Primary results of phase 2 FOENIX-CCA2: the irreversible FGFR1–4 inhibitor futibatinib in intrahepatic cholangiocarcinoma (iCCA) with FGFR2 fusions/rearrangements


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John Bridgewater1, Funda Meric-Bernstam2, Antoine Hollebecque3, Chigusa Morizane4, Juan W. Valle5, Thomas B. Karasic4, Thomas A. Abrams6, Robin Kate Kelley4, Philippe Cassier4, Junji Furuse4, Heinz-Josef Klümpen4, Heung-Moon Chang7, Li-Tzong Chen4, Yoshito Komatsu4, Kunihiro Masuda4, Daniel Ahn8, Yaohua He4, Nital Soni4, Karim A. Benhadji4, Lipika Goyal4
1UCL, 2MD Anderson Cancer Center, 3Institut Gustave Roussy, 4Other, 5University of Manchester, 6Dana-Farber Cancer Institute, 7Asan Medical Center, 8Mayo Clinic

Abstract

Background

FGFR2 fusions occur in ~15% of patients with iCCA, a rare cancer with poor prognosis. Futibatinib, a highly selective, irreversible FGFR1–4 inhibitor, has shown activity across tumor types, including iCCA, in a phase 1 study. The pivotal phase 2 FOENIX-CCA2 trial (NCT02052778) is evaluating futibatinib in iCCA harboring FGFR2 fusions/rearrangements. Here, we report the first efficacy, safety, and biomarker data for the complete FOENIX-CCA2 population.

Method

Eligible patients had unresectable/metastatic iCCA with FGFR2 fusion/rearrangements and progressive disease after ≥1 prior treatment (excluding FGFR inhibitors). Patients received futibatinib 20 mg QD until disease progression/intolerability. The primary endpoint was objective response rate (ORR) per RECIST v1.1 by independent central review (target: 20%). Secondary endpoints included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety.

Results

Among 103 patients, 53% had received ≥2 prior treatments and 78% had FGFR2 fusions (23%, FGFR2-BICC1 fusions). At data cutoff (October 1, 2020), 72 patients (70%) had discontinued treatment. The study met its primary objective with a confirmed ORR of 41.7% (43/103). Responses were durable, with a median (m) DOR of 9.7 months and 72% of responses ≥6 months. DCR was 82.5%. mPFS was 9.0 months; mOS was 21.7 months, with a 12-month OS rate of 72%. ORR was consistent across patient demographic subgroups (≥65 years: 65.2%; 2 prior treatments: 38.7%). Common treatment-related AEs (TRAEs) were hyperphosphatemia (85%), alopecia (33%), and dry mouth (30%). The most frequent grade 3 TRAE, hyperphosphatemia (30%), resolved with adequate management (median 7 days). TRAEs were managed with dosing interruptions (50%)/reductions (54%); 2 patients discontinued treatment due to TRAEs. No treatment-related deaths occurred. ORRs were consistent in patients with dosing interruptions (40.2%)/reductions (46.8%). In exploratory analyses, ORR was consistent in patients with FGFR2 fusions (43.8%)/rearrangements (34.8%) and with BICC1 (41.7%)/non-BICC1 (44.6%) fusion partners. Notably, no obvious differences in ORR were observed in patients with co-occurring genetic alterations, including TP53 comutations (ORR, 38.5% [5/13]).

Conclusion

Futibatinib resulted in frequent, durable objective responses in patients with iCCA harboring FGFR2 fusion/rearrangements, regardless of patient baseline characteristic, molecular alteration, or comutation. AEs were manageable with dosing modifications.

Impact statement