision of either prior archived tumor tissue samples (tissue samples within the first 2 years of the group) or fresh acquisitions was agreed. The specimen needs to meet the requirement that 10 sections with the thickness of 4-6 mu m can be cut out for staining and detection of tumor tissue blocks after Formalin Fixation and Paraffin Embedding (FFPE). Specimens that do not receive fine needle aspiration biopsies, cell smears from hydrothorax drainage centrifugation, bone lesions without soft tissue components or decalcified bone tumor specimens, and drill biopsy tissue are not sufficient for biomarker detection. If no tumor tissue samples or slices are archived within 2 years, the number of tumor tissue samples or slices is less than 10, and the tumor tissue samples or slices can be selected after the tumor tissue samples or slices are agreed with the sponsor discussion;

5) The major organs function normally.

6) Patients voluntarily added the study, signed informed consent, and compliance was good.

Exclusion criteria subjects presenting any of the following will not be able to enter the group study

1) Local radiotherapy has been previously accepted, and groups can be entered if the end of radiotherapy is more than 4 weeks from the beginning of the study (brain radiotherapy is more than 2 weeks), and the target lesion selected for the study is not in the area of radiotherapy, or if the target lesion is in the area of radiotherapy, but progress has been confirmed.

2) Brain metastases with symptoms or symptom control times less than 2 months;

3) Patients had other malignancies (except for cured basal cell carcinoma of the skin and cervical carcinoma in situ) either before or simultaneously within 5 years;

4) Those with various factors affecting oral medication (such as inability to swallow, post-gastrointestinal resection, chronic diarrhea, and ileus, etc.);

5) Imaging (CT or MRI) shows that tumors invade large blood vessels or are poorly demarcated from blood vessels;

6) Significant surgical treatment, open biopsy or significant traumatic injury was received within 28 days prior to the first dose;

7) Arterial/venous thrombotic events, such as cerebrovascular accidents (including transient ischemic attacks), deep venous thrombosis and pulmonary embolism, occurred within 6 months prior to the first administration;

8) Those with history of abuse of psychotic drugs, who are unable to abstain from or have psychotic disorders;

9) Other clinical trials were conducted within four weeks;

10 At the discretion of the researcher, there are concomitant diseases that seriously jeopardize patient safety or affect the completion of the research by the patient.

1.2 Exit Standard

1) Disease progression occurs and researchers judge that subjects continue to treat without benefit;

2) Adverse events occur, cannot be tolerated and cannot be relieved;

3) Subjects who developed serious adverse events and were unsuitable for continued study participation;

4) Severely deviate from or violate the protocol and affect drug safety or efficacy assessment;

5) Subjects withdraw informed consent;

6) The follow-up cannot continue to be completed on time for various reasons.

1.3 Study endpoint

First stage, secure import period

The main end point is:

Safety and tolerability of the first cycle

Secondary endpoint:

objective Remission Rate (ORR), disease Control Rate (DCR), remission Duration (DOR), progression Free Survival (PFS), total survival (OS), etc.

Second stage, formal test

Primary endpoint

Objective Remission Rate (ORR)

Secondary endpoint

Disease Control Rate (DCR), duration of remission (DOR), progression Free Survival (PFS), total survival (OS)

Etc

Incidence and severity of Adverse Events (AEs) and Severe Adverse Events (SAE), as well as abnormal laboratory inspection indicators.

Example two clinical trial design

Single arm, open, multiple queue, multiple center phase II clinical trials were used.

2.1 Sample size

The study consisted of 7 cohorts, each cohort of 10-20 (adjusted according to the specific test results).

2.2 Image evaluation design

The main efficacy endpoint of this study was ORR, and the results of the study center investigator evaluations were employed. The study was further conducted with an independent imaging panel to evaluate and review the efficacy of imaging.

2.3 Dosing regimen design

Subjects were enrolled for each patient in the first to seventh cohorts of example one.

The study was divided into two phases:

The first phase is a single arm study, a safe lead-in period. The patient will receive An Luoti nig in combination with 14C12H1L1 mab. Safety information was collected every 21 days for a treatment cycle to determine the RP2D of An Luoti nii in combination with 14C12H1L1 in patients with advanced head and neck chest tumors, after which a formal trial was conducted. The lead-in period included the following 2 dose groups:

dose group A An Luoti Ni 10mg, D1-D14+14C1H2L1 once every 3 weeks, 200 mg/time

Dosage group B An Luoti Ni 12mg, D1-D14+14C1H2L 1 once every 3 weeks, 200 mg/time

Each dose group was planned to enroll 3-6 patients and the safety of the combination was observed. Based on the prior high sample size clinical study safety data of An Luoti ni capsules, the lead-in phase planning starts dose exploration from dose group a dosing regimen (if dose group a goes into 3-6 patients in the group, the first cycle tolerability will be good, dose group B exploration will be performed for 3-6 patients). At the conclusion of the lead-in trial, RP2D was determined by major researchers and sponsors in the An Luoti-ni combination 14C12H1L1 in patients with advanced head and neck chest tumors.

