CN112915202A

CN112915202A - Pharmaceutical composition of quinoline derivative and PD-1 monoclonal antibody

Info

Publication number: CN112915202A
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: 2021-06-08

Abstract

There is provided a pharmaceutical combination of a quinoline derivative and PD-1 mab which comprises a tyrosine kinase inhibitor and an immune checkpoint inhibitor, wherein the tyrosine kinase inhibitor is a compound of formula I or a pharmaceutically acceptable salt thereof. The medicine composition has good activity of resisting head, neck and chest tumors.

Description

Pharmaceutical composition of quinoline derivative and PD-1 monoclonal antibody

Technical Field

The application belongs to the technical field of medicines and relates to a combined treatment for resisting tumors. In particular, the application relates to a combination based on quinoline derivatives and PD-1 monoclonal antibody and application thereof in resisting head-neck thoracic tumors.

Background

Tyrosine kinases are a group of enzymes catalyzing phosphorylation of tyrosine residues of proteins, play important roles in signal transduction in cells, participate in regulation, signal transmission and development of normal cells, and are closely related to proliferation, differentiation, migration and apoptosis of tumor cells. Many receptor tyrosine kinases are involved in tumor formation and are 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 their extracellular domain structures.

Anlotinib (Anlotinib) is a quinoline derivative tyrosine kinase inhibitor, and plays a role in influencing tumor angiogenesis and proliferation signal transduction as a multi-target Tyrosine Kinase Inhibitor (TKI), and main targets comprise: receptor tyrosine kinases 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) α and β, and Stem Cell Factor Receptors (SCFR)7, 8, and 9. A phase 2 trial showed that erlotinib improved progression-free survival with potential benefits for overall survival (Han B, et al Br J cancer.2018; 118 (5): 654-. A multicenter, double-blind, phase 3 randomized clinical trial showed that, among Chinese patients, Arotinib resulted in prolonged overall and progression-free survival, which indicated that Arotinib was well tolerated and is a potential three-line or further treatment for advanced NSCLC patients (Han B, et al, JAMA Oncol.2018 Nov; 4 (11): 1569-.

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, which has the formula shown in formula I:

PD-1(programmed death-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 death-ligand 1), also known as CD274 or B7-H1, is a 40kDa type 1 transmembrane protein encoded by the CD274 gene and is a ligand for PD-1. Both PD-L1 and PD-1 belong to the immunoglobulin superfamily and both 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(CD80) is on an IgV-like domain (Lin et al (2008) PNAS 105: 3011-3016). PD-L1 contains a conserved short intracellular tail region (about 30 amino acids), and PD-1 contains two cytoplasmic tyrosine-based signaling motifs, an immunoreceptor tyrosine-based inhibitory motif (ITIM) and an immunoreceptor tyrosine-based switching motif (ITSM). Following T cell stimulation, PD-1 recruits the tyrosine phosphatase SHP-2 to the ITSM motif in its cytoplasmic tail, resulting in dephosphorylation of effector molecules involved in the CD3+ T cell signaling cascade, such as CD3 ζ, PKC θ 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 leukocytes and nonhematopoietic cells in lymphoid and non-lymphoid tissues, but also in various cancer cells, is highly expressed on the surface of various tumor cells, and the degree of malignancy and poor prognosis of tumors are closely related to the expression level of PD-L1. There are clinical data indicating that high tumor expression of PD-L1 is associated with increased tumor invasiveness and poor prognosis. The formation of the PD-1/PD-L1 complex transmits inhibitory signals and negatively regulates T cell immune responses; it inhibits TCR-mediated T cell activation, cytokine production and T cell proliferation (Fife et al (2011) Nature Immunology 10: 1185-1193); induction of depletion or anergy in cognate antigen-specific T cells (Hofmeyer et al (2011) Journal of Biomedicine and Biotechnology 2011: 1-9); promote the differentiation of Th1 cells into Foxp3+ regulatory T cells (Armanath et al (2011) Science TransMed 3: 1-13; Francisco et al (2009) J. exp. Med.206: 3015-; and inducing apoptosis of effector T cells. Disruption of the PD-L1 gene resulted in an upregulated T cell response and the generation of autoreactive T cells (Latchman et al (2004) PNAS 101: 10691-10696). Antibody blockade of PD-1 or PD-L1 resulted 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 effectively block the combination of PD1 and PD-L1 and shows better antitumor activity.

The biggest challenge in the course of tumor immunotherapy in foreigners is poor treatment due to tumor immune tolerance and escape. Therefore, the small-molecule anti-tumor compound and the anti-PD-1/PD-L1 antibody are used in combination to break the immune tolerance established by the body to the tumor cells, and the method has important theoretical significance and application value.

Disclosure of Invention

It is an object of the present invention at least 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 particular embodiments, the tyrosine kinase inhibitor is a hydrochloride salt of a compound of formula I, i.e., angutinib hydrochloride.

In some embodiments, the human PD-1 antibody comprises a light chain variable region as set forth in amino acid sequence 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 14C12H1L 1.

In some embodiments, the compound of formula I may be present as a pharmaceutically acceptable salt or a pharmaceutically acceptable formulation thereof, preferably as 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, namely, nilotinib hydrochloride.

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

It is also an object of the present invention at least to provide the use of 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, for the treatment of a tumor.

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 as set forth in amino acid sequence 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 14C12H1L 1.

In some embodiments, the use for treating a tumor is for treating a head and neck thoracic tumor. In some embodiments, the head and neck thoracic tumor is an advanced head and neck thoracic tumor. In some embodiments, the head and neck thoracic tumor has previously failed or been intolerant to at least first line platinum-containing chemotherapy. In some embodiments, the head and neck thoracic tumor is a head and neck thoracic tumor that has failed standard treatment or has no standard treatment method diagnosed histologically.

In some embodiments, the tumor is treated for a recurrent/metastatic squamous cell carcinoma of the head and neck, and in some embodiments, the primary site of the recurrent/metastatic squamous cell carcinoma of the head and neck is the oral cavity, oropharynx, hypopharynx, or larynx.

In some embodiments, the use for treating a tumor is for treating non-squamous carcinoma of the head and neck. 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 standard treatment with histologic confirmation or has not been treated with standard treatment.

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

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

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

In some embodiments, the use of the treatment of a tumor is for the treatment of non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is non-squamous. In other embodiments, the non-small cell lung cancer is non-squamous non-small cell lung cancer and the subject is a stage IIIB-IV patient as defined by the IASLC staging system, version 8 TNM. In some embodiments, the non-small cell lung cancer is non-squamous non-small cell lung cancer that has failed standard therapy. In some embodiments, the non-small cell lung cancer is squamous. In some embodiments, the non-small cell lung cancer is squamous and the clinical stage is stage IIIB, stage IIIC or stage IV (as defined by the IASLC version 8 TNM staging system). In some embodiments, the tumor is treated for non-small cell lung cancer that has failed at least one platinum-or non-platinum-containing dual-drug chemotherapy regimen.

In some embodiments, the use to treat a tumor is pleural mesothelioma. In some embodiments, the pleural mesothelioma is recurrent/metastatic pleural mesothelioma, and in other embodiments, the pleural mesothelioma is recurrent/metastatic pleural mesothelioma that has been histologically confirmed, has failed at least one-line chemotherapy, and is not surgically resectable or subjected to radical radiotherapy.

In some embodiments, the tumor is treated with thymus cancer. In some embodiments, the thymus cancer is relapsed/metastatic thymus cancer, and in other embodiments, the thymus cancer is histologically confirmed, has failed at least one-line chemotherapy, and is not surgically resectable or radically treated.

The invention also provides a method for treating a subject having a head and neck thoracic tumor comprising administering to the subject a therapeutically effective amount of a tyrosine kinase inhibitor and a therapeutically effective amount of a human PD-1 antibody, the human PD-1 antibody comprising a light chain comprising light chain complementarity determining regions LCDR1, LCDR2 and LCDR3, the light chain complementarity determining regions consisting of the amino acid sequences set forth in SEQ ID No. 1, SEQ ID No. 2 and SEQ ID No. 3, respectively, and wherein the heavy chain comprises heavy chain complementarity determining regions HCDR1, HCDR2 and HCDR3, the heavy chain complementarity determining regions consisting of the amino acid sequences set forth in SEQ ID No. 4, SEQ ID No. 5 and SEQ ID No. 6, respectively. In some embodiments, the tyrosine kinase inhibitor is a compound of formula I or a hydrochloride salt thereof. In some embodiments, the human PD-1 antibody comprises a light chain variable region as set forth in amino acid sequence 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 14C12H1L 1.

The invention also provides a combination therapy for treating a subject having a head and neck thoracic tumor, the method comprising administering to the subject a therapeutically effective amount of a tyrosine kinase inhibitor alone and a therapeutically effective amount of a human PD-1 antibody alone, 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 set forth in SEQ ID No. 1, SEQ ID No. 2 and SEQ ID No. 3, respectively, and wherein the heavy chain comprises heavy chain complementarity determining regions HCDR1, HCDR2 and HCDR3 consisting of the amino acid sequences set forth 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 a cancer or tumor, said cancer or tumor being a head and neck breast tumor, said method comprising: (i) measuring the level of PD-1 and/or PD-L1 in a sample of the subject, wherein the subject is PD-1 and/or PD-L1 positive, and (ii) administering to the subject a therapeutically effective amount of an anti-PD-1 and/or PD-L1 antibody or antigen-binding portion thereof.

