TWI685341B - Use of combination of apatinib and c-met inhibitor in the preparation of medicament for treating tumor - Google Patents

Abstract

The invention relates to the use of combination of apatinib and c-Met inhibitor in the preparation of medicament for treating tumor. In particular, the invention relates to the use of apatinib in combination with compound (1) or pharmaceutically acceptable salt thereof in the preparation of medicament for treating tumor. Combination therapy showed better tumor inhibition than administration alone.

Description

Application of combination of apatinib and c-Met inhibitor in the preparation of drugs for treating tumors

This application requires the priority of the Chinese patent application CN201710865846.5 with an application date of September 22, 2017. This application cites the entire text of the aforementioned Chinese patent application.

The invention relates to the use of apatinib and c-Met inhibitor in the preparation of a medicine for treating tumors.

Tumors are a common multiple disease, in which malignant tumors have seriously affected human survival time and quality of life. With the advancement of medicine, studies have found that tumor proliferation is generally regulated through multiple pathways, and a single target drug has been difficult to meet the clinical treatment of multiple relapsed and refractory tumors. Combined use of more than one anti-tumor drug with different targets and interrelationships can give full play to the advantages of each component, which can not only improve the anti-tumor activity of a single drug but also reduce drug toxicity, and is a widely accepted anti-tumor therapy.

At present, research on vascular endothelial growth factor (VEGF) and hepatocyte growth factor receptor or tyrosine protein kinase Met (c-Met) in anti-tumor therapy has been gradually deepened. Tumor neovascularization refers to the process of capillary angiogenesis and microcirculation network induced by tumor cells. A variety of signal molecules have been reported to participate in the regulation of tumor neovascularization. VEGF is the most important positive regulatory protein that has been confirmed so far. Receptor subtype VEGFR-2 binds, causing VEGFR-2 phosphorylation, which in turn activates a series of cascade reactions, causing vascular endothelial cell proliferation and inducing angiogenesis; c-Met kinase is a protein tyrosine kinase (PTK) An important member, c-Met kinase is expressed in normal cells and tumor cells, and its continuous activation is an important cause of tissue cancer or hyperproliferation of cancer cells. c-Met abnormalities are found in many types of tumors, such as liver cancer, non-small Cell lung cancer, gastric cancer, colon cancer, etc. Many research findings indicate that simultaneous inhibition of c-Met and VEGFRs small molecule inhibitors may produce broader and more effective anti-tumor efficacy ([J]. Molecular cancer therapeutics, 2013, 12(6): 913-924), of which Lynn Reported that the administration of anti-VEGF antibody bevacizumab can effectively prevent the metastasis and invasion of c-Met-dependent tumors ([J]. Cancer discovery, 2012, 2(3): 211-213).

WO2012044577 discloses a c-Met/VEGF dual-target compound and a composition containing one or more c-Met inhibitors and apatinib for the treatment of bone cancer and prostate cancer. WO2017127495 discloses a combination of a long-acting death promoter and a kinase inhibitor for the treatment of sensitive cancer, wherein the kinase inhibitor is selected from VEGFR inhibitors and c-Met inhibitors including apatinib. Yongxin Ren et al. reported that the c-Met inhibitor Savolitinib combined with the VEGFR inhibitor Fruquintinib inhibited tumor growth in clear cell renal cell carcinoma xenograft models. The results showed that the combination therapy showed better tumors compared to single administration The inhibitory effect has implications for the clinical treatment of renal cell carcinoma ([J]. Molecular Targets and Cancer Therapeutics; November 5-9, 2015; Boston, MA). Yakes et al. reported that in vivo and in vitro studies of the VEGFR2/MET dual-target inhibitor Cabozantinib have shown to simultaneously inhibit metastasis, angiogenesis and tumor growth ([J]. Molecular cancer therapeutics, 2011, 10(12): 2298-2308). Although a variety of VEGFR inhibitors and c-Met inhibitors have been used in combination to treat tumors, the high failure rate after entering clinical trials can not be ignored. The only c-Met inhibitors currently entering phase III clinical trials are AstraZeneca’s. savolitinib and Angion's BB-3, but according to the single-arm study of savolitinib published in 2016 for the treatment of advanced papillary renal cell carcinoma, the objective response rate of patients in the MET-driven group is only 18%, which is not good The reaction rate is relatively high, and one patient died of hepatic encephalopathy due to savolitinib ([J]. Journal of Clinical Oncology, 2017: JCO. 2017.72. 2967); therefore, select the appropriate combination of VEGFR inhibitor and c-Met inhibitor The treatment of relapsed refractory tumors is still a difficult problem to be solved in clinical research.

