WO2020177678A1 - 多靶点酪氨酸激酶抑制剂与egfr抑制剂联合在制备治疗肿瘤的药物中的用途 - Google Patents

多靶点酪氨酸激酶抑制剂与egfr抑制剂联合在制备治疗肿瘤的药物中的用途 Download PDF

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WO2020177678A1
WO2020177678A1 PCT/CN2020/077520 CN2020077520W WO2020177678A1 WO 2020177678 A1 WO2020177678 A1 WO 2020177678A1 CN 2020077520 W CN2020077520 W CN 2020077520W WO 2020177678 A1 WO2020177678 A1 WO 2020177678A1
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tumor
cancer
egfr
day
tyrosine kinase
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French (fr)
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任文明
唐蜜
杨昌永
廖成
张连山
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Jiangsu Hengrui Medicine Co Ltd
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Jiangsu Hengrui Medicine Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the application relates to the use of a combination of a multi-target tyrosine kinase inhibitor and a human epidermal growth factor receptor inhibitor (EGFRi) in the preparation of drugs for treating tumors, and belongs to the field of pharmacy.
  • EGFRi human epidermal growth factor receptor inhibitor
  • lung cancer has become the leading cause of cancer deaths. In China, lung cancer ranks first in terms of cancer incidence and mortality. Although several generations of newer generations of cytotoxic drugs and targeted therapies have been introduced in the past 20 years, patients with advanced lung cancer, especially those without known driver mutation genes, still have a poor survival prognosis, and advanced or metastatic lung cancer is still a kind of There are a large number of fatal diseases with unmet medical needs.
  • Non-small cell lung cancer accounts for about 85% of all lung cancers, and about 75% of NSCLC patients are already in the advanced stage when they are discovered, and the 5-year survival rate is very low. For patients with advanced or metastatic NSCLC, there is still a great clinical need to choose an appropriate systemic treatment.
  • NSCLC can be divided into squamous cell carcinoma and non-squamous cell carcinoma.
  • Non-squamous cell carcinomas include adenocarcinoma, large cell carcinoma and other subtypes of cell carcinoma. Patients with non-squamous cell carcinoma were further classified according to the presence or absence of driver mutation genes (EGFR mutation or ALK gene rearrangement).
  • EGFR Epidermal Growth Factor Receptor
  • EGF epidermal growth factor
  • EGFR can form homodimers on the cell membrane, or form heterodimers with other receptors in the family (such as erbB2, erbB3, or erbB4).
  • the formation of these dimers can cause the phosphorylation of key tyrosine residues in EGFR cells, thereby activating multiple downstream signaling pathways in the cells. These intracellular signaling pathways play an important role in cell proliferation, survival and anti-apoptosis.
  • the dysregulation of EGFR signaling pathways can promote malignant transformation of cells, and play an important role in tumor cell proliferation, invasion, metastasis, and angiogenesis.
  • Overexpression of EGFR has been reported in many human malignant diseases, including bladder cancer, brain tumors, head and neck cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, colon cancer, prostate cancer, and kidney cancer. In many cases, the overexpression of EGFR is related to the poor prognosis of patients.
  • the anti-tumor mechanism of TKIs may be achieved through the following ways: inhibiting the damage and repair of tumor cells, blocking cell division in G1 phase, inducing and maintaining cell apoptosis, and anti-angiogenesis.
  • Overexpression of EGFR often indicates poor prognosis, fast metastasis, resistance to chemotherapy drugs, hormone resistance, and shorter survival time.
  • the FDA has approved the marketing of a variety of multi-target TKIs, such as sorafenib, vandetanib and Sunitinib (Sutent, SU-11248). Among them, Sunitinib was approved for marketing in January 2006 to treat GIST. And advanced kidney cancer.
  • WO2007085188 discloses a compound similar to Sunitinib, as shown in the following formula (I), which may be better applied to the treatment of the above-mentioned tumors.
  • the chemical name of the compound is 5-(2-diethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indole-3-ylidene-methyl)- 3-Methyl-1,5,6,7-tetrahydro-pyrrole [3,2-c]pyridin-4-one, which is known to inhibit tumor proliferation and angiogenesis, and can selectively inhibit vascular endothelial growth factor
  • VEGF vascular endothelial growth factor
  • the kinase activity of (VEGF) receptors can be used clinically for the treatment of renal cancer, gastrointestinal stromal tumors, colorectal cancer and pancreatic neuroendocrine tumors.
  • WO2016054987A discloses a 4-substituted-(2-(N-(5-allylamido)phenyl)amino)pyrimidine derivative represented by the structure of formula (II), which has the ability to inhibit L858R EGFR mutant, T790M The activity of EGFR mutants and exon 19 deletion activation mutants can be used to treat diseases mediated by EGFR mutant activity alone or in part.
  • WO2017161937 discloses the mesylate of the EGFR inhibitor represented by formula (II),
  • WO2006120557A discloses a method for treating patients with non-small cell lung cancer, including giving With the patient’s daily 25-50 mg of sunitinib malate and about 250 mg of gefitinib or 150 mg of erlotinib per day, but there is no specific experimental data in the instructions of the application, so the combined effect is impossible Know.
  • the application provides a use of a combination of a multi-target tyrosine kinase inhibitor and an EGFR inhibitor in the preparation of drugs for treating tumors.
  • the tumor described in this application can be selected from breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor, esophageal cancer, stomach cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, skin cancer, and glia Tumor, neuroblastoma, sarcoma, liposarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck tumor, multiple myeloma, malignant lymphoma, polycythemia vera, Leukemia, thyroid tumor, ureteral tumor, bladder tumor, gallbladder cancer, cholangiocarcinoma or choriocarcinoma, preferably non-small cell lung cancer.
  • the use of the multi-target tyrosine kinase inhibitor and EGFR inhibitor described in the present application in the preparation of drugs for preventing or treating tumors and the tumors are preferably tumors with EGFR mutations.
  • the EGFR-mutant tumor described in the present application is preferably non-small cell lung cancer, and the preferred EGFR mutant is selected from L858R EGFR mutant and/or T790M EGFR mutant and/or EGFR exon 20 insertion and/or EGFR exon Sub 19 is missing.
  • the non-small cell lung cancer described in this application is selected from squamous cell carcinoma and non-squamous cell carcinoma, preferably non-phosphorous cell carcinoma, wherein the non-phosphorous cell carcinoma can be adenocarcinoma, large cell carcinoma And other subtypes of cell carcinoma.
  • the multi-target tyrosine kinase inhibitor has an inhibitory effect on VEGFR kinase.