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

In some embodiments of the invention, the head and neck thoracic tumor is an advanced head and neck thoracic tumor. In some embodiments, the head and neck thoracic tumor has previously failed or been intolerant to at least first line platinum-containing chemotherapy. In some embodiments, the head and neck thoracic tumor is a head and neck thoracic tumor that has failed standard treatment or has no standard treatment method diagnosed histologically.

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

In some embodiments, the head and neck thoracic 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 been histologically diagnosed as failing a standard treatment or having no standard treatment.

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

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

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

In some embodiments, the head and neck thoracic tumor is non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is non-squamous cell lung cancer. In some embodiments, the non-small cell lung cancer is non-squamous cell lung cancer, and the treatment subject is a stage IIIB-IV patient as defined by the IASLC stage 8 system. In some embodiments, the non-small cell lung cancer is non-squamous cell lung cancer that has failed standard therapy. In some embodiments, the non-small cell lung cancer is squamous cell lung carcinoma. In some embodiments, the non-small cell lung cancer is squamous cell lung cancer and the clinical stage is stage IIIB, stage IIIC or stage IV (as defined by the IASLC stage 8 TNM staging system). In some embodiments, the head and neck thoracic tumor is non-small cell lung cancer that has failed treatment with at least one platinum or non-platinum containing dual drug chemotherapy regimen.

In some embodiments, the head and neck thoracic tumor is pleural mesothelioma. In some embodiments, the pleural mesothelioma is recurrent/metastatic pleural mesothelioma. In some embodiments, the pleural mesothelioma is a recurrent/metastatic pleural mesothelioma that has been histologically confirmed, has failed at least first-line chemotherapy, and is not surgically resectable or subjected to radical radiotherapy.

In some embodiments, the head and neck thoracic tumor is a thymus carcinoma. In some embodiments, the thymus cancer is relapsed/metastatic thymus cancer. In some embodiments, the thymus cancer is a relapsed/metastatic thymus cancer that has been histologically confirmed, failed at least first-line chemotherapy, and was not surgically resectable or subjected to radical radiation therapy.

In some embodiments, the subject has previously received surgery, chemotherapy, and/or radiation therapy. In some embodiments, the subject has re-developed disease progression after achieving complete remission following surgery, chemotherapy, and/or radiation therapy. In some embodiments, the subject has failed to complete remission or failed to partial remission following surgery, chemotherapy, and/or radiation therapy.

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

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

In some embodiments of the present application, the pharmaceutical composition comprises a compound of formula I in an amount of 6-168 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 a compound of formula I in an amount of 10mg to 12 mg. In some embodiments, the pharmaceutical composition comprises a 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 unitary 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 the human PD-1 antibody. In some embodiments, the unitized 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 administered intravenously to the human PD-1 antibody on the first day (D1) of each cycle for 2 weeks (14 days) or 3 weeks (21 days). That is, the anti-PD-1 antibody is administered at a frequency of once every two weeks (q2w) or once every three weeks (q3 w).

It is also an object of the present application to provide a unit formulation, wherein the unit formulation comprises: a compound component, 6-12 mg of a compound of formula I or a 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 packaged separately.

In some embodiments, the unit formulation comprises: compound component, 8mg, 10mg or 12mg of a compound of formula I or its hydrochloride salt; and an antibody component, 100mg or 200mg of a human PD-1 antibody or 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-described 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 and neck thoracic tumor.

In some embodiments of the present application, the administration of erlotinib in combination with 14C12H1L1, every 21 days for one treatment cycle, is administered as follows: arotinib was administered 10 mg/time or 12 mg/time, D1-D14 daily 14C12H1L1 once every 3 weeks, 200 mg/time.

In some embodiments of the present application, the administration of erlotinib in combination with 14C12H1L1 is performed in an erlotinib hydrochloride capsule: it is administered 1 time daily, 12mg or 10mg each time. 2 weeks and 1 week, i.e. 3 weeks (21 days) for a treatment period. If the administration period is missed, the time for next administration is shorter than 12 hours, and the medicine is not taken again. The administration mode of the 14C12H1L1 injection is as follows: administered 1 time every 3 weeks at 200 mg/time, and administered by intravenous infusion. The infusion time was 60. + -.10 min.

The results show that the combination of the erlotinib and the 14C12H1L1 drug has an unexpected effect in preventing or treating head-neck-chest tumors, and shows that the combination can inhibit the growth of tumor foci or reduce the tumor volume in multiple clinical applications. The experimental result surprisingly discovers that the combination of the erlotinib hydrochloride and the 14C12H1L1 medicament has obvious synergistic effect, and breaks the immune tolerance of the body to the tumor cells.

The pharmaceutical combination of the invention shows superior efficacy compared to existing therapies in squamous non-small cell lung cancer patients who relapse or metastasize following surgery and/or chemotherapy, such as docetaxel in combination with lobaplatin.

The pharmaceutical combination of the invention shows superior efficacy compared to prior therapies in non-squamous non-small cell lung cancer patients who relapse or metastasize following chemotherapy, such as pemetrexed in combination with carboplatin, pemetrexed + nedaplatin, or paclitaxel + nedaplatin.

The pharmaceutical combination of the invention shows superior efficacy compared to prior therapies in small cell lung cancer patients who relapse or metastasize following chemotherapy, such as cisplatin in combination with etoposide, pemetrexed in combination with nedaplatin, or paclitaxel in combination with nedaplatin.

The pharmaceutical combination of the invention shows superior efficacy compared to existing therapies in patients with lacrimal adenoid cystic carcinoma who recur or metastasize after surgery and/or chemotherapy.

The pharmaceutical combination of the invention shows superior efficacy compared to prior therapies in patients with squamous cell carcinoma of the head and neck that recur or metastasize following chemotherapy, such as paclitaxel in combination with cisplatin treatment or paclitaxel in combination with nedaplatin treatment.

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

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

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

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

The pharmaceutical combination of the present invention shows superior efficacy compared to the existing therapies in patients with malignant maxillary sinus tumor, which is squamous epithelial cancer, who are not suitable for receiving surgical treatment.

Arotinib

As used herein, the chemical name of said nilotinib (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, which has the following structural formula:

as used herein, the nilotinib includes its non-salt forms (e.g., free acid or free base), as well as its pharmaceutically acceptable salts, which are all included within the scope of the present application. For example, the pharmaceutically acceptable salt of the nilotinib can be the hydrochloride salt or the dihydrochloride salt. The dosage of the nilotinib or salt thereof referred to herein is calculated based on the free base of the nilotinib, 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 106977602A). In the 14C12H1L1 monoclonal antibody, LCDR1 comprises the sequence QDINTY (SEQ ID NO:1), LCDR2 comprises the sequence RAN (SEQ ID NO:2), LCDR3 comprises the sequence LQYDEFPLT (SEQ ID NO:3), HCDR1 comprises the sequence GFAFSSYD (SEQ ID NO:4), HCDR2 comprises the sequence ISGGGRYT (SEQ ID NO:5), and HCDR3 comprises the 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)。

definitions and explanations

The following terms used in the present application have the following meanings, unless otherwise specified. A particular term should not be considered as ambiguous or unclear without special definition, but rather construed according to ordinary meaning in the art. When a trade name appears in this application, it is intended to refer to its corresponding commodity, composition, or active ingredient 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 can be whole antibodies or any fragment thereof. Thus, the antibodies and fragments thereof of the present application include monoclonal antibodies or fragments thereof and antibody variants or fragments thereof, as well as immunoconjugates. Examples of antibody fragments include Fab fragments, Fab 'fragments, f (ab)' fragments, Fv fragments, isolated CDR regions, single chain Fv molecules (scFv), and other antibody fragments known in the art. Antibodies and fragments thereof can also include recombinant polypeptides, fusion proteins, and bispecific antibodies. The anti-PD-L1 antibodies and fragments thereof disclosed herein may be of the IgG1, IgG2, IgG3, or IgG4 isotype.

The term "isotype" refers to the class of antibodies 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 mouse, rat, rabbit, primate, llama, and human. The PD-1/PD-L1 antibody and fragments thereof may be chimeric, humanized or fully human.

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

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

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

As used herein, the term "EC 50" refers to the effective concentration, 50% of the maximal response of an antibody. As used herein, the term "IC 50" refers to the inhibitory concentration, 50% of the maximal 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 act of obtaining a desired pharmacological and/or physiological effect. The effect may be prophylactic, in terms of preventing the disease or its symptoms, in whole or in part; and/or may be therapeutic in terms of partially or completely stabilizing or curing the disease and/or side effects due to the disease. As used herein, "treatment" encompasses any treatment of a disease in a patient, including: (a) preventing a disease or condition in a patient susceptible to the disease or condition but not yet diagnosed as having the disease; (b) inhibiting the symptoms of the disease, i.e., arresting its development; or (c) alleviating the symptoms of the disease, i.e., causing regression of the disease or symptoms.

As used herein, the term "systemic treatment" refers to treatment in which a drug substance is transported through the bloodstream to reach and affect cells throughout the body.

