Phase I, first-in-human study of futibatinib, a highly selective, irreversible FGFR1-4 inhibitor in patients with advanced solid tumors.

Background: Futibatinib is an oral, irreversible, highly selective fibroblast growth factor receptor (FGFR)1-4 inhibitor with potent preclinical activity against tumors harboring FGFR aberrations. This first-in-human, phase I dose-escalation trial (NCT02052778) evaluates the safety and pharmacokinetics/pharmacodynamics of futibatinib in advanced solid tumors.
Patients and Methods: Following a standard 3+3 dose-escalation design, eligible patients with advanced solid tumors refractory to standard therapies received 8-200 mg futibatinib three times a week (t.i.w.) or 4-24 mg once daily (q.d.).
Results: A total of 86 patients were enrolled in the nine t.i.w. (n = 42) and five q.d. cohorts (n = 44); 71 patients (83%) had tumors harboring FGF/FGFR aberrations. Three of nine patients in the 24-mg q.d. cohort experienced dose-limiting toxicities, including grade 3 increases in alanine transaminase, aspartate transaminase, and blood bilirubin (n = 1 each). The maximum tolerated dose (MTD) was determined to be 20 mg q.d.; no MTD was defined for the t.i.w. schedule. Across cohorts (n = 86), the most common treatment-emergent adverse events (TEAEs) were hyperphosphatemia (59%), diarrhea (37%), and constipation (34%); 48% experienced grade 3 TEAEs. TEAEs led to dose interruptions, dose reductions, and treatment discontinuations in 55%, 14%, and 3% of patients, respectively. Pharmacokinetics were dose proportional across all q.d. doses but not all t.i.w. doses evaluated, with saturation observed between 80 and 200 mg t.i.w. Serum phosphorus increased dose dependently with futibatinib on both schedules, but a stronger exposure-response relationship was observed with q.d. dosing, supporting 20 mg q.d. as the recommended phase II dose (RP2D). Overall, partial responses were observed in five patients [FGFR2 fusion-positive intrahepatic cholangiocarcinoma (n = 3) and FGFR1-mutant primary brain tumor (n = 2)], and stable disease in 41 (48%).
Conclusions: Futibatinib treatment resulted in manageable safety, pharmacodynamic activity, and preliminary responses in patients with advanced solid tumors. The results of this phase I dose-escalation trial support 20 mg q.d. futibatinib as the RP2D.
Clinical Trial Registration: FOENIX-101 (ClinicalTrials.gov, NCT02052778).
Competing Interests: Disclosure RB does not have conflicts of interests to disclose. FM-B reports research support from 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., K Group, Millennium Pharmaceuticals Inc., Novartis, Pfizer Inc., PPD Investigator Services LLC, Puma Biotechnology Inc., Seattle Genetics, Taiho Pharmaceutical Co., and Zymeworks Inc.; has served on the advisory committees of ClearLight Diagnostics, Darwin Health, Grail, Immunomedics, Inflection Biosciences, Mersana Therapeutics, Puma Biotechnology Inc., Seattle Genetics, and Silverback Therapeutics, Spectrum Pharmaceuticals; has a consulting role for eFFECTOR Therapeutics, PACT Pharma, Zymeworks, Jackson Laboratory, Genentech Inc., F. Hoffman-La Roche Ltd., Parexel International, Pfizer Inc., IBM Watson, Samsung Bioepis, Aduro Biotech Inc., Kolon Life Science, OrigiMed, Sumitomo Dainippon Pharma Co., Seattle Genetics Inc., DebioPharm, Dialectica, Piers Pharmaceuticals, Xencor, and Tyra Biosciences; and has received fees/honoraria from Chugai Biopharmaceuticals, Dialectica, Mayo Clinic, and Sumitomo Dainippon Pharma. LG has a consulting/advisory role for Debiopharm, H3 Biomedicine, Incyte, QED, Alentis, Pieres, Agios, and Sirtex; serves on the IDMC for AstraZeneca; has received research funding from Taiho; and has received reimbursement for travel, accommodation, and other expenses from Taiho. BT has served in an advisory role at Amgen, Astellas, Bayer, Sanofi, BMS, Janssen-Cilag, MSD, Novartis, Tolmar, Ipsen; has received research funding from Amgen, Astellas, AstraZeneca, Bayer, BMS, Ipsen, Janssen-Cilag, Pfizer, and Servier; has served on the Speaker Bureau for Amgen, Astellas, BMS, and Janssen-Cilag; and has received travel expenses from Amgen, Astellas, Bayer, and Sanofi. BT's institution receives funding from Amgen, Aslan, Akeso, AstraZeneca, Aptevo, GSK, MSD, Novartis, Servier, and Taiho. YH, KAB, and IY are full-time employees at Taiho Oncology. KAB was an employee at Eli Lilly and owns stock in Eli Lilly. HTA is an investigator in studies sponsored by Taiho and reports an advisory role in Guardant, Roche, and Servier. IM has no conflicts of interest to disclose.
(Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)