  • the multi-target tyrosine kinase inhibitors described in this application can be selected from sunitinib, axitinib, sorafenib, nintedanib, cabozantinib S-malate, lenvatinib mesylate, regorafenib, ponatinib, MP-0250, pazopanib, anlotinib, ningetinib, rebastinib, PF -06753512, tivozanib, telatinib, AL-2846, vorolanib, BMS-817378, lucitanib hydrochloride, ODM-203, sitravatinib, fenretinide, surufatinib, vandetanib, ENMD-2076, AMC-303, brivanib alaninate, cediranib, BI-836880, dovitinib , Muparfostat sodium,
  • the EGFR inhibitor described in this application can be selected from osimertinib, gefitinib, erlotinib, olmutinib, icotinib, pyrotinib, brigatinib, dacomitinib, afatinib, neratinib, lapatinib, ABT-414, varlitinib, HLX-07, theliatinib, epitinib succinate, S- 222611, poziotinib, AST-2818, GNS-1480, mavelertinib, AP-32788, AZD-3759, clawinib, Sym-013, allitinib tosylate, tarloxotinib bromide, poziotinib, CK-101, QL-1203, JNJ-61186372, SKLB- 1028, TAS-121, Hemay-020, Hemay-02
  • the pharmaceutically acceptable salt of the drug described in the application can be hydrochloride, phosphate, hydrogen phosphate, sulfate, hydrogen sulfate, sulfite, acetate, oxalate, malonate, and valerate. , Glutamate, oleate, palmitate, stearate, laurate, borate, p-toluenesulfonate, methanesulfonate, isethionate, maleate, Malate, tartrate, benzoate, pamoate, salicylate, vanillate, mandelate, succinate, gluconate, lactobionate or lauryl sulfonate, etc.
  • the pharmaceutically acceptable salt of the compound represented by formula (I) is malate.
  • the pharmaceutically acceptable salt of the compound represented by formula (II) is methanesulfonate.
  • the pharmaceutically acceptable salt of the compound represented by formula (I) is malate, and the pharmaceutically acceptable salt of the compound represented by formula (II) is methanesulfonate.
  • the dose of the multi-target tyrosine kinase inhibitor is selected from 0.1-1000 mg, and the frequency of administration can be once a day, twice a day or three times a day; the dose of EGFR inhibitor The range is selected from 1-1000 mg, and the frequency of administration can be once a day, twice a day or three times a day.
  • the dose of the multi-target tyrosine kinase inhibitor is selected from 0.1-500 mg, and the frequency of administration can be once a day, twice a day or three times a day, preferably once a day
  • the dose range of EGFR inhibitors is selected from 1-500mg, specifically 1mg, 2.5mg, 5mg, 7.5mg, 10mg, 12.5mg, 15mg, 17.5mg, 20mg, 22.5mg, 25mg, 27.5mg, 30mg, 32.5mg , 35mg, 37.5mg, 40mg, 42.5mg, 45mg, 47.5mg, 50mg, 52.5mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 120mg, 130mg, 140mg , 150mg, 160mg, 170m
  • the dose of the multi-target tyrosine kinase inhibitor is selected from 0.1-100 mg, specifically 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8mg, 0.9mg, 1.0mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16mg, 17mg, 18mg, 19mg, 20mg, 21mg , 22mg, 23mg, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg, 30mg, 31mg, 32mg, 33mg, 34mg, 35mg, 36mg, 37mg, 38mg, 39mg, 40mg, 41mg, 42mg, 43mg, 44mg, 45m
  • the dose of the multi-target tyrosine kinase inhibitor is selected from 1-25 mg, specifically 15 mg, 20 mg, or 25 mg, and the frequency of administration may be once a day, twice a day, or a day Three times, preferably once a day, the dose range of the EGFR inhibitor is selected from 1-500 mg, specifically 55 mg, 110 mg, 220 mg or 260 mg, preferably once a day.
  • the dose of the multi-target tyrosine kinase inhibitor can be 15mg, 20mg or 25mg, the frequency of administration is once a day, and the dose of the EGFR inhibitor can be 55mg, 110mg, 220mg or 260mg. The frequency of administration is once a day.
  • the dose of the multi-target tyrosine kinase inhibitor is 15 mg, and the frequency of administration is once a day.
  • the dose of EGFR inhibitor can be 55 mg, 110 mg, 220 mg or 260 mg, and the frequency of administration is Once a day.
  • the dose of the multi-target tyrosine kinase inhibitor is 20 mg, and the frequency of administration is once a day.
  • the dose of EGFR inhibitor can be 55 mg, 110 mg, 220 mg or 260 mg, and the frequency of administration is one. Once a day.
  • the dose of the multi-target tyrosine kinase inhibitor is 25 mg, and the frequency of administration is once a day.
  • the dose of EGFR inhibitor can be 55 mg, 110 mg, 220 mg or 260 mg, and the frequency of administration is one. Once a day.
  • the dose of the multi-target tyrosine kinase inhibitor can be 15 mg, 20 mg or 25 mg, the frequency of administration is once a day, the dose of EGFR inhibitor is 55 mg, and the frequency of administration is once a day .
  • the dose of the multi-target tyrosine kinase inhibitor can be 15 mg, 20 mg or 25 mg, the frequency of administration is once a day, the dose of EGFR inhibitor is 110 mg, and the frequency of administration is once a day .
  • the dose of the multi-target tyrosine kinase inhibitor can be 15 mg, 20 mg or 25 mg, the frequency of administration is once a day, the dose of EGFR inhibitor is 220 mg, and the frequency of administration is once a day .
  • the dose of the multi-target tyrosine kinase inhibitor can be 15 mg, 20 mg or 25 mg, the frequency of administration is once a day, the dose of EGFR inhibitor is 260 mg, and the frequency of administration is once a day .
  • the multi-target tyrosine kinase inhibitor is administered according to body weight, the dosage is selected from 0.1 to 10.0 mg/kg, and the frequency of administration may be once a day or twice a day. Once or three times a day; the dose range of EGFR inhibitor is selected from 1-1000 mg, and the frequency of administration can be once a day, twice a day or three times a day.
  • the dose of the multi-target tyrosine kinase inhibitor may be 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4 mg/kg, 0.5 mg/kg, 0.6mg/kg, 0.7mg/kg, 0.8mg/kg, 0.9mg/kg, 1.0mg/kg, 1.2mg/kg, 1.4mg/kg, 1.6mg/kg, 1.8mg/kg, 2.0mg/kg, 2.2mg/kg, 2.4mg/kg, 2.6mg/kg, 2.8mg/kg, 3.0mg/kg, 3.2mg/kg, 3.4mg/kg, 3.6mg/kg, 3.8mg/kg, 4.0mg/kg, 4.2mg/kg, 4.4mg/kg, 4.6mg/kg, 4.8mg/kg, 5.0mg/kg, 5.2mg/kg, 5.4mg/kg, 5.6mg/kg
  • the route of administration of the combination described in the present application can be selected from oral administration, parenteral administration, and transdermal administration.
  • the parenteral administration includes but is not limited to intravenous injection, subcutaneous injection, intramuscular injection, preferably oral Administration.
  • the combination optionally further includes other components, and the other components include but are not limited to other drugs for treating tumors.
  • This application also provides a method for treating tumors, which comprises administering to a patient an effective amount of the above-mentioned multi-target tyrosine kinase inhibitor and an effective amount of the above-mentioned EGFR inhibitor.
  • the application also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned multi-target tyrosine kinase inhibitor and EGFR inhibitor, and one or more pharmaceutical carriers, excipients, and diluents.
  • the pharmaceutical composition can be made into any pharmaceutically acceptable dosage form. For example, it can be formulated as tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injections, sterile powders for injections and concentrated solutions for injections), suppositories, inhalants or sprays Agent.
  • composition comprising a multi-target tyrosine kinase inhibitor and an EGFR inhibitor described in this application can be administered alone or in combination with one or more therapeutic agents.
