HEPATOCELLULAR CANCER A novel small molecule targeting the FGF19-FGFR4 axis has entered early clinical trial in hepatic and other cancers

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Dec. 9, 2019

SCIENTIFIC

HEPATOCELLULAR CANCER A novel small molecule targeting the FGF19-FGFR4 axis has entered early clinical trial in hepatic and other cancers (NCT02325739). Genomic amplification of FGF19 is prevalent in a number of cancer types including bladder, head & neck and breast. FGF401, A First-In-Class Highly Selective and Potent FGFR4 Inhibitor for the Treatment of FGF19-Driven Hepatocellular Cancer

A. Weiss et al Mol Cancer Ther 2019;18:2194–206

 

Abstract

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and it is the third leading cause of cancer-related deaths worldwide. Recently, aberrant signaling through the FGF19/FGFR4 axis has been implicated in HCC. Here, we describe the development of FGF401, a highly potent and selective, first in class, reversible-covalent small-molecule inhibitor of the kinase activity of FGFR4. FGF401 is exquisitely selective for FGFR4 versus the other FGFR paralogues FGFR1, FGFR2, FGFR3, and all other kinases in the kinome. FGF401 has excellent drug-like properties showing a robust pharmacokinetic/pharmacodynamics/efficacy relationship, driven by a fraction of time above the phospho-FGFR4 IC90 value. FGF401 has remarkable antitumor activity in mice bearing HCC tumor xenografts and patient-derived xenograft models that are positive for FGF19, FGFR4, and KLB. FGF401 is the first FGFR4 inhibitor to enter clinical trials, and a phase I/II study is currently ongoing in HCC and other solid malignancies.

In summary, three novel FGFR4 selective inhibitors, FGF401 described in this manuscript, BLU-554 and H3B-6527 described elsewhere are being evaluated for the treatment of advanced HCC patients whose tumors display de-regulated FGF19/FGFR4 pathway. Since both FGF401 and BLU-554 exhibit promising clinical responses, and given the underlying complexity and molecular heterogeneity of the disease, it will be important to promptly identify the optimal drug combinations to ultimately achieve cures in this patient population