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CN-121971627-A - Targeted treatment of cancers with deregulated fibroblast growth factor receptor signaling

CN121971627ACN 121971627 ACN121971627 ACN 121971627ACN-121971627-A

Abstract

The present invention provides advantageous methods and compositions for treating a host suffering from a cancer having a disorder of FGFR signaling pathways comprising administering an effective amount of a selective CDK4/6 inhibitor described herein in combination or alternation with a fibroblast growth factor receptor inhibitor.

Inventors

  • J.C. Strum
  • C. Whiteworth
  • FRIED DAVID M

Assignees

  • 法码科思莫斯控股有限公司

Dates

Publication Date
20260505
Application Date
20201009
Priority Date
20191009

Claims (6)

  1. 1. A short acting CDK4/6 inhibitor compound of the structure: Or a pharmaceutically acceptable salt thereof in combination with a selective fibroblast growth factor receptor-tyrosine kinase inhibitor (FGFR-TKI) for the manufacture of a medicament for the treatment of a human host suffering from gastric adenocarcinoma having deregulation of FGFR signaling pathways caused by abnormalities in FGFR2, wherein the abnormalities are selected from overexpression, amplification, translocation, fusion or mutation.
  2. 2. The use of claim 1, wherein the FGFR2 abnormality is the result of FGFR2 overexpression or amplification.
  3. 3. The use of claim 1, wherein the selective FGFR-TKI is selected from the group consisting of erdasatinib, pemitinib, inflicterinib, fuzotinib, delatinib, LY287445, debio1347, PRN1371, alonib, bemarituzumab, and FIIN-2.
  4. 4. The use of claim 1, wherein the CDK4/6 inhibitor is
  5. 5. The use of claim 1, wherein the CDK4/6 inhibitor is compound IA, form B, wherein form B is characterized by an XRPD pattern comprising at least two 2Θ values selected from 6.5±0.2°, 9.5±0.2°, 14.0±0.2°, 14.4±0.2°, 18.1±0.2°, 19.9±0.2° and 22.4±0.2°.
  6. 6. The use of claim 1, wherein the CDK4/6 inhibitor and the FGFR-TKI are administered to the human host at least once daily for at least 28 consecutive days.

Description

Targeted treatment of cancers with deregulated fibroblast growth factor receptor signaling The application is a divisional application of Chinese application patent application with the application date of 2020, the application number of 202080084419.3 and the application name of 'targeted treatment of cancers with deregulated fibroblast growth factor receptor signal transduction'. RELATED APPLICATIONS The present application is related to and claims priority from U.S. provisional application No. 62/913,055 filed on 10/9 in 2019. The entire contents of this provisional application are incorporated herein by reference for all purposes. Technical Field The present invention provides compositions for the treatment of cancers having deregulated Fibroblast Growth Factor Receptor (FGFR) signalling employing a CDK4/6 inhibitor as described herein in combination with a fibroblast growth factor inhibitor, e.g. a selective FGFR-tyrosine kinase inhibitor, wherein the specific combination provides advantageous or synergistic inhibitory activity, delay the acquisition of resistance to the inhibitory effect of the FGFR inhibitor in the cancer and/or prolong the efficacy of the FGFR inhibitor. Background Fibroblast growth factor receptor belonging to family （Hallinan N, Finn S, Cuffe S, Rafee S, O'Byrne K, Gately K. Targeting the fibroblast growth factor receptor family in cancer. Cancer Treat Rev 2016; 46: 51–62, Wesche J, Haglund K, Haugsten EM. Fibroblast growth factors and their receptors in cancer. Biochem J 2011; 437: 199–213）.FGFR of 4 tyrosine kinases (FGFR 1-4) and receptor 5 lacking tyrosine kinase domain (FGFR 5) has been shown to regulate a number of key processes such as cell migration, proliferation, differentiation and survival, especially during embryonic development and in adult organisms （Hallinan N, Finn S, Cuffe S, Rafee S, O'Byrne K, Gately K. Targeting the fibroblast growth factor receptor family in cancer. Cancer Treat Rev 2016; 46: 51–62, Wesche J, Haglund K, Haugsten EM. Fibroblast growth factors and their receptors in cancer. Biochem J 2011; 437: 199–213）.FGFR activity is controlled by the FGF ligand family consisting of 22 FGF members （Touat M, Ileana E, Postel-Vinay S, Andre F, Soria JC. Targeting FGFR Signaling in Cancer. Clin Cancer Res 2015; 21: 2684–94）, which regulate FGFR tyrosine kinase activity （Itoh N, Ornitz DM. Functional evolutionary history of the mouse Fgf gene family. Dev Dyn 2008; 237: 18–27）. in an autocrine or paracrine tissue dependent setting for cancers such as breast cancer, lung cancer, gastric cancer, urothelial cancer and liver cancer (e.g. intrahepatic cholangiocarcinoma and hepatocellular carcinoma) due to the oncogenic abnormality of the FGFR family members or due to the over activation of FGFR due to the overproduction of FGF, although the nature of the oncogenic changes of each cancer type may be different. Fibroblast Growth Factor Receptor (FGFR) is a membrane-bound protein that regulates cellular functions, including cell proliferation, cell survival, differentiation and migration activation of the （Brooks AN, Kilgour E, Smith PD. Molecular pathways: fibroblast growth factor signaling: a new therapeutic opportunity in cancer. Clin Cancer Res 2012; 18: 1855-62）.FGFR family (FGFR 1, FGFR2, FGFR3 and FGFR 4) resulting in increased amplification, mutation and aberrant fusion of the （Babina IS, Turner NC. Advances and challenges in targeting FGFR signaling in cancer. Nat Rev Cancer 2017; 17: 318-32）.FGFR gene for downstream activation of MAPK and AKT, etc. oncogenic pathways resulting in constitutive activation of downstream signal transduction by these pathways, thereby enhancing cell growth and migration (DIENSTMANN R, patnaik A, garcia-Carbonero R, CERVANTES A, benavent M, etc. ,Safety and activity of the first-in-class Sym004 anti-EGFR antibody mixture in patients with refractory colorectal cancer. Cancer Discov 2015; 5: 598-609）. and, in addition, FGFR activation due to overproduction of FGF by cancer and stromal cell expansion is associated with aberrant FGFR signaling (see, e.g., zhang, et al) ,Targeting the Oncogenic FGF-FGFR Axis in Gastric Carcinogenesis. Cells 2019,8, 637; doi:10.3390/cells8060637）. Emerging clinical data for a variety of FGFR inhibitors have demonstrated that FGFR is a potential target for anti-cancer treatment. The first FGFR inhibitor evaluated clinically was a non-selective FGFR inhibitor such as brinib, duo Wei Tini and panatinib, both on-target and off-target activity likely contributed to the clinical response. Recently, FGFR selective inhibitors, such as infliximab (BGJ 398), have shown encouraging antitumor activity in clinical trials. In fact, in one phase I up-dosing trial, 6 confirmed partial remissions were observed with Infeglatiramer at a dose of > 100 mg in FGFR 1-amplified squamous NSCLC patients and FGFR 3-mutated urothelial cancer patients (Isaacs, randi and Chen, xueying and Graus Porta, diana and Parker, katie and Yu, k