As used herein, the term "systemic chemotherapy" refers to systemic chemotherapy that does not include chemotherapy for locally advanced disease as one of the links of multimodal treatment, wherein chemotherapy for locally advanced disease includes induction chemotherapy, concurrent chemotherapy with radiotherapy, and adjuvant chemotherapy.

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

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

As used herein, an "adverse event" (AE) is any adverse and often unintended or undesirable sign (including abnormal laboratory findings), symptom or disease associated with the use of medical therapy. For example, an adverse event can be associated with activation of the immune system or expansion of cells of the immune system (e.g., T cells) in response to a treatment. The medical treatment may have one or more related AEs, and each AE may have the same or different severity level. Reference to a method capable of "altering an adverse event" refers to a treatment regimen that reduces the incidence and/or severity of one or more AEs associated with the use of a different treatment regimen.

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

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

The use of the term "flat dose" refers to a dose that is administered to a patient without regard to the weight or Body Surface Area (BSA) of the patient. Thus, a uniform dose is defined as the absolute amount of the agent (e.g., anti-PD-1 antibody) rather than the mg/kg dose. For example, a 60kg human and a 100kg human will receive the same dose of antibody (e.g., 240mg anti-PD-1 antibody).

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

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

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

As used herein, "PD 1/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 predominantly on previously activated T cells in vivo and binds to both ligands PD-L1 and PD-L2. The term "PD-1" as used herein includes variants, homologs, and species homologs of human PD-1(hPD-1), hPD-1, and analogs having at least one common epitope with hPD-1.

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

"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 herein in certain contexts.

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 the onset of a disease or promotes disease regression as evidenced by a reduction in the severity of disease symptoms, an increase in the frequency and duration of disease symptom-free stages, or prevention of injury or disability caused by the affliction of the disease. The ability of a therapeutic agent to promote disease regression can be evaluated using a variety of methods known to skilled practitioners, such as in human subjects during clinical trials, in animal model systems predicting efficacy for humans, or by determining 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 "anti-cancer drug" promotes cancer regression in a subject or prevents further tumor growth. In certain embodiments, the therapeutically effective amount of the drug promotes regression of the cancer to the point of eliminating the cancer. By "promoting cancer regression" is meant the administration of an effective amount of a drug, alone or in combination with an anti-neoplastic agent, resulting in the reduction of 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 symptom-free stages, or the prevention of injury or disability resulting from the affliction of the disease. Furthermore, the terms "effective" and "effectiveness" with respect to treatment include pharmacological effectiveness and physiological safety. Pharmacological efficacy refers to the ability of a drug to promote cancer regression 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 resulting from 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 present 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.

By "immune-related" response pattern is meant the 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 beneficial therapeutic effects following an initial increase in tumor burden or the appearance of new lesions, which would be classified as disease progression and would be synonymous with drug failure in the evaluation of traditional chemotherapeutic agents. Thus, proper evaluation of immunotherapeutic agents may require long-term monitoring of the effect of these agents on the 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 anti-neoplastic agent, to a subject at risk of developing cancer (e.g., a subject with a premalignant condition) or a subject at risk of cancer recurrence. In certain embodiments, the prophylactically effective amount completely prevents the occurrence or recurrence of cancer. By "inhibiting" the occurrence or recurrence of cancer is meant reducing the likelihood of occurrence or recurrence of cancer, or completely preventing the occurrence or recurrence of cancer.

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

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

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

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

The terms "about," about, "or" consisting essentially of mean a value or composition 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 determined, i.e., the limitations of the measurement system. For example, "about," about, "or" consisting essentially of can mean within 1 or more than 1 standard deviation, as practiced in the art. Alternatively, "about" or "consisting essentially of may refer to a range that differs by up to 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, particularly with respect to biological systems or processes, the term may refer to up to an order of magnitude or up to at most 5 times the numerical value. Where a particular value or composition is provided in the application and claims, unless otherwise stated, the meaning of "about" or "consisting essentially of" should be assumed to be within an acceptable error range for that particular value or composition.

As used herein, the terms "about once per week", "about once per two weeks" or any other similar dosing interval term refer to approximations. "about once per 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, a dosing interval of about once every 6 weeks or about once every 12 weeks refers to that a first dose may be administered on any day of the first week, and then a 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 administration of a first dose on a particular day of the first week (e.g., monday) followed by administration of a second dose on the same day of the sixth or twelfth week (i.e., monday), respectively. Similar principles apply to phrases including, but not limited to, "about 1 every 2 weeks," "about 1 every month," etc. … ….

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

Unless specifically stated otherwise, "about" or "approximately" in this application means within + -5% of the specified numerical range given, preferably within + -2% of the specified numerical range given, 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 salt" includes salts of the base ion with the free acid or salts of the acid ion with the free base, including, for example, hydrochloride, hydrobromide, nitrate, sulfate, phosphate, formate, acetate, trifluoroacetate, fumarate, oxalate, maleate, citrate, succinate, methanesulfonate, benzenesulfonate or p-methylbenzenesulfonate, preferably hydrochloride, hydrobromide, sulfate, formate, acetate, trifluoroacetate, fumarate, maleate, methanesulfonate, p-methylbenzenesulfonate, sodium salt, potassium salt, ammonium salt, amino acid salt and the like. In the present application, when forming a pharmaceutically acceptable salt, the molar amount of free acid to base ion is about 1:0.5 to 1:5, preferably 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, or 1: 8. In the present application, when forming a pharmaceutically acceptable salt, the molar ratio of the free base to the acid ion is about 1:0.5 to 1:5, preferably 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7 or 1: 8.

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

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

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

The term "pharmaceutical composition" refers to a mixture of one or more of the active ingredients of the present application (e.g., an anti-PD-1 antibody or a compound of formula I) or a pharmaceutical combination thereof with pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate administration of the compounds of the present application, or 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., inhibiting the growth of colon cancer, or ameliorating symptoms of colon cancer) that is greater than the effect of the components when administered alone.

Mode of administration

The following is not intended to limit the mode of administration of the pharmaceutical combinations of the present application.

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

The components of the pharmaceutical combination of the present application may each be administered separately, 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 be administered independently of each other, or some or all of them together in a variety of routes as appropriate, including, but not limited to, oral or parenteral (by intravenous, intramuscular, topical or subcutaneous routes). In some embodiments, the components of the pharmaceutical combination of the present application may be administered orally or parenterally, such as intravenously or intraperitoneally, each independently, or together with some or all of them.

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

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

The pharmaceutical combination of the present 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 present application also includes the following:

1. a pharmaceutical combination comprising:

a) a human PD-1 antibody that comprises 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 set forth in SEQ ID NO. 1, SEQ ID NO. 2 and SEQ ID NO. 3, respectively, and wherein the heavy chain comprises heavy chain complementarity determining regions HCDR1, HCDR2 and HCDR3 consisting of the amino acid sequences set forth 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 of item 1, wherein the pharmaceutically acceptable salt of the compound of formula I is the hydrochloride salt of 1- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl ] oxy ] methyl ] cyclopropylamine, preferably the dihydrochloride.

3. The pharmaceutical combination of any one of the preceding, wherein the human PD-1 antibody comprises a light chain variable region as set forth in amino acid sequence 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, wherein the human PD-1 antibody is 14C12H1L 1.

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

6. The pharmaceutical combination of any one of the preceding, 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 the pharmaceutical combination of any of the preceding claims for the treatment or prevention of head and neck thoracic tumors.

8. The use of any one of the preceding, for the treatment of advanced head and neck thoracic tumors.

9. The use of any of the preceding claims, wherein the combination is used for the treatment of advanced head and neck thoracic tumors and has received at least systemic chemotherapy with a platinum-containing first line regimen.

10. The use of any one of the preceding, for the treatment of squamous cell carcinoma of the head and neck, non-squamous carcinoma of the head and neck, adenocarcinoma, adenoid cystic carcinoma, mucoepidermoid carcinoma, squamous carcinoma, tear adenocarcinoma, thyroid carcinoma, small-cell lung cancer, non-small-cell lung cancer, pleural mesothelioma, or thymus carcinoma.

11. The use of any one of the preceding, 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 that failed platinum-containing chemotherapy regimen, non-squamous carcinoma non-small-cell lung cancer, recurrent/metastatic pleural mesothelioma, or recurrent/metastatic thymus carcinoma.

12. The use according to any one of the preceding claims, wherein the pharmaceutical combination comprises the hydrochloride salt of the compound of formula I administered at a bolus dose of about 10 mg/dose or about 12 mg/dose and 14C12H1L1 administered at a bolus dose of about 200 mg/dose.

13. The use according to any one of the preceding claims, wherein the hydrochloride salt of the compound of formula I is administered 1 time a day, 12mg or 10mg each time, 2 weeks for 1 week on continuous oral administration, and the 14C12H1L1 injection is administered 1 time every 3 weeks, 200 mg/time.

14. An article of manufacture comprising a container containing a fixed dose of a hydrochloride salt of a compound of formula I selected from about 8mg, about 10mg, and about 12mg, and a 14C12H1L1 antibody, a fixed dose of 14C12H1L1 antibody selected from about 100mg and about 200 mg.

