WO2019096194A1 - Use of pd-1 antibody combined with vegfr inhibitor in treatment of small cell lung cancer - Google Patents

Abstract

Disclosed in the present invention is a use of PD-1 antibody combined with VEGFR inhibitor in treatment of small cell lung cancer. Particularly, disclosed in the present invention is a use of anti-PD-1 antibody combined with VEGFR inhibitor in preparation of a medicine for treatment of small cell lung cancer.

Description

Use of PD-1 antibody combined with VEGFR inhibitor in the treatment of small cell lung cancer Technical field

The present invention relates to the use of an anti-PD-1 antibody in combination with a VEGFR inhibitor for the preparation of a medicament for the treatment of small cell lung cancer.

Background technique

Small cell lung cancer (Samll Cell Lung Cancer, SCLC) originates from the bronchus and infiltrates into the lumen along the mucosa of the bronchial wall. SCLC accounts for 15%-20% of lung cancer. The clinical stage of SCLC is limited and extensive in clinical stage. The limited periodic lesion is confined to the ipsilateral thoracic cavity. The lesion can be covered by a tolerable radiation field, including the ipsilateral mediastinal lymph node, ipsilateral supraclavicular lymph node, excluding Hematogenous dissemination; extensive disease beyond the limitation period, including hematogenous dissemination. SCLC is clinically treated with chemotherapy and radiotherapy as the main treatment.

PD-1 antibody specifically recognizes and binds to PD-1 on the surface of lymphocytes, blocks the PD-1/PD-L1 signaling pathway, and activates the immune killing effect of T cells on tumors, and modulates the immune system of the body to eliminate tumor cells in vivo. WO2015085847A discloses a novel anti-PD-1 antibody which is currently in clinical trials and has shown a certain anti-tumor effect.

The small molecule tyrosine kinase inhibitor Apatinib disclosed in WO2005000232A has a highly selective competition for the ATP binding site of VEGFR-2 in cells, blocks downstream signal transduction, inhibits tumor angiogenesis, and finally reaches For the purpose of treating tumors, the structural formula of apatinib is as shown in formula (I).

CN101676267A discloses a series of salts of apatinib, such as mesylate, hydrochloride, maleate, and the like. The pre-clinical animal experiments disclosed in CN101675930A also show that apatinib combined with cytotoxic drugs such as oxaliplatin, 5-Fu, docetaxel, and doxorubicin can significantly increase the therapeutic effect.

There are currently no PD-1 antibodies and VEGFR inhibitors approved for marketing, but multiple PD-1 antibodies (other companies) and VEGFR inhibitors (such as sunitinib, sorafenib, etc.) are in clinical use. In stage II/III, indications were malignant liver cancer (sorafenib combined with PD-1 antibody) and metastatic renal cell carcinoma (sunitinib combined with PD-1 antibody). Preliminary results showed two drugs. The combined effect is better than single drug. CN105960415A discloses a use of a PD-1 antibody in combination with axitinib for the treatment of renal cell carcinoma, WO2015088847A discloses a use of a PD-1 antibody in combination with pazopanib for the treatment of renal cell carcinoma. WO2016141218A discloses a The use of PD-1 antibody in combination with levastatin for the treatment of thyroid cancer, hepatocellular carcinoma, non-small cell lung cancer, renal cell carcinoma, endometrial cancer, glioblastoma and melanoma. However, the mechanisms of action of these VEGFR inhibitors, including levovirinib, sorafenib, sunitinib, axitinib, and pazopanib, differ from that of apatinib. 2 has the strongest inhibitory effect, but has little or no inhibitory effect on other kinases, ie, apatinib is highly selective for VEGFR-2, so the disease it treats is also different from the aforementioned drugs. Differently, whether it can synergize with PD-1 to improve the efficacy is worthy of further study; in addition, according to the current clinical study of PD-1 alone, it is shown (Phase I study of the anti-PD-1 antibody SHR-1210 in Patients with advanced solid tumors. (2017): e15572-e15572), when the PD-1 antibody was treated alone, the incidence of capillary hemangioma was as high as 79.3%. Adverse reactions undoubtedly put a burden on the mental health and quality of life of cancer patients. Therefore, it is very important to reduce the adverse reactions during drug administration.