The second stage is a formal test. Patients will receive An Luoti ni in combination with 14C12H1L1 treatment:

An Luoti Ni capsule of hydrochloric acid:

Taken on an empty stomach 1 time daily (recommended within 60 minutes of the start of infusion of the 14C12H1L1 injection) at 12mg each time (final dose determined by the safe infusion period, tentative 12 mg). The oral administration is continued for 2 weeks and stopped for 1 week, i.e. 3 weeks (21 days) is a treatment period. If the medicine taking period is missed, the time from the next medicine taking period is confirmed to be shorter than 12 hours, and the medicine is not taken again.

14C12H1L1 injection:

Administered 1 time every 3 weeks, 200 mg/time, and administered by intravenous infusion. The infusion time is 60+/-10 min.

Drug administration cycle:

every 21 days, no other anti-tumor treatment can be performed during the administration period, and patients with disease control (CR+PR+SD) and adverse reaction tolerance can continue to take the medicine until the disease progresses or the disease cannot be tolerated.

Efficacy was assessed every 2 cycles. Patients with disease control (cr+pr+sd) and tolerable adverse reactions can continue to take medication until clinical benefit is lost, toxicity is intolerable, efficacy is assessed as PD, and the investigator considers unsuitable for continued medication at the end of the study.

Dosage adjustment of An Luoti Ni hydrochloride capsules:

During the course of the study, patients may down-regulate the An Luoti ni dose of hydrochloric acid (12 mg-10mg-8mg down-regulation in sequence, without allowing cross-dose adjustment) due to drug-related adverse events, and the study should be terminated if intolerable patients at the 8mg dose level. For patients with the hydrochloric acid An Luoti Ni capsule reaching 10mg or 8mg through the down-regulating dose, after the patients take the medicine for a period of time, if researchers judge that the disease is likely to progress, after the safety of the patients is stable, the up-regulating dose can be up-regulated once. At most, each patient was able to perform a dose up-regulation only and not across the dose group.

The 14C12H1L1 injection was fixed dose, with no dose down-regulation regimen.

2.4 Methods of combination administration

14C12H1L1 injection:

200mg was diluted to 100mL with physiological saline and the infusion time was 60.+ -. 10min. The administration is once every 21 days. The instillation time was started from the beginning of instillation of 14C12H1L1, the end of instillation of 14C12H1L1 and the end of the saline flush tube (20 mL saline flush tube was recommended). For subjects who cannot tolerate a 60min infusion, the infusion time can be prolonged up to 120 minutes (+ -15 minutes).

An Luoti Ni capsule of hydrochloric acid:

1 dose (12 mg) each (final dose determined by safe infusion period, tentative 12 mg) 1 time a day (pre-breakfast fasting oral), recommended to be administered on a fasting basis within ±60min of the start of infusion of the 14C12H1L1 injection. The oral administration is continued for 2 weeks and stopped for 1 week, i.e. 3 weeks (21 days) is a treatment period. There is no special case that the device is in a state of being, it is recommended to take the medicine for a fixed time every day. The patient needs to take the medicine after taking the blood or taking the medicine after the safety inspection day. If the medicine taking period is missed, the time from the next medicine taking period is confirmed to be shorter than 12 hours, and the medicine is not taken again.

Drug administration cycle:

Subjects were all patients enrolled in the first to seventh cohorts of example one.

2.5 Delayed dosing and dose adjustment

Adverse events caused by injection containing 14C12H1L1 monoclonal antibody lead to delayed administration, and administration cannot be recovered beyond 12 weeks, and treatment of injection containing 14C12H1L1 should be permanently stopped. Treatment advice for adverse events caused by 14C12H1L1 injection is described in the immune related adverse event treatment advice caused by immune checkpoint inhibitor treatment. The 14C12H1L1 injection allows delayed administration, but does not have dose adjustments.

The drug delivery of the An Luoti-day hydrochloric acid capsule is delayed when the adverse reaction related to An Luoti-day hydrochloric acid capsule occurs in the taking period (1-14 days), and the delay time is not longer than 5 days at maximum. If the patient still cannot continue to take the medicine for more than 5 days, an Luoti Ni is not used any more in the period. When the administration is started in the next period, for example, the administration can be continued to be delayed due to adverse reactions, the delay time is not longer than 2 weeks at maximum, and the patient still cannot take An Luoti Ni (including dose reduction) for more than 2 weeks, and the An Luoti Ni needs to be permanently stopped (the event caused by non-safety reasons can be excluded). During this study, an Luoti Ni hydrochloride capsules can be delayed or dose adjusted if necessary.

During the course of the study, doses were allowed to be adjusted down 12mg→10mg and 10mg→8mg when adverse events associated with An Luoti ni occurred. At the level of 8mg, the application termination medication still cannot be tolerated. After a period of time, the amount of the agent can be adjusted to the original level by allowing the next cycle to start, taking into consideration the possibility of disease progression and the safety is controllable.