Detailed Description

The present application is further described below with reference to specific examples, which, however, are only for illustration and do not limit the scope of the present application. Likewise, the present application is not limited to any particular preferred embodiment described herein. It should be understood by those skilled in the art that equivalent substitutions for the technical features of the present application or corresponding improvements are still within the scope of the present application. The reagents used in the following examples are commercially available products, and the solutions can be prepared by techniques conventional in the art, except where otherwise specified.

TABLE 1 abbreviation table

By "failure of treatment with a platinum-containing chemotherapeutic regimen" is meant disease progression or toxic side effects that are not tolerated during or after treatment with first-line chemotherapy or radiotherapy with a platinum-containing regimen.

The term "non-small cell lung cancer which fails to undergo standard treatment" means that "EGFR gene sensitive mutation positive needs to undergo treatment by at least one EGFR-TKI inhibitor; or, if a patient with the EGFR-T790M mutation is present, failure to receive a third-generation EGFR inhibitor treatment; or, ALK gene rearrangement positive: failure to undergo treatment with ALK inhibitors; or, if the patient has failed treatment with only perczotinib followed by one of the other ALK inhibitors; or, ROS1 gene rearrangement positive: failure of treatment with ROS1 inhibitors; or, the remaining gene variation positive or the driver gene negative: non-small cell lung cancer that has failed prior treatment with at least one platinum-containing dual-drug chemotherapy regimen.

By "non-small cell lung cancer that has failed a platinum or non-platinum-containing dual-drug chemotherapy regimen" is meant disease progression or intolerance of toxic side effects during or after treatment with first-line chemotherapy (including during maintenance chemotherapy), with imaging evidence of disease progression. By "recurrent/metastatic pleural mesothelioma, thymus carcinoma that has failed at least first-line chemotherapy and is not surgically resectable or subjected to radical radiotherapy" is meant that the disease progression or toxic side effects are not tolerated and there is radiographic evidence of disease progression during or after treatment with first-line systemic chemotherapy (which may include platinum or taxus based).

"14C 12H1L1 injectable solution" refers to a medical formulation for injection containing the 14C12H1L1 monoclonal antibody, which is usually administered to a patient by intravenous infusion route. In a particular embodiment, the expression "injection of 14C12H1L1, 200 mg/time" may be understood in the usual manner in the art as a liquid injectable medical formulation containing 200mg of 14C12H1L1 monoclonal antibody per administration to a patient.

Example a clinical study protocol-study criteria and endpoints

1.1 inclusion exclusion criteria

And (3) inclusion standard: the following candidates can be put into the test

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

a first queue:

a) the primary part of the patient with the recurrent/metastatic head and neck squamous cell carcinoma is oral cavity, oropharynx, hypopharynx or larynx;

b) has failed or is intolerant to at least first-line platinum-containing chemotherapy. For patients who have received new adjuvant chemotherapy, concurrent chemoradiotherapy or adjuvant chemotherapy, if recurrence/metastasis occurs within 6 months since the end of the last treatment, the treatment is counted as a first-line treatment.

And a second queue:

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

And a queue III:

patients with histologically confirmed, standard treatment failed or untreated, non-surgically resectable undifferentiated thyroid cancer, and patients are expected to have a survival time of more than 2 months.

And a queue four:

histologically confirmed small cell lung cancer patients who failed one platinum-containing chemotherapy regimen;

definition of treatment failure: disease progression or toxic side effects are not tolerated during or after treatment with platinum-containing regimens, first-line chemotherapy or chemoradiotherapy.

And a fifth queue:

a) patients in stage IIIB-IV who are diagnosed as non-squamous cell carcinoma non-small cell lung cancer by histology and defined according to IASLC 8 th edition TNM staging system;

b) failure through standard treatment is defined as follows:

positive for EGFR gene sensitive mutation: failure to undergo treatment with at least one EGFR-TKI inhibitor; if the EGFR-T790M mutation exists, the patient can be selected after the patient has failed the three-generation EGFR inhibitor treatment;

ALK gene rearrangement positive: failure to undergo treatment with ALK inhibitors; if the patient only receives the perczotinib treatment, the patient needs to receive another ALK inhibitor treatment failure;

ROS1 gene rearrangement positive: failure to treat with ROS1 inhibitors;

remaining gene variation positive or driver gene negative: which have failed prior treatment with at least one platinum-containing dual-drug chemotherapy regimen.

And a queue six:

a) histologically confirmed squamous non-small cell lung cancer and clinically staged at stage IIIB, IIIC or IV (according to the international association for lung cancer research and the american joint committee for cancer classification, TNM staging system, 8 th edition). Allowing mixed cancers with major organization of the subgroup as squamous carcinoma;

b) failure to receive at least one platinum-or non-platinum-containing dual-drug chemotherapy regimen.

Definition of treatment failure: disease progression or toxic side effects are not tolerated during or after treatment with first-line chemotherapy (including during maintenance chemotherapy), and imaging evidence is necessary to demonstrate disease progression. For adjuvant therapy (chemotherapy or chemoradiotherapy), if disease progression occurs during treatment or within 6 months after cessation of treatment, it should be counted as a first-line treatment regimen.

A seventh queue:

patients with recurrent/metastatic pleural mesothelioma and thymus cancer who have been histologically confirmed and have failed at least first-line chemotherapy and have not been surgically resected or treated with radical radiotherapy;

definition of treatment failure: disease progression or toxic side effects are not tolerated during or after treatment with first line systemic chemotherapy (which may include platinum or taxus based) and imaging evidence is necessary to demonstrate disease progression. For neoadjuvant/adjuvant therapy (chemotherapy or chemoradiotherapy), if disease progression occurs during treatment or within 6 months after cessation of treatment, it should be counted as a first-line treatment regimen.

2) Year 18; ECOG physical condition: 0-1 min; survival is expected to be over 3 months (excluding anaplastic thyroid carcinoma);

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

4) consent was provided for either a previously archived tumor tissue sample (tissue sample within 2 years prior to enrollment) or fresh harvest. The specimen needs to meet the requirement that 10 sections with the thickness of 4-6 microns can be cut out from a tumor tissue block which is fixed by formalin and embedded by paraffin wax (FFPE) for staining and detection. Specimens that do not accept fine needle aspiration biopsy, cell smears from pleural effusion drainage centrifugation, bone lesions without soft tissue components or decalcified bone tumor specimens, and tissue biopsied are insufficient for biomarker detection. If the tumor tissue samples or the number of the sections which are not archived within 2 years is less than 10, the section can be selected after the section is approved by the sponsor;

5) the major organs function normally.

6) Patients voluntarily join the study and sign informed consent, and compliance is good.

Exclusion criteria: subjects presenting any of the following subjects would not be able to enter the study

1) The patients who have received local radiotherapy before can be grouped if the following conditions are met: radiotherapy end over 4 weeks from study treatment initiation (brain radiotherapy over 2 weeks); the target focus selected in the research is not in the radiotherapy area; or the target lesion is located within the area of radiotherapy, but progression has been confirmed.

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

3) the patient has other malignant tumors (except for cured skin basal cell carcinoma and cervical carcinoma in situ) within 5 years;

4) those with various factors affecting oral medication (e.g., inability to swallow, post-gastrointestinal resection, chronic diarrhea, ileus, etc.);

5) imaging (CT or MRI) shows that the tumor invades the great vessels or is poorly demarcated from the vessels;

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

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

8) those who have a history of abuse of psychotropic drugs and are unable to abstain or have a psychotic disorder;

9) other clinical trials were enrolled within four weeks;

10) at the discretion of the investigator, there are concomitant diseases that seriously compromise patient safety or affect the patient's completion of the study.

1.2 Exit Standard

1) Disease progression occurred and the investigator judged that the subject would not benefit from continued treatment;

2) adverse events occurred, were not tolerated, not alleviated;

3) subjects who had a severe adverse event and were not eligible to continue the study;

4) those who deviate or violate a protocol severely and impact drug safety or efficacy assessments;

5) subject withdrawal of informed consent;

6) follow-up cannot be continued on time for various reasons.

1.3 study endpoint

The first stage is as follows: safe lead-in period

Primary end point:

safety and tolerability of first cycle

Secondary endpoint:

objective Remission Rate (ORR), Disease Control Rate (DCR), duration of remission (DOR), Progression Free Survival (PFS), Overall Survival (OS), and the like.

And a second stage: official 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. of

The incidence and severity of Adverse Events (AEs) and Severe Adverse Events (SAEs), and abnormal laboratory test indices.

Example two clinical trial design

Single arm, open, multi-cohort, multi-center phase II clinical trials were employed.

2.1 sample size

The study consisted of 7 cohorts, each cohort being grouped in 10-20 cases (adjusted for specific test results).

2.2 image evaluation design

The primary efficacy endpoint of this study was ORR, using results assessed by researchers at various study centers. An independent imaging group is additionally arranged in the research to carry out imaging curative effect evaluation and recheck.

2.3 dosing regimen design

The subjects were each patient enrolled from cohort one to cohort seven in example one.