Summary of the invention

The present invention provides the use of a VEGFR inhibitor and an anti-PD-1 antibody or antigen-binding fragment thereof in the preparation of a medicament for treating a small cell lung cancer patient.

The invention also provides the use of an anti-PD-1 antibody or antigen-binding fragment thereof for the preparation of a medicament for treating a small cell lung cancer patient.

In a preferred embodiment of the invention, wherein the VEGFR inhibitor is a VEGFR-2 inhibitor.

In a preferred embodiment of the invention, wherein the VEGFR-2 inhibitor is selected from the group consisting of: PAN-90806, Foretinib, Tafetinib, Kanitinib, Apatinib , Tanibirumab, Anlotinib, Lucitanib, Vatalanib, Cediranib, Chiauranib, Dovitinib, Donafinib ), Famitinib, Sitravatinib, Telatinib, L-21649, TAS-115, Cabozintinib, Thiophenib, Fruquintinib ), Brivinib, Sulfatinib, Ramucirumab, Glesatinib, Nintedanib, Puquitinib, Axitinib, EDP317, Solar Sorafenib, Metatinib, Tivozanib, Regorafenib, Midostaurin, Pazopanib, HLX-06, Altiratinib, Ningetinib, Shuni A pharmaceutically acceptable salt of Sunitinib, AL-8326, Rebastinib or the like.

In a preferred embodiment of the invention, the pharmaceutically acceptable salt of apatinib is selected from the group consisting of methanesulfonate, maleate, tartrate, succinate, acetate, difluoroacetate, Fumarate, citrate, citrate, besylate, benzoate, naphthalene sulfonate, lactate, malate, hydrochloride, hydrobromide, sulfate, and Phosphate.

In a preferred embodiment of the invention, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is selected from the group consisting of: AMP-224, GLS-010, IBI-308, REGN-2810, PDR-001, BGB-A317, Pidilizumab, PF-06801591, Genolimzumab, CA-170, MEDI-0680, JS-001, TSR-042, Camrelizumab, Pembrolizumab, LZM-009, AK-103 and Nivolumab.

In a preferred embodiment of the invention, wherein the light chain variable region of the anti-PD-1 antibody or antigen-binding fragment thereof comprises SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, respectively The LCDR1, LCDR2 and LCDR3 are shown; the heavy chain variable region comprises HCDR1, HCDR2 and HCDR3 as set forth in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, respectively.

Among them, the CDR sequences described above are shown in the following table:

name	sequence	Numbering
HCDR1	SYMMS	SEQID NO: 1
HCDR2	TISGGGANTYYPDSVKG	SEQID NO: 2
HCDR3	QLYYFDY	SEQID NO: 3
LCDR1	LASQTIGTWLT	SEQID NO: 4
LCDR2	TATSLAD	SEQID NO: 5
LCDR3	QQVYSIPWT	SEQID NO: 6

Preferably, the PD-1 antibody is a humanized antibody.

A preferred preferred humanized antibody light chain variable region sequence is the sequence set forth in SEQ ID NO: 10 or a variant thereof; said variant preferably has a 0-10 amino acid change in the light chain variable region; More preferably, it is an amino acid change of A43S. The humanized antibody heavy chain variable region sequence is the sequence set forth in SEQ ID NO: 9 or a variant thereof; the variant preferably has an amino acid change of 0-10 in the heavy chain variable region; more preferably Amino acid changes in G44R.

