Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and a deadly disease. Treatment options are limited and prognosis generally is poor. Aberrant signaling through the fibroblast growth factor 19 (FGF19) - fibroblast growth factor receptor 4 (FGFR4) axis has been implicated in the development of HCC, and recently FGF19 has been determined as a specific driver gene amplification in a subset of liver tumors and cancer cell lines. Here, we describe the cellular and in vivo profile of NVP-FGF401, a highly potent and selective, first in class, reversible-covalent small-molecule inhibitor of the kinase activity of FGFR4. NVP-FGF401 is exquisitely selective for FGFR4 versus other FGFR family members and all other kinases. We show that among the FGF19-amplified liver cancer cells in the cancer cell line encyclopedia (CCLE), only those with concomitant expression of β-klotho (KLB), a co-receptor for FGF19 that facilitates its binding to FGFR4, are sensitive to NVP-FGF401. NVP-FGF401 has good oral PK properties and shows an excellent in vivo PK/PD relationship. NVP-FGF401 has remarkable anti-tumor activity in mice bearing HCC tumor xenografts and PDX models that are positive for FGF19, FGFR4 and KLB. NVP-FGF401 is the first FGFR4 inhibitor to enter clinical trials, and a PhI/II study is currently ongoing in HCC and other types of solid tumors.

Citation Format: Andreas Weiss, Diana Graus Porta, Flavia Reimann, Alexandra Buhles, Christelle Stamm, Robin A. Fairhurst, Jacqueline Kinyamu-Akunda, Dario Sterker, Masato Murakami, Markus Wartmann, Youzhen Wang, Jeffrey A. Engelman, Francesco Hofmann, Wiliam R. Sellers. NVP-FGF401: Cellular and in vivo profile of a novel highly potent and selective FGFR4 inhibitor for the treatment of FGF19/FGFR4/KLB+ tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2103. doi:10.1158/1538-7445.AM2017-2103