CN118019537A - Medical application of SHP2 inhibitor combined with EGFR-TKI in treatment and prevention of tumor diseases - Google Patents

Medical application of SHP2 inhibitor combined with EGFR-TKI in treatment and prevention of tumor diseases Download PDF

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CN118019537A
CN118019537A CN202280063878.2A CN202280063878A CN118019537A CN 118019537 A CN118019537 A CN 118019537A CN 202280063878 A CN202280063878 A CN 202280063878A CN 118019537 A CN118019537 A CN 118019537A
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day
cancer
tki
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周远锋
孙丹妮
刘军豪
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
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    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
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    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract

Provides the medical application of the SHP2 inhibitor combined with EGFR-TKI in treating and preventing tumor diseases, and the application of the SHP2 inhibitor in preparing medicines for treating EGFR-TKI resistant tumor diseases and EGFR-TKI sensitization medicines. In particular to application of a compound shown in a formula (I) or pharmaceutically acceptable salt thereof and EGFR-TKI drugs in medicines for preventing or treating tumor diseases. The compound of the formula (I) or the pharmaceutically acceptable salt thereof is combined with EGFR-TKI drugs, so that the compound has stronger anti-tumor effect, no obvious toxic or side effect and wide application prospect.

Description

Medical application of SHP2 inhibitor combined with EGFR-TKI in treatment and prevention of tumor diseases Technical Field
The invention belongs to the field of medicines, and relates to application of an SHP2inhibitor (SHP 2 inhibitor) in preparation of a lung cancer patient after EGFR TKI treatment resistance.
Background
The lung cancer is the most common malignant tumor in China or even worldwide, the world health organization International cancer research organization (IARC) issues the global latest cancer data in 2020, which shows that the number of newly increased lung cancer is 220 ten thousand worldwide and accounts for 11.4 percent of the total cancer incidence, and the new cases of the lung cancer in China are 81 ten thousand (17.9 percent), and the incidence rate is the first place; from the aspect of mortality, 71 ten thousand Chinese lung cancer death patients are the first cancer death people. In addition to traditional treatments such as traditional radiotherapy and chemotherapy, updated several generations of cytotoxic drugs and targeted therapeutic drugs are proposed in recent years for patients with lung cancer, but patients with advanced lung cancer, particularly patients without known driving mutant genes or drug resistance after treatment by EGFR inhibitors, have poor treatment options and survival prognosis, and advanced or metastatic lung cancer is a fatal disease with a large number of unmet medical needs.
Non-small cell lung cancer (NSCLC) accounts for about 85% of all lung cancers, and about 75% of NSCLC patients have been found to be in the middle and late stages with very low survival rates of 5 years. There remains a great clinical need for selecting an appropriate systemic treatment regimen for patients with advanced or metastatic NSCLC. NSCLC can be further classified into squamous cell carcinoma and non-squamous cell carcinoma. Non-squamous cell carcinomas include adenocarcinomas, large cell carcinomas and other subtypes of cell carcinomas. Patients with non-squamous cell carcinoma are further classified according to the presence or absence of driving mutant genes (EGFR mutation, ROS1 mutation or ALK gene rearrangement), different pathological types and different optimal treatment means in different phases.
SHP2 is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene, containing two N-terminal Src homology 2 (SH 2) domains, a Protein Tyrosine Phosphatase (PTP) domain and a C-terminal. The two conformations of the protein in the body are the active conformation in the open state and the inhibition phenomenon in the closed state respectively, and are the common nodes of a plurality of activated RAS signal paths, and almost all RTKs activate the RAS signal paths by activating SHP 2. SHP2 is closely related to breast cancer, leukemia, lung cancer, liver cancer, stomach cancer, laryngeal cancer, oral cancer, and other various cancer types, and is the only confirmed proto-oncoprotein in the PTP family. Although this protein was proposed as a target as early as 2007, no suitable compound has been a candidate drug since its active site has a huge positive charge, and it is difficult for a charged molecule to pass through a cell membrane to reach the target site. In recent years, as allosteric inhibitors appear, breakthrough progress of the target inhibitor appears, but at present, no global SHP2 inhibitor is marketed, and a small amount of drugs enter a clinical stage.
EGFR gene is one of the most common driving genes in non-small cell lung cancer (NSCLC), about 50% of Chinese NSCLC patients have EGFR gene mutation, EGFR TKI is taken as the most common targeting drug for treatment, breakthrough progress is made, the first generation EGFR-TKI treatment and the second generation EGFR-TKI treatment become the standard first-line treatment of EGFR mutation positive advanced NSCLC patients, the third generation is irreversible selective TKI, the aim of overcoming T790M mediated drug resistance is achieved, encouraging curative effect is shown, and simultaneously EGFR sensitive mutation is inhibited, so that the EGFR-TKI is hopeful to become the choice of first-line treatment. However, regardless of the generation of inhibitors, acquired resistance becomes an unavoidable issue, and currently, there is no good clinical treatment regimen for patients with resistance. Studies on acquired drug resistance mechanisms and treatment regimens have been ongoing, and studies have shown that a single patient may possess multiple drug resistance mechanisms, making the drug resistant tissues a plurality of alternate drivers, the heterogeneity and plasticity of the drug resistance mechanisms making treatment for a single drug challenging. Since SHP2 mediates transduction of multiple RTK signaling pathways, and the third generation EGFR-TKI resistance mechanism involves activation of RTK signaling pathways, the use of SHP2 inhibitors becomes one possibility for the treatment or extension of resistance development.
