Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Cancer discovery	12	2	2022 02	402-415	Cancer Discov

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)

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Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role
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Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
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Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
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, Oct 2024).

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Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FGFR1 M563T	intrahepatic cholangiocarcinoma	predicted - sensitive	Futibatinib	Case Reports/Case Series	Actionable	In a Phase I trial, Lytgobi (futibatinib) 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
FGFR2 amp	triple-receptor negative breast cancer	predicted - sensitive	Futibatinib	Case Reports/Case Series	Actionable	In a Phase I trial, Lytgobi (futibatinib) 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
FGFR2 amp	stomach cancer	sensitive	Futibatinib	Case Reports/Case Series	Actionable	In a Phase I trial, Lytgobi (futibatinib) 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, Lytgobi (futibatinib) 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
FGFR2 W290C	intrahepatic cholangiocarcinoma	predicted - sensitive	Futibatinib	Case Reports/Case Series	Actionable	In a Phase I trial, Lytgobi (futibatinib) 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
FGFR3 S249C	transitional cell carcinoma	predicted - sensitive	Futibatinib	Case Reports/Case Series	Actionable	In a Phase I trial, Lytgobi (futibatinib) 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

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