2.6 Disease progression and efficacy assessment

During clinical administration of similar drugs of 14C12H1L1 injection, the subjects have pseudo-progress, and the curative effect evaluation standard of the study is based on RECIST 1.1 (curative effect evaluation standard of solid tumors). Efficacy was also confirmed using iRECIST criteria (tumor immunotherapy-related evaluation criteria). I.e., subjects who were judged to be disease Progression (PD) according to RECIST 1.1 criteria were further confirmed according to iRECIST criteria to determine whether to further follow-up medication.

Efficacy is assessed every 2 cycles, starting on the first day of the first cycle, until the subject develops tumor imaging confirmed disease progression, without the assessment changing the frequency of assessment due to the subject delaying or interrupting treatment. If subjects terminate study treatment for reasons other than disease progression, there is still a need to continue to receive the frequent oncology assessments described above until subjects begin new anti-tumor therapy, or imaging evidence of disease progression, or subject active withdrawal, or subject death, whichever occurs first.

The imaging evaluation mode of the tumor can adopt CT or MRI, but the evaluation method, the machine and the technical parameters should be consistent during the whole study period, and if no contraindications exist, contrast agents should be used. If tumor evaluation has been performed within 14 days prior to the first administration, and the same method is used in the same hospital, a baseline tumor evaluation can be made. Baseline tumor assessment should include CT or MRI of the chest, abdomen and pelvis. The screening period requires craniocerebral panning + enhancement/enhancement MRI. All suspicious lesions should be examined imagewise. For patients with bone metastases, the lesions should be followed up using bone scanning. For patients with bone metastasis, if no clinical symptoms are aggravated, the patients do not need to be reviewed every time tumor evaluation, and if the clinical symptoms are aggravated, the patients should be reviewed in time. For cases in which disease progression is suspected before the next evaluation in the plan begins, an unplanned tumor evaluation should be performed. Only the imaging examination of the focus part is carried out during the test, the suspicious part is carried out during the test, and the corresponding part image can be added.

Example III collection of biological samples

3.1 Serum anti-14C 12H1L1 antibody (ADA) detection

The time point of immunogenicity monitoring is based on the administration time of 14C12H1L1 injection, and when 14C12H1L1 is in delayed administration, the immunogenicity blood sampling is correspondingly delayed. When ADA of the subject is detected to be positive, the neutralizing antibody is added.

Collected at cycles 1, 2, 4, 8 and thereafter, every 6 cycles (-60 min) prior to dosing. And are collected at 30min (+ -5 min) after the end of infusion and at 30 days (+ -7 days) and at 90 days (+ -7 days) after the last administration at the 1 st and 8 th cycles. Every time 5mL of venous blood is required to be sampled, the venous blood is placed in a blood collection tube containing coagulation promoting separation gel, the venous blood is placed at room temperature for 30min, after natural coagulation, 3000g of venous blood is centrifuged for 10min, the venous blood is averagely split into 4 freezing storage tubes (3 parts of detection tubes, 1 part of backup tube and not less than 0.5mL of each detection tube), and serum marks are taken and then stored in a refrigerator at-40 to-80 ℃ for detecting immunogenicity and 14C12H1L1 blood concentration.

During the test, unexpected adverse events related to immunity occur, and 1 additional blood sampling is needed to be carried out after the confirmation of the adverse events, so that immunogenicity and 14C12H1L1 blood concentration can be detected, but the time for the last blood sample collection is less than 24 hours, and the collection can be omitted.

Note that neutralizing antibodies were subsequently assayed if necessary based on ADA results.

3.2 Biomarker assays

The participation in this study requires the provision of tumor tissue specimens for biomarker studies including PD-L1 expression, mismatch repair/microsatellite instability (MMR/MSI) detection, and the like.

Samples for biomarker detection are preferably selected from fresh biopsy samples within 1 month of group entry. When taking fresh tissue samples, 1 needle and above are penetrated through skin. Subject blood samples of 10mL prior to group entry (within 7 days prior to dosing) and at group exit (±3 days) were collected for ctDNA detection bTMB levels, etc.

Example IV evaluation of effectiveness and safety

4.1. Analysis of major efficacy index

4.1.1. Objective remission rate (Objective response rate, ORR):

The ratio of the number of objective remission cases (PR+CR) to the total number of cases in each group was calculated as 95% CI. The 95% CI for ORR is calculated based on the exact two-term method of F distribution.

4.1.2. Analysis of secondary efficacy indicators

4.1.2.1. Progression Free Survival (PFS)

The median PFS was estimated by Kaplan-Meier method and survival plots were drawn.

4.1.2.2. Total lifetime (OS)

The median OS was estimated by Kaplan-Meier method and survival plots were drawn.

4.1.2.3. Duration of remission (Duration of response, DOR)

Median PFS and 95% ci were estimated using Kaplan-Meier method and survival plots were plotted.

4.1.2.4. Disease Control Rate (DCR):

The ratio of disease control cases (cr+pr+sd) to total cases was calculated as 95% ci. The 95% ci of DCR is calculated based on the exact two-term method of F distribution.

