Background: Fibroblast growth factor receptors (FGFRs) play a role in cell proliferation and survival. Genetic alterations of FGFRs can lead to deregulated activation in various cancers, including squamous cell carcinoma (SCC) of the lung and urothelial bladder cancer. Here, we report on a phase I study of BGJ398 a potent, selective pan-FGFR inhibitor.

Methods: Eligible patients (pts; ≥ 18 years of age) had tumors with any FGFR genetic alteration identified by central or local prescreening. Pts received BGJ398 once or twice daily (qd or bid) in 28-day cycles in escalating cohorts. Dose-limiting toxicities (DLTs) were predefined and included both severe events and those resulting in significant dosing delays. Upon determination of maximum tolerated dose (MTD), 3 expansion arms were treated: arm 1 included FGFR1-amplified SCC of the lung (continuous qd dosing); arms 2 and 3 included FGFR-altered solid tumors given qd continuous doses (arm 2) or qd doses on a 3-weeks-on/1-week-off schedule (arm 3).

Results: As of September 24, 2013, 94 pts were enrolled (median age 57.5 years). Pts were treated in qd dose cohorts (5-150 mg; n = 90) or a bid dose cohort (50 mg; n = 4). Arms 1 and 3 are ongoing. Of the 82 pts who discontinued, the most common reasons were disease progression (n = 56), consent withdrawal (n = 12), and adverse events (AEs; n = 10). DLTs during dose escalation were grade 3 aminotransferase increases (1 each at 100 and 125 mg), hyperphosphatemia (125 mg), and grade 1 corneal toxicity (150 mg). The 125-mg qd dose was identified as the MTD. Common treatment-emergent AEs (any grade, suspected to be related) at 125 mg qd (n = 41) include hyperphosphatemia (78%), stomatitis (37%), alopecia (32%), decreased appetite (32%), and fatigue (22%) and were generally mild, with stomatitis (7%) the only grade 3/4 AE occurring ≥ 5%. Elevated serum phosphate levels, a pharmacodynamic marker of FGFR pathway inhibition, could be managed through diet, phosphate lowering therapy, and drug interruptions. Preliminary analysis of efficacy data indicates tumor regressions in pts with various FGFR genetic alterations, including 4 of 5 pts with urothelial cell carcinomas (4 of which originated in the bladder) with FGFR3-activating mutations (with tumor reductions ranging from 27% to 48%). Additionally, 1 pt with FGFR1-amplified SCC lung cancer achieved confirmed partial response (PR) while another pt achieved a PR confirmed after 27 days. Tumor reductions were also observed in cholangiocarcinoma with an FGFR2 gene fusion, and FGFR1-amplified breast cancer.

Conclusions: BGJ398 had a tolerable safety profile and demonstrated single-agent activity in pts with FGFR-genetically altered solid tumors. The 3-weeks-on/1-week-off schedule has been chosen for future studies based on its improved safety profile. Clinical activity was observed in multiple tumor types, and pts with FGFR3-mutated bladder cancer may be especially sensitive to BGJ398.

Citation Format: Lecia V. Sequist, Phillippe Cassier, Andrea Varga, Josep Tabernero, Jan HM Schellens, Jean-Pierre Delord, Patricia LoRusso, D. Ross Camidge, Manuel Hidalgo Medina, Martin Schuler, Mario Campone, G. Gary Tian, Steven Wong, Jesus Corral, Randi Isaacs, Suman K. Sen, Diana Graus Porta, Swarupa G. Kulkarni, Caroline Lefebvre, Jürgen Wolf. Phase I study of BGJ398, a selective pan-FGFR inhibitor in genetically preselected advanced solid tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT326. doi:10.1158/1538-7445.AM2014-CT326