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Ref Type Journal Article
PMID (34551969)
Authors Meric-Bernstam F, Bahleda R, Hierro C, Sanson M, Bridgewater J, Arkenau HT, Tran B, Kelley RK, Park JO, Javle M, He Y, Benhadji KA, Goyal L
Title Futibatinib, an Irreversible FGFR1-4 Inhibitor, in Patients with Advanced Solid Tumors Harboring FGF/FGFR Aberrations: A Phase I Dose-Expansion Study.
Journal Cancer discovery
Vol 12
Issue 2
Date 2022 02
URL
Abstract Text Futibatinib, a highly selective, irreversible FGFR1-4 inhibitor, was evaluated in a large multihistology phase I dose-expansion trial that enrolled 197 patients with advanced solid tumors. Futibatinib demonstrated an objective response rate (ORR) of 13.7%, with responses in a broad spectrum of tumors (cholangiocarcinoma and gastric, urothelial, central nervous system, head and neck, and breast cancer) bearing both known and previously uncharacterized FGFR1-3 aberrations. The greatest activity was observed in FGFR2 fusion/rearrangement-positive intrahepatic cholangiocarcinoma (ORR, 25.4%). Some patients with acquired resistance to a prior FGFR inhibitor also experienced responses with futibatinib. Futibatinib demonstrated a manageable safety profile. The most common treatment-emergent adverse events were hyperphosphatemia (81.2%), diarrhea (33.5%), and nausea (30.4%). These results formed the basis for ongoing futibatinib phase II/III trials and demonstrate the potential of genomically selected early-phase trials to help identify molecular subsets likely to benefit from targeted therapy. SIGNIFICANCE: This phase I dose-expansion trial demonstrated clinical activity and tolerability of the irreversible FGFR1-4 inhibitor futibatinib across a broad spectrum of FGFR-aberrant tumors. These results formed the rationale for ongoing phase II/III futibatinib trials in cholangiocarcinoma, breast cancer, gastroesophageal cancer, and a genomically selected disease-agnostic population.This article is highlighted in the In This Issue feature, p. 275.

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Molecular Profile Treatment Approach
FGFR1 rearrange FGFR Inhibitor (Pan)
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 PLAG1 FGFR1 - PLAG1 fusion unknown FGFR1-PLAG1 results from the fusion of FGFR1 and PLAG1 (PMID: 29084941). FGFR1-PLAG1 has been identified in head and neck cancer (PMID: 34551969) and myoepithelial carcinoma, and is associated with increased Plag1 expression in patient samples (PMID: 29084941), but has not been fully biochemically characterized and therefore, the effect on protein function is unknown (PubMed, Jun 2022).
FGFR1 M563T missense unknown FGFR1 M563T (corresponds to M532T in the canonical isoform) lies within the protein kinase domain of the Fgfr1 protein (UniProt.org). M563T has been identified in the scientific literature (PMID: 34551969), but has not been biochemically characterized and therefore, its effect on Fgfr1 protein function is unknown (PubMed, Jun 2022).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR2 - KIAA1217 intrahepatic cholangiocarcinoma sensitive Futibatinib Case Reports/Case Series Actionable In a Phase I trial, Futibatinib (TAS-120) treatment at a dose of 16mg led to a partial response in 42.1% (8/19) of patients with intrahepatic cholangiocarcinoma harboring FGF or FGFR alterations, including a partial response with a progression-free survival of 6.8 months and a duration of response of 5.6 months in a patient harboring FGFR2-KIAA1217 (PMID: 34551969; NCT02052778). 34551969
FGFR3 - TACC3 stomach cancer predicted - sensitive Futibatinib Case Reports/Case Series Actionable In a Phase I trial, Futibatinib (TAS-120) treatment led to an overall objective response rate of 22% (2/9, 2 partial responses) and a disease control rate of 55.6% (5/9) in patients with gastric cancer harboring an FGFR2 amplification or FGFR3 rearrangement, including a partial response with a progression-free survival of 6.7 months and a duration of response of 5.4 months in a gastric cancer patient harboring FGFR3-TACC3 (PMID: 34551969; NCT02052778). 34551969
FGFR2 amp head and neck cancer predicted - sensitive Futibatinib Case Reports/Case Series Actionable In a Phase I trial, Futibatinib (TAS-120) treatment led to a partial response lasting 5.6 months and progression-free survival of 6.9 months in a head and neck cancer patient harboring FGFR1-PLAG1 (PMID: 34551969; NCT02052778). 34551969
FGFR2 amp stomach cancer predicted - sensitive Futibatinib Case Reports/Case Series Actionable In a Phase I trial, Futibatinib (TAS-120) treatment led to an overall objective response rate of 22% (2/9, 2 partial responses) and a disease control rate of 55.6% (5/9) in patients with gastric cancer harboring an FGFR2 amplification or FGFR3 rearrangement, including a progression-free survival of 4.8 months and a duration of response of 3.5 months in a patient with FGFR2 amplification (PMID: 34551969; NCT02052778). 34551969
