Futibatinib in patients with FGFR2-rearranged intrahepatic cholangiocarcinoma: Responder analyses of efficacy and safety from the phase 2 FOENIX-CCA2 study

Fibroblast growth factor receptor 2 ( FGFR2 ) fusions or rearrangements occur in up to 14% of patients with intrahepatic cholangiocarcinoma (iCCA). Futibatinib is a highly selective, covalent inhibitor of FGFR1–4. In a global phase 2 trial (FOENIX-CCA2; NCT02052778), 42% of patients treated with futibatinib had a response (median duration of response, 9.7 months), with a median progression-free survival (PFS) and overall survival (OS) of 9.0 months and 21.7 months, respectively. The findings led to the accelerated approval of futibatinib by the U.S. Food & Drug Administration for patients with advanced, previously treated, FGFR2 fusion/rearrangement–positive iCCA. Here, we present descriptive analyses to evaluate baseline characteristics and clinical outcomes in patients with and without a response to futibatinib in the FOENIX-CCA2 study.

FOENIX-CCA2 was a multinational, single-arm, phase 2 study of patients with locally advanced, unresectable or metastatic FGFR2 fusion/rearrangement–positive iCCA and disease progression after ≥1 previous line of platinum-based systemic therapy. Patients received oral futibatinib at a dose of 20 mg once daily in a continuous dosing regimen. The primary endpoint was objective response according to RECIST 1.1, as assessed by independent central review. In this analysis, demographics, PFS, OS, and genomic alterations were assessed in patients with and without a confirmed objective response to futibatinib.

Of 103 enrolled patients, 43 (41.7%) had a confirmed response to futibatinib and 60 (58.3%) were non-responders. Patient demographics were generally comparable. At the data cut-off (October 30, 2020), 51.2% versus 83.3% of responders and non-responders, respectively, had discontinued treatment, most commonly because of disease progression. Median PFS was 13.3 months (95% CI, 11.0–16.7) among responders and 5.1 months (95% CI, 4.1–6.9) among non-responders; median OS was 26.4 months (95% CI, not evaluable) and 14.6 months (95% CI, 10.3–21.7), respectively. Dose reductions/interruptions due to adverse events (AEs) occurred in 65%/70% of responders and 52%/63% of non-responders, respectively. Median time to first dose reduction/interruption due to AEs was 85/52 days in responders, and 36/22 days in non-responders, respectively. The median duration of interruption was 23 days in responders and 14 days in non-responders. There were no major differences in co-occurring baseline genomic alterations between responders and non-responders, including patients with p53 alterations. Genomic alterations that were detected numerically more frequently in responders (>5% increase vs non-responders) included MLL2, PIK3C2B, IKBKE, MDM4, AKT3, CDC73, DDR2, BTG2, FH, RAD21, SDHC, H3F3A, CREBBP, NOTCH2, PARP1, and BCORL1. Numerically more frequent alterations among non-responders (>5% increase vs responders) were in BAP1, PBRM1, TET2, CALR, and JAK1.

Compared with non-responders, OS and PFS were longer among patients with iCCA and a confirmed response to futibatinib. Co-occurring genomic alterations as potential predictors of response to FGFR inhibitors warrants further investigation.

NCT02052778.

Medical writing assistance was provided by Envision Pharma Group, funded by Taiho Oncology, Inc.

The authors.

Taiho Oncology, Inc.