The study is divided into two phases:

the first phase is a one-armed study, the safe lead-in period. Patients will receive treatment with erlotinib in combination with 14C12H1L1 mab. Safety information was collected every 21 days for one treatment cycle to determine whether or not the combination of erlotinib with 14C12H1L1 was in a formal trial after RP2D in patients with advanced head and neck thoracic tumors. The lead-in period included the following 2 dose groups:

dose group a: 10mg of nilotinib, D1-D14+14C12H1L1 once every 3 weeks, 200 mg/time

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

Each dose group was scheduled for 3-6 patients and the safety of the combination was observed. Based on the safety data from the previous large sample size clinical study of the anirtinib capsules, the lead-in phase schedule began dose exploration from the dose group a dosing regimen (if 3-6 patients in dose group a were well tolerated in the first cycle, 3-6 patients in dose group B would be explored). At the end of the introduction trial, the combination of anrtinib with 14C12H1L1 was determined to be RP2D in patients with advanced head and neck thoracic tumors, as discussed by the primary investigator and the sponsor.

The second stage is the official test. Patients will receive an erlotinib combination 14C12H1L1 treatment:

anrotinib hydrochloride capsules:

the administration is 1 time daily (recommended to start infusion at 14C12H1L1 injection + -60min with internal abdominal administration), 12mg each time (final dose is determined by safe lead-in period, 12mg is tentatively determined). 2 weeks and 1 week, i.e. 3 weeks (21 days) for a treatment period. If the administration period is missed, the time for next administration is shorter than 12 hours, and the medicine is not taken again.

14C12H1L1 injecta:

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

The medication period is as follows:

every 21 days is a treatment period, and other anti-tumor treatments can not be carried out during the administration period; patients in disease control (CR + PR + SD) and with tolerable adverse effects continue to be dosed until disease progression or intolerance.

Efficacy was assessed every 2 cycles. Patients with disease control (CR + PR + SD) and tolerable adverse reactions continue to take their medications until clinical benefit is lost, toxicity is not tolerable, efficacy is assessed as PD, and the study is concluded when the investigator deems it inappropriate to continue taking medications.

Adjusting the dosage of the hydrochloric acid Arotinib capsule:

during the study, the patient may downregulate the aritinib hydrochloride dose due to drug related adverse events (12mg-10mg-8mg are downregulated sequentially, not allowing for cross-dose adjustments), and if the patient is intolerant at the 8mg dose level, the study should be terminated. For patients with the Arotinib hydrochloride capsule with the dosage being adjusted down to 10mg or 8mg, after the drug is taken for a period of time, if researchers judge that the disease is possible to progress and the safety of the patients is stable, the dosage can be adjusted up once. Each patient can only make one dose up-regulation at most and cannot adjust across dose groups.

14C12H1L1 injection fixed dose, without a dose down-regulation scheme.

2.4 methods of combination administration

14C12H1L1 injecta:

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

Anrotinib hydrochloride capsules:

1 daily (oral on empty stomach before breakfast) 1 capsule (12mg) each time (final dose determined by safe lead-in period, temporary 12mg), is recommended to be infused starting in 14C12H1L1 injection ± 60min for administration in empty stomach. 2 weeks and 1 week, i.e. 3 weeks (21 days) for a treatment period. Without special circumstances, it is recommended to take the medicine at a fixed time every day. On the day of blood sampling or safety inspection, the medicine is taken after blood sampling. If the administration period is missed, the time for next administration is shorter than 12 hours, and the medicine is not taken again.

The medication period is as follows:

The subjects were all patients enrolled from cohort one to cohort seven in example one.

2.5 delayed administration and dose adjustment

Adverse events caused by the injection containing 14C12H1L1 mab resulted in delayed dosing, failure to resume dosing beyond 12 weeks, and treatment with the injection containing 14C12H1L1 should be terminated permanently. The treatment of adverse events caused by 14C12H1L1 injection is suggested in the treatment of immune related adverse events caused by immune checkpoint inhibitor treatment. The 14C12H1L1 injection allows for delayed dosing without dose adjustment.

In the drug taking period (1-14 days) of the erlotinib hydrochloride capsule per cycle, adverse reactions related to the erlotinib occur, and the delay time cannot exceed 5 days at most when drug taking needs to be delayed. If the drug can not be taken continuously for more than 5 days, the residual Arotinib in the period is not used any more. Patients who can not take the anitinib (including reduced dose) for more than 2 weeks at the beginning of the next cycle, such as when the drug can be delayed due to adverse reactions, and the drug can not be taken for more than 2 weeks, need to stop the anitinib permanently (except for the event caused by non-safety reasons). The aritinib hydrochloride capsules may be delayed or dose adjusted during the study if desired.

During the study, downregulation of the dose was allowed when adverse events associated with nilotinib occurred, 12mg → 10mg and 10mg → 8 mg. At the 8mg level, discontinuation of the drug regimen is still not tolerated. After a period of time of down-dosing, the dose can be up-dosed to the original level, allowing for the possibility of progression of the disease and for controlled safety, from the next cycle on.

2.6 disease progression and efficacy assessment

In the period of clinical application of the same kind of 14C12H1L1 injection, the subjects have false progress, and the therapeutic effect evaluation standard of the study is based on RECIST 1.1 (therapeutic effect evaluation standard of solid tumors). The efficacy was also confirmed using the irrecist criteria (tumor immunotherapy-related evaluation criteria). That is, subjects judged to be disease Progression (PD) according to RECIST 1.1 criteria were further confirmed according to irrecist criteria to determine whether to further observe the drug.

Efficacy is assessed every 2 cycles, starting on the first day of the first cycle, until the subject develops tumor-image confirmed disease progression, which does not change the frequency of assessment as the subject delays or discontinues treatment. If the subject terminates study treatment for reasons other than disease progression, it is still necessary to continue receiving the frequent tumor imaging assessments until the subject begins new anti-tumor therapy, or imaging-evidence of disease progression, or the subject actively withdraws, or the subject dies, whichever comes first.

The imaging evaluation mode of the tumor can adopt CT or MRI, but the evaluation method, machine and technical parameters are consistent during the whole research period; if no contraindications are indicated, contrast agents should be used. If tumor assessments were made within 14 days prior to the first dose and the same procedure was used in the same hospital, this could be taken as a baseline tumor assessment. Baseline tumor assessments should include CT or MRI of the chest, abdomen and pelvic cavities. During the screening period, craniocerebral flat scan and enhancement/enhancement MRI examination are required. All suspicious lesion sites should be examined imagewise. For patients with bone metastases, bone scans should be used to follow up on the lesions. For patients with bone metastasis, if no clinical symptoms are aggravated, the tumor evaluation is not required to be performed for recheck every time, and if the clinical symptoms are aggravated, the patient should be rechecked in time. For cases suspected of disease progression before the start of the next evaluation in the plan, an unplanned tumor assessment should be performed. During the test period, only the imaging examination of the focus part is performed, and during the test period, the image of the corresponding part can be examined if the suspicious part exists.

EXAMPLE III Collection of biological samples

3.1 serum anti-14C 12H1L1 antibody (ADA) assay

The immunogenicity monitoring time point is based on the administration time of the 14C12H1L1 injection; when 14C12H1L1 was given late, there was a corresponding delay in immunogenic blood sampling. If the subject is detected to be positive for ADA, the neutralizing antibody is measured.

Collection was taken before dosing (-60min) at cycles 1, 2, 4, 8 and every 6 cycles thereafter. Simultaneous collection was done 30min (+ -5 min) after the end of infusion in cycle 1 and cycle 8 and 30 days (+ -7 days), 90 days (+ -7 days) after the last dose. 5mL of venous blood is required to be collected each time, the venous blood is placed in a blood collection tube containing procoagulant separation gel for 30min at room temperature, after natural coagulation, 3000g of the venous blood is centrifuged for 10min, the venous blood is averagely distributed into 4 freezing storage tubes (3 parts of detection tubes and 1 part of backup tube, wherein each detection tube is not less than 0.5mL), and serum is taken as a marker and then stored in a refrigerator at the temperature of-40 to-80 ℃ for detecting immunogenicity and 14C12H1L1 blood concentration.

Unexpected adverse events related to immunity occurred during the test, and additional 1 blood sampling was required to test immunogenicity and 14C12H1L1 blood concentration after the adverse event was confirmed, but the time from the last blood sampling was less than 24H and the sampling could not be performed.

Note that: based on the ADA results, neutralizing antibodies are subsequently tested if necessary.

3.2 biomarker assays

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

The samples for biomarker detection were selected from fresh biopsy samples within 1 month prior to group entry. When a fresh tissue sample is taken, 1 needle or more is punctured through the skin. Blood samples of 10mL were collected from subjects before enrollment (within 7 days before dosing) and at time of enrollment (+ -3 days) for ctDNA detection of bTMB levels, etc.

Example four evaluation of effectiveness and safety

4.1. Analysis of the main efficacy index

4.1.1. Objective Remission Rate (ORR):

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

4.1.2. Analysis of secondary efficacy index

4.1.2.1. Progression Free Survival (PFS)

And estimating the median PFS by adopting a Kaplan-Meier method, and drawing a survival curve graph.

4.1.2.2. Overall lifetime (OS)

And estimating the median OS by adopting a Kaplan-Meier method, and drawing a survival curve graph.

4.1.2.3. Duration of remission (DOR)

The median PFS and 95% CI thereof are estimated by adopting a Kaplan-Meier method, and a survival curve graph is drawn.

