Reference Detail

Ref Type

Journal Article

PMID

(38771739)

Authors

Grivas P, Garralda E, Meric-Bernstam F, Mellinghoff IK, Goyal L, Harding JJ, Dees EC, Bahleda R, Azad NS, Karippot A, Kurzrock R, Tabernero J, Kononen J, Ng MCH, Mehta R, Uboha NV, Bigot F, Boni V, Bowyer SE, Breder V, Cervantes A, Chan N, Cleary JM, Dhawan M, Eefsen RL, Ewing J, Graham DM, Guren TK, Won Kim J, Koynov K, Oh DY, Redman R, Yen CJ, Spetzler D, Roubaudi-Fraschini MC, Nicolas-Metral V, Ait-Sarkouh R, Zanna C, Ennaji A, Pokorska-Bocci A, Flaherty KT

Title

Evaluating Debio 1347 in Patients with FGFR Fusion-Positive Advanced Solid Tumors from the FUZE Multicenter, Open-Label, Phase II Basket Trial.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research			2024 May 21		Clin Cancer Res

URL

Abstract Text

This multicenter phase II basket trial investigated the efficacy, safety and pharmacokinetics of Debio 1347, an investigational, oral, highly selective, ATP-competitive, small molecule inhibitor of FGFR1-3, in patients with solid tumors harboring a functional FGFR1-3 fusion.Eligible adults had a previously treated locally advanced (unresectable) or metastatic biliary tract (cohort 1), urothelial (cohort 2) or other histologic cancer type (cohort 3). Debio 1347 was administered at 80 mg once daily, continuously, in 28-day cycles. The primary endpoint was the objective response rate (ORR). Secondary endpoints included duration of response, progression-free survival, overall survival, pharmacokinetics, and incidence of adverse events.Between March 22, 2019 and January 8, 2020, 63 patients were enrolled and treated, 30 in cohort 1, four in cohort 2, and 29 in cohort 3. An unplanned preliminary statistical review showed that the efficacy of Debio 1347 was lower than predicted and the trial was terminated. Three of 58 evaluable patients had partial responses, representing an ORR of 5%, with a further 26 (45%) having stable disease (≥6 weeks duration). Grade ≥3 treatment-related adverse events occurred in 22 (35%) of 63 patients, with the most common being hyperphosphatemia (13%) and stomatitis (5%). Two patients (3%) discontinued treatment due to adverse events.Debio 1347 had manageable toxicity; however, the efficacy in patients with tumors harboring FGFR fusions did not support further clinical evaluation in this setting. Our transcriptomic-based analysis characterized in detail the incidence and nature of FGFR fusions across solid tumors.

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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

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FGFR1 fusion	Advanced Solid Tumor	no benefit	Zoligratinib	Phase II	Actionable	In a Phase II trial (FUZE), Debio 1347 treatment demonstrated manageable toxicity but limited efficacy in patients with advanced solid tumors harboring a fusion in FGFR1, FGFR2, or FGFR3, resulting in an objective response rate of 5% (3/58, all partial responses), with stable disease in in 45% (26/58) of patients, and a median progression-free survival of 3.55 months at a median follow-up of 3.6 months, and further enrollment to the trial was terminated due to lack of efficacy (PMID: 38771739; NCT03834220).	38771739
FGFR2 fusion	Advanced Solid Tumor	no benefit	Zoligratinib	Phase II	Actionable	In a Phase II trial (FUZE), Debio 1347 treatment demonstrated manageable toxicity but limited efficacy in patients with advanced solid tumors harboring a fusion in FGFR1, FGFR2, or FGFR3, resulting in an objective response rate of 5% (3/58, all partial responses), with stable disease in in 45% (26/58) of patients, and a median progression-free survival of 3.55 months at a median follow-up of 3.6 months, and further enrollment to the trial was terminated due to lack of efficacy (PMID: 38771739; NCT03834220).	38771739
FGFR3 fusion	Advanced Solid Tumor	no benefit	Zoligratinib	Phase II	Actionable	In a Phase II trial (FUZE), Debio 1347 treatment demonstrated manageable toxicity but limited efficacy in patients with advanced solid tumors harboring a fusion in FGFR1, FGFR2, or FGFR3, resulting in an objective response rate of 5% (3/58, all partial responses), with stable disease in in 45% (26/58) of patients, and a median progression-free survival of 3.55 months at a median follow-up of 3.6 months, and further enrollment to the trial was terminated due to lack of efficacy (PMID: 38771739; NCT03834220).	38771739