In patent WO2020073949, a protein tyrosine phosphatase-2C (SHP 2) inhibitor is developed, the structure of which is shown in the formula (I):
Patent WO2017161937 discloses a small molecule EGFR-TKI, chemical name: n- (5- ((4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acryloylamide) having the structure according to formula (II):
Disclosure of Invention
The invention provides an application of an SHP2 inhibitor in preparing a medicament for preventing or treating tumor diseases.
The invention also provides application of the SHP2 inhibitor in preparing EGFR-TKI sensitization drugs.
The invention further provides application of the SHP2 inhibitor in preparing medicines for treating EGFR-TKI drug-resistant tumor diseases.
The invention also provides application of the SHP2 inhibitor combined with EGFR-TKI in preparing medicines for preventing or treating tumor diseases.
The neoplastic disease of the invention is selected from the group consisting of breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, renal cancer, skin cancer, glioblastoma, neuroblastoma, sarcoma, liposarcoma, osteochondrioma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck tumor, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid tumor, ureter tumor, bladder tumor, gallbladder cancer, bile duct cancer, or chorionic epithelial cancer; lung cancer is preferred, and non-small cell lung cancer is more preferred.
In a preferred embodiment of the invention, the non-small cell lung cancer is selected from squamous cell carcinoma or non-squamous cell carcinoma; non-squamous cell carcinoma is preferred, wherein the non-squamous cell carcinoma may be adenocarcinoma, large cell carcinoma, and other subtypes of cell carcinoma.
In a preferred embodiment of the invention, the neoplastic disease is an EGFR mutated neoplastic disease.
In a preferred embodiment of the invention, the EGFR mutated neoplastic disease is non-small cell lung cancer, preferably having EGFR mutations that contain common or rare EGFR mutations or combinations thereof, wherein the common mutations are EGFR 19 exon deletions (EGFR Del 19), 858 site mutations (L858R); rare mutations are 289 site (G289V), 598 site (G598V), 709 site (E709X), 865 site (E865K), etc., preferably 719 site (G719X), 861 site (L861Q), 768 site (S768I), or any combination thereof, preferably EGFR L858R/T790M or EGFR Del19/T790M.
In a preferred embodiment of the invention, the EGFR mutated neoplastic disease has one or more EGFR mutations; preferably with 1-18 nucleotide point mutations, insertions and/or deletions at exons 18, 19, 20 or 21; more preferably, the EGFR L861Q, D761Y, L747S, S768I, G719C, G D, G719S and exon 20 insertion.
In a preferred embodiment of the invention, the tumor disease is an EGFR-TKI resistant tumor disease, preferably a third generation EGFR-TKI resistant tumor disease, more preferably an Oxitinib, ameitinib, nostinib, fumeitinib, olmesatinib, eweitinib, bei Futi ni, RASER tinib, CK101, ASK120067, ASP8273 or Nazatinib or a pharmaceutically acceptable salt thereof resistant tumor disease, further preferably an Oxitinib or an Ameitinib or a pharmaceutically acceptable salt thereof resistant tumor disease.
In a preferred embodiment of the invention, the neoplastic disease is EGFR-TKI resistant lung cancer, preferably third generation EGFR-TKI resistant lung cancer, more preferably Oxitinib, aamitinib, nostinib, vomertinib, olmesatinib, evultinib, bei Futi b, RASER tinib, CK101, ASK120067, ASP8273 or nazatinib or a pharmaceutically acceptable salt thereof resistant lung cancer, even more preferably Oxitinib or Aamitinib or a pharmaceutically acceptable salt thereof resistant lung cancer.
In a preferred embodiment of the invention, the tumor disease is EGFR-TKI resistant non-small cell lung cancer, preferably third generation EGFR-TKI resistant non-small cell lung cancer, more preferably non-small cell lung cancer resistant to octreotide, ametinib, nostinib, vomertinib, olmesatinib, eweitinib, bei Futi, RASER tinib, CK101, ASK120067, ASP8273 or nazatinib or a pharmaceutically acceptable salt thereof, further preferably non-small cell lung cancer resistant to octreotide or ametinib or a pharmaceutically acceptable salt thereof.
In a preferred embodiment of the present invention, the SHP2 inhibitor is a sensitizer for EGFR-TKI, which can prolong or treat drug resistance, eliminate drug resistance phenomenon of EGFR-TKI, and exhibit good therapeutic effect.
In a preferred embodiment of the invention, the SHP2 inhibitor is selected from a compound of formula (I):
In a further preferred embodiment of the present invention, the pharmaceutically acceptable salt of the compound of formula (I) is selected from the group consisting of hydrochloride, phosphate, hydrogen phosphate, sulfate, bisulfate, sulfite, acetate, oxalate, malonate, valerate, glutamate, oleate, palmitate, stearate, laurate, borate, p-toluenesulfonate, methanesulfonate, isethionate, maleate. Malate, tartrate, benzoate, pamoate, salicylate, vanillate, mandelate, succinate, gluconate, lactate or laurylsulfonate.
