Rearrangements or fusions of the fibroblast growth factor receptor 2 (FGFR2) gene are common in intrahepatic cholangiocarcinomas (ICC). In consequence, FGFR2 alterations are promising drug targets in this setting. In previously treated patients with FGFR2-rearranged ICC, the use of futibatinib led to measurable clinical benefit in the phase II FOENIX-CCA2 trial. These results were published in the prestigious New England Journal of Medicine.
Intrahepatic cholangiocarcinomas (ICC) are aggressive cancers arising from the epithelial cells of intrahepatic bile ducts. Rearrangements or fusions of the FGFR2 gene are seen in around 14% of ICC patients. Treatment approaches targeting this oncogenic driver include two promising selective FGFR2 inhibitors, pemigatinib and infigratinib. Both of them are approved by the FDA in this setting, and show patient responses of 35.5% and 23.1%, respectively. Goyal et al. investigated the efficacy and safety of a next-generation FGFR inhibitor, futibatinib, for ICC patients with FGFR2 rearrangement.
The open-label, multinational, phase II FOENIX-CCA2 study enrolled 103 patients with unresectable or metastatic FGFR2 fusion-positive or FGFR2 rearrangement-positive ICC and disease progression after one or more lines of systemic therapy (excluding FGFR inhibitor). The participants received futibatinib (20 mg daily) until disease progression or unacceptable toxicity. The primary endpoint was objective response (partial or complete) assessed by an independent review committee. Secondary endpoints included the response duration, progression-free and overall survival, safety, and patient-reported outcomes.
In total, 43/103 patients (42%) had a response, with a median duration of response of 9.7 months. Responses were consistent across the subgroups, including heavily pretreated patients (54.2%), older adults (65.2%) and patients with co-occurring TP53 mutation (38.5%). 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 grade 3 adverse events (TRAEs) were hyperphosphatemia (30%), increased aspartate aminotransferase level (7%), stomatitis (6%) and fatigue (6%). TRAEs led to treatment discontinuation in 2% of the patients. Importantly, no treatment-related deaths occurred and quality of life was maintained throughout treatment.
The use of futibatinib led to measurable clinical benefit in previously treated patients with FGFR2 fusion or rearrangement-positive ICC. Future studies are ongoing comparing its efficacy with chemotherapy and its impact on overall survival.