  • the application also provides a pharmaceutical kit, wherein the pharmaceutical composition comprising the multi-target tyrosine kinase inhibitor and the EGFR inhibitor described in the application is packaged.
  • the combined administration of a multi-target tyrosine kinase inhibitor and an EGFR inhibitor improves the therapeutic effect.
  • the “combination” mentioned in this application is a mode of administration, which refers to the administration of at least one dose of multi-target tyrosine kinase inhibitor and at least one dose of EGFR inhibitor within a certain period of time, wherein two All substances show pharmacological effects.
  • the time limit can be within one administration cycle, preferably within 4 weeks, within 3 weeks, within 2 weeks, within 1 week or within 24 hours.
  • Multi-target tyrosine kinase inhibitors and EGFR inhibitors can be administered simultaneously or sequentially. This period includes treatments in which the multi-target tyrosine kinase inhibitor and the EGFR inhibitor are administered by the same route of administration or different routes of administration.
  • a therapeutically effective amount of the drug can reduce the number of cancer cells; reduce the size of the tumor; inhibit (ie, slow down and preferably prevent) the infiltration of cancer cells into the surrounding organs; inhibit (ie, slow down to a certain extent) Preferably prevent) tumor metastasis; inhibit tumor growth to a certain extent; and/or reduce one or more symptoms related to the disease to a certain extent.
  • the drug can prevent the growth of and/or kill existing cancer cells, it can be cytostatic and/or cytotoxic.
  • in vivo efficacy can be measured by assessing survival duration, progression-free survival (PFS) duration, response rate (RR), response duration, and/or quality of life.
  • Figure 1 The efficacy of drug A and drug B alone or in combination on human lung cancer H1975 nude mice subcutaneously transplanted tumor;
  • Figure 3 The efficacy of drug A and drug B alone or in combination on human lung cancer PC-9 subcutaneous transplantation tumor in nude mice;
  • Figure 4 The effect of drug A and drug B alone or in combination on body weight of tumor-bearing nude mice.
  • Example 1 Evaluation of the compound malate of formula (I) (compound A), the compound methanesulfonate of formula (II) (drug B) alone or a combination of both for subcutaneous transplantation of human lung cancer H1975 nude mice Tumor efficacy
  • Drug A was prepared according to the method disclosed in WO2007085188;
  • Drug B was prepared according to the co-preparation method of WO2017161937; the drug formulations were all prepared and diluted with 0.1% Tween-80 + 0.5% CMC.
  • H1975 cells were purchased from American Type Culture Collection. Use a 10-cm petri dish for adherent culture. The culture conditions are RPMI 1640 medium with 10% fetal bovine serum, penicillin and streptomycin, and culture at 37°C in an incubator with 5% CO 2 air. Passage 2-3 times a week, when the cells are in the exponential growth phase, trypsin digestion, collect the cells, count, and inoculate.
  • BALB/c nude mice, 6-7 weeks, ⁇ purchased from Shanghai Lingchang Biotechnology Co., Ltd.
  • mice were subcutaneously inoculated with human lung cancer H1975 cells. After the tumor grew to 100-150 mm 3 , the animals were divided into groups according to the tumor volume (D0). Mice were administered intragastrically (ig), 1 day (QD; administration volume 10mL/kg; the solvent group was given the same volume of "solvent" (0.1% Tween-80 + 0.5% CMC); specific dosage and administration The drug protocol is shown in Table 1. The tumor volume was measured twice a week, the mice were weighed, and the data was recorded.
  • the experimental index is to investigate the effect of drugs on tumor growth, and the specific index is T/C% or tumor inhibition rate TGI (%).
  • V 1/2 ⁇ a ⁇ b 2 where a and b represent 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.
  • TGI Tumor inhibition rate
  • TGI tumor inhibition rate
  • the tumor is smaller than the initial volume, that is, when T ⁇ T0 or C ⁇ C0, it is defined as partial tumor regression (PR); if the tumor disappears completely, it is defined as complete tumor regression (CR).
  • PR partial tumor regression
  • CR complete tumor regression
  • the end of the experiment was reached, or the tumor volume reached 1500 mm 3 , the animals were killed under CO 2 anesthesia, and then the tumors were dissected and taken and photographed.
  • Drug B (3, 5mg/kg, ig, QD ⁇ 17) dose-dependently inhibited the growth of human lung cancer H1975 (EGFRL858R/T790M) subcutaneously transplanted tumors in nude mice, and the tumor inhibition rates were 44% and 74%; drug A ( The inhibitory rate of 10mg/kg, ig, QD ⁇ 17) against H1975 subcutaneous xenograft tumor is 37%; drug B (3, 5mg/kg, ig, QD ⁇ 17) and drug A (10mg/kg, ig, QD ⁇ 17) The tumor inhibition rate increased to 85% and 98% respectively, which was significantly better than the single-agent efficacy (P ⁇ 0.05, compared with single-agent).
  • mice can tolerate the above drugs well, and there is no significant weight loss and other symptoms.
  • the results show that the combination of drug B and drug A has a synergistic effect on human lung cancer H1975 nude mice subcutaneously transplanted tumors.
  • Drug B 5mg/kg, ig, QD ⁇ 17
  • drug A 10mg/kg, ig, QD ⁇ 17
  • the combination of the two has a significant synergistic effect (P ⁇ 0.05, compared with the single drug)
  • tumor-bearing mice can tolerate the above drugs in combination.
  • Example 2 Evaluation of the compound represented by formula (I) malate (compound A), the compound represented by formula (II) methanesulfonate (drug B) alone or in combination on human lung cancer PC-9 nude mice Efficacy of subcutaneous transplantation tumor
  • Drug A was prepared according to the method disclosed in WO2007085188;
  • Drug B was prepared according to the co-preparation method of WO2017161937; the drug formulations were all prepared and diluted with 0.1% Tween-80 + 0.5% CMC.
  • PC-9 cells are adhered to the wall in a 10-cm petri dish.
  • the culture conditions are RPMI 1640 medium with 10% fetal bovine serum, penicillin and streptomycin, and culture in an incubator at 37°C and 5% CO 2 air. . Passage 2-3 times a week, when the cells are in the exponential growth phase, trypsin digestion, collect the cells, count, and inoculate.
  • BALB/c nude mice, 6-7 weeks, ⁇ purchased from Shanghai Lingchang Biotechnology Co., Ltd.
  • mice were subcutaneously inoculated with human lung cancer PC-9 cells. After the tumor grew to 100-150 mm 3 , the animals were divided into groups according to the tumor volume (D 0 ). Mice were administered intragastrically (ig), 1 day (QD; administration volume 10mL/kg; the solvent group was given the same volume of "solvent" (0.1% Tween-80 + 0.5% CMC); specific dosage and administration The drug protocol is shown in Table 3. The tumor volume was measured twice a week, the mice were weighed, and the data was recorded.
  • the experimental index is to investigate the effect of drugs on tumor growth, and the specific index is T/C% or tumor inhibition rate TGI (%).
  • V 1/2 ⁇ a ⁇ b 2 , where a and b represent 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.
  • TGI Tumor inhibition rate
  • TGI tumor inhibition rate
  • the tumor is smaller than the initial volume, that is, when T ⁇ T0 or C ⁇ C0, it is defined as partial tumor regression (PR); if the tumor disappears completely, it is defined as complete tumor regression (CR).
