HK1255299B - Use of combination of anti-pd-1 antibody and vegfr inhibitor in preparation of drug for treating cancers - Google Patents

Description

Application of combination of anti-PD-1 antibody and VEGFR (vascular endothelial growth factor receptor) inhibitor in preparation of medicine for treating cancer

Technical Field

The invention relates to application of a combination of an anti-PD-1 antibody and a VEGFR inhibitor in preparation of a medicament for treating cancer.

Background

The PD-1 antibody specifically recognizes and binds to the PD-1 on the surface of the lymphocyte, blocks a PD-1/PD-L1 signal channel, further activates the immune killing effect of the T cell on the tumor, mobilizes the immune system of the organism and eliminates the tumor cells in the body. WO201508584 discloses a novel anti-PD-1 antibody, which is currently in clinical trials and has shown some anti-tumor effect.

Apatinib is the first oral anti-angiogenesis drug for late gastric cancer in the world, has high selectivity on VEGFR-2, and has strong anti-angiogenesis effect. In a multicenter Randomized, Double-Blind Placebo-Controlled Phase III Trial on Patients with Metastatic gastro/Gastroesophageal junction cancer treated second line of Apatinib, the results showed that Apatinib single drug prolonged median overall survival by 1.8 months, median progression-free survival by 0.8 months, and adverse events were Controlled compared to Placebo (Randomized, Double-Blind, Placebo-Controlled Phase III triple of Apatinib Patients WithChemotherapy-Refractory Advance or Metastatic Adenoceromosma of the Stomachor Gastroesophageal junction. J Clin col, Feb 2016 b 16). The structural formula of the apatinib is shown as the formula (I).

CN101676267A discloses a series of salts of apatinib, such as mesylate, hydrochloride, and the like. The animal experiment before clinical application disclosed in CN101675930A also shows that apatinib can obviously increase the curative effect of apatinib combined with cytotoxic drugs such as oxaliplatin, 5-Fu, docetaxel and adriamycin.

At present, no combination of PD-1 antibody and VEGFR inhibitor is sold on the market, but a plurality of PD-1 antibodies (of other companies) and VEGFR inhibitors (such as sunitinib and sorafenib and the like) are in clinical II/III stages, indications are malignant liver cancer (combination of sorafenib and PD-1 antibody) and metastatic renal cell carcinoma (combination of sunitinib and PD-1 antibody), and preliminary results show that the combination effect of the two drugs is superior to that of a single drug.

WO2015119930 discloses the use of a PD-1 antibody in combination with axitinib, and WO2015088847 discloses the use of a PD-1 antibody in combination with pazopanib. However, the VEGFR inhibitors, including sorafenib, sunitinib, axitinib and pazopanib, have different action mechanisms, and apatinib has the strongest inhibition effect on VEGFR-2, but has poor or no inhibition effect on other kinases, i.e., apatinib has high selectivity on VEGFR-2, so that the diseases treated by the VEGFR inhibitors are different from the medicines, and whether the VEGFR inhibitors generate synergistic effect with PD-1 or not can be realized, so that the curative effect is improved, and the VEGFR inhibitors are worthy of further research; in addition, according to the current clinical study of PD-1 single administration (PhaseI study of the anti-PD-1 anti SHR-1210 in patients with advanced soluble tumors (2017): e15572-e15572), when the PD-1 antibody is used for single treatment, the incidence rate of capillary hemangioma is as high as 79.3%, the incidence rate of hypothyroidism is 29.3%, the incidence rate of pruritus is 19.0%, and the incidence rate of diarrhea is 10.3%, so the high adverse reaction undoubtedly causes burden on mental health and life quality of tumor patients; therefore, it is very important to reduce the adverse reaction when the medicine is taken

Disclosure of Invention

The invention provides an application of a combination of an anti-PD-1 antibody and a VEGFR inhibitor in preparing a medicament for treating cancer.

Preferably, wherein the VEGFR inhibitor is a VEGFR-2 inhibitor.