FGFR2 C383R intrahepatic cholangiocarcinoma predicted - sensitive Futibatinib Case Reports/Case Series Actionable In a Phase I trial, Futibatinib (TAS-120) treatment at a dose of 20mg led to an objective response rate of 15.6% (10/64) and a median progression-free survival of 5.1 months in patients with cholangiocarcinoma harboring FGF or FGFR 1-4 alterations, including a partial response with a progression-free survival of 9.2 months and a duration of response of 6.5 months in a patient with intrahepatic cholangiocarcinoma harboring FGFR2 C383R (PMID: 34551969; NCT02052778). 34551969
FGFR3 S249C transitional cell carcinoma predicted - sensitive Futibatinib Case Reports/Case Series Actionable In a Phase I trial, Futibatinib (TAS-120) treatment led to an overall objective response rate of 15.8% (3/19, 3 partial responses) and a disease control rate of 47.4% (9/19), with stable disease in 6, in urothelial cancer patients harboring an FGFR3 mutation or FGFR1 mutation, including partial responses in 2 patients with urothelial cancer harboring FGFR3 S249C with a progression-free survival of 2.7 and 4.7 mo, and a duration of response of 1.4 and 3.4 mo, respectively (PMID: 34551969; NCT02052778). 34551969
FGFR2 W290C intrahepatic cholangiocarcinoma predicted - sensitive Futibatinib Case Reports/Case Series Actionable In a Phase I trial, Futibatinib (TAS-120) treatment at a dose of 20mg led to an objective response rate of 15.6% (10/64) and a median progression-free survival of 5.1 months in patients with cholangiocarcinoma harboring FGF or FGFR 1-4 alterations, including a partial response with a progression-free survival of 12.7 months and a duration of response of 9.9 months in an intrahepatic cholantiocarcinoma patient harboring FGFR2 W290C (PMID: 34551969; NCT02052778). 34551969
FGFR2 - WAC intrahepatic cholangiocarcinoma predicted - sensitive Futibatinib Case Reports/Case Series Actionable In a Phase I trial, Futibatinib (TAS-120) treatment at a dose of 16mg led to a partial response in 42.1% (8/19) of patients with intrahepatic cholangiocarcinoma harboring FGF or FGFR alterations, including a partial response with a progression-free survival of 6.9 months and a duration of response of 4.2 months in a patient harboring FGFR2-WAC (PMID: 34551969; NCT02052778). 34551969
FGFR2 - TTC28 intrahepatic cholangiocarcinoma predicted - sensitive Futibatinib Case Reports/Case Series Actionable In a Phase I trial, Futibatinib (TAS-120) treatment at a dose of 16mg led to a partial response in 42.1% (8/19) of patients with intrahepatic cholangiocarcinoma harboring FGF or FGFR alterations, including a partial response with a progression-free survival of 24.1 months and a duration of response of 12.7 months in a patient harboring FGFR2-TTC28 (PMID: 34551969; NCT02052778). 34551969
FGFR1 M563T intrahepatic cholangiocarcinoma predicted - sensitive Futibatinib Case Reports/Case Series Actionable In a Phase I trial, Futibatinib (TAS-120) treatment led to an overall objective response rate of 15.8% (3/19, 3 partial responses) and a disease control rate of 47.4% (9/19), with stable disease in 6, in patients with urothelial cancer harboring an FGFR3 mutation or FGFR1 mutation, including a partial response with a progression-free survival of 6.8 mo and a duration of response of 5.6 mo in a urothelial cancer patient harboring FGFR1 M563T and amplifications in FGF3 and FGF19 (PMID: 34551969; NCT02052778). 34551969
FGFR1 - TACC1 glioblastoma predicted - sensitive Futibatinib Case Reports/Case Series Actionable In a Phase I trial, Futibatinib (TAS-120) treatment led to a partial response lasting 5.8 months and progression-free survival of 7.0 months in a glioblastoma patient harboring FGFR1-TACC1 (PMID: 34551969; NCT02052778). 34551969
FGFR2 - TNS1 intrahepatic cholangiocarcinoma predicted - sensitive Futibatinib Case Reports/Case Series Actionable In a Phase I trial, Futibatinib (TAS-120) treatment at a dose of 16mg led to a partial response in 42.1% (8/19) of patients with intrahepatic cholangiocarcinoma harboring FGF or FGFR alterations, including a partial response with a progression-free survival of 11 months and a duration of response of 9.1 months in a patient harboring FGFR2-TNS1 (PMID: 34551969; NCT02052778). 34551969
FGFR2 - CCDC6 intrahepatic cholangiocarcinoma predicted - sensitive Futibatinib Case Reports/Case Series Actionable In a Phase I trial, Futibatinib (TAS-120) treatment at a dose of 16mg led to a partial response in 42.1% (8/19) of patients with intrahepatic cholangiocarcinoma harboring FGF or FGFR alterations, including a partial response with a progression-free survival of 6.8 months and a duration of response of 8.8 months in a patient harboring FGFR2-CCDC6 (PMID: 34551969; NCT02052778). 34551969
FGFR2 amp triple-receptor negative breast cancer predicted - sensitive Futibatinib Case Reports/Case Series Actionable In a Phase I trial, Futibatinib (TAS-120) treatment led to a partial response lasting 20.8 months and progression-free survival of 22.1 months in a triple-receptor negative breast cancer patient harboring an FGFR2 amplification (PMID: 34551969; NCT02052778). 34551969