In a preferred embodiment of the invention, the EGFR-TKI is selected from osimertinib (Ornitinib), gefitinib (gefitinib), erlotinib (erlotinib), olmutinib (Omatinib), icotinib (BPI-2009H), pyrotinib (pyrroltinib), brigatinib (Bugatitinib), dacomitinib (dacatinib), afatinib (Afatinib), neratinib (Lapatinib), lapatinib (Lapatinib), ABT-414, varlitinib (ASLAN 001), HLX-07, tesevatinib (KD 019), theliatinib (HMPL-309), epitinib succinate (Eptifinib succinate), S-222611, poziotinib (wave Ji Tini), AST-2818, GNS-1480, mavelertinib (PF-06747775), AP-32788, AZD-3759, nazartinib (Naatinib )、Sym-013、tesevatinib(KD019)、allitinib tosylate(AST-1306(TsOH))、tarloxotinib bromide(TH-4000)、poziotinib( wave Ji Tini )、CK-101、QL-1203、JNJ-61186372、SKLB-1028、TAS-121、Hemay-020、Hemay-022、NRC-2694-A、simotinib hydrochloride() tematinib hydrochloride )、SPH-1188-11、GR-1401、SYN-004、ABBV-221、MP-0274、GC-1118、BPI-15000、DBPR-112、Pirotinib(KBP-5209)、PB-357、lifirafenib(BGB-283)、SCT-200、QLNC-120、agerafenib hydrochloride( or an pharmaceutically acceptable salt thereof.
In a further preferred embodiment of the invention, the EGFR-TKI is selected from olmutinib, afatinib, osimertinib, CK-101, erlotinib, icotinib, gefitinib or ametinib or a pharmaceutically acceptable salt thereof.
In a further preferred embodiment of the invention, the EGFR-TKI is ametinib or a pharmaceutically acceptable salt thereof.
In a further preferred embodiment of the invention, the EGFR-TKI is an ametinib acceptable salt; preferably, the drug is ametinib mesylate.
In a further preferred embodiment of the invention, the use of an SHP2 inhibitor in combination with an EGFR-TKI for the preparation of a medicament for the prevention or treatment of a neoplastic disease characterized in that said neoplastic disease has one or more EGFR mutations in EGFR L858R, T790M and Del 19.
In a further preferred embodiment of the invention, the SHP2 inhibitor is selected from a compound of formula (I) or a pharmaceutically acceptable salt thereof, and the EGFR-TKI is selected from osimertinib、gefitinib、erlotinib、olmutinib、icotinib、 pyrotinib、brigatinib、dacomitinib、afatinib、neratinib、lapatinib、ABT-414、varlitinib、HLX-07、tesevatinib、theliatinib、epitinib succinate、S-222611、poziotinib、AST-2818、GNS-1480、mavelertinib、AP-32788、AZD-3759、nazartinib、Sym-013、tesevatinib、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 or ametinib or a pharmaceutically acceptable salt thereof.
In a further preferred embodiment of the invention, the single administration dose of the SHP2 inhibitor is in the range of from 1 to 100mg, preferably from 1 to 50mg, more preferably from 1 to 20mg, even more preferably from 3 to 15mg.
In a further preferred embodiment of the invention, the frequency of administration of the SHP2 inhibitor is selected from once a day, twice a day or three times a day.
In a further preferred embodiment of the invention, the SHP2inhibitor is administered once a day at a single dose selected from 3-20 mg, preferably 3mg, 6mg, 10mg or 20mg.
In a preferred embodiment of the invention, the SHP2 inhibitor is administered in a single dose ranging from 1 to 100mg, exemplary doses being selected from 1mg、1.5mg、2.0mg、2.5mg、3mg、3.5mg、4mg、4.5mg、5mg、5.5mg、6.0mg、6.5mg、7.0mg、7.5mg、8.0mg、8.5mg、9.0mg、9.5mg、10mg、10.5mg、11mg、11.5mg、12mg、12.5mg、13mg、13.5mg、14mg、14.5mg、15mg、15.5mg、16mg、16.5mg、17mg、17.5mg、18mg、18.5mg、19mg、19.5mg、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.
In a further preferred embodiment of the invention, the SHP2 inhibitor is administered 1mg once a day, 1.5mg once a day, 2mg once a day, 2.5mg once a day, 3mg once a day, 3.5mg once a day, 4mg once a day, 4.5mg once a day, 5mg once a day, 5.5mg once a day, 6mg once a day, 6.5mg once a day, 7mg once a day, 7.5mg once a day, 8mg once a day, 8.5mg once a day, 9mg once a day, once 9.5mg, once a day, once 10mg, once a day, once 10.5mg, once a day, once 11mg, once a day, once 11.5mg, once a day, once 12mg, once a day, once 12.5mg, once a day, once 13mg, once a day, once 13.5mg, once a day, once 14mg, once a day, once 14.5mg, once a day, once 15mg, once a day, once 15.5mg, once a day, once 16mg, once a day, once 16.5mg, once a day, once 17mg, once a day, once 17.5mg, once a day, once 18mg, once a day, once 19.5mg, once a day, 20mg.
In a preferred embodiment of the invention, the EGFR-KTI is administered in a single dose range selected from 1 to 500mg, and exemplary doses are selected from 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、165mg、170mg、180mg、190mg、200mg、210mg、220mg、230mg、240mg、250mg、260mg、270mg、275mg、280mg、290mg、300mg、330mg、385mg、440mg、495mg.
In a further preferred embodiment of the invention, the single dose of EGFR-TKI is selected from the range of 20 to 500mg.
