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EP-4096671-B1 - COMBINATION THERAPY FOR TREATING ABNORMAL CELL GROWTH

EP4096671B1EP 4096671 B1EP4096671 B1EP 4096671B1EP-4096671-B1

Inventors

  • PACHTER, JONATHAN A.
  • COMA, Silvia

Dates

Publication Date
20260506
Application Date
20210128

Claims (13)

  1. A combination of a KRAS G12C inhibitor and CH5126766, having the structure: or a pharmaceutically acceptable salt thereof, for use in a method of treating a cancer in a subject in need thereof, wherein the cancer is a cancer with a KRAS G12C mutation, wherein the KRAS G12C inhibitor is: (a) AMG-510 or a pharmaceutically acceptable salt thereof; or (b) MRTX849 or a pharmaceutically acceptable salt thereof.
  2. The combination for use according to claim 1, wherein the KRAS G12C inhibitor is: (a) dosed at about 100 mg to about 2000 mg; (b) administered once daily or twice daily; and/or (c) administered orally.
  3. The combination for use according to claim 1 or claim 2, wherein the CH5126766, or a pharmaceutically acceptable salt thereof, is dosed at least once a week (e.g., once a week, twice a week, three times a week, four times a week, five times a week, or six times a week); optionally wherein the CH5126766, or a pharmaceutically acceptable salt thereof is: (a) dosed once a week; (b) dosed twice a week; (c) dosed once daily; or (d) dosed twice daily.
  4. The combination for use according to any of the preceding claims, wherein the CH5126766, or a pharmaceutically acceptable salt thereof, is dosed at about 0.1 mg to about 100 mg; and/or is administered orally.
  5. The combination for use according to any of the preceding claims, wherein the CH5126766, or a pharmaceutically acceptable salt thereof, is administered: (a) before the KRAS G12C inhibitor is administered; (b) after the KRAS G12C inhibitor is administered; (c) concurrently with the KRAS G12C inhibitor; or (d) in a separate composition to the KRAS G12C inhibitor.
  6. The combination for use according to any of the preceding claims, wherein the cancer is lung adenocarcinoma, non-small cell lung carcinoma, colorectal cancer (CRC), uterine endometrioid carcinoma, bladder urothelial carcinoma, breast invasive lobular carcinoma, cervical squamous cell carcinoma, cutaneous melanoma, endocervical adenocarcinoma, hepatocellular carcinoma, pancreatic adenocarcinoma, biphasic type pleural mesothelioma, renal clear cell carcinoma, renal clear cell carcinoma, stomach adenocarcinoma, tubular stomach adenocarcinoma, uterine carcinosarcoma, or uterine malignant mixed Mullerian tumor.
  7. A combination of a KRAS G12C inhibitor and defactinib, or a pharmaceutically acceptable salt thereof, for use in a method of treating a cancer in a subject in need thereof, wherein the cancer is a cancer with a KRAS G12C mutation, wherein the KRAS G12C inhibitor is: (a) AMG-510 or a pharmaceutically acceptable salt thereof; or (b) MRTX849 or a pharmaceutically acceptable salt thereof.
  8. The combination for use according to claim 7, wherein the method further comprises administering CH5126766 or a pharmaceutically acceptable salt thereof.
  9. The combination for use according to claim 7 or claim 8, wherein the defactinib, or a pharmaceutically acceptable salt thereof, is: (a) dosed twice daily or once daily; (b) dosed at about 100 mg to about 1000 mg optionally at about 200 mg to about 400 mg; optionally at 200 mg or at 400 mg; and/or (c) administered orally.
  10. The combination for use according to any one of claims 7 to 9, wherein the KRAS G12C inhibitor is: (a) dosed at about 100 mg to about 2000 mg; (b) administered once daily or twice daily; and/or (c) administered orally.
  11. The combination for use according to any one of claims 7 to 10, wherein the defactinib, or a pharmaceutically acceptable salt thereof, is: (a) administered before the KRAS G12C inhibitor is administered; (b) administered after the KRAS G12C inhibitor is administered; (c) administered concurrently with the KRAS G12C inhibitor; or (d) in a separate composition to the KRAS G12C inhibitor.
  12. The combination for use according to any one of claims 8 to 11, wherein the CH5126766 or a pharmaceutically acceptable salt thereof is: (a) dosed at least once a week (e.g., once a week, twice a week, three times a week, four times a week, five times a week, or six times a week); optionally wherein the CH5126766 or a pharmaceutically acceptable salt thereof is dosed once a week; or twice a week; or (b) dosed once daily; or twice daily; and/or (c) dosed at about 0.1 mg to about 100 mg; and/or (d) administered orally.