  • PR partial tumor regression
  • CR complete tumor regression
  • the end of the experiment was reached, or the tumor volume reached 1500 mm 3 , the animals were killed under CO 2 anesthesia, and then the tumors were dissected and taken and photographed.
  • drug A 10 mg/kg + drug B 1 mg/kg has a maximum weight change of -6.3% on day 11; drug A 10 mg/kg + drug B 3 mg/kg has a maximum weight change of -4.7% on day 11.
  • D0 Time of first administration; P value refers to the comparison with the solvent; **P ⁇ 0.01, compared with the drug A 10mg/kg group; ##P ⁇ 0.01, compared with the drug B 3mg/kg group; $$P ⁇ 0.01, compared with drug B 1mg/kg group.
  • Drug B (1, 3mg/kg, ig, QD ⁇ 20) dose-dependently inhibited the growth of human lung cancer PC-9 (EGFR ex19del) subcutaneously transplanted tumors in nude mice, with tumor inhibition rates of 27% and 59%, respectively;
  • Drug A (10mg/kg, ig, QD ⁇ 20) the tumor inhibition rate of PC-9 subcutaneous transplantation tumor is 59%;
  • drug B (1, 3mg/kg, ig, QD ⁇ 20) and drug A (10mg/kg, ig ,QD ⁇ 20)
  • the combined tumor inhibition rate increased to 74% and 96%, respectively, which was significantly stronger than the single drug efficacy (P ⁇ 0.01).
  • Drug B (1, 3 mg/kg, ig, QD ⁇ 20) and drug A (10 mg/kg, ig, QD ⁇ 20) inhibit the growth of human lung cancer PC-9 (EGFR ex19del) subcutaneously transplanted tumor in nude mice
  • PC-9 EGFR ex19del
  • the combination of the two has a significant synergistic effect (P ⁇ 0.01, compared with the single drug); the combined group caused a transient weight loss in mice, and other tumor-bearing mice could well tolerate the above drugs.

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Abstract

本申请公开了一种多靶点酪氨酸激酶抑制剂与EGFR抑制剂联合在制备治疗肿瘤的药物中的用途。具体而言，本申请所述的多靶点酪氨酸激酶抑制剂选自式(I)所示化合物或其可药用盐，EGFR抑制剂选自式(II)化合物或其立体异构体、复合物或其可药用盐。

Description

多靶点酪氨酸激酶抑制剂与EGFR抑制剂联合在制备治疗肿瘤的药物中的用途
本申请要求申请日为2019年03月04日的中国专利申请201910160268.4的优先权。本申请引用上述中国专利申请的全文。
技术领域
本申请涉及一种多靶点酪氨酸激酶抑制剂与人表皮生长因子受体抑制剂(EGFRi)联合在制备治疗肿瘤的药物中的用途，属于制药领域。
背景技术
在世界范围内，肺癌已成为癌症死亡的主要原因。在中国，不论是癌症发生率还是死亡率，肺癌都占据了首位。尽管在过去20年内推出了更新的几代细胞毒性药物和靶向治疗，但是晚期肺癌患者、特别是没有已知的驱动突变基因的患者生存预后仍很差，晚期或转移性肺癌仍是一种有大量医疗需求未被满足的致死性疾病。
非小细胞肺癌(NSCLC)约占所有肺癌的85％，约75％的NSCLC患者发现时已处于中晚期，5年生存率很低。对于晚期或转移性NSCLC患者选择合适的系统性治疗方式仍在临床上存在很大的需求。NSCLC又可分为鳞状细胞癌与非鳞状细胞癌。非鳞状细胞癌包括腺癌、大细胞癌及其他亚型细胞癌。非鳞状细胞癌患者再按照有无驱动突变基因(EGFR突变或ALK基因重排)进一步分类。
EGFR(Epidermal Growth Factor Receptor)是跨膜蛋白酪氨酸激酶erbB受体家族的一员。通过与其配体-例如表皮生长因子(EGF)的结合，EGFR在细胞膜上可以形成同源二聚体，或者与家族中其他的受体(比如erbB2、erbB3或erbB4)形成异源二聚体。这些二聚体的形成，可引起EGFR细胞内关键的酪氨酸残基磷酸化，从而激活细胞内多个下游的信号通路。这些细 胞内信号通路在细胞增殖、生存及抗凋亡中起重要作用。EGFR信号传导通路失调，包括配体及受体的表达增高、EGFR基因扩增以及突变等，可促进细胞向恶性转化，并在肿瘤细胞的增殖、侵袭、转移以及血管形成中起重要作用。EGFR的过度表达已在许多人类恶性疾病中报道，包括膀胱癌、脑肿瘤、头颈癌、胰腺癌、肺癌、乳腺癌、卵巢癌、结肠癌、前列腺癌和肾脏癌。在许多情况下，EGFR的过度表达与患者的预后不良有关。
氨酸激酶抑制剂(TKIs)的抗肿瘤作用机制可能通过以下途径实现：抑制肿瘤细胞的损伤修复、使细胞分裂阻滞在G1期、诱导和维持细胞凋亡、抗新生血管形成等。EGFR过度表达常预示病人预后差、转移快、对化疗药物抗拒、激素耐药、生存期较短等。FDA已批准多种多靶点TKIs上市，如：索拉非尼(sorafenib)、凡德他尼(vandetanib)和Sunitinib(Sutent，SU-11248)，其中Sunitinib于2006年1月份批准上市，治疗GIST和晚期肾癌。由于目前临床上除了伊马替尼外，没有治疗晚期GIST的药物，治疗肾癌的药物也很少，所以Sunitinib的结果令人鼓舞。WO2007085188公开了一种与Sunitinib类似的化合物，如下式(I)所示，其可能更好地应用于上述肿瘤的治疗。该化合物化学名为5-(2-二乙胺基-乙基)-2-(5-氟-2-氧代-1,2-二氢-吲哚-3-亚基-甲基)-3-甲基-1,5,6,7-四氢-吡咯[3,2-c]吡啶-4-酮，已知其具有抑制参与肿瘤增殖和血管生成，能够选择性抑制血管内皮生长因子(VEGF)受体的激酶活性，临床上可用于肾癌、胃肠间质瘤、结直肠癌和胰腺神经内分泌瘤等多种肿瘤的治疗。