The variable region sequences of the heavy and light chains of the aforementioned humanized antibodies are as follows:

Heavy chain variable region

Light chain variable region

A preferred humanized antibody light chain sequence is the sequence set forth in SEQ ID NO: 8 or a variant thereof; said variant preferably has a 0-10 amino acid change in the light chain variable region; more preferably A43S Amino acid changes. The humanized antibody heavy chain sequence is the sequence set forth in SEQ ID NO: 7 or a variant thereof; the variant preferably has an amino acid change of 0-10 in the heavy chain variable region; more preferably an amino acid of G44R Variety.

In a preferred embodiment of the invention, the humanized antibody light chain sequence is the sequence set forth in SEQ ID NO: 8, and the heavy chain sequence is the sequence set forth in SEQ ID NO: 7.

The sequences of the aforementioned humanized antibody heavy and light chains are as follows:

Heavy chain

Light chain

In a preferred embodiment of the invention, the small cell lung cancer is extensive stage small cell lung cancer.

In a preferred embodiment of the invention wherein the patient is treated with a platinum drug. For example, patients who have failed platinum therapy or are intolerable.

In a preferred embodiment of the invention, wherein the platinum drug treatment is selected from the group consisting of: etoposide/cisplatin combination chemotherapy, etoposide/carboplatin combination chemotherapy, etoposide/cisplatin combination chemotherapy and radiotherapy, etoposide / Carboplatin combined with chemotherapy and radiotherapy.

In a preferred embodiment of the invention, wherein the dose of the PD-1 antibody or antigen-binding fragment thereof is selected from the group consisting of 1-10 mg/kg, preferably from 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, more preferably 1 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 10 mg/kg.

In a preferred embodiment of the invention, wherein the PD-1 antibody or antigen-binding fragment thereof is selected from the group consisting of 50-600 mg, preferably from 50 mg, 60 mg, 70 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 600 mg, more preferably from 60 mg, 100 mg, 200 mg, 400 mg, 600 mg.

In a preferred embodiment of the invention, wherein the VEGFR inhibitor dose is selected from the group consisting of 0.01 to 500 mg, preferably from 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg. , 8mg, 9mg, 10mg, 11mg, 12mg, 12.5mg, 15mg, 17.5mg, 20mg, 22.5mg, 25mg, 30mg, 45mg, 50mg, 60mg, 70mg, 75mg, 80mg, 90mg, 100mg, 125mg, 150mg, 175mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 400 mg, 500 mg, more preferably 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 10 mg, 15 mg, 20 mg, 30 mg, 45 mg, 50 mg, 60 mg, 75 mg, 100 mg.

In a preferred embodiment of the present invention, wherein the PD-1 antibody or antigen-binding fragment thereof is administered once a day, twice a day, three times a day, once a week, once every two weeks, once every three weeks. Once a month, the frequency of administration of the VEGFR inhibitor is once a day, twice a day, three times a day, once a week, once every two weeks, once every three weeks, once a month.

The combined administration routes of the present invention are selected from the group consisting of oral administration, parenteral administration, and transdermal administration, and include, but are not limited to, intravenous injection, subcutaneous injection, and intramuscular injection.

In a preferred embodiment of the present invention, wherein the PD-1 antibody is administered in an amount of 60 to 600 mg, intravenously infused every three to three weeks, and the VEGFR inhibitor is used in an amount of 250 mg to 500 mg. Oral, once every two days.

In a preferred embodiment of the present invention, wherein the PD-1 antibody is administered in an amount of 60 to 600 mg, intravenously infused every three to three weeks, and the VEGFR inhibitor is used in an amount of 250 mg to 500 mg. Oral, administration for 5 days to stop the drug for 2 days.

In a preferred embodiment of the present invention, wherein the PD-1 antibody is administered in an amount of 60 to 600 mg, intravenously infused every three to three weeks, and the VEGFR inhibitor is used in an amount of 250 mg to 500 mg. Oral, 7 days of drug withdrawal for 7 days.