A. Hollebecque: Honoraria (Institution): Astra-Zeneca, Roche; Advisory / Consultancy: Abbvie, Amgen, Basilea, BMS, Incyte, Servier, QED therapeutics, Relay Therapeutics, Seagen, Taiho; Research grant / Funding (self): Incyte; Research grant / Funding (institution): AstraZeneca; Travel / Accommodation / Expenses: AstraZeneca. L. Goyal: Advisory / Consultancy: Alentis Therapeutics AG, Black Diamond, H3Biomedicine, Incyte Corp., QED Therapeutics, Servier, Sirtex Medical Ltd., Taiho Oncology; Research grant / Funding (self): AstraZeneca (DMSC); Research grant / Funding (institution): Adaptimmune, Bayer, Eisai, Merck, Macrogenics, Genentech, Novartis, Incyte, Eli Lilly, Loxo Oncology, Relay Therapeutics, QED Therapeutics Inc, Servier, Taiho Oncology, Bristol Meyers Squibb, Nucana, Alentis, Exelixis; Full / Part-time employment: Massachusetts General Brigham, Mass General Hospital Cancer Center. F. Meric-Bernstam: Honoraria (self): Chugai Biopharmaceuticals; Advisory / Consultancy: Black Diamond, Biovica, Eisai, FogPharma, Immunomedics, Inflection Biosciences, Karyopharm Therapeutics, Loxo Oncology, Mersana Therapeutics, OnCusp Therapeutics, Puma Biotechnology Inc., Seattle Genetics, Sanofi, Silverback Therapeutics, Spectrum Pharmaceuticals, Zentalis, AbbVie, Aduro BioTech Inc., Alkermes, AstraZeneca, Daiichi Sankyo Co. Ltd., DebioPharm, Ecor1 Capital, eFFECTOR Therapeutics, F. Hoffman-La Roche Ltd., GT Apeiron, Genentech Inc., Harbinger Health, IBM Watson, Infinity Pharmaceuticals, Jackson Laboratory, Kolon Life Science, Lengo Therapeutics, Menarini Group, OrigiMed, PACT Pharma, Parexel International, Pfizer Inc., Protai Bio Ltd, Samsung Bioepis, Seattle Genetics Inc., Tallac Therapeutics, Tyra Biosciences, Xencor, Zymeworks; Research grant / Funding (institution): Aileron Therapeutics, Inc. AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences Inc., Curis Inc., CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., Debiopharm International, eFFECTOR Therapeutics, Genentech Inc., Guardant Health Inc., Klus Pharma, Takeda Pharmaceutical, Novartis, Puma Biotechnology Inc., Taiho Pharmaceutical Co.; Travel / Accommodation / Expenses: European Organisation for Research and Treatment of Cancer (EORTC), European Society for Medical Oncology (ESMO). M. Moehler: Honoraria (self): Falk, Nordic, Amgen, mci, Lilly, MSD, Taiho, Merck, Pfizer, FifePrime, BMS, ESMO, Novartis, Beigene ; Advisory / Consultancy: Lilly, BMS, MSD, Amgen, Merck, Pfizer, Beigene, Taiho, Nordic, Servier; Leadership role: Head GI Oncology, Mainz university Center; Research grant / Funding (institution): Merck, Amgen, BMS, MSD, AIO, EORTC, Taiho DFG, BMBF, Horizon Europe; Travel / Accommodation / Expenses: BMS, MSD, Amgen, Merck, Nordic, Servier . A. Vogel: Honoraria (self): AstraZeneca, Amgen, BeiGene, Böhringer Mannheim, BMS, BTG, Daichi-Sankyo, EISAI, GSK, Imaging Equipment Ltd (AAA), Incyte, Ipsen, Jiangsu Hengrui Medicines MSD, PierreFabre, Roche, Servier, Sirtex, Tahio, Terumo; Advisory / Consultancy: AstraZeneca, Amgen, BeiGene, Böhringer Mannheim, BMS, BTG, Daichi-Sankyo, EISAI, Incyte, Ipsen, MSD, PierreFabre, Roche, Servier, Sirtex, Tahio, Terumo. X. Liu: Full / Part-time employment: Taiho Oncology. V. Wacheck: Leadership role: Taiho Oncology; Travel / Accommodation / Expenses: Taiho Oncology; Full / Part-time employment: Taiho Oncology. J. Bridgewater: Honoraria (self): TAIHO, Incyte, Servier; Research grant / Funding (institution): Incyte. The author has declared no conflicts of interest.