Figure PCTCN2020077520-appb-000001
WO2016054987A公开了一种式(II)结构所示的4-取代-(2-(N-(5-烯丙 酰胺基)苯基)氨基)嘧啶衍生物，该化合物具有抑制L858R EGFR突变体、T790M EGFR突变体和外显子19缺失激活突变体的活性，可以用来治疗单独或部分地由EGFR突变体活性介导疾病，WO2017161937公开了式(II)所示EGFR抑制剂的甲磺酸盐，
Figure PCTCN2020077520-appb-000002
关于多靶点酪氨酸激酶抑制剂与EGFR抑制剂的联合，虽然现有技术有公开，但并没有具体的实验数据，例如WO2006120557A公开了一种治疗非小细胞肺癌的患者的方法，包括给与患者每日25-50mg的苹果酸舒尼替尼和每日约250mg的吉非替尼或者150mg的厄洛替尼，但该申请的说明书中并没有具体的实验数据，故联用效果无从知晓。
发明内容
本申请提供一种多靶点酪氨酸激酶抑制剂与EGFR抑制剂联合在制备治疗肿瘤的药物中的用途。
本申请中所述肿瘤可选自乳腺癌、卵巢癌、前列腺癌、黑色素瘤、脑瘤、食管癌、胃癌、肝癌、胰腺癌、结肠直肠癌、肺癌、肾癌、皮肤癌、成胶质细胞瘤、神经母细胞瘤、肉瘤、脂肪肉瘤、骨软骨瘤、骨瘤、骨肉瘤、精原细胞瘤、睾丸肿瘤、子宫癌、头颈肿瘤、多发性骨髓瘤、恶性淋巴瘤、真性红细胞增多症、白血病、甲状腺肿瘤、输尿管肿瘤、膀胱肿瘤、胆囊癌、胆管癌或绒毛膜上皮癌，优选非小细胞肺癌。
本申请中所述多靶点酪氨酸激酶抑制剂与EGFR抑制剂联合在制备预 防或治疗肿瘤的药物中的用途，所述肿瘤优选为EGFR突变的肿瘤。
本申请中所述的EGFR突变的肿瘤优选为非小细胞肺癌，优选的EGFR突变体选自L858R EGFR突变体和/或T790M EGFR突变体和/或EGFR外显子20插入和/或EGFR外显子19缺失。
在一些实施方案中，本申请中所述的非小细胞肺癌选自鳞状细胞癌和非鳞状细胞癌，优选非磷状细胞癌，其中非磷状细胞癌可以是腺癌、大细胞癌及其他亚型细胞癌。
在可选的实施方案中，所述的多靶点酪氨酸激酶抑制剂对VEGFR激酶产生抑制作用。
本申请所述的多靶点酪氨酸激酶抑制剂可选自sunitinib、axitinib、sorafenib、nintedanib、cabozantinib S-malate、lenvatinib mesylate、regorafenib、ponatinib、MP-0250、pazopanib、anlotinib、ningetinib、rebastinib、PF-06753512、tivozanib、telatinib、AL-2846、vorolanib、BMS-817378、lucitanib hydrochloride、ODM-203、sitravatinib、fenretinide、surufatinib、vandetanib、ENMD-2076、AMC-303、brivanib alaninate、cediranib、BI-836880、dovitinib、muparfostat sodium、CYC-116、tesevatinib、chiauranib、ilorasertib、altiratinib或式(I)所示化合物或其药学上可接受的盐，优选式(I)所示化合物或其药学上可接受的盐，
Figure PCTCN2020077520-appb-000003
本申请所述的EGFR抑制剂可选自osimertinib、gefitinib、erlotinib、olmutinib、icotinib、pyrotinib、brigatinib、dacomitinib、afatinib、neratinib、lapatinib、ABT-414、varlitinib、HLX-07、theliatinib、epitinib succinate、S-222611、 poziotinib、AST-2818、GNS-1480、mavelertinib、AP-32788、AZD-3759、nazartinib、Sym-013、allitinib tosylate、tarloxotinib bromide、poziotinib、CK-101、QL-1203、JNJ-61186372、SKLB-1028、TAS-121、Hemay-020、Hemay-022、NRC-2694-A、simotinib hydrochloride、SPH-1188-11、GR-1401、SYN-004、ABBV-221、MP-0274、GC-1118、BPI-15000、DBPR-112、Pirotinib、PB-357、lifirafenib、SCT-200、QLNC-120、agerafenib hydrochloride或式(II)化合物或其立体异构体、复合物或其可药用盐，优选olmutinib、afatinib、osimertinib、CK-101、erlotinib、icotinib、gefitinib或式(II)化合物或其立体异构体、复合物或其可药用盐，最优选式(II)化合物或其立体异构体、复合物或其可药用盐，
Figure PCTCN2020077520-appb-000004
本申请所述药物的可药用盐可以是盐酸盐、磷酸盐、磷酸氢盐、硫酸盐、硫酸氢盐、亚硫酸盐、乙酸盐、草酸盐、丙二酸盐、戊酸盐、谷氨酸盐、油酸盐、棕榈酸盐、硬脂酸盐、月桂酸盐、硼酸盐、对甲苯磺酸盐、甲磺酸盐、羟乙基磺酸盐、马来酸盐、苹果酸盐、酒石酸盐、苯甲酸盐、双羟萘酸盐、水杨酸盐、香草酸盐、扁桃酸盐、琥珀酸盐、葡萄糖酸盐、乳糖酸盐或月桂基磺酸盐等。
在可选实施方式中，所述式(I)所示化合物的可药用盐为苹果酸盐。
在可选实施方案中，所述式(II)所示化合物的可药用盐为甲磺酸盐。
在优选的实施方案中，所述式(I)所示化合物的可药用盐为苹果酸盐，所述式(II)所示化合物的可药用盐为甲磺酸盐。
本申请的一些实施方案中，所述多靶点酪氨酸激酶抑制剂的剂量选自0.1-1000mg，给药频次可以是一日一次、一日二次或一日三次；EGFR抑制剂的剂量范围选自1-1000mg，给药频次可以是一日一次、一日二次或一日三次。
在本申请的一些实施方案中，所述多靶点酪氨酸激酶抑制剂的剂量选自0.1-500mg，给药频次可以是一日一次、一日二次或一日三次，优选一日一次；EGFR抑制剂的剂量范围选自1-500mg，具体可选1mg、2.5mg、5mg、7.5mg、10mg、12.5mg、15mg、17.5mg、20mg、22.5mg、25mg、27.5mg、30mg、32.5mg、35mg、37.5mg、40mg、42.5mg、45mg、47.5mg、50mg、52.5mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、105mg、110mg、120mg、130mg、140mg、150mg、160mg、170mg、180mg、190mg、200mg、210mg、220mg、230mg、240mg、250mg、260mg、270mg、280mg、290mg、300mg、350mg、400mg、450mg或500mg，给药频次可以是一日一次、一日二次或一日三次，优选一日一次。
