Indications
Futibatinib is indicated for the treatment of adults with previously treated, unresectable, locally advanced, or metastatic intrahepatic cholangiocarcinoma that harbors fibroblast growth factor receptor 2 (FGFR2) gene fusions or other rearrangements. In the European context, it is specifically indicated for use in patients whose disease has demonstrated progression following a minimum of one prior systemic therapy. The drug has received accelerated approval in the United States and conditional marketing authorization in Europe. It is important to note that the currently approved indications could be subject to revision as they are contingent upon confirmation and description of clinical benefits in further trials.
Pharmacodynamics
Futibatinib functions as an anticancer agent with evident anti-tumor efficacy, as demonstrated in mouse and rat xenograft models of human tumors exhibiting activating FGFR genetic alterations. The drug is not expected to impact cell lines that lack FGFR genomic aberrations. Its mechanism of action involves inhibiting tumor growth in a dose-dependent manner, suggesting an increase in efficacy with higher doses.
Absorption
The time to reach maximum plasma concentration (Tmax) of futibatinib ranges from 1.2 to 22.8 hours, with a median Tmax of approximately two hours. In studies involving healthy subjects, the presence of a high-fat, high-calorie meal, comprising approximately 900 to 1000 calories with 50% of the calories derived from fat, resulted in a decrease of futibatinib's area under the curve (AUC) by 11% and a reduction in the maximum concentration (Cmax) by 42%.
Metabolism
In vitro studies indicate that futibatinib is mainly metabolized by the cytochrome P450 enzyme CYP3A, with minor contributions from CYP2C9 and CYP2D6. In healthy subjects, unchanged futibatinib accounts for 59% of the total radioactivity in plasma, highlighting that it is the predominant drug-related entity present.
Mechanism of Action
Futibatinib is a targeted therapeutic agent that functions as a selective, irreversible inhibitor of fibroblast growth factor receptors (FGFR) 1, 2, 3, and 4, demonstrating IC50 values of under 4 nM. It exerts its effect by covalently binding to a cysteine residue in the ATP-binding pocket of the FGFR kinase domain. This binding effectively inhibits FGFR phosphorylation and disrupts subsequent downstream signalling pathways, including the RAS-dependent MAPK, PI3K/Akt/mTOR, PLCγ, and JAK/STAT pathways. By interfering with these critical pathways, futibatinib reduces the viability of cancer cells that exhibit FGFR alterations such as fusions, rearrangements, amplifications, and mutations.
