Hepatocellular carcinoma (HCC) is the seventh most common cancer worldwide and the third leading cause of cancer-related death. Sorafenib is the only targeted agent to show a marginal improvement in overall survival (OS) for patients with advanced HCC. Recent data have implicated aberrant activation of the FGF19-FGFR4/KLB axis as the driver of certain forms of HCC, making this pathway a novel therapeutic target in this disease. The first evidence for this is the finding that aberrant expression of FGF19, as a consequence of gene amplification and other not yet known mechanisms, occurs in subsets of HCC’s and HCC cell lines leading to constitutive FGFR4 activation. In this setting, conditional knock down of FGF19, as well as its receptors FGFR4 and KLB, suppresses proliferation of HCC cell lines, supporting the notion that FGF19 activates FGFR4 in an autocrine fashion. Secondly, in transgenic mouse models, FGF19 produced by non-tumor cells at an ectopic site (skeletal muscle) acts in a paracrine fashion on the liver hepatocytes leading to liver dysplasia and HCC. In these mice, tumorigenesis is abolished in an FGFR4 null background, as well as upon treatment with anti-FGF19 and anti-FGFR4 blocking antibodies. Thus, we anticipate that targeted therapies aimed at blocking the FGFR4 pathway might be efficacious in subsets of HCC’s. We have identified and developed NVP-FGF401, a first in class, highly selective and potent FGFR4 inhibitor that is currently in PhI/II clinical testing. NVP-FGF401 binds in a reversible covalent manner to the FGFR4 kinase domain and it inhibits FGFR4 with an IC50 of 1.1 nM. In biochemical assays, it shows at least 1,000 fold selectivity against of panel of 65 kinases and in a kinome wide scan, consisting of 456 kinases, FGFR4 was the only target of NVP-FGF401. In xenograft animal models in vivo, NVP-FGF401 showed a consistent pharmacokinetic / pharmacodynamic (PK/PD) relationship with phospho-FGFR4 over total FGFR4 (p/tFGFR4) levels in tumor robustly inhibited in a dose dependent manner. The data support a lowest observed trough concentration (Ctrough) driven PD/efficacy relationship. The anti-tumor activity was confirmed across several xenograft animal models, as well as in patient-derived tumor xenografts (PDX) established in mice. The excellent drug-like properties of NVP-FGF401 drove us to test its efficacy in HCC patients in a PhI/II study, being the first selective FGFR4 inhibitor to ever enter into clinical trials (NCT02325739).

Citation Format: Diana Graus Porta, Andreas Weiss, Robin A. Fairhurst, Markus Wartmann, Christelle Stamm, Flavia Reimann, Alexandra Buhles, Jaqueline Kinyamu-Akunda, Dario Sterker, Masato Murakami, Youzhen Wang, Jeffrey Engelman, Francesco Hofmann, William R. Sellers. NVP-FGF401, a first-in-class highly selective and potent FGFR4 inhibitor for the treatment of HCC [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 2098. doi:10.1158/1538-7445.AM2017-2098