Preferred VEGFR inhibitors of the invention are those which have an IC50 of less than 100nM for VEGFR kinase and no inhibitory activity for EGFR, HER2, FGFR (IC50 > 10000nM) according to the assay disclosed in CN101676267A, and particularly preferred VEGFR inhibitors are VEGFR-2 inhibitors which have an IC50 of less than 50nM, preferably less than 20nM, more preferably less than 10nM, and most preferably less than 5nM for VEGFR-2 kinase, while at the same time having a poor inhibitory effect on VEGFR-1 or VEGFR-3, e.g. an IC50 of greater than 20nM, preferably greater than 50 nM.

In a preferred embodiment of the invention, the VEGFR-2 inhibitor is apatinib or a pharmaceutically acceptable salt thereof.

PD-1 antibodies are known, preferably the light chain variable region of said PD-1 antibody comprises the amino acid sequences as set forth in SEQ ID NOs: 4. SEQ ID NO:5 and SEQ ID NO: LCDR1, LCDR2 and LCDR3 shown in fig. 6.

The heavy chain variable region of the PD-1 antibody comprises the amino acid sequences respectively shown as SEQ ID NO: 1. SEQ ID NO:2 and SEQ ID NO:3 HCDR1, HCDR2 and HCDR 3.

Wherein, the CDR sequences are shown in the following table:

name (R)	Sequence of	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.

Preferred humanized antibody light chain sequences are as set forth in SEQ ID NO:8 or a variant thereof; the variant preferably has 0-10 amino acid changes in the light chain variable region; more preferably the amino acid change of A43S.

The humanized antibody heavy chain sequence is as shown in SEQ ID NO:7 or a variant thereof; the variant preferably has 0-10 amino acid changes in the heavy chain variable region; more preferably the amino acid change of G44R.

Particularly preferred light chain sequences of the humanized antibodies are as shown in SEQ ID NO:8, and the heavy chain sequence is shown as SEQ ID NO:7, or a sequence shown in the figure.

The sequences of the heavy and light chains of the humanized antibodies are shown below:

heavy chain

Light chain

In a preferred embodiment of the invention, the VEGFR inhibitor is further selected from the group consisting of MP-0250, DE-120, ALN-VSP, Afliberceptit, Anecortave, BI-695502, Bevacizumab, PF-06439535, Carboxyamidotriazole, Vanecizumab, RG-7716, Bevacizumab analogs, Navicixizumab, Ranibizumab analogs, Conbercept, IBI-302, BI-836880, ARQ-736, RPI-4610, LMG-324, PTC-299, ABT-165, AG-13958, Brotinizumab, PAN-90806, Vatalaniib, ODM-203, Altiratinib, OPT-302, TG-5639, CEP-7055, TAS-70115, TARTAIRTAIRTAIRTAIN, Tatarin-5, TabanuibI-26483327, TabaniB-359, TabanuibNinitorubib, Tabanicn-26483327, TabanicuibJNb, Tabani-3645, Tabanicuib-26483327, Tabanib, Tabaniunbuib-3645, Tabanuib-358, Tabanuib, Tabanuiberb-358, Tabani-V-1, Tabani-III, Tabani-D, Tabani-III, Tabani-V-D, Tabani-D-V-E-D, Tabani-D-E-D, Tabani-E-D-E-D, RAF265, Puquitinib, SU-014813, Tivozanib, Fruquintinib, Sitravatinib, Pegaptanib, Pazopanib, Vandertinib, Axitinib, Sulfatinib, Ramucirumab, Plutidepsin, Orantinib, Alacizumab pegol, Telatinib, Ponatinib, Cabozantinib, Lenvatinib, Brivanib Alaninate, Linifinib.

In the use of the present invention, the cancer is preferably a cancer expressing PD-L1; more preferably breast cancer, lung cancer, gastric cancer, intestinal cancer, renal cancer, liver cancer, melanoma, non-small cell lung cancer; non-small cell lung cancer, melanoma, renal cancer, intestinal cancer including large intestine cancer, colorectal cancer, etc. are most preferred. When administered, apatinib is preferably administered in the form of a pharmaceutically acceptable salt, which can be selected from the group consisting of mesylate, hydrochloride.

Specifically, the PD-1 antibody can be used in an amount of 0.5-30mg/kg, preferably 2-10mg/kg, more preferably 2-6mg/kg, and most preferably 3mg/kg when administered; administration may be once every 1 to 3 weeks, preferably once every 2 weeks. For adult humans, fixed doses may also be used, for example 100-. The dose of the VEGFR inhibitor may be 3-200mg/kg, and for adult humans, a fixed dose may be used, such as 100-.