In a preferred embodiment of the invention, wherein the PD-1 antibody is administered in an amount of 200 mg, administered intravenously every two weeks; the VEGFR inhibitor is administered in an amount of 375 mg orally, once daily. .

In a preferred embodiment of the present invention, when administered, wherein the amount of the PD-1 antibody is 200 mg, intravenous infusion every two weeks; the amount of the VEGFR inhibitor is 375 mg, orally, administration 5 The drug was stopped for 2 days.

In a preferred embodiment of the present invention, wherein the PD-1 antibody is administered in an amount of 200 mg, administered intravenously every two weeks; and the VEGFR inhibitor is administered in an amount of 375 mg orally, administered 7 The drug was stopped for 7 days.

In a preferred embodiment of the invention, the PD-1 antibody is administered by injection, for example subcutaneously or intravenously, and the PD-1 antibody is formulated in an injectable form prior to injection. A particularly preferred injectable form of the PD-1 antibody is an injection or lyophilized powder comprising a PD-1 antibody, a buffer, a stabilizer, and optionally a surfactant. The buffering agent may be selected from one or more of the group consisting of acetate, citrate, succinate, and phosphate. The stabilizer may be selected from sugars or amino acids, preferably disaccharides such as sucrose, lactose, trehalose, maltose. The surfactant is selected from the group consisting of polyoxyethylene hydrogenated castor oil, glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, preferably the polyoxyethylene sorbitan fatty acid ester is polysorbate 20, 40, 60 or 80. Most preferred is polysorbate 20. Injectable forms of the most preferred PD-1 antibodies comprise PD-1 antibody, acetate buffer, trehalose and polysorbate 20.

The present invention provides the above anti-PD-1 antibody in combination with the above VEGFR as a drug for reducing adverse drug reactions. Preferably, the adverse drug reaction is selected from an anti-PD-1 antibody or caused by a VEGFR inhibitor.

In a preferred embodiment of the invention, when the PD-1 antibody is used in combination with a VEGFR inhibitor, the adverse drug reaction mediated by the anti-PD-1 antibody and/or immune can be reduced; preferably, the adverse reaction Selected from vascular-related adverse reactions.

The present invention provides a method of treating a tumor/cancer comprising administering to a patient an anti-PD-1 antibody or antigen-binding fragment thereof as described above and the above-described VEGFR inhibitor.

The present invention also provides a pharmaceutical kit or pharmaceutical kit comprising the above anti-PD-1 antibody or antigen-binding fragment thereof and the above VEGFR inhibitor.

Detailed description of the invention

First, the term

In order to more easily understand the present invention, certain technical and scientific terms are specifically defined below. Unless otherwise expressly defined in this document, all other technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs.

The term "humanized antibody", also known as CDR-grafted antibody, refers to the transplantation of mouse CDR sequences into human antibody variable region frameworks, ie different types of human germline An antibody produced in an antibody framework sequence. It is possible to overcome the strong antibody variable antibody response induced by chimeric antibodies by carrying a large amount of mouse protein components. Such framework sequences can be obtained from public DNA databases including germline antibody gene sequences or published references. The germline DNA sequences of human heavy and light chain variable region genes can be found in the "VBase" human germline sequence database (available on the Internet at www.mrccpe.com.ac.uk/vbase), as well as in Kabat, EA, etc. Human, 1991 Sequences of Proteins of Immunological Interest, found in the 5th edition. In a preferred embodiment of the invention, the CDR sequence of the PD-1 humanized antibody is selected from the group consisting of SEQ ID NOs: 1, 2, 3, 4, 5, 6.