4.2. Safety evaluation

4.2.1. Drug exposure and compliance

Drug exposure was described in terms of mean, standard deviation, maximum, minimum, median.

Summarizing the exposure of the subject to study drug treatment, the number of patient completed cycles, the dose adjustment during treatment, the cumulative number of dose adjustments during treatment, etc.

The study drug administration total dose and daily average dose and study drug dose compliance are statistically described for the study drug treatment time during the treatment period.

Study drug dose compliance will be calculated based on the daily actual study drug total dose and regimen prescribed study drug total dose recorded by eCRF.

The comparison of the treatment time of each study drug, the total dose of the study drug taken and the daily average dose and the compliance of the study drug dose adopts single factor analysis of variance, and the comparison of the compliance classification adopts chi-square test or Fisher accurate probability method.

4.2.2. Adverse events

Summary adverse events, pre-first-dose adverse events, during-treatment unexpected adverse events, during-treatment significant adverse events, during-treatment adverse events of particular concern, during-treatment grade 3 and above adverse events, during-treatment severe adverse events, during-treatment adverse events related to study drug, during-treatment SAEs related to study drug, during-treatment adverse events leading to dose adjustment, treatment permanent cessation, trial termination, patient death, number of instances, and incidence of adverse events, summarized by SOC, PT classification.

Adverse events with the occurrence rate of more than or equal to 5% during treatment are summarized according to PT classification.

Drug-related adverse events graded as grade 3 or grade 4 for CTC AEs during treatment were summarized according to PT classification.

Adverse events with the occurrence rate of more than or equal to 10% during treatment are summarized according to PT classification.

The first occurrence time in the adverse event of particular concern.

4.2.3. Vital signs

The mean ± standard deviation, maximum, minimum, median were used to describe the measured and varying values before and after treatment.

4.2.4. Laboratory inspection index

Table 2 inspection item table

Blood routine, blood biochemistry, thyroid function, blood coagulation function, amylase and lipase adopt mean ± standard deviation, maximum value, minimum value and median to describe measured values and change values before and after treatment, and in-group comparison adopts paired t test. The cross classification table is used for describing the normal and abnormal change conditions before and after treatment.

Urine routine the cross-classification table is used to describe the normal and abnormal changes before and after treatment.

It is conventional to use a cross-classification table to describe the normal and abnormal changes before and after treatment.

The proportion of "abnormal, clinically significant" in subjects describing abnormal changes, with the presence or absence of an abnormality being judged by the investigator.

4.2.5. Electrocardiogram

Electrocardiogram, which describes the normal and abnormal changes before and after treatment according to the normal and abnormal conditions judged by researchers.

Heart rate, PR interval, QRS interval, QT interval, and QTc describe measured and varying values before and after administration using mean ± standard deviation, maximum, minimum, median. The overall electrocardiographic evaluation result adopts a cross classification table to describe the normal and abnormal change conditions before and after administration. The proportion of "clinically significant" of abnormalities in subjects describing abnormal changes, with the clinical significance of the presence or absence of abnormalities being judged by the investigator. The list presents an abnormal list after administration.

4.2.6. Physical examination

Describes the normal and abnormal changes before and after treatment.

Example five clinical application

1. E09002-squamous cell carcinoma of head and neck of patient

A56-year-old male, 5 months and 29 days in 2020, has a pathological diagnosis of severe dysplastic cancer of squamous epithelium. CT at 5 months and 20 days in 2020 suggests postoperative change of lower right lung leaf cancer, and increase of right lung portal soft tissue, and disease progress. The patient has the past chemotherapy history of 120mg of docetaxel and 50mg of lobaplatin for injection from 10 months 09 in 2019 to 12 months 17 in 2019, and the treatment effect is evaluated as SD in 3 cycles of chemotherapy. Docetaxel 100 mg+lobaplatin 40mg for chemotherapy 1 cycle was injected at 20 months of 2020. CT on 5/20/2020 suggested progress.

The drug is orally taken once daily for 12mg of the An Luoti-Ni capsule for 2 weeks for 1 week, and is continuously taken for 14C12H1L1200mg for 3 weeks on the 6 th month 13 th year 2020. The patient has good overall tolerance during the taking period, and can continue taking medicine.

Screening period, target focus of 1.1 mm, non-target focus of pulmonary artery window multiple lymph node

Following period 2 dosing, target lesions were 22.4mm (PR), non-target lesions were non-CR/non-PD

After period 4, the target lesions were 22mm (PR) and the non-target lesions were non-CR/non-PD

Following cycle 6 dosing, target lesions <10mm (CR), non-target lesions non-CR/non-PD