In the present invention, the term "combination" is intended to include administration of two drugs sequentially or simultaneously, and the term "simultaneously" is intended to mean that the PD-1 antibody and the VEGFR inhibitor are administered in the same administration cycle, e.g., within 2 days, or within 1 day. By "sequential" administration, it is meant to include separate administrations of the PD-1 antibody and VEGFR inhibitor over different administration periods. These administration modes are all the combination administration described in the present invention.

In a preferred embodiment of the invention, the PD-1 antibody is administered by injection, for example subcutaneously or intravenously, the PD-1 antibody being formulated in an injectable form prior to injection. A particularly preferred injectable form of the PD-1 antibody is an injection solution or a lyophilized powder injection, which comprises the PD-1 antibody, a buffer, a stabilizer, and optionally a surfactant. The buffer can be one or more selected from 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 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 preferably polysorbate 20. The most preferred injectable form of the PD-1 antibody comprises the PD-1 antibody, acetate buffer, trehalose, and polysorbate 20.

The invention provides the anti-PD-1 antibody combined with the VEGFR for preparing a medicament for treating tumors.

The present invention provides the above-described anti-PD-1 antibody in combination with the above-described VEGFR as a medicament for reducing an adverse drug reaction, preferably, the adverse drug reaction is selected from the group consisting of an anti-PD-1 antibody or a VEGFR inhibitor.

The present invention provides the above-described anti-PD-1 antibody in combination with the above-described VEGFR as a medicament for reducing the dose of the anti-PD-1 antibody administered alone and/or the dose of the VEGFR inhibitor administered alone.

In the present invention, there is provided a method for treating tumor/cancer comprising administering to a patient the above-described anti-PD-1 antibody and the above-described VEGFR inhibitor.

In the present invention, there is provided a method of reducing the dose of an anti-PD-1 antibody administered alone and/or a VEGFR inhibitor administered alone, comprising administering to a patient the above-described anti-PD-1 antibody in combination with the above-described VEGFR inhibitor.

Preferably, when used in combination with PD-1, the VEGFR inhibitor is administered at a dose that is 10% to 100%, preferably 10% to 75%, more preferably 75%, 50%, 25%, 12.5% of its dose administered alone.

Preferably, when used in combination with VEGFR, the anti-PD-1 antibody dose is 10% to 100%, preferably 10% to 50% of the dose of anti-PD-1 antibody administered alone.

In a preferred embodiment of the invention, when the PD-1 antibody is used in combination with a VEGFR inhibitor, adverse drug reactions mediated by the anti-PD-1 antibody and/or immunity are reduced; preferably, the adverse reaction is selected from vascular adverse reactions, gland hypofunction, skin adverse reactions, respiratory system adverse reactions, liver related adverse reactions, endocrine related adverse reactions, digestive system adverse reactions, kidney related adverse reactions, fatigue and fever; said preferred vascular-related adverse reactions are selected from the group consisting of hemangioma, vasculitis, lymphangioma, and said gland hypofunction is selected from the group consisting of hypothyroidism, hypoparathyroidism, pancreatopathy, and prostate hypofunction; said adverse skin reactions are selected from the group consisting of pruritus, urticaria, rashes, toxic epidermal necroses; the adverse reaction of the respiratory system is selected from pneumonia, bronchitis, chronic obstructive pulmonary disease and pulmonary fibrosis; the liver-related adverse reaction is selected from hepatitis, abnormal liver function; the endocrine-related adverse reactions are selected from type I diabetes, type II diabetes, hypoglycemia; renal related adverse reactions selected from nephritis, renal failure; the digestive system adverse reaction is selected from diarrhea, nausea, emesis, enteritis, constipation; more preferably, the adverse drug reactions are selected from the group consisting of hemangioma, hypothyroidism, hypoparathyroidism, pruritus, pneumonia, hepatitis, liver dysfunction, type I diabetes, nephritis, renal failure.

The invention also provides a pharmaceutical kit or a pharmaceutical pack containing the VEGFR inhibitor and PD-1 antibody described above.

