Clinical response to futibatinib in intrahepatic cholangiocarcinoma with acquired resistance to non-covalent Fibroblast Growth Factor Receptor 2 inhibitors

Background Fibroblast growth factor receptor 2 (FGFR2) fusions occur in approximately 4–8% of intrahepatic cholangiocarcinoma (iCCA). Non-covalent FGFR inhibitors demon-strate clinical activity, but resistance frequently develops through secondary FGFR2 kinase-domain mutations. Futibatinib is a covalent inhibitor that may overcome sev-eral of these mutations. The optimal choice between non-covalent and covalent in-hibitors, as well as their potential sequential use, remains unresolved. We evaluated the efficacy and safety of futibatinib following progression on non-covalent inhibi-tors in patients with FGFR2-rearranged iCCA. Patients and methods We conducted a retrospective multicenter study including patients with advanced iCCA treated with futibatinib after progression on a non-covalent FGFR inhibitor between January 2020 and January 2024. The primary endpoints were disease control rate (DCR) and progression-free survival (PFS). Molecular profiling at baseline and, when feasible, at progression was performed using next-generation sequencing. Results Sixteen patients were included. The first non-covalent FGFR inhibitor was pemigat-inib (75.0%) or derazantinib (25.0%). Molecular profiling at progression was avail-able for 11 patients and identified acquired FGFR2 resistance mutations in all cases, most commonly involving the N549 residue (81.8%). Futibatinib was administered at a median treatment line of four. The ORR was 31.3% with a DCR of 50.0%. Median PFS and OS were 4.5 months (95% CI 2.0–9.1) and 9.9 months (95% CI 5.7–not reached), respectively. Patients harboring FGFR2 resistance mutations without additional co-occurring alterations showed a trend toward improved out-comes. Treatment was well tolerated, with infrequent grade ≥3 adverse events. Conclusions In this series, futibatinib demonstrated clinically meaningful activity and manageable toxicity in patients with iCCA who had previously been treated with non-covalent FGFR inhibitors. These findings confirm the role of futibatinib in the management paradigm of patients with CCA with FGFR2 rearrangement, suggesting that this covalent inhibitor could represent a rational therapeutic option also in the post-non-covalent inhibitor setting.