Dysregulation of the fibroblast growth factor receptor (FGFR) signaling pathway due to receptor overexpression, gene amplification, point mutations or fusions/chromosomal translocations is associated with cancer development and progression. In gastric cancer, alterations of FGFR2 are observed in a subset of patients, overexpression being more frequently observed as compared to FGFR2 amplifications. In addition, FGFR2 amplification and ERBB2, EGFR, MET and KRAS amplifications are mutually exclusive suggesting that FGFR targeted therapy would be most effective in the FGFR2-amplified subgroup of patients. Debio 1347 (CH5183284) is an oral selective FGFR inhibitor currently in clinical development. The aim of the study was to investigate the preclinical activity of Debio 1347 in patient derived xenograft (PDX) mouse models harboring diverse FGFR alterations in multiple indications, including gastric cancer.

The mouse trial was conducted in 39 different PDX models selected according to FGFR1, 2 and 3 alterations status. Debio 1347 was administered orally once daily and tumor volume was monitored for 14 consecutive days. PDX tumors were extensively characterized using FISH, RNAseq, nCounter Gene Expression and immunohistochemistry (IHC), and FGFR molecular alterations were correlated with Debio 1347 efficacy. The level of tumor heterogeneity for FGFR2 amplification and expression and its impact on drug response were also assessed.

In gastric cancer, Debio 1347 induced tumor regression in models harboring the commonly found FGFR2 amplification. Interestingly, Debio 1347 was also highly effective in models with high FGFR2 expression but without FGFR2 amplification, indicating that not only gene amplification drives the activity of Debio 1347 in this indication, but also the expression level of FGFR2.

Altogether, these data demonstrate that Debio 1347 could be highly effective in gastric cancer patients harboring FGFR2 amplification and/or high FGFR2 expression. Debio 1347 is currently investigated in a Phase I trial in selected patients harboring FGFR alterations (NCT01948297).

Citation Format: Brichory Franck, Anna Pokorska-Bocci, Paolo Nuciforo, Stefania Rigotti, Nathalie Lembrez, Grégoire Vuagniaux, Corinne Moulon, Anne Vaslin. FGFR-selective inhibitor Debio 1347 induces tumor regressions in FGFR2-altered gastric cancer PDX models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4784.