In a further preferred embodiment of the invention, the single dose of EGFR-TKI is selected from 50 to 300mg, further preferably 55mg, 110mg or 165mg.
In a further preferred embodiment of the invention, the frequency of administration of EGFR-TKI is selected from once a day, twice a day or three times a day.
In a further preferred embodiment of the invention, the EGFR-TKI is administered once a day, the single dose being selected from 55mg, 110mg, 165mg, 220mg, 260mg.
In a further preferred embodiment of the invention, the EGFR-TKI is administered 55mg once a day, 110mg once a day, 165mg once a day, 220mg once a day.
In a further preferred embodiment of the invention, the dose ratio of SHP2inhibitor to EGFR-TKI is selected from 1:50 to 1:5, preferably 1:40 to 1:2, more preferably 1:20 to 1:5.
In a further preferred embodiment of the present invention, the dose ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the Ametinib or a pharmaceutically acceptable salt thereof is selected from 1:40 to 1:2, preferably 1:20 to 1:2, more preferably 1:20 to 1:5, even more preferably 1:15 to 1:5.
In a further preferred embodiment of the invention, the SHP2 inhibitor is applied simultaneously, concurrently, independently or sequentially with the EGFR-TKI.
In a further preferred embodiment of the invention, the SHP2 inhibitor is administered simultaneously, concurrently, separately or sequentially with the EGFR-TKI after EGFR-TKI resistance.
The present invention also provides a pharmaceutical composition comprising:
(a) One or more SHP2 inhibitors;
(b) One or more EGFR-TKIs.
In a further preferred embodiment of the invention, the SHP2 inhibitor is selected from a compound of formula (I):
In a further preferred embodiment of the invention, the EGFR-TKI is selected from osimertinib、gefitinib、erlotinib、olmutinib、icotinib、pyrotinib、brigatinib、dacomitinib、afatinib、neratinib、lapatinib、ABT-414、varlitinib、HLX-07、tesevatinib、theliatinib、epitinib succinate、S-222611、poziotinib、AST-2818、GNS-1480、mavelertinib、AP-32788、AZD-3759、nazartinib、Sym-013、tesevatinib、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 or Amitinib or a pharmaceutically acceptable salt thereof according to the pharmaceutical composition of the invention.
The invention also provides the application of the pharmaceutical composition in treating tumor diseases.
The invention also provides application of the pharmaceutical composition in preparing medicines for preventing or treating tumor diseases.
In a preferred embodiment of the invention, the neoplastic disease is selected from the group consisting of breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, skin cancer, glioblastoma, neuroblastoma, sarcoma, liposarcoma, osteochondria, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck tumor, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid tumor, ureteral tumor, bladder tumor, gall bladder cancer, bile duct cancer or chorionic epithelial cancer according to the use of the pharmaceutical composition of the invention.
In a further preferred embodiment of the invention, the tumour disease is lung cancer, preferably non-small cell lung cancer, according to the use of the pharmaceutical composition of the invention; more preferred are non-small cell lung cancer with one or more EGFR mutations in EGFR L858R, T790M and Del 19.
In a further preferred embodiment of the invention, the SHP2 inhibitor is administered 1mg once a day, 1.5mg once a day, 2mg once a day, 2.5mg once a day, 3mg once a day, 3.5mg once a day, 4mg once a day, 4.5mg once a day, 5mg once a day, 5.5mg once a day, 6mg once a day, 6.5mg once a day, 7mg once a day, 7.5mg once a day, 8mg once a day, 8.5mg once a day, 9mg once a day, once 9.5mg, once a day, once 10mg, once a day, once 10.5mg, once a day, once 11mg, once a day, once 11.5mg, once a day, once 12mg, once a day, once 12.5mg, once a day, once 13mg, once a day, once 13.5mg, once a day, once 14mg, once a day, once 14.5mg, once a day, once 15mg, once a day, once 15.5mg, once a day, once 16mg, once a day, once 16.5mg, once a day, once 17mg, once a day, once 17.5mg, once a day, once 18mg, once a day, once 19.5mg, once a day, 20mg.
In a further preferred embodiment of the invention, the EGFR-TKI is administered 55mg once a day, 110mg once a day, 165mg once a day, 220mg once a day.
The present invention also provides a combined preparation comprising:
(a) One or more SHP2 inhibitors;
(b) One or more EGFR-TKIs.
In a preferred embodiment of the invention, the SHP2 inhibitor is selected from a compound of formula (I):
In a further preferred embodiment of the invention, the EGFR-TKI is selected from osimertinib、gefitinib、erlotinib、olmutinib、icotinib、pyrotinib、brigatinib、dacomitinib、afatinib、neratinib、lapatinib、ABT-414、varlitinib、HLX-07、tesevatinib、theliatinib、epitinib succinate、S-222611、poziotinib、AST-2818、GNS-1480、mavelertinib、AP-32788、AZD-3759、nazartinib、Sym-013、tesevatinib、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 or Amitinib or a pharmaceutically acceptable salt thereof, according to a combination formulation of the invention.
The invention also provides the use of the combined preparation for treating neoplastic diseases.
The invention also provides application of the combined preparation in preparing a medicament for preventing or treating tumor diseases.
