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EP-4740947-A1 - PHARMACEUTICAL COMBINATION OF EGFR KINASE INHIBITOR AND C-MET KINASE INHIBITOR FOR TREATING TUMOR DISEASES

EP4740947A1EP 4740947 A1EP4740947 A1EP 4740947A1EP-4740947-A1

Abstract

The present invention relates to a drug combination of an EGFR kinase inhibitor and a c-Met kinase inhibitor, and use thereof in the preparation of a drug for treating tumor diseases. Specifically, a drug combination of a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a compound of Formula (II) or a pharmaceutically acceptable salt thereof is provided. The drug combination shows a stronger anti-tumor activity, has no obvious toxic side effects, and has wide prospects of application.

Inventors

  • CHEN, HONGYU
  • SONG, TINGTING
  • XU, ZHENG
  • SUN, Jiye
  • ZONG, Zaiwei
  • HAN, Luwei
  • CHEN, JING

Assignees

  • Jiangsu AoSaiKang Pharmaceutical Co., Ltd.

Dates

Publication Date
20260513
Application Date
20240801

Claims (9)

  1. A drug combination for treating tumor diseases, comprising (i) an EGFR kinase inhibitor; and (ii) a c-Met kinase inhibitor, wherein the EGFR kinase inhibitor is selected from a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and the c-Met kinase inhibitor is selected from a compound of Formula (II) or a pharmaceutically acceptable salt thereof,
  2. Use of a combination of a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a compound of Formula (II) or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating tumor diseases;
  3. The drug combination according to claim 1 or the use according to claim 2, wherein the tumor diseases are selected from breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor, esophageal carcinoma, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, skin cancer, glioblastoma, neuroblastoma, sarcoma, liposarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, cervical cancer, head and neck tumor, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid neoplasm, ureteral tumor, bladder cancer, gallbladder cancer, bile duct carcinoma or chorionepithilioma, preferably lung cancer, and further preferably non-small cell lung cancer.
  4. The drug combination according to claim 1 or the use according to claim 2, wherein the tumor diseases are tumor diseases in patients resistant to EGFR kinase inhibitors; and preferably non-small cell lung cancer resistant to EGFR kinase inhibitors.
  5. The drug combination according to claim 1 or the use according to claim 2, wherein the tumor diseases are tumor diseases associated with EGFR mutation and/or MET alteration; preferably non-small cell lung cancers associated with EGFR mutation and/or MET alteration; and further preferably non-small cell lung cancers associated with one or more of EGFR 19del, MET alteration, EGFR L858R, and EGFR T790M.
  6. The drug combination according to claim 1 or the use according to claim 2, wherein the tumor diseases are non-small cell lung cancer that has disease progression after treatment with EGFR kinase inhibitors previously and is associated with MET alteration.
  7. The drug combination according to claim 1 or the use according to claim 2, wherein the single dosage of the compound of Formula (I) or the pharmaceutically acceptable salt thereof is 40-320 mg, preferably 60-240 mg, and further preferably 80-160 mg; the frequency of administration of the compound of Formula (I) or the pharmaceutically acceptable salt thereof is once a day, twice a day, three times a day or once every two days; the single dosage of the compound of Formula (II) or the pharmaceutically acceptable salt thereof is 40-640 mg, preferably 40-320 mg, and further preferably 60-320 mg; and the frequency of administration of the compound of Formula (II) or the pharmaceutically acceptable salt thereof is once a day, twice a day, three times a day or once every two days.
  8. The drug combination according to claim 1 or the use according to claim 2, wherein the compound of Formula (I) or the pharmaceutically acceptable salt thereof and the compound of Formula (II) or the pharmaceutically acceptable salt thereof are administered simultaneously or at different times.
  9. A pharmaceutical preparation, comprising the drug combination according to claim 1 and one or more pharmaceutically acceptable carriers.

