Phase 1, First-in-Human Study of Futibatinib, a Highly Selective, Irreversible FGFR1–4 Inhibitor in Patients with Advanced Solid Tumors
Mené sur 86 patients atteints d’une tumeur solide de stade avancé, cet essai de phase I évalue la dose maximale tolérée du futibatinib (un inhibiteur de FGFR1-4) et analyse ses caractéristiques pharmacodynamiques et pharmacocinétiques
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 1 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 thrice weekly (TIW) or 4–24 mg once daily (QD). Results : Eighty-six patients were enrolled in the nine TIW (n=42) and five QD cohorts (n=44); 71 (83%) had tumors harboring FGF/FGFR aberrations. Three of 9 patients in the 24-mg QD cohort experienced dose-limiting toxicities (DLTs) 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 QD; no MTD was defined for the TIW 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 QD but not all TIW doses evaluated, with saturation observed between 80 and 200 mg TIW. Serum phosphorus increased dose-dependently with futibatinib on both schedules, but a stronger exposure–response relationship was observed with QD dosing, supporting 20 mg QD as the recommended phase 2 dose (RP2D). Overall, partial responses were observed in 5 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 1 dose-escalation trial support 20 mg QD futibatinib as the RP2D.
Annals of Oncology 2020