The incidence of intrahepatic cholangiocarcinoma, an aggressive cancer of the intrahepatic bile ducts, is increasing worldwide.1-3 Surgery is the main curative option, but up to two thirds of patients have disease recurrence.4 Patients with intrahepatic cholangiocarcinoma have a 5-year overall survival rate of less than 8%, and among those with advanced disease, the median overall survival is approximately 1 year.5,6 After failure of first-line gemcitabine–cisplatin, FOLFOX (fluorouracil, leucovorin, and oxaliplatin) is the established second-line standard of care1; however, efficacy is modest, with an objective response of 5% and a median overall survival of 6.2 months.7
Fibroblast growth factor receptor 2 (FGFR2) fusions or rearrangements occur in up to 14% of patients with intrahepatic cholangiocarcinoma.8-10 Two selective FGFR1–3 inhibitors, pemigatinib and infigratinib, have received accelerated Food and Drug Administration approval for the treatment of advanced, refractory, metastatic cholangiocarcinoma with confirmed FGFR2 fusions or rearrangements; the responses with these agents have been reported to be 35.5% and 23.1%, respectively.11-13 These FGFR inhibitors are ATP-competitive, binding reversibly to the ATP-binding pocket in the FGFR kinase domain (Fig. S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org). Their efficacy has been shown to be limited by the development of acquired resistance mutations affecting amino acid residues in the kinase domain. These mutations interfere sterically with drug binding, lead to increased receptor activity, or both.14-22
Futibatinib (TAS-120) is a highly selective, irreversible inhibitor of FGFR1–4. Unlike reversible ATP-competitive inhibitors, it forms a covalent adduct with a conserved cysteine residue in the FGFR kinase domain P-loop structure. The irreversible nature of binding and its distinct binding site23,24 make futibatinib less susceptible to on-target resistance mutations than pemigatinib and infigratinib.24 In preclinical experiments, futibatinib showed stronger activity against a wider spectrum of FGFR2 kinase domain mutations, including mutations in gatekeeper and molecular brake residues (a triad of residues in the hinge region that is autoinhibitory), than other FGFR inhibitors (Figure 1).24,25 Furthermore, fewer drug-resistant clones emerged with futibatinib treatment.24 Clinical data from a phase 1 study and case series provided support for these findings and showed sustained clinical benefit with futibatinib in patients with FGFR-altered cholangiocarcinoma who had had disease…
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