在本申请的一些实施方案中，所述多靶点酪氨酸激酶抑制剂的剂量选自0.1-100mg，具体可选0.1mg、0.2mg、0.3mg、0.4mg、0.5mg、0.6mg、0.7mg、0.8mg、0.9mg、1.0mg、2mg、3mg、4mg、5mg、6mg、7mg、8mg、9mg、10mg、11mg、12mg、13mg、14mg、15mg、16mg、17mg、18mg、19mg、20mg、21mg、22mg、23mg、24mg、25mg、26mg、27mg、28mg、29mg、30mg、31mg、32mg、33mg、34mg、35mg、36mg、37mg、38mg、39mg、40mg、41mg、42mg、43mg、44mg、45mg、46mg、47mg、48mg、49mg、50mg、51mg、52mg、53mg、54mg、55mg、56mg、57mg、58mg、59mg、60mg、61mg、62mg、63mg、64mg、65mg、66mg、67mg、68mg、69mg、70mg、71mg、72mg、73mg、74mg、75mg、76mg、77mg、78mg、79mg、80mg、81mg、82mg、83mg、84mg、85mg、86mg、87mg、88mg、89mg、90mg、91mg、92mg、93mg、94mg、95mg、96mg、97mg、98mg、99mg或100mg，给药频次可以是一日一次、一日二次或一日三次，优选一日一次； EGFR抑制剂的剂量范围选自1-500mg，具体可选1mg、2.5mg、5mg、7.5mg、10mg、12.5mg、15mg、17.5mg、20mg、22.5mg、25mg、27.5mg、30mg、32.5mg、35mg、37.5mg、40mg、42.5mg、45mg、47.5mg、50mg、52.5mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、105mg、110mg、120mg、130mg、140mg、150mg、160mg、170mg、180mg、190mg、200mg、210mg、220mg、230mg、240mg、250mg、260mg、270mg、280mg、290mg、300mg、350mg、400mg、450mg或500mg，给药频次可以是一日一次、一日二次或一日三次，优选一日一次。
在可选的实施方案中，多靶点酪氨酸激酶抑制剂的剂量选自1-25mg，具体可选15mg、20mg或25mg，给药频次可以是一日一次、一日二次或一日三次，优选一日一次，EGFR抑制剂的剂量范围选自1-500mg，具体可选55mg、110mg、220mg或260mg，优选一日一次。
本申请优选的实施方案中，多靶点酪氨酸激酶抑制剂的剂量可选15mg、20mg或25mg，给药频次是一日一次，EGFR抑制剂的剂量可选55mg、110mg、220mg或260mg，给药频次是一日一次。
在本申请优选的实施方案中，多靶点酪氨酸激酶抑制剂的剂量是15mg，给药频次是一日一次，EGFR抑制剂的剂量可选55mg、110mg、220mg或260mg，给药频次是一日一次。
本申请优选的实施方案中，多靶点酪氨酸激酶抑制剂的剂量是20mg，给药频次是一日一次，EGFR抑制剂的剂量可选55mg、110mg、220mg或260mg，给药频次是一日一次。
本申请优选的实施方案中，多靶点酪氨酸激酶抑制剂的剂量为25mg，给药频次是一日一次，EGFR抑制剂的剂量可选55mg、110mg、220mg或260mg，给药频次是一日一次。
本申请优选的实施方案中，多靶点酪氨酸激酶抑制剂的剂量可选15mg、20mg或25mg，给药频次是一日一次，EGFR抑制剂的剂量为55mg，给药频 次是一日一次。
本申请优选的实施方案中，多靶点酪氨酸激酶抑制剂的剂量可选15mg、20mg或25mg，给药频次是一日一次，EGFR抑制剂的剂量为110mg，给药频次是一日一次。
本申请优选的实施方案中，多靶点酪氨酸激酶抑制剂的剂量可选15mg、20mg或25mg，给药频次是一日一次，EGFR抑制剂的剂量为220mg，给药频次是一日一次。
本申请优选的实施方案中，多靶点酪氨酸激酶抑制剂的剂量可选15mg、20mg或25mg，给药频次是一日一次，EGFR抑制剂的剂量为260mg，给药频次是一日一次。
本申请可选的实施方案中，所述多靶点酪氨酸激酶抑制剂按体重给药，所述的剂量选自0.1～10.0mg/kg，给药频次可以是一日一次、一日二次或一日三次；EGFR抑制剂的剂量范围选自1-1000mg，给药频次可以是一日一次、一日二次或一日三次。
在上述按照体重给药的方案中，所述多靶点酪氨酸激酶抑制剂的剂量可以为0.1mg/kg、0.2mg/kg、0.3mg/kg、0.4mg/kg、0.5mg/kg、0.6mg/kg、0.7mg/kg、0.8mg/kg、0.9mg/kg、1.0mg/kg、1.2mg/kg、1.4mg/kg、1.6mg/kg、1.8mg/kg、2.0mg/kg、2.2mg/kg、2.4mg/kg、2.6mg/kg、2.8mg/kg、3.0mg/kg、3.2mg/kg、3.4mg/kg、3.6mg/kg、3.8mg/kg、4.0mg/kg、4.2mg/kg、4.4mg/kg、4.6mg/kg、4.8mg/kg、5.0mg/kg、5.2mg/kg、5.4mg/kg、5.6mg/kg、5.8mg/kg、6.0mg/kg、6.2mg/kg、6.4mg/kg、6.6mg/kg、6.8mg/kg、7.0mg/kg、7.2mg/kg、7.4mg/kg、7.6mg/kg、7.8mg/kg、8.0mg/kg、8.2mg/kg、8.4mg/kg、8.6mg/kg、8.8mg/kg、9.0mg/kg、9.2mg/kg、9.4mg/kg、9.6mg/kg、9.8mg/kg或10.0mg/kg。
本申请所述联合的给药途径可选自经口给药、胃肠外给药、经皮给药，所述胃肠外给药包括但不限于静脉注射、皮下注射、肌肉注射，优选口服给药。
本申请提供的多靶点酪氨酸激酶抑制剂与EGFR抑制剂联合在制备治疗肿瘤的药物中的用途，所述多靶点酪氨酸激酶抑制剂优选经口给药。
本申请提供的多靶点酪氨酸激酶抑制剂与EGFR抑制剂联合在制备治疗肿瘤的药物中的用途，所述的EGFR抑制剂优选经口给药。
本申请所述的方案中，所述的联合任选的还包含其他组分，所述其他组分包括但不限于其他治疗肿瘤的药物。
本申请还提供了一种治疗肿瘤的方法，包括向患者施用有效量上述多靶点酪氨酸激酶抑制剂与有效量上述EGFR抑制剂。
本申请还涉及一种包含上述多靶点酪氨酸激酶抑制剂与EGFR抑制剂以及一种或多种药用载体、赋形剂、稀释剂的药物组合物。所述药物组合物可以制成药学上可接受的任意剂型。例如，可以配制为片剂、胶囊剂、丸剂、颗粒剂、溶液剂、混悬剂、糖浆剂、注射剂(包括注射液、注射用无菌粉末与注射用浓溶液)、栓剂、吸入剂或喷雾剂。
本申请所述的包含多靶点酪氨酸激酶抑制剂与EGFR抑制剂的药物组合物，可以单独给药，或者与一种或多种治疗剂联合使用。
本申请还提供了一种药物试剂盒，其中包装有本申请所述的包含多靶点酪氨酸激酶抑制剂与EGFR抑制剂的药物组合物。
本申请将多靶点酪氨酸激酶抑制剂与EGFR抑制剂联合给药改善了治疗效果。