2. Patients E02003/S02005-lacrimal adenocarcinoma/adenoid cystic carcinoma

Past history of 27 years men, 7 months 2007 were treated with left eye orbital tumor surgery for removal of the tumor, postoperative pathology, left tear adenoid cystic carcinoma. No related treatment was performed after the operation. The left orbital tumor was found again in 2011, treated with surgery, postoperative pathology, adenoid cystic carcinoma. Post-operative particle implantation treatment (not specifically detailed). CT is reviewed in 2018 and 9, and the section shadow of the soft tissue of the inner proximal and outer side walls of the left orbit is increased. Left orbital tumor resection was performed again at 9 months 2018, postoperative pathology, adenoid cystic carcinoma. Two-cycle AP protocol chemotherapy and particle implantation treatment (not detailed) follow the procedure. The tumor is accessible outside the mandible at the left side of 2019, and the tumor cells are visible by puncture biopsy, and the tumor is suspected to be a low-grade malignant epithelial tumor. The nuclear magnetism was reviewed in 10 months 2019, the abnormal changes in the left orbit, the intraorbital tumor involved the temporal fossa and the temporal polar intracranial, the bilateral inferior alveolar nerve thickened and significantly strengthened, and the left tumor spread along the nerve, considering recurrence. Left mandibular tumor enlarged resection at 11.18.2019, post-operative pathology adenoid cystic carcinoma. Postoperative radiotherapy is performed from 12 months in 2019 to 16 days in 1 month in 2020.

Pathological report of adenoid cystic carcinoma

Dosage of medication: an Luoti Ni hydrochloride 12mg,14C12H1L1:200mg

Efficacy evaluation:

the screening period is 25mm for target focus and 25mm for non-target focus for mediastinal lymph node

After period 2, the target lesion was 19mm, the non-target lesion was non-CR/non-PD

3. E10007-squamous cell carcinoma of head and neck

The patient is subjected to TP scheme chemotherapy in 2020-03-11, 2020-04-02, 2020-04-22, 2020-05-13 and 2020-06-03 after 2020-03, 2020-02, 2020-05-13 and 2020-06-03, and is subjected to anti-emetic and fluid replacement treatment simultaneously with other symptomatic support treatment, and the tumor control is poor after the chemotherapy. Then, an Luoti is given in combination with 14C12H1L 1.

Dosage of medication: an Luoti Ni hydrochloride 12mg,14C12H1L1:200mg

The whole tolerance is good during the taking period, and the medicine can be continuously taken.

Efficacy evaluation:

Screening stage including target focus of 30mm cyst solid tumor in subleft mandibular region and non-target focus of 30mm cyst solid tumor in subleft mandibular region

After period 2, the target focus was 28mm, the non-target focus was non-CR/non-PD

After period 4, the target lesions were 28mm, the non-target lesions were non-CR/non-PD

After period 6, the target lesion was 28mm, the non-target lesion was non-CR/non-PD

4. S07007/E07005-squamous cell carcinoma of head and neck

A past history of 51 year old men, pathological examination of day 1 and 28 in 2019 showed moderate or about atypical hyperplasia of squamous epithelium. Histological report (left lingual abdomen) superficial hyperdifferentiated squamous carcinoma epithelium at 1 day of 2 months 2019. The 22-day histological report of 2019, 2, suggested (tongue primary foci) high-medium differentiated squamous carcinoma, P16-. CT report of 20 days 3 month in 2020 shows that the tumor of the upper right lung near the portal area is enlarged more anterior, the upper right lung is obstructive and the lymph node is enlarged more anterior, and the curative effect is evaluated as PD. The patient CT report of 31 st 2020 to 23 nd 2020 shows that the mediastinal lymph node part is enlarged before and the curative effect is evaluated as PD, and the patient CT report of 31 st 2020 to 23 nd 2020 shows that the treatment is carried out by 395mg of albumin taxol+120 mg of nedaplatin for 2 cycles.

C1D1 is administered on 6/10 th/2020, 12mg of An Luoti Ni capsule of hydrochloric acid is administered on an empty stomach once daily, two weeks and one week are stopped continuously, three weeks are one period, and 14C12H1L1 is administered once every period. The whole tolerance of the patient is good during the taking period, and the medicine can be continuously taken

The dosage of the medicine is ALTN:12mg,14C12H1L1:200mg;

Efficacy evaluation:

screening period: 65mm (upper right lung nodule + mediastinal lymph node) of target lesion;

Non-target lesion, mediastinal lymph node.

Following period 2, the drug was administered with target lesions SD (52 mm) and non-target lesions non-CR/non-PD.

After period 4, the target lesions were PR (40 mm) and non-target lesions were non-CR/non-PD.

After period 6, the target lesions were PR (40 mm) and non-target lesions were non-CR/non-PD.

5. S07002/E07002-non-small cell lung cancer

The prior history of 61 years old men and 10 months and 23 days of 2019 show that the pathological examination of (right lung tumor puncture) is not small cell cancer with poor differentiation, and the supplement immunohistochemical report shows that (right lung tumor puncture) HE is combined with immunohistochemical adenocarcinoma with poor differentiation. Gene detection showed EGFR, ALK, ROS that both were negative. 4 cycles of treatment with 750mg of risperidone plus 500mg of carboplatin from 11.3.2019 to 1.12.2020. The patient's 22-day CT report of 4 months 2020 shows that the upper right lung She Zhongkuai is contracted earlier and that the lower right lung is new with nodules, with a high likelihood of metastasis being considered. The soft tissue nodules and tumors in the right diaphragmatic corner area are increased forward, the right chest wall is invaded, and the curative effect is evaluated as PD.

