In patients with previously treated FGFR2 fusion or rearrangement–positive intrahepatic cholangiocarcinoma, the use of a covalent FGFR inhibitor, futibatinib led to measurable clinical benefit. Data from the FOENIX-CCA2 study demonstrate response in 42% of the patients who received futibatinib, as determined by independent central review. The use of futibatinib resulted in durable responses and survival that surpassed those indicated by historical data with chemotherapy in patients with refractory intrahepatic cholangiocarcinoma. Futibatinib-related adverse events were common and consistent with those associated with other FGFR inhibitors. Serious events occurred in 10% of the patients, but treatment discontinuation owing to treatment-related adverse events was rare. Quality-of-life was maintained throughout treatment. The study findings are published by Dr. Lipika Goyal of the Stanford Cancer Center in Palo Alto, CA, US and colleagues on 19 January 2023 in The New England Journal of Medicine.

The authors wrote in the background that the incidence of intrahepatic cholangiocarcinoma is increasing worldwide. Surgery is the main curative option, but up to two thirds of patients have disease recurrence. A 5-year overall survival (OS) rate is less than 8%, and among those patients with advanced disease, the median OS is approximately 1 year. After failure of first-line gemcitabine–cisplatin, FOLFOX regimen is established second-line treatment. However, efficacy is modest, with an objective response of 5% and a median OS of 6.2 months.

FGFR2 fusions or rearrangements occur in up to 14% of patients with intrahepatic cholangiocarcinoma. The responses with two selective FGFR1–3 inhibitors, pemigatinib and infigratinib, have been reported in 35.5% and 23.1% of patients. These FGFR inhibitors are ATP-competitive, and their efficacy has been 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.

Futibatinib is a highly selective, irreversible inhibitor of FGFR1–4. The irreversible nature of binding and its distinct binding site make futibatinib less susceptible to on-target resistance mutations than pemigatinib and infigratinib. In preclinical experiments, futibatinib showed stronger activity against a wider spectrum of FGFR2 kinase domain mutations, including mutations in gatekeeper and molecular brake residues, than other FGFR inhibitors. Furthermore, fewer drug-resistant clones emerged with futibatinib treatment. Clinical data from a phase I 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 progression after previous treatment with FGFR inhibitor.

Data from the dose-escalation portion of a multinational phase I/II study and a Japanese phase I study established 20 mg of oral futibatinib once daily as the recommended dose for the phase II study. Futibatinib showed antitumour activity and generally low-grade side effects in heavily pretreated patients with advanced, FGFR-altered tumours. In the multinational, phase I, dose-expansion part of the study, 25.4% of the patients with intrahepatic cholangiocarcinoma harbouring FGFR2 fusions or rearrangements had a response.

In FOENIX-CCA2, multinational, open-label, single-group, phase II study, the investigators enroled 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 treatment excluding FGFR inhibitors. The patients received oral futibatinib at a dose of 20 mg once daily in a continuous regimen. The primary endpoint was objective response (partial or complete response), as assessed by independent central review. Secondary endpoints included the response duration, progression-free survival (PFS), OS, safety, and patient-reported outcomes. Correlative research was also performed to assess the use of circulating tumour DNA (ctDNA) profiling of plasma samples for the detection of FGFR2 fusions and rearrangements.

Between 16 April 2018 and 29 November 2019, a total of 103 patients were enroled and received futibatinib. A total of 43 of 103 patients (42%; 95% confidence interval, 32 to 52) had a response, and the median duration of response was 9.7 months. Responses were consistent across patient subgroups, including patients with heavily pretreated disease, older adults, and patients who had co-occurring TP53 mutations. At a median follow-up of 17.1 months, the median PFS was 9.0 months and OS was 21.7 months.

Common treatment-related grade 3 adverse events were hyperphosphatemia in 30% of the patients, an increased aspartate aminotransferase level in 7%, stomatitis in 6%, and fatigue in 6%. Treatment-related adverse events led to permanent discontinuation of futibatinib in 2% of the patients. No treatment-related deaths occurred. Quality of life was maintained throughout treatment.

The authors commented that a major strength of the study is the correlative biomarker analysis. The failure rate of tissue-biopsy profiling in metastatic biliary tract cancer is 26.8%, and ctDNA profiling offers a non-invasive alternative. Although the detection of FGFR2 fusion by ctDNA assays has historically been low with some platforms, the partner-agnostic ctDNA platform used in the correlative analyses in this study identified FGFR2 fusions or rearrangements in 87% of evaluated patients. Further studies are warranted to assess the clinical performance of ctDNA profiling assays in identifying patients who would benefit from treatment with FGFR inhibitors.

The authors concluded that clinical and translational research data from this study show the value of molecular profiling in identifying tumours that are likely to respond to FGFR2 inhibition.

The study was supported by Taiho Oncology and Taiho Pharmaceutical. 


Goyal L, Meric-Bernstam F, Hollebecque A, et al. Futibatinib for FGFR2-Rearranged Intrahepatic Cholangiocarcinoma. N Engl J Med 2023; 388:228-239.