Drawings

FIG. 1. Effect of administration of antibodies and compounds on the relative volume of transplanted tumors in tumor-bearing mouse MC38 (PD-L1);

FIG. 2. Effect of administration of antibodies and compounds on the body weight of mice bearing MC38(PD-L1) transplanted tumors, wherein p < 0.05, vs. placebo;

FIG. 3 therapeutic efficacy of the administered antibodies and compounds on transplanted tumors of tumor-bearing mouse MC38(PD-L1) -tumor weight.

Detailed Description

The present invention will be further described with reference to the following examples, which are not intended to limit the scope of the present invention.

Example 1: curative effect of PD-1 antibody, apatinib mesylate alone or in combination on mouse colon cancer cell MC-38(PD-L1) transplanted tumor C57 human PD-1 transgenic mouse with PD-L1 gene

1. Purpose of study

The efficacy of the combination of PD-1 antibody and apatinib on the transplantation tumor of mouse colon cancer cell MC-38(PD-L1) with transferred PD-L1 gene and C57 human PD-1 transgenic mouse is evaluated by taking the human PD-1 transgenic mouse as a test animal.

2. Test antibodies and compounds

The PD-1 antibody was prepared according to the method disclosed in WO2015085847, corresponding to the code H005-1, and the heavy and light chain sequences are shown in seq id NO:7 and SEQ ID NO: 8. batch number: p1512, 200 mg/bottle, 20mg/ml is prepared for standby.

Apatinib mesylate, prepared according to the method disclosed in CN101676267A, batch No.: 668160401, respectively; molecular weight: 493.58, respectively; purity: 99.60 percent.

3. Laboratory animal

Human PD-1 transgenic C57 mice, SPF, uneven body weight, sex. Purchased from Isisininovation Limited, UK.

4. Pharmaceutical formulation

PD-1 antibody (3 mg/kg): PD-1 antibody stock solution (20mg/ml) was made up to a concentration of 0.3mg/ml with PBS and an intraperitoneal injection volume of 0.2 ml/mouse.

Apatinib (200 mpk): 400mg of apatinib is dissolved in 20ml of 0.5% NaCMC to prepare 20mg/ml, and each gavage is 0.2 ml.

The vehicle was HIgG (3 mpk): dissolving in 0.5% CMC, and making into 0.3mg/ml, and intraperitoneal injection volume of 0.2 ml/mouse.

5. Test method

5.1C 57 mice were acclimatized to the laboratory for > 5 days.

5.2 tumor cell transplantation

Human PD-1 transgenic C57 mice were prepped one day in advance and inoculated subcutaneously with MC38(PD-L1) cells (5X 10) in the right flank on day 12/6⁶One), the tumor grew for 8 days to 142.17 + -13.30 mm³The animals were then randomly grouped (d0) into 8 groups (where the first four were males and the last four were females) for 4 groups.

5.3 dosage and method of administration

PD-1 antibody i.p., Q2D x 7 (once every 2 days, 7 total), apatinib, oral gavage, QD x 14 (once a day, 14 total days). Specific drug dosing regimens are shown in table 1.

5.4 transplant tumor volume and mouse body weight determination

Tumor volume and body weight were measured 2 times per week and data were recorded.

5.5 data statistics

Using Excel 2003 statistical software: the average is calculated as avg; the SD value is calculated as STDEV; SEM values were calculated as STDEV/SQRT; p-values for differences between groups were calculated as TTEST.

Tumor volume (V) was calculated as: v1/2 xl_{Long and long}×L_{Short length} ²

Relative volume (RTV) ═ V_T/V₀

Tumor inhibition rate (%) ═ C_RTV-T_RTV)/C_RTV(％)

Wherein V₀、V_TTumor volumes at the beginning and end of the experiment, respectively. C_RTV、T_RTVRelative tumor volumes of the blank control group and the experimental group at the end of the experiment, respectively.

6. Test results

The results of this experiment showed intraperitoneal injection of PD-1 antibody, Q2D × 7. The compound apatinib, oral gavage, QD x 14. The tumor inhibition rate of the PD-1 antibody (3mpk) reaches 20.40 percent and the tumor inhibition rate of the apatinib (200mpk) single-use group reaches 35.67 percent at 21 days; the tumor inhibition rate of the PD-1 antibody (3mpk) + and apatinib (200mpk) combined group reaches 63.07% (compared with the HIgG control group), and other single groups have no significant difference compared with the HIgG control group. From the experimental results, the drug effect of the combined group of PD-1 antibody (3mpk) + apatinib (200mpk) is better than that of the single group of PD-1 antibody and apatinib. The weight of each group of mice after administration is normal, and the medicament has no obvious toxic or side effect. The data are shown in Table 1 and FIGS. 1-3.