The present invention provides a new VEGFR inhibitor and a new c-Met inhibitor for the preparation of tumor drugs, wherein the VEGFR inhibitor is selected from apatinib or a pharmaceutically acceptable salt thereof, and its structure is as follows:

Apatinib was approved as a VEGFR2 inhibitor in China in 2014 for the treatment of gastric cancer. Patent CN1281590C discloses its preparation method; c-Met inhibitor is selected from compound (1) or its pharmaceutically acceptable salt, and its structure is as follows As shown:

Patent WO2014180182 discloses the preparation method of compound (1), the use in the preparation of drugs for treating cancer, and the use of simultaneously regulating the catalytic activity of VEGFR and c-Met tyrosine kinase.

The invention relates to the use of apatinib or a pharmaceutically acceptable salt thereof in combination with a c-Met inhibitor in the preparation of a medicament for treating tumors.

。In a preferred embodiment of the present invention, the c-Met inhibitor is selected from compound (1) or a pharmaceutically acceptable salt thereof,

.

In another preferred embodiment of the present invention, the c-Met inhibitor may also be selected from SPH-3348, SAIT-301, HOPE-777, ABBV-399, SAB-Y14, Sym-015, sitravatinib, JNJ- 61186372, NOV-1105, crizotinib, ARGX-111, cabozantinib, emibetuzumab, ABT-700, MM-131, ficlatuzumab, onartuzumab, CBA-0710, FS-101, KTN-0073, HH-SCC-244, capmatinib, savolitinib, TAS-115, JNJ-38877618, OMO-1, HS-10241, merestinib, tepotinib, MP-0250, altiratinib, BB-3, SIMM-559, Eos-004, doxorubicin, ningetinib, RXDX-106, PLB-1001 AMC-303, NDX-1017, glesatinib, OMO-2, ASLAN-002, NK4, bispecific-centyrins, SAR-125844, CM-118, ABN-401, REG-101, BPI-9016M, ChronSeal, AL-2846, REG-103, HQP-8361, PRS-110, NX-125, QBH-196, KRC-00831, LS-177, PIG-KM, APG-8361, bicyclol valine ester, Debio-1144, X-379, SL- 188, SL-186, SL-012, SCR-1515, LMV-12, preferably from Sym-015, sitravatinib, emibetuzumab, ficlatuzumab, capmatinib, savolitinib, crizotinib, TAS-115, merestinib, tepotinib, MP-0250, BB- 3. glesatinib, glesatinib glycolate, ASLAN-002, SAR-125844, APG-8361.

In a preferred embodiment of the present invention, the tumor is selected from malignant tumor and benign tumor; the malignant tumor is selected from malignant epithelial tumor, sarcoma, myeloma, leukemia, lymphoma, melanoma, head and neck tumor, brain Tumor, mixed tumor, childhood malignant tumor; the malignant epithelial tumor is selected from lung cancer, breast cancer, liver cancer, pancreatic cancer, colorectal cancer, stomach cancer, esophageal cancer, small intestine cancer, cardia cancer, endometrial cancer, ovarian cancer, fallopian tube Cancer, vulvar cancer, testicular cancer, prostate cancer, penile cancer, kidney cancer, bladder cancer, anal cancer, gallbladder cancer, cholangiocarcinoma, teratoma, heart tumor; the head and neck tumors are selected from nasopharyngeal cancer, larynx cancer, Thyroid cancer, tongue cancer, oral cancer; the sarcoma is selected from Askin tumor, chondrosarcoma, Ewing's sarcoma, malignant hemangioendothelioma, malignant schwannoma, osteosarcoma, soft tissue sarcoma; the myeloma is selected from isolated myeloma , Multiple myeloma, diffuse myeloma, leukemia myeloma, extramedullary myeloma; the leukemia is selected from acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myelogenous leukemia, hairy cell Leukemia, T-cell lymphocytic leukemia, large-particle lymphocytic leukemia, adult T-cell leukemia; the lymphoma is selected from non-Hodgkin's lymphoma, Hodgkin's lymphoma; the brain tumor is selected from neuroepithelial tissue tumors , Cranial nerve and spinal cord nerve tumors, meningeal tissue tumors; the childhood malignant tumors are selected from the group consisting of nephroblastoma, neuroblastoma, retinoblastoma, and germ cell tumor in children.