The term "antigen-binding fragment" refers to a Fab fragment having antigen-binding activity, a Fab' fragment, an F(ab')2 fragment, and an Fv fragment sFv fragment that binds to human PD-1; and an antibody comprising the antibody of the present invention is selected from the group consisting of One or more CDR regions of SEQ ID NO: 1 to SEQ ID NO: 6. The Fv fragment contains the antibody heavy chain variable region and the light chain variable region, but has no constant region and has the smallest antibody fragment of the entire antigen binding site. In general, Fv antibodies also comprise a polypeptide linker between the VH and VL domains and are capable of forming the desired structure for antigen binding. The two antibody variable regions can also be joined by a different linker into a single polypeptide chain, referred to as a single chain antibody or a single chain Fv (sFv). The term "binding to PD-1" as used herein refers to the ability to interact with human PD-1. The term "antigen binding site" as used in the present invention refers to a three-dimensional spatial site that is discrete on an antigen and is recognized by an antibody or antigen-binding fragment of the present invention.

The term "immunotherapy" refers to the use of the immune system to treat diseases, and in the present invention mainly refers to stimulating and enhancing the body's anti-tumor immune response by increasing the immunogenicity of tumor cells and sensitivity to effector cell killing, and applying The immune cells and effector molecules are infused into the host to cooperate with the body's immune system to kill tumors and inhibit tumor growth.

The invention relates to "combination" as a mode of administration, which means administering at least one dose of apafitini and at least one dose of PD-1 antibody or antigen-binding fragment thereof, within two time periods, of which two substances are administered. Both show pharmacological effects. The time period may be within one administration period, preferably within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours, more preferably within 12 hours. The apatinib and PD-1 antibodies or antigen-binding fragments thereof can be administered simultaneously or sequentially. Such a term includes a treatment in which apatinib and a PD-1 antibody or antigen-binding fragment thereof are administered by the same route of administration or by different routes of administration. The combined modes of administration of the present invention are selected from the group consisting of simultaneous administration, independent formulation and co-administration or independently formulated and administered sequentially.

"Treatment failure" as used in the present invention means that the subject is accompanied by a measurable tumor lesion at baseline, according to the RECIST 1.1 efficacy evaluation criteria for disease progression (PD), toxicity is intolerable or the investigator judges that the subject cannot Continue clinical benefit.

The term "toxic intolerance" as used in the present invention means that the adverse reactions caused by the drug cannot continue to be treated.

Progression free survival (PFS): The time from the onset of randomization to the first recording of the objective progression of the tumor or to any cause of death, whichever occurs first.

Total survival (OS) refers to the date from a random date to any cause of death. For subjects who survived at the last follow-up, their OS was censored as data at the last follow-up. In the subjects who were lost to follow-up, the OS was counted as data censored by the last confirmed survival time before the loss of follow-up. The data censored OS is defined as a random date to a censored date.

Objective Remission Rate (ORR): The proportion of subjects defined as the best overall response (BoR), CR, and PR who were dosed at least once in each treatment group. BOR is defined as the optimal response between the start of the random date and the date of objective recording or the date of subsequent anti-tumor treatment, whichever occurs first. For subjects who have not recorded progression or follow-up anti-tumor treatment, The BOR is determined based on all mitigation assessment results.

Duration of Remission (DoR): The time from the first PR or CR to the first PD or death.

Disease Control Rate (DCR): The proportion of subjects with CR, PR, and SD who were at least once in each treatment group. The best mitigation index between the DCR from the random date to the objective recorded progression date or the follow-up anti-tumor treatment date (whichever occurs first), for all subjects who have not recorded progression or follow-up anti-tumor treatment, will be based on all The mitigation assessment results determine the DCR.

Efficacy assessment criteria were divided into complete response (CR), partial response (PR), stable (SD), and progression (PD) according to RECIST 1.1 criteria.

Target lesion assessment:

Complete remission (CR): All target lesions disappeared and the short diameter of all pathological lymph nodes (including target nodules and non-target nodules) must be reduced to <10 mm.

Partial remission (PR): The sum of the target lesion diameters is at least 30% less than the baseline level.