  13. The combination for use according to any one of claims 7 to 12, wherein the cancer is lung adenocarcinoma, non-small cell lung carcinoma, colorectal cancer (CRC), uterine endometrioid carcinoma, bladder urothelial carcinoma, breast invasive lobular carcinoma, cervical squamous cell carcinoma, cutaneous melanoma, endocervical adenocarcinoma, hepatocellular carcinoma, pancreatic adenocarcinoma, biphasic type pleural mesothelioma, renal clear cell carcinoma, renal clear cell carcinoma, stomach adenocarcinoma, tubular stomach adenocarcinoma, uterine carcinosarcoma, or uterine malignant mixed Mullerian tumor.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Patent Application Number 62/968,615, filed January 31, 2020, and 63/115,433, filed November 18, 2020. BACKGROUND Convincing evidence suggests that Focal Adhesion Kinase (FAK), a cytoplasmic, non-receptor tyrosine kinase, plays an essential role in cell survival, proliferation, migration, invasion, and adhesion (Clark and Brugge 1995, Science 268: 233-239) and its aberrant activation is associated with an increase in the metastatic potential of tumors (Owens et al. 1995, Cancer Research 55: 2752-2755). Selective inhibitors of certain non-receptor tyrosine kinases, such as FAK, ICK, SRC, ABL or serine/threonine kinases (e.g., cyclin dependent kinases), are useful in the treatment of abnormal cell growth, in particular cancer, in mammals. FAK is also known as the Protein-Tyrosine Kinase 2, PTK2. FAK expression and/or activity has been reported to be upregulated in a range of malignancies, including uveal melanoma and cancers of the thyroid, prostate, cervix, colon, rectum, oral epithelium, ovary, and breast. FAK inhibitor, defactinib, has been shown to reduce tumor in patients with KRAS mt NSCLC (Gerber et al., https://www.verastem.com/wp-content/uploads/2018/03/WCLC-2015-NSCLC_Gerber.pdf). Kirsten Rat Sarcoma 2 Viral Oncogene Homolog (KRAS) is a small GTPase and a member of the Ras family of oncogenes. KRAS serves as a molecular switch cycling between inactive (GDP-bound) and active (GTP-bound) states to transduce upstream cellular signals received from multiple tyrosine kinases to downstream effectors to regulate a wide variety of processes, including cellular proliferation (e.g., see Alamgeer et al., (2013) Current Opin Pharmcol. 13:394-401). KRAS gene mutations are common in cancer, for example, pancreatic cancer, lung adenocarcinoma, colorectal cancer (CRC), gall bladder cancer, thyroid cancer, and bile duct cancer (Kodaz et al., EIMO 2017). KRAS mutations are observed in about 30% of patients with lung adenocarcinoma, 40% of patients with CRC and 67% of patients with pancreatic adenocarcinomas. Whereas KRAS is a major driver in lung adenocarcinomas and in pancreatic cancers, KRAS is not a primary initiating event in colorectal cancer (McCormick, 2015). KRAS G12C inhibitors, AMG-510 and MRTC849, have been show to possess anti-tumoral activity, (Cannon et al., Nature 2019, DOI: 10.1038/ s41586-019-1694-1, Hallin et al., Cancer Discovery 2020, DOI: 10.1158/2159-8290.c.6547879.v1). Components of the RAS/RAF/MEK/ERK signal transduction pathway also represent opportunities for the treatment of abnormal cell growth, e.g., cancer. Selective inhibitors of certain components of the RAS/RAF/MEK/ERK signal transduction pathway, such as RAS, RAF, MEK and ERK, are useful in the treatment of abnormal cell growth, in particular cancer, in mammals. CH5126766 is an attractive dual RAF/MEK inhibitor in RAS-mutated malignant tumor cells (Wado et al. Plos One 2014, DOI: 10.1371/journal.pone.0113217). Due to the severity and breadth of diseases and disorders associated with abnormal cell growth (e.g., cancer), there is a need for effective therapeutic means and methods for treatment. The compounds, compound combinations, compositions, and methods described herein are directed toward this end. SUMMARY The present invention is defined by the claims. A combination of a KRAS G12C inhibitor and CH51226766, or a pharmaceutically acceptable salt thereof, for use in a method of treating a cancer in a subject in need thereof, wherein the cancer is a cancer with a KRAS G12C mutation,wherein the KRAS G12C inhibitor is:(a) AMG-510 or a pharmaceutically acceptable salt thereof; or (b) MRTX849 or a pharmaceutically acceptable salt thereof. A combination of a KRAS G12C inhibitor and defactinib, or a pharmaceutically acceptable salt thereof, for use in a method of treating a cancer in a subject in need thereof, wherein the cancer is a cancer with a KRAS G12C mutation,wherein the KRAS G12C inhibitor is:(a) AMG-510 or a pharmaceutically acceptable salt thereof; or (b) MRTX849 or a pharmaceutically acceptable salt thereof. Any subject-matter falling outside the scope of the claims is provided for information only. Methods of treatment of the human body by therapy, referred to in this description, are not part of the present invention as such, but are described here in relation to compounds and pharmaceutical compositions for use in said methods for treatment of the human body by therapy, according to the present invention. Thus, in an aspect, provided herein is a method of treating a cancer in a subject in need thereof, the method comprising administering to the subject a KRAS G12C inhibitor (e.g., ARS-853, ARS-1620, ARS-3248, LY3499446, AMG-510, and MRTX849) or a pharmaceutically acceptable salt thereof in combination with a FAK inhibitor (e.g., defactinib, TAE226, BI-853520 (IN10018), GSK2256098, PF-03814735, BI-4464, VS-4718, and