In another preferred embodiment of the present invention, the lung cancer is selected from the group consisting of non-small cell lung cancer and small cell lung cancer, preferably non-small cell lung cancer; the breast cancer is selected from the breast cancer selected from hormone receptors (HR) Positive breast cancer, Human epidermal growth factor receptor-2 (HER2) positive breast cancer, Sanyin breast cancer; The kidney cancer is selected from clear renal cell carcinoma, mastoid renal cell carcinoma, refractory cell renal cell carcinoma, pool Tube carcinoma; the neuroepithelial tissue tumor is selected from preferably astrocytoma, poorly differentiated astrocytoma, glioblastoma; the liver cancer is selected from primary liver cancer, secondary liver cancer, the primary liver cancer It is selected from hepatocellular carcinoma, cholangiocarcinoma and mixed liver cancer; the colorectal cancer is selected from colon cancer and rectal cancer.

In the above preferred embodiment of the present invention, the tumor is selected from VEFGR hyperphenotype and/or c-Met moderately express tumor, VEFGR hyperphenotype and/or c-Met hyperphenotype tumor.

In the above preferred embodiment of the present invention, the tumor is selected from mid-advanced tumors, relapsed refractory tumors, failed first-line chemotherapy drug treatment and/or relapsed tumors, failed radiotherapy and/or relapsed tumors, and targeted drug treatments failed And/or one or more of the recurrent tumors, the chemotherapeutic agent is selected from alkylating agents, platinum complexing agents, metabolic antagonists, plant alkaloids (such as vinblastine, cephaloside), hormone anticancer agents, proteasome One or more of inhibitors, aromatase inhibitors, and immunomodulators; in another preferred embodiment, the chemotherapeutic drugs include but are not limited to cyclophosphamide, ifosfamide, melphalan, and white Xiaoan, nimustine, ramustine, dacarbazine, temozolomide, nitrogen mustard, dibromomannitol, cisplatin, carboplatin, oxaliplatin, nedaplatin, methotrexate, 5- Fluorouracil, tegafur, gemcitabine, capecitabine, fulvestrant, pemetrexed, anthracycline antibiotics, mitomycin, bleomycin, actinomycin, vinblastine, camptothecin , Taxols, vincristine, vinblastine, vindesine, etoposide, docetaxel, paclitaxel, albumin-bound paclitaxel, paclitaxel liposomes, irinotecan, vinorelbine, mitoxantrone, Vinflunine, topotecan, leuprolide, goserelin, dutasteride, fulvestrant, dexamethasone, tamoxifen, bortezomib, lenalidomide, etc. Tan, letrozole, anastrozole.

In the above preferred embodiment of the present invention, the targeted drug is selected from EGFR inhibitors, ALK inhibitors, PARP inhibitors, CDK inhibitors, MEK inhibitors, VEGF antibodies and VEGFR inhibitors, mTOR inhibitors One or more treatments. These targeted drugs are well known in the art, for example, EGFR inhibitors can be selected from gefitinib, erlotinib, icotinib, and afatinib, cetuximab, trastuzumab One or more of them; ALK inhibitors can be selected from crizotinib, and ceritinib, axitinib, Brigatinib; VEGF antibodies are selected from bevacizumab; VEGFR inhibitors are selected from sunitinib, One or more of apatinib and famitinib. The tumor immunotherapy is selected from one or more of nivolumab, pembrolizumab, atezolizumab and SHR-1210.

In the above preferred embodiment of the present invention, the weight ratio of the apatinib or its pharmaceutically acceptable salt to the compound (1) or its pharmaceutically acceptable salt is selected from 0.01-100:1, preferably from 1:12 , 1:10, 1:9, 1:8, 2:15, 1:7, 1:6, 1:5, 5:24, 2:9, 1:4, 4:15, 5:18, 2 :7, 3:10, 5:16, 1:3, 5:14, 3:8, 2:5, 5:12, 3:7, 4:9, 1:2, 8:15, 5:9 , 4:7, 7:12, 3:5, 5:8, 2:3, 7:10, 5:7, 3:4, 7:9, 4:5, 5:6, 6:7, 7 :8, 8:9, 9:10, 14:15, 15:16, 1:1, 6:5, 5:4, 4:3, 3:2, 8:5, 2:1, 5:2 , 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, more preferably from 1:1, 1:6, 1:5, 1: 4, 1:3, 2:5, 5:12, 1:2, 3:5, 5:8, 2:3, 3:4, 4:5, 5:6, 6:5, 5:4, 4:3, 3:2, 8:5, 2:1, 5:2, 3:1, 4:1, 5:1.