In a preferred embodiment of the invention, the tumour disease is selected from breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumour, oesophageal cancer, stomach cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, skin cancer, glioblastoma, neuroblastoma, sarcoma, liposarcoma, osteochondral tumour, osteoma, osteosarcoma, seminoma, testicular tumour, uterine cancer, head and neck tumour, multiple myeloma, malignant lymphoma, polycythemia vera, leukaemia, thyroid tumour, ureteral tumour, bladder tumour, gall bladder cancer, bile duct cancer or chorionic epithelial cancer according to the use of the combination preparation according to the invention.
In a further preferred embodiment of the invention, the tumour disease is lung cancer, preferably non-small cell lung cancer, according to the use of the combination preparation according to the invention.
In a further preferred embodiment of the invention, the SHP2 inhibitor is administered 1mg once a day, 1.5mg once a day, 2mg once a day, 2.5mg once a day, 3mg once a day, 3.5mg once a day, 4mg once a day, 4.5mg once a day, 5mg once a day, 5.5mg once a day, 6mg once a day, 6.5mg once a day, 7mg once a day, 7.5mg once a day, 8mg once a day, 8.5mg once a day, 9mg once a day, once 9.5mg, once a day, once 10mg, once a day, once 10.5mg, once a day, once 11mg, once a day, once 11.5mg, once a day, once 12mg, once a day, once 12.5mg, once a day, once 13mg, once a day, once 13.5mg, once a day, once 14mg, once a day, once 14.5mg, once a day, once 15mg, once a day, once 15.5mg, once a day, once 16mg, once a day, once 16.5mg, once a day, once 17mg, once a day, once 17.5mg, once a day, once 18mg, once a day, once 19.5mg, once a day, 20mg.
In a further preferred embodiment of the invention, the EGFR-TKI is administered 55mg once a day, 110mg once a day, 165mg once a day, 220mg once a day.
The invention also provides a method of preventing or treating a neoplastic disease comprising administering an effective dose of a combination of the following compounds:
(a) One or more SHP2 inhibitors;
(b) One or more EGFR-TKIs;
In a further preferred embodiment of the invention, the SHP2 inhibitor is administered 1mg once a day, 1.5mg once a day, 2mg once a day, 2.5mg once a day, 3mg once a day, 3.5mg once a day, 4mg once a day, 4.5mg once a day, 5mg once a day, 5.5mg once a day, 6mg once a day, 6.5mg once a day, 7mg once a day, 7.5mg once a day, 8mg once a day, 8.5mg once a day, 9mg once a day, once 9.5mg, once a day, once 10mg, once a day, once 10.5mg, once a day, once 11mg, once a day, once 11.5mg, once a day, once 12mg, once a day, once 12.5mg, once a day, once 13mg, once a day, once 13.5mg, once a day, once 14mg, once a day, once 14.5mg, once a day, once 15mg, once a day, once 15.5mg, once a day, once 16mg, once a day, once 16.5mg, once a day, once 17mg, once a day, once 17.5mg, once a day, once 18mg, once a day, once 19.5mg, once a day, 20mg.
In a further preferred embodiment of the invention, the EGFR-TKI is administered 55mg once a day, 110mg once a day, 165mg once a day, 220mg once a day.
The SHP2 inhibitor is administered simultaneously, concurrently, independently or sequentially with the EGFR-TKI, preferably the SHP2 inhibitor is administered simultaneously, concurrently, independently or sequentially with the EGFR-TKI after EGFR-TKI resistance.
In a preferred embodiment of the invention, the method for preventing or treating a neoplastic disease according to the invention, wherein the EGFR-TKI is selected from osimertinib、gefitinib、erlotinib、olmutinib、icotinib、pyrotinib、brigatinib、dacomitinib、afatinib、neratinib、lapatinib、ABT-414、varlitinib、HLX-07、tesevatinib、theliatinib、epitinib succinate、S-222611、poziotinib、AST-2818、GNS-1480、mavelertinib、AP-32788、AZD-3759、nazartinib、Sym-013、tesevatinib、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 or Amitinib or a pharmaceutically acceptable salt thereof.
In a further preferred embodiment of the invention, the method according to the invention for preventing or treating a neoplastic disease, wherein the SHP2 inhibitor is selected from the group consisting of compounds of formula (I):
In a further preferred embodiment of the invention, the method according to the invention for preventing or treating a neoplastic disease selected from the group consisting of 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, glioblastoma, neuroblastoma, sarcoma, liposarcoma, osteochondral tumor, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck tumor, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid tumor, ureteral tumor, bladder tumor, gall bladder cancer, bile duct cancer or chorionic epithelial cancer; lung cancer is preferred, and non-small cell lung cancer is more preferred.
Unless otherwise indicated, the terms used in the present invention have the following meanings:
The term "combination" as used herein refers to a mode of administration, meaning that at least one dose of an SHP2 inhibitor and at least one dose of an EGFR-TKI are administered over a period of time, wherein both agents exhibit pharmacological effects. The period of time may be within one administration cycle, preferably within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours. The SHP2 inhibitor and EGFR-TKI may be administered simultaneously or sequentially. Such a period includes treatment in which the SHP2 inhibitor and EGFR-TKI are administered by the same route of administration or by different routes of administration.