The administration of C1D1 is carried out on 5 months and 9 days of 2020, 10mg of the An Luoti-Ni capsule hydrochloride is started to be taken once daily on an empty stomach, two weeks are stopped for one week, three weeks are taken as a period, and 14C12H1L1 is administered once every period. The whole tolerance of the patient is good during the taking period, and the medicine can be continuously taken.

Dosage of medication: an Luoti% hydrochloric acid 10mg,14C12H1L1:200mg;

Efficacy evaluation:

Screening period: 135mm (right anterior chest wall + right diaphragmatic angle + right upper lung anterior segment) of target lesion;

non-target focus, no.

After period 2, the target lesions were SD (101 mm) and non-target lesions were NA.

After period 4, the target lesions were PR (72 mm) and non-target lesions were NA.

After the 6 th period of administration, the target lesions were PR (72 mm) and the non-target lesions were NA.

After the 8 th period of administration, the target lesion was PR (69 mm) and the non-target lesion was NA.

6. E10002-head, neck and chest tumor of patient

Male, 60 years old, patient's history of 1 month of head MR: brain metastasis in 2020, CT hint of 1. Left upper lobe lung portal soft tissue density shadow, central lung cancer with distant lung tension, multiple metastasis of liver and spleen, mediastinum, neck, portal and pancreatic multiple lymph node metastasis, 2. Lobular central emphysema: double lung multiple nodule: 3. Heart enlargement, aortic and coronary sclerosis, 4. Small minor spleen, left kidney cyst: EP regimen in 2020-02-06, 2020-03-04, 2020-03-30 2020-04-24, 2020-05-14 lines 5, while administration of antiemetic, symptomatic etc. treatment. The whole tolerance is good during the taking period, and the medicine can be continuously taken.

The dosage of the medicine is An Luoti Ni hydrochloride 12mg po,14C12H1L1:200mg

Efficacy evaluation:

Screening period

Target lesion, 58mm of left submaxillary lymph node metastasis, 42mm of left upper lobe near hilar region solid tumor, 57mm of hilar lymph node metastasis, 27mm of spleen solid nodule

Non-target lesion including lymphadenectasis of double neck, lymphadenectasis of left side axillary, multiple lymph nodes around gastric body small curve lateral abdominal cavity, solid nodule in left lower lung leaf near lung portal area, multiple brain metastasis of bilateral brain and cerebellum hemisphere

After the administration of the 2 nd period, the target focus is that the lymph node of the lower left jaw is metastasized for 34mm, the upper left lung leaf is close to the real tumor of the portal area for 42mm, the lymph node of the portal area is metastasized for 36mm, the spleen real nodule is 18mm, and the non-target focus is that the non-CR/non-PD is

After the 4 th period of administration, the target focus is that the lymph node of the lower left jaw is metastasized for 24mm, the upper left lung leaf is close to the real tumor of the portal area for 43mm, the lymph node of the portal area is metastasized for 34mm, the spleen real nodule is 17mm, and the non-target focus is that the non-CR/non-PD is

After the 6 th period of administration, the target focus is that the lymph node of the lower left jaw is metastasized for 24mm, the upper left lung leaf is close to the real tumor of the portal area for 43mm, the lymph node of the portal area is metastasized for 32mm, the spleen real nodule is 16mm, and the non-target focus is that the non-CR/non-PD is

7. Patient S07018/E07012-thyroid cancer

A31 year old female is shown in 7 months and 23 days pathological examination in 2020 that (bilateral thyroid gland 6/7 area, mediastinal lymph node) (proximal left leaf of thyroid isthmus) is malignant tumor, and undifferentiated carcinoma is considered, and the mediastinal lymph node is seen as metastasis. Double sided thyroidectomy, VI, VII cervical lymph node dissection, 7 months 2020. CT for patients on 8 th and 5 th 2020 shows that the postoperative change of thyroid cancer, left anterior superior mediastinum soft tissue tumor, and the possibility of metastasis and esophageal invasion are considered to be high. Efficacy evaluation, PD.

The administration of C1D1 is carried out on 18 days of 8 months in 2020, 12mg of the An Luoti Ni capsule hydrochloride is started to be taken once daily on an empty stomach, two weeks are stopped for one week, three weeks are taken as a period, and 14C12H1L1 is administered once every period. C3D21 cycle follow-up in line with 19 days of 10 months 2020, due to hypertension grade III AE, the drug dosage of An Luoti Ni hydrochloride capsule is adjusted down to 10mg, and the whole tolerance of patients during the drug administration period is good, and the drug administration can be continued

The dosage of the medicine is C1D1-C3D21 hydrochloric acid An Luoti n, 12mg,14C12H1L1:200mg;

Dosage of medication: C4D 1-to date An Luoti Ni hydrochloride: 10mg,14C12H1L1:200mg;

Efficacy evaluation:

Screening period: 43mm (left anterior superior mediastinum) of target lesion;

Non-target lesion, right anterior superior mediastinal intravascular lymph node

Following period 2, the target lesions were PR (22 mm) and non-target lesions were non-CR/non-PD.