In the above preferred embodiment of the present invention, the dose of apatinib or a pharmaceutically acceptable salt thereof is selected from 100-1000 mg, preferably from 200 mg, 250 mg, 300 mg, 350 mg, 375 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600mg, 700mg, 750mg, 800mg, 850mg, 900mg, 1000mg, more preferably from 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 600mg, 700mg, 750mg; compound (1) or a pharmaceutically acceptable salt dose selected from 10- 1200mg, preferably from 20mg, 50mg, 55mg, 60mg, 75mg, 100mg, 110mg, 200mg, 220mg, 250mg, 260mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 700mg, 750mg, 800mg, 900mg, 1000mg, More preferred are 100 mg, 110 mg, 200 mg, 220 mg, 250 mg, 260 mg, 300 mg, 350 mg, 400 mg, 450 mg, and 500 mg.

In the above preferred embodiment of the present invention, the apatinib or its pharmaceutically acceptable salt is selected from mesylate, hydrochloride, preferably from mesylate; the compound (1) or its The pharmaceutically acceptable salt is selected from hydrochloride, methanesulfonate, maleate, malate, benzenesulfonate, preferably from mesylate.

The term "combination" of the present invention refers to a mode of administration, which refers to the administration of at least one dose of apatinib and at least one dose of compound (1) or a pharmaceutically acceptable salt thereof within a certain period of time, in which both substances are shown Pharmacological effects. The said time period is one administration cycle, preferably within 24 hours, more preferably within 12 hours. Apatinib and compound (1) or a pharmaceutically acceptable salt thereof can be administered simultaneously or sequentially. This period includes treatments in which apatinib and compound (1) or a pharmaceutically acceptable salt thereof are administered through the same route of administration or different routes of administration. The combined administration method of the present invention is selected from simultaneous administration, independently formulated and co-administered, or independently formulated and sequentially administered.

The combined administration route of the present invention is selected from oral administration, parenteral administration, and transdermal administration. The parenteral administration includes but is not limited to intravenous injection, subcutaneous injection, and intramuscular injection.

The present invention further relates to the use of apatinib or a pharmaceutically acceptable salt thereof in combination with compound (1) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating diabetes and/or diabetic complications, wherein apatinib or The administration frequency of the pharmaceutically acceptable salt 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, preferably once a day; Compound (1) or its The administration frequency of the pharmaceutical salt 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, preferably once a day or twice a day.

The present invention also relates to a pharmaceutical composition containing apatinib or a pharmaceutically acceptable salt thereof, compound (1) or a pharmaceutically acceptable salt thereof, optionally including one or more pharmaceutically acceptable carriers, excipients and/or dilutions Agent. The pharmaceutical composition can be made into any pharmaceutically acceptable dosage form. For example, a pharmaceutical preparation containing apatinib or a pharmaceutically acceptable salt thereof, compound (1) or a pharmaceutically acceptable salt thereof, can be formulated as tablets, capsules, pills, granules, solutions, suspensions, syrups Agent, injection (including injection, sterile powder for injection and concentrated solution for injection), suppository, inhalation or spray.

The pharmaceutical composition containing apatinib or a pharmaceutically acceptable salt thereof, compound (1) or a pharmaceutically acceptable salt thereof according to the present invention can be administered alone or in combination with one or more therapeutic agents.

The following examples are used to further describe the present invention, but these examples do not limit the scope of the present invention.

Example 1

1. The tested drug

Drug source: commercially available apatinib mesylate; compound (1) mesylate salt was prepared according to the method described in patent WO2016015653.

Preparation method: Apatinib mesylate was prepared with 0.5% carboxymethyl cellulose solution; Compound (1) mesylate was prepared with 0.5% carboxymethyl cellulose mixed with 0.1% Tween 80 solution.

2. Source of laboratory animals and tissues

BALB/c nude mice, 6-8 weeks old, male, were purchased from Beijing Viton Lihua Experimental Animal Technology Co., Ltd. Laboratory animal use license number: SCXK (Shanghai) 2015-0022; animal certificate number: 11400700166108 feeding environment: SPF level.