4.1.2.4. Disease Control Rate (DCR):

the ratio of the number of disease control cases (CR + PR + SD) to the total number of cases and 95% CI were calculated. The 95% CI for the DCR was calculated based on the exact binomial method of F distribution.

4.2. Evaluation of safety

4.2.1. Drug exposure and compliance

The drug exposure is described by mean, standard deviation, maximum, minimum, median.

Summary of subject exposure to study drug treatment, patient cycle count, dose adjustments during treatment, cumulative number of doses adjusted during treatment, etc.

Statistical descriptions of study drug treatment time, study drug total dose and daily average dose and study drug dose compliance over the treatment period are presented.

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

The comparison of the treatment time of each study drug, the total dose and the daily average dose of the study drug and the study drug dose compliance adopts one-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, adverse events prior to first administration, adverse events during treatment, unexpected adverse events during treatment, significant adverse events during treatment, adverse events of particular interest during treatment, adverse events of grade 3 and above during treatment, severe adverse events during treatment, adverse events related to study drug during treatment, SAEs related to study drug during treatment, instances, number of instances, and incidence of adverse events that lead to dose adjustments during treatment, permanent cessation of treatment, termination of trial, patient death were categorized and summarized according to SOC, PT.

Adverse events with incidence rate of more than or equal to 5% during treatment and drug-related adverse events are summarized according to PT classification.

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

Adverse events with incidence rate of more than or equal to 10% during treatment and drug-related adverse events are summarized according to PT classification.

The median first occurrence time of adverse events of particular concern.

4.2.3. Vital signs

Mean ± standard deviation, maximum, minimum, median are used to describe the measurements and changes before and after treatment.

4.2.4. Laboratory test index

Table 2 examination item table

The measured values and the changed values before and after treatment are described by mean values +/-standard deviation, maximum values, minimum values and median values for blood routine, blood biochemistry, thyroid function, blood coagulation function, amylase and lipase, and the paired t test is adopted for group comparison. And describing normal and abnormal change conditions before and after treatment by adopting a cross classification table.

The routine of urine: and describing normal and abnormal change conditions before and after treatment by adopting a cross classification table.

And (3) conventionally: and describing normal and abnormal change conditions before and after treatment by adopting a cross classification table.

Describes the proportion of "abnormal, clinically significant" in subjects with abnormal changes, where the presence or absence of an abnormality is judged by the investigator.

4.2.5. Electrocardiogram

Electrocardiogram: according to the normal and abnormal conditions judged by the researchers, the change conditions of the normal and abnormal conditions before and after treatment are described.

The heart rate, PR interval, QRS interval, QT interval and QTc describe the measured values and the variation values before and after administration by using the mean value plus or minus standard deviation, the maximum value, the minimum value and the median. The electrocardiogram total evaluation result adopts a cross classification table to describe normal and abnormal change conditions before and after administration. The proportion of "clinically significant" abnormalities in subjects who describe abnormal changes, where the presence or absence of abnormalities is judged by the investigator. The list presents a post-administration exception list.

4.2.6. Physical examination

The changes of normal and abnormal before and after treatment are described.

EXAMPLE V clinical applications

1. The patients: e09002-squamous cell carcinoma of head and neck

A 56 year old male, 2020, 5/29, with a postoperative pathological diagnosis of: squamous epithelium is heavily dysplastic and cancerous. CT 20 days after 5 months in 2020 suggests postoperative change of right lung inferior lobe cancer, increase of right lung portal soft tissue and disease progression. History of previous chemotherapy of patients: docetaxel 120mg + lobaplatin needle 50mg was injected from 09 months 10 in 2019 to 17 months 12 in 2019, and the treatment effect was evaluated as SD for 3 cycles of chemotherapy. Chemotherapy with docetaxel 100mg + lobaplatin 40mg for 1 cycle was started on 20 days 2 months in 2020. CT cue progresses at 5/20/2020.

On day 13/6 of 2020, 12mg of an oral erlotinib hydrochloride capsule is taken once daily for 2 weeks and 1 week, and 14C12H1L1200mg is used for treatment, wherein each 3 weeks is a dosing cycle. The patient has good tolerance during administration, and can continue to take medicine.

And (3) screening period: target lesion: 33.1 mm; non-target lesions: multiple lymph nodes in the pulmonary artery window

After cycle 2 dosing: target lesion: 22.4mm (PR); non-target lesions: non-CR/non-PD

After cycle 4 dosing: target lesion: 22mm (PR); non-target lesions: non-CR/non-PD

After cycle 6 dosing: target lesion: < 10mm (CR); non-target lesions: non-CR/non-PD

2. The patients: E02003/S02005-tear adenocarcinoma/adenoid cystic carcinoma

The past medical history: 27 year old male, 7 months 2007, left eye lacrimal gland adenoid cystic carcinoma, postoperative pathology, left eye orbital lump excision operation. No relevant treatment is performed after the operation. In 2011, orbital tumors are found again in the left eye, and the treatment, pathology and adenoid cystic carcinoma are treated by operation. The particle implantation treatment is performed after operation (details are not shown). CT was reviewed in 2018 in 9 months: the soft tissue segment near the lateral wall in the left orbit is enlarged. In 2018, 9 months, the left orbital lump excision is performed again, and postoperative pathology: adenoid cystic carcinoma. Two cycles of AP regimen chemotherapy and particle implantation therapy (details are not given) follow-up. The left mandible outside can touch the tumor in 2019 and 9 months, and the tumor cells and the suspicious low-grade malignant epithelial tumors can be seen after the puncture biopsy. Nuclear magnetic resonance is reviewed in 2019 for 10 months, abnormal changes in left eye orbit exist, and orbital tumors are accumulated in the temporal fossa and temporalis pole intracranial areas; bilateral inferior alveolar nerves are thickened and strengthened obviously, and left-side tumor spreads along the nerves, considering recurrence. Left mandible lump enlargement resection in 11 and 18 months in 2019, postoperative pathology: adenoid cystic carcinoma. Postoperative radiation therapy was performed between 12 and 16 days in 2019 and 23 days in 2020 and 1 month.

And (3) pathological report: adenoid cystic carcinoma

The dosage is as follows: arotinib hydrochloride 12mg, 14C12H1L1200mg

And (3) evaluating the curative effect:

and (3) screening period: target lesion: 25 mm; non-target lesions: mediastinal lymph node

After cycle 2 dosing: target lesion: 19 mm; non-target lesions: non-CR/non-PD

3. The patients: e10007-squamous cell carcinoma of head and neck

The medical history: the patient carries out the oropharynx CT and MRI in 2020-02-20 to indicate that the tumor of the right oropharynx and the pathological section diagnosis: the breast cancer shows low differentiated cancer infiltration in the tissues and skeletal muscles, immunohistochemistry indicates squamous cell cancer, then the TP scheme chemotherapy is given to a patient after 2020-03-11, 2020-04-02, 2020-04-22, 2020-05-13 and 2020-06-03, and the chemotherapy is given with antiemetic, fluid replacement and other symptomatic support treatments, and the tumor control is poor after the chemotherapy. Followed by administration of erlotinib in combination with 14C12H1L 1.

The dosage is as follows: arotinib hydrochloride 12mg, 14C12H1L1200mg

The whole tolerance is good during the administration period, and the administration can be continued.

And (3) evaluating the curative effect:

and (3) screening period: target lesion: a left submandibular area cystic mass of 30 mm; non-target lesions: multiple bursal solid mass in left submandibular region

After cycle 2 dosing: target lesion: 28 mm; non-target lesions: non-CR/non-PD

After cycle 4 dosing: target lesion: 28 mm; non-target lesions: non-CR/non-PD

After cycle 6 dosing: target lesion: 28 mm; non-target lesions: non-CR/non-PD

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

The past medical history: 51-year-old male, pathological examination on 1/28/2019 shows: (biopsy of mass of tongue at the bottom of mouth) squamous epithelium with moderate or low atypical hyperplasia. Day 1, 2 months 2019, histology reports: (left tongue abdomen) superficial highly differentiated squamous carcinoma metaplasia. Histology report on 2/22/2019: (primary foci of tongue) high-grade differentiation of squamous carcinoma, P16-. Patient CT report 3 month 20 days 2020: the mass of the near-pulmonal region of the right upper lung is enlarged more anteriorly, the obstructive pulmonary atelectasis of the right upper lung and the enlarged lymph node of the mediastinal diaphragm are slightly enlarged more anteriorly, and the curative effect is evaluated as follows: PD. Albumin paclitaxel 395mg + nedaplatin 120mg for 2 cycles from 31/3/2020 to 23/4/2020, patient CT report at 28/5/2020: the mediastinal lymph node part is enlarged compared with the former, and the curative effect is evaluated: PD.

The administration of C1D1 was performed on 10 days 6.2020, and 12mg of Arotinib hydrochloride capsules were started once daily on an empty stomach, and were stopped for one week for two consecutive weeks, one cycle for three consecutive weeks, and once per cycle for 14C12H1L 1. The patient has good overall tolerance during taking the medicine and can continue to take the medicine

The dosage is as follows: ALTN: 12mg, 14C12H1L1:200 mg;

and (3) evaluating the curative effect:

and (3) screening period: target lesion: 65mm (right upper lung nodule + mediastinal lymph node);

non-target lesions: mediastinal lymph nodes.