Progression of disease (PD): reference to the minimum of the sum of all measured target lesion diameters throughout the experimental study, with a diameter and relative increase of at least 20% (referenced to baseline values if the baseline measurement is minimal); In addition, the absolute value of the diameter and the absolute value must be increased by at least 5 mm (one or more new lesions are also considered to be disease progression).

Stable disease (SD): The extent of target lesion reduction did not reach PR, and the degree of increase did not reach PD level. Between the two, the minimum value of the sum of diameters could be used as a reference.

Detailed ways

The invention is further described in the following examples, but these examples are not intended to limit the scope of the invention.

Example 1: Phase II clinical study of anti-PD-1 antibody combined with apatinib mesylate in the treatment of extensive small cell lung cancer

1. Test antibodies and compounds

The sequence of the heavy and light chain of the PD-1 antibody is SEQ ID NO: 7 and SEQ ID NO: 8. 200 mg/sp. in the present invention, and is formulated into 20 mg/ml for use.

Commercially available apatinib mesylate tablets.

2, the inclusion criteria: (1) extensive stage small cell lung cancer; (2) received a first-line platinum-based treatment for extensive small cell lung cancer, and objective imaging progress; (3) with measurable lesions; 4) ECOG score 0-1 points.

3. Administration method: 18 subjects who passed the screening were randomly assigned to the following three groups according to 1:1:1:

Group A: PD-1 antibody 200mg, intravenous infusion, once every two weeks + 375mg apatinib, oral, once daily

Group B: PD-1 antibody 200mg, intravenous infusion, once every two weeks + 375mg of apatinib, orally (administered for 5 days for 2 days)

Group C: PD-1 antibody 200mg, intravenous infusion, once every two weeks + 375mg of apatinib, orally (administered for 7 days 7 days)

data analysis:

	Group A (n=6)	Group B (n=6)	Group C (n=6)
ORR	83.3%	33%	17%
PFS	3.7	1.7	3.2
DCR	83.3%	100%	50%

From the above clinical data, the objective response rate (ORR) of 375 mg once daily and daily dose of 375 mg apatinib combined with PD-1 antibody for extensive small cell lung cancer was 83.3%, and the disease control rate (DCR) was 83.3. % has shown excellent effects in the treatment of extensive stage small cell lung cancer.

Claims (18)

