• Martin H Voss, Cinta Hierro, Rebecca S Heist, James M Cleary, Funda Meric-Bernstam, Josep Tabernero, Filip Janku, Leena Gandhi, A John Iafrate, Darrell R Borger, Nobuya Ishii, Youyou Hu, Yulia Kirpicheva, Valerie Nicolas-Metral, Anna Pokorska-Bocci, Anne Vaslin Chessex, Claudio Zanna, Keith T Flaherty, and Jose Baselga.
• Memorial Sloan Kettering Cancer Center, New York, New York. vossm@mskcc.org.
• Clin Cancer Res. 2019 May 1; 25 (9): 2699-2707.

PurposeTo investigate tolerability, efficacy, and pharmacokinetics/pharmacodynamics of Debio 1347, a selective FGFR inhibitor.Patients And MethodsThis was a first-in-human, multicenter, open-label study in patients with advanced solid tumors harboring FGFR1-3 gene alterations. Eligible patients received oral Debio 1347 at escalating doses once daily until disease progression or intolerable toxicity. Dose-limiting toxicities (DLT) were evaluated during the first 4 weeks on treatment, pharmacokinetics/pharmacodynamics postfirst dose and after 4 weeks.ResultsA total of 71 patients were screened and 58 treated with Debio 1347 at doses from 10 to 150 mg/day. Predominant tumor types were breast and biliary duct cancer, most common gene alterations were FGFR1 amplifications (40%) and mutations in FGFR2 (12%) and FGFR3 (17%); 12 patients (21%) showed FGFR fusions. Five patients at three dose levels had six DLTs (dry mouth/eyes, hyperamylasemia, hypercalcemia, hyperbilirubinemia, hyperphosphatemia, and stomatitis). The maximum tolerated dose was not reached, but dermatologic toxicity became sometimes dose limiting beyond the DLT period at ≥80 mg/day. Adverse events required dose modifications in 52% of patients, mostly due to dose-dependent, asymptomatic hyperphosphatemia (22%). RECIST responses were seen across tumor types and mechanisms of FGFR activation. Six patients, 3 with FGFR fusions, demonstrated partial responses, 10 additional patients' tumor size regressions of ≤30%. Plasma half-life was 11.5 hours. Serum phosphate increased with Debio 1347 plasma levels and confirmed target engagement at doses ≥60 mg/day.ConclusionsPreliminary efficacy was encouraging and tolerability acceptable up to 80 mg/day, which is now used in an extension part of the study.©2019 American Association for Cancer Research.

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