After period 4, the target lesions were PR (16 mm) and non-target lesions were non-CR/non-PD.

8. Patients E08001/S08001-thyroid cancer

Pathological report of anaplastic thyroid cancer

Dosage of medication: an Luoti Ni hydrochloride 12mg,14C12H1L1:200mg

Efficacy evaluation:

Female age 66, 21 st 2013, 6 th month, and postoperative pathological diagnosis of anaplastic thyroid cancer. 2013.6.21 a double thyroidectomy, 2019.2.15 a right cervical lymphopenia (group III) procedure, 2020.6.11 a right cervical clearance procedure. 2020-7-1 PET CT suggested that cervical multiple lymphadenectasis, considered malignant, and the rest did not see clear malignant lesions. The CT enhancement of the chest, abdomen and basin of the patient from 2020-7-29 to 2020-8-18 shows that the thyroid gland changes after double-leaf operation, is approximately the same as before, and the changes after the right neck operation are newly seen, the operation area is accumulated with air, the operation area is subject to subcutaneous exudation, the tissue density of the operation area is increased, and the changes of the double-lung subpleural multiple nodules are less than the previous changes. Neck soft tissue enhanced MRI, right neck multiple tumor shadow, considering multiple lymph node metastasis, the original focus part disappears after operation, part of focuses are enlarged before, and multiple focuses are newly seen. 2020-8-12, for course 1 14C12H1L1 in combination with An Luoti Ni, one dosing cycle every 3 weeks.

The CT results are as follows:

the screening period is 61.9mm for target lesion and 61.9mm for non-target lesion

After period 2, the target focus was 18.0mm, and non-target focus was present

After the administration of the 4 th period, 15.5mm target focus and 15.5mm non-target focus exist

9. Patients E11002/S11003-adenocarcinoma

The prior medical history is that 69 years old female is treated by Ca radical treatment on the upper right lung under 2018.4.27 th general anesthesia thoracoscope of trachea cannula, four times of chemotherapy (taxol+nedaplatin) are respectively carried out on 2018.6.13, 2018.7.18, 2018.9.3 and 2018.10.15 lines, three times of chemotherapy (pemetrexed+nedaplatin) are carried out on 2019.12.18, 2020.1.11 and 2018.2.22 lines, and 2020-08-05 chest CT shows that the right pleura is thickened at a plurality of places and has soft tissue density nodules, the major long diameter is about 0.9cm, and the pleural metastasis is suggested. Prompting the progress of the illness.

2020-08-17C1D1, starting to take the hydrochloric acid An Luoti Ni capsule orally once daily, 12mg each time, stopping taking the capsule orally for two weeks continuously for one week, and taking the 14C12H1L1 once every three weeks, wherein the infusion time is 60+/-10 min. Every 21 days is a cycle until the disease progresses or is intolerable. 2020-09-22 due to hand and foot syndrome CS grade III, the third cycle of the dose of erlotinib is 10mg,2020-10-13 due to oral pain CS grade III, the fourth cycle delays An Luoti by one cycle of dose, 2020-11-11 subjects return to < grade 2, and An Luoti to 8mg is down-regulated for continued dose.

Pathology report 2018-04-18 "right lung" puncture tissue adenocarcinoma.

The dosage of the medicine is C1D1-C2D21, an Luoti Ni hydrochloride 12mg,14C12H1L1:200mg

The dosage of the medicine is C3D1-C3D21, an Luoti Ni hydrochloride 10mg,14C12H1L1:200mg

C4D1-C4D21:14C12H1L1:200mg

C5D1-C5D21 hydrochloric acid An Luoti Ni 8mg,14C12H1L1:200mg

Efficacy evaluation, second period PR, fourth period SD

Screening stage including target focus 13.9mm, non-target focus including right lung lower field proximal diaphragmatic surface nodule and right pleura multiple nodule

After period 2, the target focus was 8mm, the non-target focus was non-CR/non-PD

After period 4, the target lesions were 11.6mm, the non-target lesions were non-CR/non-PD

10. Patients E11003/S11006-squamous cell carcinoma

The traditional medical history of 2020-02-05 is that the pathological diagnosis is squamous cell carcinoma, 2020-08-19 chest CT shows that the left collarbone, the right lower lung portal area, the bronchus opening and the lower leaf dorsal segment and the rear basal segment are irregular, the bronchis narrow, the soft tissue shadow is enlarged forwards, a plurality of solid nodules are newly added to the double lung, most of metastasis is considered to be enlarged forwards, the left collarbone, the upper and lower fossa, the mediastinum, the double lung portal and the liver and stomach ligament area are enlarged, the lymph nodes are partially necrotized and enlarged forwards. Prompting the progress of the illness.

