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

Abstract

Background: Futibatinib is an oral, irreversible, highly selective fibroblast growth factor receptor (FGFR)1e4 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 3þ3 dose-escalation design, eligible patients with advanced solid tumors refractory to standard therapies received 8e200 mg futibatinib three times a week (t.i.w.) or 4e24 mg once daily (q.d.). Results: A total of 86 patients were enrolled in the nine t.i.w. (n ¼ 42) and five q.d. cohorts (n ¼ 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 ¼ 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 ¼ 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 exposureeresponse 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 ¼ 3) and FGFR1-mutant primary brain tumor (n ¼ 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).

Novel Pharmacological Options in the Treatment of Cholangiocarcinoma: Mechanisms of Resistance

“…Futibatinib (TAS-120) is an oral irreversible pan-FGFR inhibitor (FGFR1–4). The phase I FOENIX-101 trial showed partial responses in FGFR2 fusion-positive iCCA patients who had shown refractoriness to standard chemotherapy [ 64 ]. Besides, promising results were obtained in iCCA patients with acquired resistance to other FGFR inhibitors [ 50 ].…”

Next generation sequencing for biliary tract cancers

“…harboring FGFR aberrations is futibatinib, an irreversible FGFR1-4 inhibitor, which is currently being evaluated in phase II/III trials across multiple histologies [12]. Preliminary analysis of FOENIX-CCA2 (NCT02052778), a single-arm multicenter phase II study evaluating futibatinib in patients with IHCCA and FGFR2 fusions or rearrangements, demonstrated a 37.3% objective response rate (ORR) and 82% disease control rate (DCR) [13].…”

Recent Progress in the Systemic Treatment of Advanced/Metastatic Cholangiocarcinoma

“…Another phase-1/2 study of the irreversible pan-FGFR inhibitor (FGFR 1-4), TAS-120, futibatenib, enrolled 45 chemotherapy-refractory CCA patients harbouring FGFR aberrations (FGFR2 fusions, mutations, amplifications or re-arrangements) and resulted in an ORR of 25% and a disease control rate (DCR) of 78.6%. Interestingly, 13 patients received prior treatment with at least one reversible FGFR-inhibitor, and of those, four patients achieved a partial response [ 17 , 18 ].…”

“…NA: not available. Drug ( Mechanism of Action ) Target Phase Total Number of CCA Patients Enrolled Outcome in CCA Pemigatinib ( FGFR1-3 inhibitor ) FGFR alterations 2 146 ORR = 36% CR ( n = 3) PR ( n = 35) DOR > 12 mo ( n = 7) [ 13 , 14 ] Infigratinib ( FGFR1-3 inhibitor ) FGFR2 fusions 2 61 ORR = 14.8% PFS = 5.8 mo [ 15 ] Futibatenib ( FGFR 1-4 inhibitor ) FGFR2 fusions, mutations, amplifications or re-arrangements 1/2 45 ORR = 25% PR ( n = 4) [ 17 , 18 ] Futibatenib ( FGFR 1-4 inhibitor ) FGFR alterations + acquired resistance to FGFR inhibitors N/A 6 PR ( n = 2) SD ( n = 2) [ 19 ] Ivosidenib ( IDH1 inhbitor ) IDH1 mutations 3 185 ORR = 2.4% PFS = 32% at 6 mo; 21.9% at 12 mo; OS = 9.7 mo [ 20 ] …”