Futibatinib Is a Novel Irreversible FGFR 1–4 Inhibitor That Shows Selective Antitumor Activity against FGFR-Deregulated Tumors

Abstract

Fibroblast growth factor receptor (FGFR) signaling is deregulated in many human cancers and FGFR is considered a valid target in FGFR-deregulated tumors. Here we examine the preclinical profile of futibatinib (TAS-120; 1-[(3S)-[4-amino-3-[(3,5-dimethoxyphenyl)ethynyl]-1Hpyrazolo[3,4-d] pyrimidin-1-yl]-1-pyrrolidinyl]-2-propen-1-one), a structurally novel, irreversible FGFR1-4 inhibitor. Among a panel of 296 human kinases, futibatinib selectively inhibited FGFR1-4 with half-maximal inhibitory concentration (IC 50) values of 1.4-3.7 nmol/L. Futibatinib covalently bound the FGFR kinase domain, inhibiting FGFR phosphorylation and, in turn, downstream signaling in FGFR-deregulated tumor cell lines. Futibatinib exhibited potent, selective growth inhibition of several tumor cell lines (gastric, lung, multiple myeloma, bladder, endometrial, and breast) harboring various FGFR genomic aberrations. Oral administration of futibatinib led to significant dose-dependent tumor reduction in various FGFR-driven human tumor xenograft models and tumor reduction was associated with sustained FGFR inhibition, which was proportional to the administered dose. The frequency of appearance of drug-resistant clones was lower with futibatinib than a reversible ATP-competitive FGFR inhibitor, and futibatinib inhibited several drug-resistant FGFR2 mutants, including the FGFR2 V565I/L gatekeeper mutants, with greater potency than any reversible FGFR inhibitors tested (IC 50 , 1.3-50.6 nmol/L). These results indicate that futibatinib is a novel orally available, potent, selective, and irreversible inhibitor of FGFR1-4 with a broad spectrum of antitumor activity in cell lines and xenograft models. These findings provide a strong rationale for testing futibatinib in patients with tumors oncogenically driven by FGFR genomic aberrations, with phase 1-3 trials ongoing. Research.

Molecular Targets for Gastric Cancer Treatment and Future Perspectives from a Clinical and Translational Point of View

“…Moreover, a novel covalent, irreversible FGFR inhibitor (TAS-120, Frutibatinib) is in clinical development [103]. This TKI overcomes resistance to ATP-competitive FGFR inhibitors [104].…”

Targeted Therapies in Advanced Cholangiocarcinoma: A Focus on FGFR Inhibitors

“…The highly selective, irreversible FGFR1, FGFR2, FGFR3, and FGFR4 inhibitor futibatinib (TAS-120) was firstly evaluated in a phase I study, the FOENIX-101, where 86 patients with previously treated advanced malignancies received this molecule (NCT02052778) [ 42 , 83 , 84 , 85 ]. According to the results of this dose-escalation trial, 20 mg once daily was established as the recommended phase II dose, with PR reported in five patients and SD in 41 subjects [ 83 , 84 , 85 ]. Based on these preliminary findings, futibatinib was assessed in the phase II FOENIX-CCA2 trial evaluating the FGFR inhibitor in CCA patients who had experienced disease progression on standard treatments or were not eligible for standard therapy [ 42 , 86 ].…”

Current options and future directions of systemic therapy for advanced biliary tract cancer

“…Futibatinib is an oral FGFR1-4 highly selective irreversible inhibitor administered orally at a dose of 20 mg once daily in 21-day cycles [44]. A recently presented interim analysis of the FOENIX-CCA2…”