The term "effective dose" refers to an amount of a drug effective to treat a disease or disorder in a mammal. In the case of cancer, a therapeutically effective dose of the drug may reduce the number of cancer cells; reducing the size of the tumor; inhibit (i.e., slow and preferably prevent to some extent) infiltration of cancer cells into surrounding organs; inhibit (i.e., slow and preferably prevent to some extent) tumor metastasis; inhibit tumor growth to a certain extent; and/or to some extent, alleviate one or more symptoms associated with the disorder. Depending on the extent to which the drug may prevent the growth of and/or kill existing cancer cells, it may be cytostatic and/or cytotoxic. For cancer treatment, in vivo efficacy may be measured by assessing survival duration, progression Free Survival (PFS) duration, response Rate (RR), response duration, and/or quality of life.
The SHP2 inhibitor is combined with EGFR-TKI, can eliminate the drug resistance phenomenon of EGFR-TKI, has good treatment effect, has stronger anti-tumor effect and no obvious toxic or side effect, provides a new exploration for improving the sensitivity of EGFR-TKI and a treatment method of tumor diseases, and has wide application prospect.
Drawings
FIG. 1 shows the curative effect of drug A on PC-9 human lung cancer transplantation tumor after the drug A is resistant to the Ameitinib.
Figure 2. Effect of drug A on body weight of PC-9 tumor-bearing mice after Ameitinib resistance.
Figure 3. Therapeutic effect of drug A in combination with Ameitinib on Ameitinib resistant PC-9 human lung cancer transplants.
FIG. 4. Effect of drug A in combination with African on body weight of PC-9 tumor-bearing mice after African drug resistance.
Detailed Description
The present invention will be explained in more detail with reference to the following examples, which are only for illustrating the technical aspects of the present invention and do not limit the spirit and scope of the present invention.
Example 1
Purpose of experiment
The inhibition effect of the compound (drug A) shown in the formula (I) on PC-9 human lung cancer mouse xenograft tumor after the drug resistance of the Ameitinib is evaluated.
Experimental materials
Drug a: prepared according to the method disclosed in WO2020073949, 0.5% hpmc for pharmaceutical formulation;
Drug B: ametinib, prepared according to the method disclosed in WO2017161937, is formulated with a pH4.18 acetate buffer;
Human lung cancer PC-9 cells were cultured in vitro in monolayer by adding 10% fetal bovine serum to RPMI 1640 medium, 100U/mL penicillin and 100 μg/mL streptomycin, and culturing in a 5% CO2 cell incubator at 37deg.C. Passaging was performed twice a week with conventional digestion treatments with pancreatin-EDTA. When the saturation of the cells is 80% -90% and the number reaches the requirement, the cells are collected, counted and inoculated.
BALB/c nude mice, females, weight 19-23g.
Experimental method
Injecting PC-9 cells of 5×10 6 human lung cancer cells into the back of nude mice, after the tumor grows to a proper volume, selecting animals with tumor volume of 100-200mm 3 for drug resistance induction of armetinib, and adding drug A for treatment after drug resistance of the tumor occurs. Mice were given intragastric administration (p.o), 1 time daily (qd); the administration volume is 10mL/kg; the solvent group was given the same volume of "solvent" (PH 4.18 acetate buffer); the specific dosages and schedules are shown in Table 1. Tumor volume was measured, mice body weight was weighed, and data were recorded:
TABLE 1 dosing regimen for drug A in the treatment of an Ameitinib resistant PC-9 model
First stage (induction stage)
Group of Grouping Dosage for administration Period of administration Route of administration
1 Solvent(s) - qd*21 p.o
2 Ameitinib 5mg/kg qd*48 p.o
Second stage (treatment stage)
Group of Grouping Dosage for administration Period of administration Route of administration
2-1 Ameitinib 5mg/kg qd*29 p.o
2-2 Ametinib+drug A 5mg/kg+6mg/kg qd*29+qd*29 p.o+p.o
Experimental parameters
The experimental index is to examine the influence of the drug on the tumor growth, and the specific index is T/C% or tumor inhibition rate TGI (%).
The tumor diameter is measured by a vernier caliper, and the calculation formula of the tumor volume (V) is as follows: v=1/2×a×b 2, where a and b represent length and width, respectively.
T/C (%) = (T-T 0)/(C-C 0) ×100, where T, C is the tumor volume at the end of the experiment and T 0、C 0 is the tumor volume at the beginning of the experiment.
Tumor inhibition ratio (TGI) (%) =100-T/C (%).
Tumor inhibition ratio (TGI) (%) =100- (T-T 0)/T 0 ×100 when tumor regression occurs
Tumor Partial Regression (PR) is defined if the tumor is reduced from the starting volume, i.e., T < T 0 or C < C 0; if the tumor completely disappeared, it is defined as complete tumor regression (CR).
After the experiment is finished, the end point of the experiment is reached, or the tumor volume reaches 2000mm 3,CO 2 to be anesthetized and sacrificed, then the tumor is dissected and photographed.
Data processing
Experimental data were analyzed and plotted using GRAPHPAD PRISM 8.4.3. Comparison between two tumor volumes was performed using a two-tailed T-test. One-way ANOVA repeated measure for comparison between three or more groups should be used for multiple comparisons using Dunnett's after ANOVA analysis if there is a significant difference in the F values. P <0.05 was defined as statistically significant.
