Intrahepatic cholangiocarcinoma is a rare cancer with a poor prognosis where alterations in fibroblast growth factor receptor 2 (FGFR2), occurring in up to 14% of patients, have emerged as promising drug targets; a new phase II study, recently published on The New England Journal of Medicine, shows that futibatinib, a next generation covalent FGFR1-4 inhibitor, can lead to measurable clinical benefits in patients with this tumor, including patients with heavily pretreated disease.
Two selective FGFR1–3 inhibitors, pemigatinib and infigratinib, have received accelerated Food and Drug Administration approval for the treatment of advanced, refractory, metastatic cholangio-carcinoma with confirmed FGFR2 fusions or rearrangements. The irreversible, covalent nature of futibatinib binding and its distinct binding site make this drug less susceptible to on-target resistance mutations than pemigatinib and infigratinib, thus it has been tested in an open-label, single-group phase II study enrolling 103 patients with unresectable or metastatic FGFR2 fusion-positive or FGFR2 rearrangement–positive intrahepatic cholangiocarcinoma and disease progression after one or more previous lines of systemic therapy (excluding FGFR inhibitors). The patients received oral futibatinib (20 mg) once daily in a continuous regimen; a total of 43 of 103 patients had a response, and the median duration of response was 9.7 months with responses consistent across patients subgroups, including heavily pretreated patients. At a median follow-up of 17.1 months, the median progression-free survival was 9.0 months and overall survival was 21.7 months. Treatment-related adverse events led to permanent discontinuation of futibatinib in 2% of the patients; no treatment-related deaths occurred and quality of life was maintained throughout treatment. «Clinical and translational research has shown that FGFR2 fusion or rearrangement–positive intrahepatic cholangiocarcinoma is a treatable cancer. Data from this study establish futibatinib as having measurable clinical benefit in patients with this disease and show the value of molecular profiling in identifying tumors that are likely to respond to FGFR2 inhibition», authors conclude.