本申请中所述的“联合”是一种给药方式，是指在一定时间期限内给予至少一种剂量的多靶点酪氨酸激酶抑制剂和至少一种剂量的EGFR抑制剂，其中两种物质都显示药理学作用。所述的时间期限可以是一个给药周期内，优选4周内、3周内、2周内、1周内或24小时以内。可以同时或依次给予多靶点酪氨酸激酶抑制剂和EGFR抑制剂。这种期限包括这样的治疗，其中通过相同给药途径或不同给药途径给予多靶点酪氨酸激酶抑制剂和EGFR抑制剂。
术语“有效量”指在哺乳动物中有效治疗疾病或病症的药物量。在癌症的 情况中，治疗有效量的药物可减少癌细胞的数目；缩小肿瘤的尺寸；抑制(即一定程度的减缓和优选阻止)癌细胞浸润到周围器官中；抑制(即一定程度的减缓和优选阻止)肿瘤转移；一定程度的抑制肿瘤生长；和/或一定程度的减轻一种或多种与该病症有关的症状。根据药物可阻止现有癌细胞生长和/或杀死现有癌细胞的程度，它可以是细胞抑制性的和/或细胞毒性的。对于癌症治疗，可通过评估存活持续时间、无进展存活(PFS)持续时间、响应率(RR)、响应持续时间和/或生活质量来测量体内功效。
附图说明
图1.药物A、药物B单用或二者合用对人肺癌H1975裸小鼠皮下移植瘤的疗效；
图2.药物A、药物B单用或二者合用对荷瘤裸小鼠体重的影响；
图3.药物A、药物B单用或二者合用对人肺癌PC-9裸小鼠皮下移植瘤的疗效；
图4.药物A、药物B单用或二者合用对荷瘤裸小鼠体重的影响。
具体实施方式
以下将结合实施例更详细地解释本申请，本申请的实施例仅用于说明本申请的技术方案，并非限定本申请的实质和范围。
实施例1.评价式(I)所示化合物苹果酸盐(化合物A)、式(II)所示化合物甲磺酸盐(药物B)单用或二者合用对人肺癌H1975裸小鼠皮下移植瘤的疗效
1、实验材料
药物A依据WO2007085188公开方法制备；
药物B依据WO2017161937共开的方法制备；药物配置均用0.1％Tween-80+0.5％CMC配制并稀释。
H1975细胞购自American Type Culture Collection。用10-cm培养皿贴壁培养，培养条件为RPMI 1640培养基中加10％胎牛血清以及青、链霉素，于37℃、含5％CO 2空气的培养箱中培养。一周2-3次传代，当细胞呈指数生长期时，胰酶消化，收集细胞，计数，接种。
BALB/c裸小鼠，6-7周，♀，购自上海灵畅生物科技有限公司。
2、实验方法
裸小鼠皮下接种人肺癌H1975细胞，待肿瘤生长至100-150mm 3后，根据肿瘤体积将动物分组(D0)。小鼠灌胃给药(i.g.)，每日1(QD；给药体积10mL/kg；溶剂组给予相同体积的“溶剂”(0.1％Tween-80+0.5％CMC)；具体给药剂量和给药方案见表1。每周测2次肿瘤体积，称小鼠体重，记录数据。
实验指标为考察药物对肿瘤生长的影响，具体指标为T/C％或抑瘤率TGI(％)。
每周二次用游标卡尺测量肿瘤直径，肿瘤体积(V)计算公式为：
V＝1/2×a×b 2其中a、b分别表示长、宽。
T/C(％)＝(T-T0)/(C-C0)×100其中T、C为实验结束时的肿瘤体积；T0、C0为实验开始时的肿瘤体积。
抑瘤率(TGI)(％)＝100-T/C(％)。
当肿瘤出现消退时，抑瘤率(TGI)(％)＝100-(T-T0)/T0×100
如果肿瘤比起始体积缩小，即T<T0或C<C0时，即定义为肿瘤部分消退(PR)；如果肿瘤完全消失，即定义为肿瘤完全消退(CR)。
实验结束(D21)、达到实验终点、或肿瘤体积达到1500mm 3，CO 2麻醉处死动物，随后解剖取瘤并拍照。
二组肿瘤体积之间比较采用双尾Student’s t检验，P<0.05定义为差异有统计学显著性。
表1
Figure PCTCN2020077520-appb-000005
Figure PCTCN2020077520-appb-000006
3、实验结果
表2.药物A、药物B单用或二者合用对人肺癌H1975裸小鼠皮下移植瘤的疗效
Figure PCTCN2020077520-appb-000007
D0:第一次给药时间；P值指与溶剂相比；**P<0.01，与药物A 10mg/kg组比较；##P<0.01，与药物B 3mg/kg组比较；$P<0.05，与药物B 5mg/kg组比较；n＝8。
药物A、药物B单用或二者合用对人肺癌H1975裸小鼠皮下移植瘤的 疗效见附图1，药物A、药物B单用或二者合用对荷瘤裸小鼠体重的影响见附图2。
药物B(3、5mg/kg,i.g.,QD×17)剂量依赖性抑制人肺癌H1975(EGFRL858R/T790M)裸小鼠皮下移植瘤的生长，抑瘤率分别为44％和74％；药物A(10mg/kg,i.g.,QD×17)对H1975皮下移植瘤的抑瘤率为37％；药物B(3、5mg/kg,i.g.,QD×17)与药物A(10mg/kg,i.g.,QD×17)合用抑瘤率分别提高到85％和98％，显著强于单药疗效(P<0.05，与单药比较)，其中药物B 5mg/kg合用组有4/8肿瘤部分消退；荷瘤小鼠对以上药物均能很好耐受，没有明显体重减轻等症状发生。结果说明药物B、药物A二者合用对人肺癌H1975裸小鼠皮下移植瘤有协同增效作用。
结论：药物B(3、5mg/kg,i.g.,QD×17)、药物A(10mg/kg,i.g.,QD×17)抑制人肺癌H1975(EGFR L858R/T790M)裸小鼠皮下移植瘤的生长；二者合用有显著协同增效作用(P<0.05，与单药比较)；荷瘤小鼠对以上药物合用均能很好耐受。
实施例2.评价式(I)所示化合物苹果酸盐(化合物A)、式(II)所示化合物甲磺酸盐(药物B)单用或二者合用对人肺癌PC-9裸小鼠皮下移植瘤的疗效
1、实验材料
药物A依据WO2007085188公开方法制备；
药物B依据WO2017161937共开的方法制备；药物配置均用0.1％Tween-80+0.5％CMC配制并稀释。
PC-9细胞用10-cm培养皿贴壁培养，培养条件为RPMI 1640培养基中加10％胎牛血清以及青、链霉素，于37℃、含5％CO 2空气的培养箱中培养。一周2-3次传代，当细胞呈指数生长期时，胰酶消化，收集细胞，计数，接种。
BALB/c裸小鼠，6-7周，♀，购自上海灵畅生物科技有限公司。
2、实验方法
裸小鼠皮下接种人肺癌PC-9细胞，待肿瘤生长至100-150mm 3后，根据肿瘤体积将动物分组(D 0)。小鼠灌胃给药(i.g.)，每日1(QD；给药体积10mL/kg；溶剂组给予相同体积的“溶剂”(0.1％Tween-80+0.5％CMC)；具体给药剂量和给药方案见表3。每周测2次肿瘤体积，称小鼠体重，记录数据。
实验指标为考察药物对肿瘤生长的影响，具体指标为T/C％或抑瘤率TGI(％)。
每周二次用游标卡尺测量肿瘤直径，肿瘤体积(V)计算公式为：
V＝1/2×a×b 2，其中a、b分别表示长、宽。
T/C(％)＝(T-T0)/(C-C0)×100，其中T、C为实验结束时的肿瘤体积；T0、C0为实验开始时的肿瘤体积。
抑瘤率(TGI)(％)＝100-T/C(％)。
当肿瘤出现消退时，抑瘤率(TGI)(％)＝100-(T-T0)/T0×100。
如果肿瘤比起始体积缩小，即T<T0或C<C0时，即定义为肿瘤部分消退(PR)；如果肿瘤完全消失，即定义为肿瘤完全消退(CR)。
实验结束(D21)、达到实验终点、或肿瘤体积达到1500mm 3，CO 2麻醉处死动物，随后解剖取瘤并拍照。
二组肿瘤体积之间比较采用双尾Student’s t检验，P<0.05定义为有统计学显著性差异。
表3
Figure PCTCN2020077520-appb-000008
Figure PCTCN2020077520-appb-000009