Experimental results
The curative effect of the drug A on PC-9 human lung cancer transplants after the drug A is resistant to the African is shown in table 2 and figure 1:
TABLE 2 growth inhibition of African drug resistance PC-9 model by drug A
P value D77: the average volumes of the two groups of tumors are analyzed by using a T-test;
Experimental results show that the average tumor volume of the continuous administration of the amotinib to the 21 st day, the 49 th day and the 77 th day is 47mm 3、108mm 3、406mm 3 respectively, the tumor volume shows a growth trend, a certain drug resistance phenomenon is shown, and the average tumor volume of the combined treatment of the drug A added in the drug resistance growth stage is 83mm 3 on the 77 th day, and the average tumor volume has a statistical difference (p < 0.05) compared with the single treatment group of the amotinib, so that the drug A can prolong the drug resistance time of the amotinib.
The effect of drug A on PC-9 tumor-bearing mice body weight after Ametinib resistance is shown in Table 3 and FIG. 2:
TABLE 3 weight changes in animals of the second stage groups
A: the day of dosing (day 0) was started to calculate the experimental time;
b: data are expressed as "mean ± standard error%
The results show that the tumor-bearing mice can well tolerate the drug dosage in the whole experimental process, and no obvious weight loss symptoms occur.
Conclusion: in general, drug A in combination with Ametinib can prolong the occurrence of drug resistance, shows stronger anti-tumor effect, and does not show obvious toxic or side effect.
Example 2
Purpose of experiment
The inhibition effect of the combination of the compound (drug A) shown in the formula (I) and the amotinib on the PC-9 humanized lung cancer mice xenograft tumor resistant to the amotinib is evaluated.
Experimental materials
Drug a: prepared according to the method disclosed in WO2020073949, 0.5% hpmc for pharmaceutical formulation;
Drug B: ametinib, prepared according to the method disclosed in WO2017161937, is formulated with a pH4.18 acetate buffer;
Ametinib resistant PC-9 graft: the transplantation tumor model is an ametinib drug resistance model built in the applicant, and PC-20R transplantation tumor is obtained after the sensitive PC-9 parent transplantation tumor model treated by the ametinib for a long time is adopted to induce drug resistance to the ametinib.
BALB/c nude mice, females, weight 19-23g.
Experimental method
The induced ametinib drug-resistant transplantation tumor (PC-20R) is sheared into tumor tissue with the size of 1-2mm by using surgical scissors, a puncture needle is adopted to inoculate the tumor tissue under the back of the right upper part of a nude mouse, and after the tumor grows to a proper volume, animals with the tumor-bearing volume of 100-200mm 3 are selected for grouping administration. The specific dosages and schedules are shown in Table 4. Tumor volume was measured, mice body weight was weighed, and data were recorded:
TABLE 4 dosing regimen for drug A in combination with Ameitinib for treatment of the Ameitinib resistant PC-9 model
Group of Grouping Dosage for administration Period of administration Route of administration
1 Solvent(s) - qd*22 p.o
2 Ameitinib 20mg/kg qd*22 p.o
3 Medicine A 6mg/kg qd*22 p.o
4 Ametinib+drug A 20mg/kg+6mg/kg qd*22 p.o
Experimental parameters
The experimental index is to examine the influence of the drug on the tumor growth, and the specific index is T/C% or tumor inhibition rate TGI (%).
The tumor diameter is measured by a vernier caliper, and the calculation formula of the tumor volume (V) is as follows: v=1/2×a×b 2, where a and b represent length and width, respectively.
T/C (%) = (T-T 0)/(C-C 0) ×100, where T, C is the tumor volume at the end of the experiment and T 0、C 0 is the tumor volume at the beginning of the experiment.
Tumor inhibition ratio (TGI) (%) =100-T/C (%).
Tumor inhibition ratio (TGI) (%) =100- (T-T 0)/T 0 ×100 when tumor regression occurs
Tumor Partial Regression (PR) is defined if the tumor is reduced from the starting volume, i.e., T < T 0 or C < C 0; if the tumor completely disappeared, it is defined as complete tumor regression (CR).
After the experiment is finished, the end point of the experiment is reached, or the tumor volume reaches 2000mm 3,CO 2 to be anesthetized and sacrificed, then the tumor is dissected and photographed.
Data processing
Experimental data were analyzed and plotted using GRAPHPAD PRISM 8.4.3. Comparison between two tumor volumes was performed using a two-tailed T-test. One-way ANOVA repeated measure for comparison between three or more groups should be used for multiple comparisons using Dunnett's after ANOVA analysis if there is a significant difference in the F values. P <0.05 was defined as statistically significant.
Experimental results
The therapeutic effects of drug A combined with the Amatinib on the Amatinib resistant PC-9 human lung cancer transplantation tumor are shown in Table 5 and figures 3-4:
TABLE 5 growth inhibition of Ameitinib resistant PC-9 model by drug A in combination with Ameitinib
Experimental results show that in an African drug-resistant PC-9 grafted tumor model, the growth of tumors in the African combined drug A treatment group is significantly inhibited compared with the single treatment group. After 22 days of continuous dosing, the tumor volume of the combination group was 104mm 3, significantly reduced compared to 852mm 3、615mm 3 tumor volumes of the amotinib and drug a alone treatment group, with statistical differences (p < 0.05). The drug A and the ametinib combined drug can obviously inhibit the growth of the ametinib drug-resistant transplanted tumor and have a synergistic effect. During the course of treatment, no significant abnormalities in mouse body weight were seen.