LIV#061 tumor tissue originated from a 51-year-old female patient. Histopathological diagnosis was hepatocellular carcinoma (HCC, T1N0M0). The tumor tissue was a KDR Q472H site mutation with moderate c-MET performance.

3. Experimental steps

LIV#061, a patient's liver cancer tumor tissue, was cut into small pieces of 15-30 mm ³ in 1640 culture medium and inoculated subcutaneously in nude mice. After the tumors grew to 600-700 mm ³ , they were passaged in nude mice. When the sixth-generation (P6) tumors reached 600-700 mm ³ , the tumors were cut into 16-30 mm ³ pieces in 1640 culture medium for subcutaneous inoculation in experimental nude mice. After the tumor grows to 150-250 mm ³ , the animals are randomly divided (D0) and administered. See Table 1 for the dosage and schedule. Measure the tumor volume 2-3 times a week, weigh the rats, and record the data. The calculation formula of tumor volume (V) is: V=1/2×a×b ² , where a and b denote length and width, respectively.

T/C(%)=(T-T0)/(C-C0)×100%, where T and C are the tumor volume at the end of the experiment; T0 and C0 are the tumor volume at the beginning of the experiment.

4. Results

D0：第一次給藥時間；QD：每日給藥一次；PO：經口給藥；P值指與溶劑相比；採用單因子變異數分析（one way Anova）。實驗開始時小鼠數目：n=6。The results are shown in Table 1. Apatinib mesylate alone (75 mg/kg) can inhibit the growth of human liver cancer LIV#061 subcutaneously transplanted tumor in nude mice. On the 21st day of administration, the tumor suppression rate was 62.3%. However, compound (1) mesylate alone (30 mg/kg) did not significantly inhibit the growth of human liver cancer subcutaneously transplanted tumor in nude mice. On the 21st day of administration, the tumor suppression rate was 14.4%. Compound (1) mesylate (30 mg/kg, once daily for 21 days) and apatinib mesylate (75 mg/kg, once daily for 21 days) The anti-tumor effect is significant, and the inhibition rate is significantly different from the two alone. The tumor inhibition rate is 85.7%. None of the tumor-bearing mice showed significant weight loss, indicating that the tumor-bearing mice were well tolerated by the drug alone or in combination. Table 1. Efficacy of apatinib mesylate combined with compound (1) mesylate on human liver cancer LIV#061 subcutaneously transplanted tumor in nude mice

D0: time of first administration; QD: once-daily administration; PO: oral administration; P value refers to comparison with solvent; one-way variance analysis (one way Anova) was used. Number of mice at the beginning of the experiment: n=6.

Example 2

Phase I clinical study on the tolerability, safety, pharmacokinetics and efficacy of compound (1) mesylate combined with apatinib mesylate in patients with advanced solid tumors.

1. The tested drug

Drug source: commercially available apatinib mesylate; compound (1) mesylate salt was prepared according to the method described in patent WO2016015653.

2. Inclusion criteria: (1) 18-75 years old (both ends included), both male and female; (2) patients with advanced solid tumors diagnosed by pathology who are not effective or have no standard effective treatment plan; (3 ) No factors affecting oral medications (such as inability to swallow, chronic diarrhea, and intestinal obstruction); (4) ECOG PS score of 0 to 1; (5) The expected survival period is not less than 3 months.

3. Dosing regimen

Compound (1) methanesulfonate: tablet; specification 100 mg/tablet; oral, dose 200 mg/day; 2 times a day; apatinib mesylate tablet: specification 250 mg/tablet; oral, each Once a day, 500 mg/day; Apatinib mesylate tablets: 375 mg/tablet; Oral, once a day.

4. Results

Up to now: compound (1) mesylate (200mg) combined with apatinib (500mg) has been enrolled in 3 subjects, esophageal cancer (1 case), rectal cancer (1 case) laryngeal cancer (1 case) The best efficacy evaluation is SD. One of the patients received 4 cycles of study drug treatment, and all the subjects in this dose group have been out of PD. Compound (1) mesylate (200 mg) combined with apatinib (375 mg) has been enrolled in 3 subjects. Breast cancer (1 case) and rectal cancer (2 cases). The best efficacy evaluations were all SD.

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Figure 1 shows the efficacy of combining apatinib mesylate and compound (1) mesylate on subcutaneously transplanted tumors in tumor-bearing nude mice with human liver cancer PDX model LIV#061.