Description

TECHNICAL FIELD The present invention belongs to the field of medicine, and specifically relates to a drug combination of an EGFR kinase inhibitor and a c-Met kinase inhibitor, and use thereof in the preparation of a drug for treating tumor diseases. BACKGROUND Lung cancer is the most common malignant tumor in China and even in the world. The latest global cancer data released by the International Agency for Research on Cancer (IARC) of the World Health Organization in 2020 shows that the number of newly found patients with lung cancer in the world is 2.2 million, with the incidence ranked the 2nd place and the mortality ranked the 1st place. In China, the incidence and mortality of lung cancer are ranked the 1st place out those of all malignant tumors, and the incidence and mortality increase with age. Histopathologically, lung cancer can be classified into non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), where NSCLC accounts for about 85% of all lung cancers, and about 75% of patients with NSCLC are in the middle and advanced stage at the time of diagnosis, with low 5-year survival rate and poor prognosis. For unresectable middle-stage and advanced lung cancer, although the traditional radiotherapy and chemotherapy have made some progress, the treatment efficiency is still low, and the advanced or metastatic lung cancer is still a fatal disease with a large number of unmet medical needs. Epidermal growth factor receptor (EGFR) gene is one of the most common driver genes in NSCLC, and about 50% of patients with NSCLC in China have EGFR gene mutation (J Thorac Oncol, 2014, 9(9):e70). EGFR tyrosine kinase inhibitors (TKIs), as the most commonly used targeted drugs, have made a breakthrough, and EGFR kinase inhibitors have become the standard first-line treatment for patients with EGFR mutation-positive advanced NSCLC. Although EGFR kinase inhibitors have become the standard first-line treatment for patients with EGFR mutation induced NSCLC, the patients have developed drug resistance after 9-14 months of treatment, due to the mechanism including new mutation or amplification of EGFR or other genes. The existing research data show that the amplification of mesenchymal epithelial transition factor (MET) gene may be one of the causes leading to acquired resistance in patients to EGFR kinase inhibitors. MET alteration occurs in some patients with NSCLC that are EGFR mutation positive and have acquired resistance to EGFR kinase inhibitors. Therefore, the combination of an EGFR kinase inhibitor and a c-MET kinase inhibitor has potential application value in the treatment of NSCLC patients with drug resistance caused by MET gene amplification or MET protein overexpression. WO2016/082713A1 discloses a class of 2-aminopyrimidine compounds, which can potently inhibit the activity of a kinase having the drug resistance inducing mutation EGFR T790M and sensitive EGFR mutation, and show significant anti-tumor activity in vitro and in vivo for tumors driven by EGFR mutation. The compound N-((5-((5-chloro-4-((naphthalen-2-yl)amino)) pyrimidin-2-yl)amino)-2-((N-methyl-N-dimethylaminoethyl)amino)-4-methoxyphenyl) acrylamide has a structure of Formula (I): WO2020/156453A1 discloses a class of tricyclic compounds containing a pyrimidinyl group, which can effectively and selectively inhibit the activity of c-MET kinase, and can be used to treat diseases mediated by MET alteration, and specifically discloses compounds of Formula (II): SUMMARY In a first aspect of the present invention, a drug combination for treating tumor diseases is provided. The drug combination comprises (i) an EGFR kinase inhibitor; and (ii) a c-Met kinase inhibitor. In some embodiments, the EGFR kinase inhibitor is selected from a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and Gefitinib, Erlotinib, Icotinib, Lapatinib, Afatinib, Dacomitinib, Neratinib, Osimertinib, Almonertinib, Rociletinib, Furmonertinib, Rociletinib, Abivertinib, Befotertinib, Lazertinib, CK-101, ASP8273, nazartinib or a pharmaceutically acceptable salt thereof. In some embodiments, the c-Met kinase inhibitor is selected from a compound of Formula (II) or a pharmaceutically acceptable salt thereof, and Crizotinib, Cabozantinib, Capmatinib, Tepotinib, Volitinib, Gumarontinib, Sitravatinib, EMD-1214063, Elzovantinib, Bozitinib, XL-092, AL-2846, TAS-115, AMG-337, HS-10241, TQ-B3139, ABN-401or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the EGFR kinase inhibitor is selected from a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and the c-Met kinase inhibitor is selected from a compound of Formula (II) or a pharmaceutically acceptable salt. In a second aspect of the present invention, use of a combination of the compound of Formula (I) or a pharmaceutically acceptable salt thereof and the compound of Formula (II) or a pharmaceutically acceptable salt thereof in the preparation of a drug for tre