2020-09-10, The capsule of An Luoti Ni hydrochloride is orally taken once daily, 12mg each time, and 14C12H1L1 is orally taken for two weeks and one time every three weeks, and the intravenous infusion is carried out for 60+/-10 min. Every 21 days is a cycle. The patient has good tolerance during the taking period and can continue to take the medicine.

Pathological report < lower right pulmonary bronchoscope biopsy > squamous cell carcinoma

Dosage of medication: an Luoti Ni hydrochloride 12mg,14C12H1L1:200mg

Evaluation of efficacy SD

The screening period is that the target focus is 101.7mm, and the non-target focus is left lung lymph node

After period 2, the target lesions were 89.5mm, the non-target lesions were non-CR/non-PD

11. E09003-small cell carcinoma of patient

A68-year-old male, 2019, 3-5, is diagnosed with small cell carcinoma. CT 3/30 in 2020 suggests that the left lower lung leaf is slightly more restricted in height than before, and that the enlarged lymph node beside the aortic arch is slightly larger than before, thus suggesting the progress of the disease. The patient has past chemotherapy history of 30mg of cisplatin plus 0.1g of etoposide for chemotherapy from 3 months of 2019 to 7 months of 2019 for 5 cycles. Chemotherapy starts from 2 days of 9 in 2019 to 6 days of 9 in 2019 with 20mg of cisplatin plus 0.1g of etoposide for 1 cycle of chemotherapy. Radiation therapy is performed from 4 days of 11 months in 2019 to 23 days of 12 months in 2019. CT 3/30/2020 suggested progress.

The oral administration of the An Luoti Ni HCL capsule for 12mg is started once daily for 7 months and 8 days in 2020, and the continuous administration of the capsule for 2 weeks is stopped for 1 week, and the treatment of the capsule for 14C12H1L is started for 1200mg, wherein every 3 weeks is an administration period. The patient is currently in the follow-up visit of the C6 period, the whole tolerance is good during the taking period, and the medicine can be continuously taken.

The screening period is that the target focus is 56.9mm, and the non-target focus is left lung portal soft tissue shadow

After period 2, target lesions 25.5mm PR, non-target lesions non-CR/non-PD

After period 4, the target lesions were 16.9mm PR, non-target lesions were non-CR/non-PD

12. E10001-head, neck and chest tumor of patient

Male 52 years old, left nasal obstruction and stuffiness with left palate bulge, facial skin numbness is collected at 2020.05.18 by 'left maxillary sinus tumor to be checked', 2020.05.27 puncture pathology, namely myoepithelial cancer, preliminary diagnosis, maxillary sinus malignancy, difficult operation of a tumor hair growing part, no standard treatment scheme, and clinical study is considered to be added, and 2020.06.12 is put into a group.

The dosage of the medicine is An Luoti Ni hydrochloride at 2020.06.12, 12mg and 14C12H1L1:200mg, the patient is currently in C8 period medicine taking, the whole tolerance is good during the medicine taking period, and the medicine taking can be continued.

Efficacy evaluation:

screening period:

Target focus, 71mm of right upper jaw solid tumor;

non-target focus double cervical gap multiple lymph node

After period 2, 51mm target lesions, non-target lesions non-CR/non-PD

After period 4, 50mm target lesions, non-target lesions non-CR/non-PD

After the 6 th period of administration, the target focus was 52mm, the non-target focus was non-CR/non-PD

In accordance with the present disclosure, while the compositions and methods of this application have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the application.

The disclosures of all documents cited herein are hereby incorporated by reference to the extent that they provide exemplary, procedural and other details supplementary to those set forth herein.

Sequence listing

<110> The pharmaceutical industry group Co., ltd

<120> Pharmaceutical combinations of quinoline derivatives and PD-1 mAbs

<130> 2020.11.27

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<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

<400> 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

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<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 human PD-1 antibodies and tyrosine kinase inhibitors in the preparation of drugs for the treatment of head and neck squamous cell carcinoma,

The human PD-1 antibody comprises a light chain and a heavy chain, wherein the light chain comprises light chain complementary determining regions LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, respectively, and the heavy chain comprises heavy chain complementary determining regions HCDR1, HCDR2, and HCDR3 as 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 of 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl]cyclopropylamine.

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

4. The method according to claim 1, wherein the human PD-1 antibody comprises a light chain variable region having an amino acid sequence as shown in SEQ ID NO: 7 and a heavy chain variable region having an amino acid sequence as shown in SEQ ID NO: 8.

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

6. Use of human PD-1 antibodies in the preparation of medicaments for the treatment of head and neck squamous cell carcinoma in combination with tyrosine kinase inhibitors,

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

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

9. The method according to claim 6, wherein the human PD-1 antibody comprises a light chain variable region having an amino acid sequence as shown in SEQ ID NO: 7 and a heavy chain variable region having an amino acid sequence 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 to 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 to 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 to 10, wherein the human PD-1 antibody is administered once every 2 weeks or once every 3 weeks.

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

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