Figure 2 shows the effect of the combination of apatinib mesylate and compound (1) mesylate on the body weight of tumor-bearing nude mice in the human liver cancer PDX model LIV#061.

Claims (16)

Use of a pharmaceutical composition comprising apatinib or a pharmaceutically acceptable salt thereof and a c-Met inhibitor selected from Compound (1) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating tumors, wherein the apatinib The weight ratio of nicotine or its pharmaceutically acceptable salt to compound (1) or its pharmaceutically acceptable salt is selected from 1-5:1, the tumor is selected from liver cancer, esophageal cancer, laryngeal cancer, colorectal cancer,

The use according to claim 1, wherein the liver cancer is selected from primary liver cancer and secondary liver cancer, and the primary liver cancer is selected from hepatocellular carcinoma, cholangiocarcinoma, and mixed liver cancer; the colorectal cancer It is selected from colon cancer and rectal cancer. The use according to claim 1 or 2, wherein the tumor is selected from VEFGR hyperphenotype and/or c-Met hyperphenotype tumors, VEFGR hyperphenotype and/or c-Met moderate phenotype tumors. The use according to claim 1 or 2, wherein the tumor is selected from mid-advanced tumors, relapsed and refractory tumors, failed first-line chemotherapy drug treatment and/or relapsed tumors, failed radiotherapy and/or relapsed tumors, targeted Failed drug treatment and/or relapsed tumor; the chemotherapy drug is selected from alkylating agents, platinum complexing agents, metabolic antagonists, plant alkaloids, hormonal anticancer agents, proteasome inhibitors, aromatase inhibitors, immunomodulators One or more of; the targeted drug is selected from EGFR inhibitors, ALK inhibitors, PARP inhibitors, CDK inhibitors, MEK inhibitors, VEGF antibodies, VEGFR inhibitors, BTK inhibitors, mTOR inhibitors. The use according to claim 1 or 2, wherein the weight ratio of the apatinib or its pharmaceutically acceptable salt to the compound (1) or its pharmaceutically acceptable salt is selected from 1:1, 6:5, 5: 4, 4:3, 3:2, 8:5, 2:1, 5:2, 3:1, 4:1, 5:1. The use according to claim 1 or 2, wherein the dose of apatinib or a pharmaceutically acceptable salt thereof is selected from 100-1000 mg. The use according to claim 1 or 2, wherein the dose of apatinib or a pharmaceutically acceptable salt thereof is selected from 200 mg, 250 mg, 300 mg, 350 mg, 375 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 700 mg, 750 mg , 800mg, 850mg, 900mg, 1000mg. The use according to claim 1 or 2, wherein the dose of apatinib or a pharmaceutically acceptable salt thereof is selected from 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 600 mg, 700 mg, and 750 mg. The use according to claim 1 or 2, wherein the dosage of the compound (1) or a pharmaceutically acceptable salt thereof is selected from 10-1200 mg. The use according to claim 1 or 2, wherein the dose of the compound (1) or a pharmaceutically acceptable salt thereof is selected from 20 mg, 50 mg, 55 mg, 60 mg, 75 mg, 100 mg, 110 mg, 200 mg, 220 mg, 250 mg, 260 mg, and 300 mg , 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 700mg, 750mg, 800mg, 900mg, 1000mg. The use according to claim 1 or 2, wherein the dose of the compound (1) or a pharmaceutically acceptable salt thereof is selected from 100 mg, 110 mg, 200 mg, 220 mg, 250 mg, 260 mg, 300 mg, 350 mg, 400 mg, 450 mg, and 500 mg. The use according to claim 1 or 2, wherein the apatinib or a pharmaceutically acceptable salt thereof is selected from mesylate and hydrochloride. The use according to claim 1 or 2, wherein the apatinib or a pharmaceutically acceptable salt thereof is apatinib mesylate. The use according to claim 1 or 2, wherein the compound (1) or a pharmaceutically acceptable salt thereof is selected from hydrochloride, methanesulfonate, maleate, malate, and benzenesulfonate. The use according to claim 1 or 2, wherein the compound (1) or a pharmaceutically acceptable salt thereof is mesylate. A pharmaceutical composition comprising apatinib or a pharmaceutically acceptable salt thereof according to any one of claims 1-15 and compound (1) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients Agent, diluent or carrier.

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