1. Use of a VEGFR inhibitor and an anti-PD-1 antibody or antigen-binding fragment thereof in the manufacture of a medicament for treating a small cell lung cancer patient.
2. The use according to claim 1 wherein the VEGFR inhibitor is a VEGFR-2 inhibitor.
3. The use according to claim 2, wherein the VEGFR-2 inhibitor is selected from the group consisting of PAN-90806, Foretinib, Tafetinib, Kanitinib, Apatinib, Tanibirumab, Anlotinib, Lucitanib, Vatalanib, Cediranib, Chiauranib, Dovitinib, Donafenib , Famitinib, Sitravatinib, Telatinib, L-21649, TAS-115, Cabozintinib, Thiophenib, Fruquintinib , Brivinib, Sulfatinib, Ramucirumab, Glesatinib, Nintedanib, Puquitinib, Axitinib, EDP317, Solafi Sorafenib, Metatinib, Tivozanib, Regorafenib, Midostaurin, Pazopanib, HLX-06, Altiratinib, Ningetinib, Sunitit Sunitinib, AL-8326, Rebastinib or a pharmaceutically acceptable salt of the above.
4. The use according to claim 3, wherein the pharmaceutically acceptable salt of apatinib is selected from the group consisting of mesylate, maleate, tartrate, succinate, acetate, difluoroacetate, rich Caprate, citrate, citrate, besylate, benzoate, naphthalene sulfonate, lactate, malate, hydrochloride, hydrobromide, sulfate, and phosphate .
5. The use according to claim 1, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is selected from the group consisting of: AMP-224, GLS-010, IBI-308, REGN-2810, PDR-001, BGB-A317, Pidilizumab PF-06801591, Genolimzumab, CA-170, MEDI-0680, JS-001, TSR-042, Camrelizumab, Pembrolizumab, LZM-009, AK-103 and Nivolumab.
6. The use according to claim 1, wherein the light chain variable region of the anti-PD-1 antibody or antigen-binding fragment thereof comprises SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, respectively. The heavy chain variable region of the PD-1 antibody described by LCDR1, LCDR2 and LCDR3 comprises HCDR1, HCDR2 and HCDR3 as set forth in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, respectively.
7. The use according to claim 6, wherein the anti-PD-1 antibody is a humanized antibody.
8. The use according to claim 7, wherein the light chain variable region sequence of the humanized antibody is the sequence shown in SEQ ID NO: 10 or a variant thereof, and the variant is preferably variable in the light chain The region has an amino acid change of 0-10, more preferably an amino acid change of A43S; the heavy chain variable region sequence is the sequence set forth in SEQ ID NO: 9 or a variant thereof, preferably in the heavy chain variable region There is a 0-10 amino acid change, more preferably an amino acid change of G44R.
9. The use according to claim 8, wherein the humanized antibody light chain sequence is the sequence set forth in SEQ ID NO: 8 or a variant thereof, said variant preferably having 0- in the light chain variable region Amino acid change of 10, more preferably amino acid change of A43S; heavy chain sequence is a sequence as shown in SEQ ID NO: 7 or a variant thereof, preferably having a 0-10 amino acid change in the heavy chain variable region More preferably, it is an amino acid change of G44R.
10. The use according to claim 9, wherein the humanized antibody light chain sequence is the sequence set forth in SEQ ID NO: 8, and the heavy chain sequence is the sequence set forth in SEQ ID NO: 7.
11. The use according to claim 1, wherein the small cell lung cancer is extensive stage small cell lung cancer.
12. The use according to claim 1 wherein the patient is treated with a platinum drug.
13. The use according to claim 12, wherein the platinum drug treatment is selected from the group consisting of: etoposide/cisplatin combined chemotherapy, etoposide/carboplatin combined chemotherapy, etoposide/cisplatin combined chemotherapy and radiotherapy, etoposide/ Carboplatin combined with chemotherapy and radiation therapy.
14. The use according to any one of claims 1 to 13, wherein the dose of the PD-1 antibody or antigen-binding fragment thereof is selected from the group consisting of 1-10 mg/kg, preferably from 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, more preferably 1 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 10 mg/kg.
15. The use according to any one of claims 1 to 13, wherein the PD-1 antibody or antigen-binding fragment thereof is selected from the group consisting of 50-600 mg, preferably from 50 mg, 60 mg, 70 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 600 mg, more preferably from 60 mg, 100 mg, 200 mg, 400 mg, 600 mg.
16. The use according to any one of claims 1 to 13, wherein the VEGFR inhibitor dose is selected from the group consisting of 0.01 to 500 mg, preferably from 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg. , 6mg, 7mg, 8mg, 9mg, 10mg, 11mg, 12mg, 12.5mg, 15mg, 17.5mg, 20mg, 22.5mg, 25mg, 30mg, 45mg, 50mg, 60mg, 70mg, 75mg, 80mg, 90mg, 100mg, 125mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 400 mg, 500 mg, more preferably 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 10 mg, 15 mg, 20 mg, 30 mg, 45 mg, 50 mg, 60 mg, 75 mg, 100mg.
17. A method of reducing an adverse reaction caused by an anti-PD-1 antibody or a VEGFR inhibitor, comprising administering to a patient a VEGFR inhibitor according to any one of claims 1 to 16 and an anti-PD-1 antibody or antigen-binding thereof Fragment.
18. A pharmaceutical kit comprising the VEGFR inhibitor and the anti-PD-1 antibody or antigen-binding fragment thereof according to any one of claims 1-16.