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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.
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
FGFR2 fusion Advanced Solid Tumor no benefit Debio 1347 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 Debio 1347 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
FGFR1 fusion Advanced Solid Tumor no benefit Debio 1347 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