3、实验结果
表4.药物A、药物B单用或二者合用对人肺癌PC-9裸小鼠皮下移植瘤的疗效
Figure PCTCN2020077520-appb-000010
其中药物A 10mg/kg+药物B 1mg/kg在第11天具有-6.3％的最大体重变化；药物A 10mg/kg+药物B 3mg/kg在第11天具有-4.7％的最大体重变化。
D0:第一次给药时间；P值指与溶剂相比；**P<0.01，与药物A 10mg/kg组比较；##P<0.01，与药物B 3mg/kg组比较；$$P<0.01，与药物B 1mg/kg组比较。
药物A、药物B单用或二者合用对人肺癌PC-9裸小鼠皮下移植瘤的疗效见附图3，药物A、药物B单用或二者合用对荷瘤裸小鼠体重的影响见附图4。
药物B(1、3mg/kg,i.g.,QD×20)剂量依赖性抑制人肺癌PC-9(EGFR ex19del)裸小鼠皮下移植瘤的生长，抑瘤率分别为27％和59％；药物 A(10mg/kg,i.g.,QD×20)对PC-9皮下移植瘤的抑瘤率为59％；药物B(1、3mg/kg,i.g.,QD×20)与药物A(10mg/kg,i.g.,QD×20)合用抑瘤率分别提高到74％和96％，显著强于单药疗效(P<0.01)，其中药物B 3mg/kg合用组有3/8肿瘤部分消退，药效显著强于单药疗效(P<0.01)；药物B 1mg/kg、3mg/kg合用组分别引起小鼠最大体重下降6.3％(D11)和4.7％(D11)；其他荷瘤小鼠对以上药物均能很好耐受，没有明显体重减轻等症状发生。结果说明药物A、药物B二者合用对人肺癌PC-9裸小鼠皮下移植瘤有协同增效作用。
结论：药物B(1、3mg/kg,i.g.,QD×20)、药物A(10mg/kg,i.g.,QD×20)均抑制人肺癌PC-9(EGFR ex19del)裸小鼠皮下移植瘤的生长；二者合用有显著协同增效作用(P<0.01，与单药比较)；合用组引起小鼠一过性体重下降，其他荷瘤小鼠对以上药物均能很好耐受。

Claims (14)

  1. 一种多靶点酪氨酸激酶抑制剂与EGFR抑制剂联合在制备治疗肿瘤的药物中的用途。
  2. 如权利要求1所述的用途，其中所述的肿瘤选自乳腺癌、卵巢癌、前列腺癌、黑色素瘤、脑瘤、食管癌、胃癌、肝癌、胰腺癌、结肠直肠癌、肺癌、肾癌、皮肤癌、成胶质细胞瘤、神经母细胞瘤、肉瘤、脂肪肉瘤、骨软骨瘤、骨瘤、骨肉瘤、精原细胞瘤、睾丸肿瘤、子宫癌、头颈肿瘤、多发性骨髓瘤、恶性淋巴瘤、真性红细胞增多症、白血病、甲状腺肿瘤、输尿管肿瘤、膀胱肿瘤、胆囊癌、胆管癌或绒毛膜上皮癌，优选非小细胞肺癌。
  3. 如权利要求1所述的用途，其中所述的肿瘤为EGFR突变的肿瘤。
  4. 如权利要求3所述的用途，其中所述的EGFR突变的肿瘤为非小细胞肺癌，优选的EGFR突变体选自L858R EGFR突变体和/或T790M EGFR突变体和/或EGFR外显子20插入和/或EGFR外显子19缺失。
  5. 如权利要求2所述的用途，其中所述的非小细胞肺癌选自鳞状细胞癌和非鳞状细胞癌，优选非磷状细胞癌。
  6. 如权利要求1-5中任一项所述的用途，其中所述的多靶点酪氨酸激酶抑制剂对VEGFR激酶产生抑制作用。
  7. 如权利要求1-5中任一项所述的用途，其中所述的多靶点酪氨酸激酶抑制剂选自sunitinib、axitinib、sorafenib、nintedanib、cabozantinib S-malate、lenvatinib mesylate、regorafenib、ponatinib、MP-0250、pazopanib、anlotinib、ningetinib、rebastinib、PF-06753512、tivozanib、telatinib、AL-2846、vorolanib、BMS-817378、lucitanib hydrochloride、ODM-203、sitravatinib、fenretinide、surufatinib、vandetanib、ENMD-2076、AMC-303、brivanib alaninate、cediranib、BI-836880、dovitinib、muparfostat sodium、CYC-116、tesevatinib、chiauranib、ilorasertib、altiratinib或式(I)所示化合物或其可药用盐，优选式(I)所示化合物或其可药用盐，
    Figure PCTCN2020077520-appb-100001
  8. 如权利要求1-5中任一项所述的用途，其中所述的EGFR抑制剂选自osiertinib、gefitinib、erlotinib、olmutinib、icotinib、pyrotinib、brigatinib、dacomitinib、afatinib、neratinib、lapatinib、ABT-414、varlitinib、HLX-07、theliatinib、epitinib succinate、S-222611、poziotinib、AST-2818、GNS-1480、mavelertinib、AP-32788、AZD-3759、nazartinib、Sym-013、allitinib tosylate、tarloxotinib bromide、poziotinib、CK-101、QL-1203、JNJ-61186372、SKLB-1028、TAS-121、Hemay-020、Hemay-022、NRC-2694-A、simotinib hydrochloride、SPH-1188-11、GR-1401、SYN-004、ABBV-221、MP-0274、GC-1118、BPI-15000、DBPR-112、Pirotinib、PB-357、lifirafenib、SCT-200、QLNC-120、agerafenib hydrochloride或式(II)化合物或其立体异构体、复合物或其可药用盐，优选olmutinib、afatinib、CK-101、osimertinib、erlotinib、icotinib、gefitinib或式(II)化合物或其立体异构体、复合物或其可药用盐，最优选式(II)化合物或其立体异构体、复合物或其可药用盐，
    Figure PCTCN2020077520-appb-100002
  9. 如权利要求7所述的用途，其中所述式(I)所示化合物的可药用盐为苹果酸盐。
  10. 如权利要求8所述的用途，其中所述式(II)所示化合物的可药用盐为甲磺酸盐。
  11. 如权利要求1-10中任一项所述的用途，其中所述多靶点酪氨酸激酶抑制剂的剂量选自0.1-1000mg，给药频次为一日一次、一日二次或一日三次；EGFR抑制剂的剂量范围选自1-1000mg，给药频次为一日一次、一日二次或一日三次。
  12. 如权利要求11所述的用途，其中所述的多靶点酪氨酸激酶抑制剂一日一次给药，给药剂量选自15mg、20mg或25mg；EGFR抑制剂一日一次给药，给药剂量选自55mg、110mg、220mg或260mg。
  13. 一种药物组合物，包含如权利要求1-12中任一项所述的多靶点酪氨酸激酶抑制剂与EGFR抑制剂，以及一种或多种可药用载体、赋形剂、稀释剂。
  14. 一种药物试剂盒，包含如权利要求13所述的药物组合物。
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