After cycle 2 dosing: target lesion: SD (52 mm); non-target lesions: non-CR/non-PD.

After cycle 4 dosing: target lesion: PR (40 mm); non-target lesions: non-CR/non-PD.

After cycle 6 dosing: target lesion: PR (40 mm); non-target lesions: non-CR/non-PD.

5. The patients: S07002/E07002-non-small cell lung cancer

The past medical history: 61 year old male, pathological examination on day 23, 10 months in 2019 shows: (right lung mass puncture) poorly differentiated non-small cell carcinoma, supplemented immunohistochemical reports: (right lung mass puncture) HE binding immunohistochemistry was consistent with poorly differentiated adenocarcinomas. Gene detection shows that: EGFR, ALK, ROS1 are all negative. Pemetrexed 750mg + carboplatin 500mg for 4 cycles between 11/3/2019 and 12/2020/1/12. Patient CT report on 4 months and 22 days 2020: the upper lobe mass of the right lung is reduced more anteriorly; the lower right lung has new nodules, and the possibility of taking into account the metastatic tumors is high. The soft tissue nodules and masses in the right heart diaphragm corner area are enlarged more anteriorly, and the right chest wall is invaded, and the curative effect is evaluated as follows: PD.

The administration is carried out on day 9 in month 5 in 2020 on day C1D1, 10mg of the erlotinib hydrochloride capsule is started to be taken once a day on an empty stomach, the administration is stopped for one week for two weeks continuously, one cycle is carried out for three weeks continuously, and the administration is carried out once per cycle for 14C12H1L 1. The whole tolerance of the patient is good during taking the medicine, and the medicine can be continuously taken.

The dosage is as follows: arotinib hydrochloride: 10mg, 14C12H1L1:200 mg;

and (3) evaluating the curative effect:

and (3) screening period: target lesion: 135mm (right anterior chest wall + right heart diaphragm angle + right upper anterior lung);

non-target lesions: none.

After cycle 2 dosing: target lesion: SD (101 mm); non-target lesions: and (4) NA.

After cycle 4 dosing: target lesion: PR (72 mm); non-target lesions: and (4) NA.

After cycle 6 dosing: target lesion: PR (72 mm); non-target lesions: and (4) NA.

After cycle 8 dosing: target lesion: PR (69 mm); non-target lesions: and (4) NA.

6. The patients: e10002-head neck chest tumor

Male, 60 years old, history of disease: the patient carries out skull MR and brain metastatic tumor in 1 month in 2020, CT prompts are 1, soft tissue density shadow beside the pulmonia of the upper lobe of the left lung is shown, and the malignant tumor of the lung, central lung cancer with atelectasis of the distant lung, multiple metastasis of the liver and the spleen, multiple lymph node metastasis beside the mediastinum, the neck, the hepatic portal and the pancreatic head are considered; 2. lobular central emphysema, double lung multiple nodules 3. enlarged heart shadow, aortic and coronary arteriosclerosis; 4. small accessory spleen, cyst of left kidney: chemotherapy is given in the EP scheme of No. 5 at lines 2020-02-06, No. 2020-03-04, No. 2020-03-302020-04-24 and No. 2020-05-14, and antiemetic and symptomatic treatment are given. The whole tolerance is good during the administration period, and the administration can be continued.

The dosage is as follows: arotinib hydrochloride 12mg po, 14C12H1L1200mg

And (3) evaluating the curative effect:

screening period

Target lesion: lymph node metastasis to the left submaxillary area 58 mm; 42mm of solid tumor mass in the suprahepatic lobe of the left lung near the pulmonic region, 57mm of metastasis of lymph nodes in the hepatic portal region, and 27mm of solid nodules in the spleen

Non-target lesions: enlargement of the lymph nodes in the neck; enlargement of left axillary lymph nodes; multiple lymph nodes around the abdominal trunk at the lesser curvature of the stomach; solid nodules in the inferior left lobe near the hilum of the lung; multiple brain metastases to bilateral and cerebellar hemispheres

After cycle 2 dosing: target lesion: lymph node metastasis to the left submaxillary area 34 mm; the parenchymal tumor mass of the upper lobe of the left lung near the pulmonal region is 42mm, the metastasis of the lymph nodes of the hepatic portal is 36mm, and the parenchymal nodule of the spleen is 18 mm; non-target lesions: non-CR/non-PD

After cycle 4 dosing: target lesion: lymph node metastasis to the left submaxillary area 24 mm; the parenchymal tumor mass of the upper lobe of the left lung near the pulmonal region is 43mm, the metastasis of the lymph nodes of the hepatic portal is 34mm, and the parenchymal nodule of the spleen is 17 mm; non-target lesions: non-CR/non-PD

After cycle 6 dosing: target lesion: lymph node metastasis to the left submaxillary area 24 mm; the parenchymal tumor mass of the upper lobe of the left lung near the pulmonal region is 43mm, the metastasis of the lymph nodes of the hepatic portal is 32mm, and the parenchymal nodule of the spleen is 16 mm; non-target lesions: non-CR/non-PD

7. The patients: S07018/E07012-thyroid carcinoma

The past medical history: 31 year old female, pathological examination on 7/23/2020: (bilateral thyroid 6/7 area, mediastinal lymph node) (near the left lobe of the thyroid isthmus) malignant tumor, undifferentiated carcinoma was considered, and metastasis was seen in mediastinal lymph node. Bilateral thyroid gland lobule resection, VI and VII cervical lymph node cleaning are performed on 21 days 7 and 2020. CT of patient 8/5/2020: postoperative changes after thyroid cancer, a lump of soft tissue in the left anterior superior mediastinum, considered metastatic and highly esophageal invasive. And (3) evaluating the curative effect: PD.

The administration of C1D1 was performed on 8/18 days in 2020, and 12mg of Arotinib hydrochloride capsules were started once daily on an empty stomach, and were stopped for one week for two consecutive weeks, one cycle for three consecutive weeks, and once per cycle for 14C12H1L 1. The follow-up visit of C3D21 cycle is carried out at 19 days 10 months 10 in 2020, and due to the occurrence of III-grade AE of hypertension, the Arotinib hydrochloride capsule is reduced to 10mg dose for administration, the whole tolerance of the patient is good during the administration period, and the patient can continue to take the medicine

The dosage is as follows: C1D1-C3D21 Arotinib hydrochloride: 12mg, 14C12H1L1:200 mg;

the dosage is as follows: C4D 1-to date, erlotinib hydrochloride: 10mg, 14C12H1L1:200 mg;

and (3) evaluating the curative effect:

and (3) screening period: target lesion: 43mm (left anterior superior mediastinum);

non-target lesions: right anterior superior mediastinal interna lymph node

After cycle 2 dosing: target lesion: PR (22 mm); non-target lesions: non-CR/non-PD.

After cycle 4 dosing: target lesion: PR (16 mm); non-target lesions: non-CR/non-PD.

8. The patients: E08001/S08001-thyroid cancer

And (3) pathological report: anaplastic thyroid cancer

The dosage is as follows: arotinib hydrochloride 12mg, 14C12H1L1200mg

And (3) evaluating the curative effect:

a female aged 66 years, 6 months and 21 days in 2013, and the postoperative pathological diagnosis is anaplastic thyroid cancer. 2013.6.21 thyroid bilobal resection, 2019.2.15 right cervical lymphotomy (group III), 2020.6.11 right cervical clearance. 2020-7-1 PET CT indicates that the neck is enlarged with multiple lymph nodes, and the malignant disease is considered, and clear malignant lesions are not seen in the rest. Patients were shown in 2020-7-29 to 2020-8-18 thoraco-abdominal basin enhanced CT: thyroid bileave postoperative change, roughly as before; the change of the right neck after the operation, the pneumatosis in the operation area, the subcutaneous exudation in the operation area and the tissue density in the operation area are increased; there are many nodules under the pleura of both lungs, which are less variable than before. Cervical soft tissue enhancement MRI: the multiple lump shadow on the right neck is considered to be multiple lymph node metastasis, the original focus part disappears after the operation, and part focus is enlarged than before and is newly seen as multiple focus. 2020-8-12 is administered as 1 st course 14C12H1L1 combination erlotinib therapy with one dosing cycle every 3 weeks.

The CT results were as follows:

and (3) screening period: target lesion: 61.9 mm; non-target lesions: lymph nodes

After cycle 2 dosing: target lesion: 18.0 mm; non-target lesions: exist of

After cycle 4 dosing: target lesion: 15.5 mm; non-target lesions: exist of

9. The patients: E11002/S11003 adenocarcinoma

The past medical history: for a 69 year old female, Ca radical treatment of the upper right lung lobe under endotracheal intubation thoracoscopy at 2018.4.27, four times of chemotherapy (paclitaxel + nedaplatin) at 2018.6.13, 2018.7.18, 2018.9.3 and 2018.10.15, respectively; 2019.12.18, 2020.1.11, 2018.2.22 line three times chemotherapy (pemetrexed + nedaplatin), 2020-08-05 chest CT: the right pleura is thickened at multiple positions and has multiple soft tissue density nodules, and the major diameter of the pleura is about 0.9cm, which indicates pleural metastasis. Prompting the progress of the disease.