Example 2: clinical study on anti-PD-1 antibody and apatinib mesylate for treating advanced malignant tumor

Grouping standard: (1) advanced malignant tumors; (2) failure of first-line or second-line or beyond chemotherapy; (3) has measurable lesions; (4) ECOG score 0-1.

The tested drugs are: commercially available apatinib mesylate tablets; PD-1 antibody in example 1.

The administration method comprises the following steps: a total of 31 subjects were screened by 2017, month 9 and day 20, and 30 subjects were enrolled (14 of these subjects had been withdrawn from treatment and 16 subjects were included in the study).

The administration method of 001-005 cases is intravenous drip of PD-1 antibody, 3mg/kg, 2 weeks/time; apatinib, 500mg, was administered orally once a day; the 006-010-example administration method is intravenous drip of PD-1 antibody, 200mg, 2 weeks/time; apatinib, 125mg, was administered orally once a day; 011 cases 031 PD-1 antibody intravenous drip, 200mg, 2 weeks/time; apatinib was administered orally, 250mg once daily.

Clinical results: on effectiveness, 24 evaluable treatment data DCR in 6 weeks is 83.3% (20/24), 19 evaluable treatment data DCR in 12 weeks is 63.2% (12/19), 10 evaluable treatment data DCR in 18 weeks is 70% (7/10), 5 evaluable treatment data DCR in 24 weeks is 80% (4/5), 24-week treatment effect of 2 hepatocellular carcinoma subjects is PR at present, and PFS is more than 6 months. The best efficacy of 24 evaluable data is 4 PR, 15 SD, 5 PD, although ORR is only 16.7%, DCR is as high as 79%, disease control rate is high and PFS of some subjects is more than 6 months, and the specific results are shown in table 2, table 3 and table 4. In addition, the dose of apatinib in single-drug application for treating solid tumors (such as gastric cancer, gastroesophageal junction adenocarcinoma, liver cancer and the like) is usually as high as 850 mg/day (apatinib specification), and in the embodiment of the invention, the apatinib is combined with the PD-1 antibody, so that the apatinib dose is reduced to 125 mg/day, and the effectiveness and safety are better compared with that of the apatinib administration alone. On safety, 8 subjects reported 11 total Severe Adverse Events (SAEs) by 9 months and 20 days, with an SAE incidence of 26.7% (8/30). Most serious adverse reactions occur due to 7 SAE cases in 001-005 subjects (the exploring dose of the apatinib is higher and 500mg in the initial period of the test), and after the dose is adjusted in the subsequent modification scheme, the excellent tumor inhibition effect can be continuously maintained, and the adverse drug reactions caused by the high dose of the apatinib are obviously reduced; in addition, in the clinical study, it was surprisingly found that apatinib and PD-1 antibody in the combined treatment of malignant tumor hardly had hemangioma-related adverse effects compared to the use of PD-1 antibody alone, and only 1 subject had hemangioma due to intolerance of the combination of the two selected to use PD-1 antibody alone.

Example 3: phase II clinical study of anti-PD-1 antibody in combination with apatinib mesylate in treating advanced non-small cell lung cancer

Grouping standard: (1) advanced non-small cell lung cancer; (2) failure of first-line or second-line or beyond chemotherapy; (3) has measurable lesions; (4) ECOG score 0-1.

The tested drugs are: commercially available apatinib mesylate tablets; PD-1 antibody in example 1.

The administration method comprises the following steps: PD-1 antibody, once 2 weeks, by intravenous drip, 200mg each time; apatinib mesylate is administered orally once daily, 250mg or 375mg or 500mg each time.

