Abstract 52P
Background
The irreversible FGFR1–4 inhibitor futibatinib has demonstrated efficacy in patients (pts) with intrahepatic CCA (iCCA) with FGFR2 fusions/rearrangements along with a manageable safety profile in a pivotal phase II study. Here, we report an integrated E–R analysis of futibatinib safety and efficacy.
Methods
Pts with advanced solid tumors receiving futibatinib once daily (QD; 4–24mg) or thrice weekly (TIW, 8–200 mg) in a global phase I/II study (NCT02052778) or a Japanese phase I study (JapicCTI-142552) and for whom individual-predicted exposure metrics were generated with a nonlinear mixed-effects population pharmacokinetic (PopPK) model were included in the safety analysis. The efficacy E–R analysis comprised pts with iCCA from the phase II study who received futibatinib 20 mg QD. E–R relationships between efficacy endpoints (including objective response rate [ORR] and duration of response) or safety endpoints (including adverse events of special interest [AESIs]) and PopPK model-based estimated exposure metrics were determined.
Results
As of October 1, 2020, 318 pts were included in the analysis. Exposure–safety analyses showed a significant relationship between hyperphosphatemia and futibatinib exposure; for grade ≥3 hyperphosphatemia, there was a significant correlation with QD dosing (N=247), with a steep increase at 24 mg QD. In multivariate analyses, higher baseline serum phosphate was an independent predictor for hyperphosphatemia, and increase from baseline correlated with futibatinib exposure. The only other AESIs with statistically significant E-R relationships were any-grade nail toxicities (QD only) and retinal toxicities (TIW only). Baseline body weight, age, and race showed no influence on exposure–safety relationships. No statistically significant relationships were observed between any efficacy parameter and futibatinib exposure metrics (N=98), although a trend toward higher ORR was observed with increasing steady-state futibatinib trough concentrations.
Conclusions
The E–R results support 20 mg QD as the starting dose for futibatinib, with dose adjustments as needed for the management of hyperphosphatemia.
Clinical trial identification
NCT02052778 JapicCTI-142552.
Editorial acknowledgement
Medical writing support for the development of this manuscript, under the direction of the authors, was provided by Vasupradha Vethantham, PhD, and editing support was provided by Jennifer Robertson, PhD, both of Ashfield MedComms, an Ashfield Health company, and funded by Taiho Oncology, Inc.
Legal entity responsible for the study
Taiho Oncology, Inc.
Funding
Taiho Oncology, Inc.
Disclosure
A. Hollebecque: Financial Interests, Personal, Other, Personal fees: Amgen; BMS; Eisai; Incyte; Other, Personal, Other: AstraZeneca; Roche; Servier; Financial Interests, Personal, Invited Speaker: Debiopharm; QED Therapeutics; Non-Financial Interests, Personal, Other: Lily; Incyte. J.A. Bridgewater: Financial Interests, Personal, Advisory Board: Taiho Oncology, Inc.; Financial Interests, Personal, Advisory Role: Taiho Oncology, Inc.. F. Meric-Bernstam: Financial Interests, Institutional, Research Grant: Taiho Oncology, Aileron Therapeutics, AstraZeneca, Bayer Healthcare, Calithera Biosciences, Curis, CytomX Therapeutics, Daiichi Sankyo, Debiopharm, eFFECTOR Therapeutics, Genentech, Guardant Health, Klus Pharma, Takeda Pharmaceutical, Novartis, Puma Biote; Financial Interests, Personal, Other, Consulting fees: AbbVie, Aduro BioTech, Alkermes, AstraZeneca, Debiopharm, eFFECTOR Therapeutics, F Hoffmann La Roche, Genentech, IBM Watson, Infinity Pharmaceutical, Jackson Laboratory, Kolon Life Science, OrgiMed, PACT Pharma, Parexel International, Pfizer Inc, Samsung; Financial Interests, Personal, Invited Speaker: Chugai Biopharmaceuticals; Financial Interests, Personal, Advisory Board: Immunomedics, Inflection Biosciences, Mersana Therapeutics, Puma Biotechnology, Seattle Genetics, Silverback Therapeutics, Spectrum Pharmaceuticals, Zentalis. L. Goyal: Financial Interests, Institutional, Research Grant: Agios, Adaptimmune, Bayer, Eisai, Merck, Macrogenics, Genentech, Novartis, Incyte, Eli Lilly, Loxo Oncology, Relay Therapeutics, QED Therapeutics, Taiho Oncology, Leap Therapeutics, Bristol Meyers Squibb, Nucana; Financial Interests, Personal, Invited Speaker: Agios Pharmaceuticals Inc, Alentis Therapeutics, Genentech, Exelixis, Incyte Corporation, QED Therapeutics, Sirtex Medical Ltd., Taiho Oncology Inc.; Financial Interests, Personal, Other, Data safety monitoring: AstraZeneca. I. Yamamiya: Financial Interests, Personal, Full or part-time Employment: Taiho Oncology, Inc.. F. Yamashita: Financial Interests, Personal, Full or part-time Employment: Taiho Oncology, Inc.; Taiho Pharmaceutical Co., Ltd.. K. Li: Financial Interests, Personal, Full or part-time Employment: Taiho Oncology, Inc.. V. Wacheck: Financial Interests, Personal, Full or part-time Employment: Taiho Oncology, Inc. T. Doi: Financial Interests, Institutional, Research Grant: Lilly, MSD, Daiichi Sankyo, Sumitomo Dainippon, Taiho, Novartis, Merck Serono, Janssen, Boehringer Ingelheim, Pfizer, BMS, Abbvie, IQVIA, Eisai; Financial Interests, Personal, Advisory Board: MSD, Daiichi Sankyo, Amgen, Novartis, Janssen, Boehringer Ingelheim, Abbvie, Bayer, Astellas; Financial Interests, Personal, Advisory Role: Sumitomo Dainippon, Taiho, Takeda, Chugai, Rakuten Medical, Otsuka, Oncolys Biopharma. All other authors have declared no conflicts of interest.