2020-08-17C1D1, starting once daily oral administration of Arotinib hydrochloride capsule, 12mg each time, continuously oral administration for two weeks and stopping for one week, and 14C12H1L1 once every three weeks, intravenous infusion administration, with infusion time of 60 + -10 min. Every 21 days is a cycle until the disease progresses or is intolerant. 2020-09-22 The dose of the erlotinib for the hand-foot syndrome CS III grade, the dose of the erlotinib for the third period is 10mg, the dose of the erlotinib for the 2020-10-13 The dose of the erlotinib for the fourth period is delayed for one period, the 2020-11-11 subjects recover to the < 2 grade, and the administration of the erlotinib is continued by regulating the dose of the erlotinib to 8 mg.

And (3) pathological report: 2018-04-18 "Right Lung" puncture tissue adenocarcinoma.

The dosage is as follows: C1D1-C2D 21: arotinib hydrochloride 12mg, 14C12H1L1200mg

The dosage is as follows: C3D1-C3D 21: 10mg of Arotinib hydrochloride, and 200mg of 14C12H1L1

C4D1-C4D21：14C12H1L1:200mg

C5D1-C5D 21: 8mg of Arotinib hydrochloride, and 200mg of 14C12H1L1

And (3) evaluating the curative effect: second period PR, fourth period SD

And (3) screening period: target lesion: 13.9 mm; non-target lesions: nodes near the diaphragm of the lower right lung and multiple nodes in the right pleural membrane

After cycle 2 dosing: target lesion: 8 mm; non-target lesions: non-CR/non-PD

After cycle 4 dosing: target lesion: 11.6 mm; non-target lesions: non-CR/non-PD

10. The patients: E11003/S11006-squamous cell carcinoma

The past medical history: 2020-02-05 pathological diagnosis is squamous cell carcinoma, 2020-08-19 chest CT shows: irregular soft tissue shadow beside the bronchus opening of the right lower lung portal area, bronchus stenosis of the lower lobar back section and the posterior basal section, the soft tissue shadow is enlarged more than before, a plurality of solid nodules are newly added to the double lungs, and most of the solid nodules are considered to be metastatic tumors, so that the soft tissue shadow is enlarged more than before, and the multiple lymphadenopathy of the left clavicle, the upper fossa, the lower fossa, the mediastinum, the double lung portal area and the liver and stomach ligament area is enlarged, and part of the soft tissue shadow. Prompting the progress of the disease.

2020-09-10 orally administering the erlotinib hydrochloride capsule once daily, each time 12mg, continuously for two weeks for one week, and administering 14C12H1L1 once every three weeks by intravenous infusion for 60 + -10 min. Every 21 days is a cycle. The patient has good tolerance during taking the medicine, and can continue to take the medicine.

And (3) pathological report: < lower right bronchofiberscope biopsy > squamous cell carcinoma

The dosage is as follows: arotinib hydrochloride 12mg, 14C12H1L1200mg

And (3) evaluating the curative effect: SD

And (3) screening period: target lesion: 101.7 mm; non-target lesions: lymph node of left Lung

After cycle 2 dosing: target lesion: 89.5 mm; non-target lesions: non-CR/non-PD

11. The patients: e09003-small cell carcinoma

In a 68-year-old male, 3 and 5 months in 2019, the postoperative pathological diagnosis is as follows: small cell carcinoma. CT (computed tomography) of 3-30 days in 2020 indicates that the inferior lobe height of the left lung is slightly more limited than that of the anterior lobe height, and the enlarged lymph nodes beside the aortic arch are slightly more advanced, thus indicating the progress of the disease. History of previous chemotherapy of patients: cisplatin 30mg + etoposide 0.1g for daily chemotherapy from 3/8/2019 to 7/2019 for 5 cycles of chemotherapy. Chemotherapy with cisplatin 20mg + etoposide 0.1g was started from 2.9/2019 to 6.9/2019 for 1 cycle of chemotherapy. Radiotherapy is carried out from 11/4 days in 2019 to 12/23 days in 2019. CT prompts progress at 3, 30 and 2020.

On 8 days 7/2020, the oral administration of 12mg of an erlotinib hydrochloride capsule once a day is started for 2 weeks and stopped for 1 week, and the 14C12H1L1200mg treatment is carried out, wherein each 3 weeks is a dosing cycle. The patient is currently under C6 cycle follow-up, has good overall tolerance during administration, and can continue to take medicine.

And (3) screening period: target lesion: 56.9 mm; non-target lesions: left lung portal soft tissue shadow

After cycle 2 dosing: target lesion: 25.5mm PR; non-target lesions: non-CR/non-PD

After cycle 4 dosing: target lesion: 16.9mm PR; non-target lesions: non-CR/non-PD

12. The patients: e10001-head neck chest tumor

Male 52 years old, left nasal obstruction stuffiness with left palate uplifting, facial skin numb 2020.05.18 to be captured as "left maxillary sinus tumor nature under examination", 2020.05.27 puncture pathology: myoepithelial cancer, preliminary diagnosis, malignant maxillary sinus tumor, no standard treatment scheme because the tumor germinate part is difficult to operate, and the clinical research is considered to be added, 2020.06.12 is added into the group.

The dosage is as follows: 12mg of erlotinib hydrochloride and 200mg of 14C12H1L1 begin at 2020.06.12, and the patient is currently in C8 cycle medication, has good overall tolerance during medication and can continue to take the medication.

And (3) evaluating the curative effect:

and (3) screening period:

target lesion: the upper right jawbone lump is 71 mm;

non-target lesions: multiple lymph nodes in the gap between the two necks

After cycle 2 dosing: target lesion: 51 mm; non-target lesions: non-CR/non-PD

After cycle 4 dosing: target lesion: 50 mm; non-target lesions: non-CR/non-PD

After cycle 6 dosing: target lesion: 52 mm; non-target lesions: non-CR/non-PD

While the compositions and methods of this application have been described in terms of preferred embodiments in light of the present disclosure, 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 incorporated by reference herein, to the extent that they provide exemplary, procedural and other details supplementary to those set forth herein.

Sequence listing

<110> Ningda Ningqing pharmaceutical industry group, Inc

<120> pharmaceutical composition of quinoline derivative and PD-1 monoclonal antibody

<130> 2020.11.27

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Arg Ala Asn

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Leu Gln Tyr Asp Glu Phe Pro Leu Thr

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Gly Phe Ala Phe Ser Ser Tyr Asp

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Ala Asn Arg Tyr Gly Glu Ala Trp Phe Ala Tyr

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Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Met Ser Ala Ser Val Gly

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115

Claims

1. A drug combination comprising:

a) a human PD-1 antibody, the human PD-1 antibody comprising a light chain and a heavy chain, wherein the light chain comprises light chain complementarity determining regions LCDR1, LCDR2 and LCDR3, the light chain complementarity determining regions are respectively represented by SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3 amino acid sequences, and wherein the heavy chain comprises heavy chain complementarity determining regions HCDR1, HCDR2 and HCDR3, the heavy chain complementarity determining regions are respectively represented by SEQ ID The amino acid sequence composition shown in NO:4, SEQ ID NO:5 and SEQ ID NO:6, and

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

3. The pharmaceutical combination according to any one of claims 1-2, 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 light chain variable region as shown in SEQ ID NO:8 The heavy chain variable region shown.

4. The pharmaceutical combination of any one of claims 1-3, wherein the human PD-1 antibody is 14C12H1L1.

5. Use of the pharmaceutical combination according to any one of claims 1-4 in the treatment or prevention of head, neck and chest tumors.

6. The use according to claim 5, wherein the drug combination is used for the treatment of advanced head, neck and chest tumors.

7. The use according to any one of claims 5-6, wherein the drug combination is used for the treatment of squamous cell carcinoma of the head and neck, non-squamous cell carcinoma of the head and neck, squamous epithelial carcinoma, adenocarcinoma, adenoid cystic carcinoma, mucoepidermoid carcinoma, lacrimal gland carcinoma, thyroid carcinoma, small cell lung cancer, non-small cell lung cancer, pleural mesothelioma, or thymic carcinoma.

8. purposes according to any one of claim 5-7, described medicine combination is used for the treatment of recurrent/metastatic head and neck squamous cell carcinoma, advanced/metastatic head and neck non-squamous cell carcinoma, anaplastic thyroid carcinoma , Small cell lung cancer, non-squamous non-small cell lung cancer, squamous non-small cell lung cancer, recurrent/metastatic pleural mesothelioma, or recurrent/metastatic thymic carcinoma for whom platinum-containing chemotherapy has failed.

9. purposes according to any one of claim 5-8, the unified administration dosage of formula I compound hydrochloride in described pharmaceutical combination is about 10mg/time or 12mg/time, the unified administration dose of 14C12H1L1 is about 200mg/time .

10. The use according to any one of claims 5-9, the administration mode of the compound hydrochloride of Chinese formula I in the pharmaceutical combination is once a day, 12 mg or 10 mg each time, continuous oral administration for 2 weeks and then stop for 1 week, 14C12H1L1 The injection mode of administration is once every 3 weeks, 200 mg/time.