Claims (16)

  1. Use of an SHP2 inhibitor in the manufacture of a medicament for the prevention or treatment of a neoplastic disease, optionally in combination with an EGFR-TKI, characterized in that the SHP2 inhibitor is selected from a compound of formula (I):
    Preferably, the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, phosphate, hydrogen phosphate, sulfate, bisulfate, sulfite, acetate, oxalate, malonate, valerate, glutamate, oleate, palmitate, stearate, laurate, borate, p-toluenesulfonate, methanesulfonate, isethionate, maleate, malate, tartrate, benzoate, pamoate, salicylate, vanillin, mandelate, succinate, gluconate, lactobionate, or laurylsulfonate.
  2. The use according to claim 1, wherein the neoplastic disease is selected from breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, skin cancer, glioblastoma, neuroblastoma, sarcoma, liposarcoma, osteochondrioma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck tumor, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid tumor, ureter tumor, bladder tumor, gall bladder cancer, bile duct cancer or chorionic epithelial cancer; lung cancer is preferred; more preferably non-small cell lung cancer.
  3. The use according to claim 1 or 2, wherein the neoplastic disease has one or more EGFR mutations; preferably with 1-18 nucleotide point mutations, insertions and/or deletions at exons 18, 19, 20 or 21; more preferably, it has an EGFR 19 exon deletion, 858, 289, 598, 709, 865, preferably 719, 861 or 768 site mutation; further preferred are mutations with one or more of EGFR L858R, T790M, del, T790M L861Q, D761Y, L747S, S768I, G719C, G D, G719S and exon 20 insertion.
  4. The use according to claim 3, wherein the neoplastic disease is EGFR-TKI resistant neoplastic disease; non-small cell lung cancer with EGFR-TKI resistance is preferred; more preferably, the third generation EGFR-TKI resistant non-small cell lung cancer; further preferred are non-small cell lung cancers that are resistant to octreotide, ametinib, nostinib, vomertinib, olmesatinib, ivertinib, bei Futi b, RASER tinib, CK101, ASK120067, ASP8273, or nazatinib or a pharmaceutically acceptable salt thereof; still further preferred are non-small cell lung cancers that are resistant to either octenib or ametinib or pharmaceutically acceptable salts thereof.
  5. The use according to claim 1, wherein the EGFR-TKI is selected from osimertinib、gefitinib、erlotinib、olmutinib、icotinib、pyrotinib、brigatinib、dacomitinib、afatinib、neratinib、lapatinib、ABT-414、varlitinib、HLX-07、tesevatinib、theliatinib、epitinibsuccinate、S-222611、poziotinib、AST-2818、GNS-1480、mavelertinib、AP-32788、AZD-3759、nazartinib、Sym-013、tesevatinib、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 or ametinib; preferably olmutinib, afatinib, osimertinib, CK-101, erlotinib, icotinib, gefitinib or ametinib; most preferably, almitinib; armetinib mesylate is preferred.
  6. The use according to any one of claims 1-5, wherein the EGFR-TKI is ametinib or a pharmaceutically acceptable salt thereof and the neoplastic disease has one or more EGFR mutations in EGFR L858R, T790M and Del 19.
  7. Use according to any one of claims 1 to 5, wherein the single administration dose of the SHP2inhibitor is in the range of 1 to 100mg; preferably 1 to 20mg; more preferably 3 to 15mg.
  8. The use according to any one of claims 1 to 5, wherein the frequency of administration of the SHP2 inhibitor is selected from once a day, twice a day or three times a day.
  9. The use according to any one of claims 1-5, wherein the single dose of the SHP2 inhibitor is 3mg, the once-daily, single dose is 6mg, the once-daily, single dose is 10mg, the once-daily or single dose is 20mg, once-daily.
  10. The use according to any one of claims 1 to 5, wherein the single administration dose of EGFR-TKI is selected from 1 to 500mg, preferably 20 to 500mg, more preferably 50 to 300mg, even more preferably 55mg, 110mg, 165mg or 220mg.
  11. The use according to any one of claims 1 to 5, wherein the frequency of administration of EGFR-TKI is selected from once a day, twice a day or three times a day.
  12. The use according to any one of claims 1 to 5, wherein the EGFR-TKI is administered once daily, at a single dose of 110mg, once daily, at a single dose of 165mg, once daily or once daily, at a single dose of 220mg.
  13. The use according to any one of claims 1 to 5, wherein the dosage ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to amotinib or a pharmaceutically acceptable salt thereof is selected from 1:40 to 1:2; preferably 1:20 to 1:2; more preferably 1:20 to 1:5.
  14. The use according to any one of claims 1 to 5, wherein the SHP2 inhibitor is administered simultaneously, concurrently, separately or sequentially with the EGFR-TKI, preferably wherein the SHP2 inhibitor is administered simultaneously, concurrently, separately or sequentially with the EGFR-TKI after EGFR-TKI resistance.
  15. A pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and an EGFR-TKI or a pharmaceutically acceptable salt thereof; preferably, the compound shown in the formula (I) or pharmaceutically acceptable salt thereof and the Ametinib or pharmaceutically acceptable salt thereof.
  16. The pharmaceutical composition according to claim 15, wherein the use in the manufacture of a medicament for the prevention or treatment of non-small cell lung cancer; non-small cell lung cancer with one or more EGFR mutations in EGFR L858R, T790M and Del19 is preferred.
CN202280063878.2A 2021-09-28 2022-09-28 Medical application of SHP2 inhibitor combined with EGFR-TKI in treatment and prevention of tumor diseases Pending CN118019537A (en)

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