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Ref Type Journal Article
PMID (32622884)
Authors Bahleda R, Meric-Bernstam F, Goyal L, Tran B, He Y, Yamamiya I, Benhadji KA, Matos I, Arkenau HT
Title Phase I, first-in-human study of futibatinib, a highly selective, irreversible FGFR1-4 inhibitor in patients with advanced solid tumors.
Journal Vol Issue Date Pages Journal Short Title
Annals of oncology : official journal of the European Society for Medical Oncology 31 10 2020 10 1405-1412 Ann Oncol
URL
Abstract Text 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.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.).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%).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.FOENIX-101 (ClinicalTrials.gov, NCT02052778).

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
FGFR1 K687E missense unknown FGFR1 K687E (corresponds to K656E in the canonical isoform) lies within the protein kinase domain of the Fgfr1 protein (UniProt.org). K687E has been identified in the scientific literature (PMID: 32622884, PMID: 34250399, PMID: 35952322), but has not been biochemically characterized and therefore, its effect on Fgfr1 protein function is unknown (PubMed, Oct 2024).
FGFR1 M563I missense unknown FGFR1 M563I (corresponds to M532I in the canonical isoform) lies within the protein kinase domain of the Fgfr1 protein (UniProt.org). M563I has been identified in the scientific literature (PMID: 32622884), but has not been biochemically characterized and therefore, its effect on Fgfr1 protein function is unknown (PubMed, Oct 2024).
FGFR1 N546D missense unknown FGFR1 N546D lies within the protein kinase domain of the Fgfr1 protein (UniProt.org). N546D has been identified in the scientific literature (PMID: 32622884, PMID: 29728520), but has not been biochemically characterized and therefore, its effect on Fgfr1 protein function is unknown (PubMed, Oct 2024).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR2 amp Advanced Solid Tumor predicted - sensitive Futibatinib Phase I Actionable In a Phase I trial (FOENIX-101), Lytgobi (futibatinib) treatment demonstrated manageable safety profile, and resulted in a partial response in 6% (5/86) and stable disease in 48% (41/86) of patients with advanced solid tumors harboring FGF/FGFR aberrations, among whom 5% (4/74) harbored FGFR2 amplification (PMID: 32622884; NCT02052778). 32622884
FGFR1 M563I FGFR1 K687E oligodendroglioma predicted - sensitive Futibatinib Case Reports/Case Series Actionable In a Phase I trial (FOENIX-101), Lytgobi (futibatinib) treatment resulted in a partial response in a patient with anaplastic oligodendroglioma harboring FGFR1 M563I and FGFR1 K687E (PMID: 32622884; NCT02052778). 32622884
FGFR2 fusion Advanced Solid Tumor predicted - sensitive Futibatinib Phase I Actionable In a Phase I trial (FOENIX-101), Lytgobi (futibatinib) treatment demonstrated manageable safety profile, and resulted in a partial response in 6% (5/86) and stable disease in 48% (41/86) of patients with advanced solid tumors harboring FGF/FGFR aberrations, among whom 20% (15/74) harbored FGFR2 fusions (PMID: 32622884; NCT02052778). 32622884
FGFR1 N546D intrahepatic cholangiocarcinoma predicted - sensitive Futibatinib Case Reports/Case Series Actionable In a Phase I trial (FOENIX-101), Lytgobi (futibatinib) treatment resulted in a partial response in a patient with glioblastoma harboring FGFR1 N546D (PMID: 32622884; NCT02052778). 32622884
FGFR1 amp Advanced Solid Tumor predicted - sensitive Futibatinib Phase I Actionable In a Phase I trial (FOENIX-101), Lytgobi (futibatinib) treatment demonstrated manageable safety profile, and resulted in a partial response in 6% (5/86) and stable disease in 48% (41/86) of patients with advanced solid tumors harboring FGF/FGFR aberrations, among whom 20% (15/74) harbored FGFR1 amplification (PMID: 32622884; NCT02052778). 32622884