Clinical results: by day 28, 7 months, a total of 15 subjects were screened, of which 12 had been included. A total of 12 subjects completed at least 1 cycle of dosing observation, with 10 patients (10/12) with stable disease and 1 patient with partial remission. See table 5 for details. In addition, in the process of combining the apatinib mesylate and the PD-1 antibody, the surprising discovery shows that the combination enhances the curative effect and simultaneously reduces the adverse reaction of the PD-1 antibody when being used alone. In the research, common adverse reactions are generally grade 1-II, the incidence rate of PD-1 antibodies or immune-related adverse reactions such as capillary hemangioma is only 8% (1 case), the incidence rate of hypothyroidism is only 8% (1 case), and no gastrointestinal adverse reactions such as diarrhea and skin adverse reactions such as pruritus are caused to patients; phase I clinical reports of the PD-1 antibody disclosed in the ASCO in 2017 alone for treating solid tumors show that when the PD-1 antibody is used alone for treatment, the incidence rate of capillary hemangioma is up to 79.3%, the incidence rate of hypothyroidism is 29.3% and the incidence rate of pruritus is 19.0% (Phase I study of the anti-PD-1 antibody SHR-1210 in tissues with advanced soluble tumors (2017): e15572-e 15572). The incidence of diarrhea was 10.3%. Therefore, the combination of the apatinib mesylate and the PD-1 antibody can relieve or control the tumor proliferation of the non-small cell lung cancer which fails to be treated by the chemotherapy at the late stage, reduce the adverse reaction related to the treatment of the PD-1 antibody or related to immune mediation, and improve the survival quality of patients.

TABLE 5 treatment efficacy assessment of patients enrolled

Claims (21)

1. Use of an anti-PD-1 antibody and a VEGFR inhibitor in combination for the manufacture of a medicament for the treatment of cancer, wherein the light chain variable region of the PD-1 antibody comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO 4, SEQ ID NO 5 and SEQ ID NO 6, respectively, and the heavy chain variable region of the PD-1 antibody comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO 1, SEQ ID NO 2 and SEQ ID NO 3, respectively, wherein the VEGFR inhibitor is apatinib or a pharmaceutically acceptable salt thereof.

2. The use of claim 1, wherein the PD-1 antibody is a humanized antibody.

3. The use of claim 2, wherein the humanized antibody light chain sequence is that shown as SEQ ID NO 8 or a variant thereof.

4. The use according to claim 3, wherein said variant has 0-10 amino acid changes in the light chain variable region.

5. The use according to claim 3, wherein said variant has an amino acid change of A43S in the light chain variable region.

6. The use of claim 2, wherein the humanized antibody heavy chain sequence is that shown as SEQ ID NO 7 or a variant thereof.

7. The use of claim 6, wherein the humanized antibody has 0-10 amino acid changes in the heavy chain variable region.

8. The use of claim 6, wherein the humanized antibody has an amino acid change of G44R in the heavy chain variable region.

9. The use of claim 2, wherein the humanized antibody light chain sequence is as shown in SEQ ID NO 8 and the heavy chain sequence is as shown in SEQ ID NO 7.

10. The use of claim 1, wherein the cancer is a PD-L1-expressing cancer.

11. The use of claim 1, wherein the cancer is breast cancer, lung cancer, liver cancer, stomach cancer, intestinal cancer, kidney cancer, melanoma.

12. The use of claim 1, wherein the cancer is non-small cell lung cancer, melanoma, liver cancer, or renal cancer.

13. The use of claim 1, wherein the PD-1 antibody or VEGFR inhibitor is reduced relative to a dose administered alone.

14. The use according to claim 1, wherein the pharmaceutically acceptable salt of apatinib is selected from the group consisting of the mesylate salt and the hydrochloride salt.

15. The use according to claim 1, wherein the amount of PD-1 antibody is 100-1000mg each time.

16. The use according to claim 1, wherein the amount of the PD-1 antibody is 200-600mg each time.

17. The use of claim 1, wherein the VEGFR inhibitor is present in an amount of 250-1000 mg.

18. The use of claim 1, wherein the VEGFR inhibitor is present in an amount of 400 to 850 mg.

19. The use according to any one of claims 1 to 18, wherein the PD-1 antibody and the VEGFR inhibitor are administered during the same dosing cycle.

20. The use of claim 19, wherein the PD-1 antibody and the VEGFR inhibitor are administered within 2 days or within 1 day.

21. A pharmaceutical pack containing a VEGFR inhibitor as claimed in claim 1 and a PD-1 antibody as claimed in any one of claims 1 to 9.