Abstract P5-08-12: Efficacy of futibatinib, an irreversible fibroblast growth factor receptor (FGFR) inhibitor, in breast cancer models with FGFR alterations

Abstract

Abstract Purpose: Several FGFR alterations have been found in breast cancer, however, their role as a therapeutic target in breast has been controversial. Futibatinib (TAS-120; Taiho) is a novel, selective pan-FGFR inhibitor which irreversibly binds to and inhibits FGFR1-4 at nanomolar concentrations. We sought to determine the efficacy of futibatinib in breast cancer models with differing FGFR alterations. Experimental Design: In vivo, antitumor efficacy was evaluated by tumor growth curves and event-free survival in a panel of patient-derived xenografts (PDXs) from breast cancer patients with different FGFR1-4 alterations. Genomic alterations in the PDXs were characterized by next generation sequencing. Correlation of FGFR gene expression in matched patient tumors and PDXs was analyzed by RNA sequencing. In vitro, FGFR2 Y375C mutant and FGFR2-BICC1 fusion expressing MCF10A cell lines were generated, and effect on cell proliferation, colony formation assay, and cell signaling was assessed with and without futibatinib. Frequency of FGFR mutations and FGFR2 amplification was compiled from internal and public databases. Results: Breast cancer PDXs varied in their expression of FGFR1-4. FGFR gene expression significantly correlated between matched patient tumors and PDXs derived from them, however, PDXs had higher levels of FGFR3 and FGFR4 expression compared to patient samples. Futibatinib inhibited tumor growth in three of 10 PDX models, with tumor stabilization in a FGFR2 amplified model and prolonged tumor regression (more than 110 days) in a PDX bearing a FGFR2 Y375C mutation. In vitro, expression of FGFR2 Y375C, as well as FGFR2-BICC fusion in normal-like MCF10A cells enhanced growth, colony formation ability and FGFR signaling. Cells expressing FGFR2 Y375C as well as FGFR2-BICC fusions were more sensitive to futibatinib. In the five breast cancer genomic series we analyzed, FGFR2 mutations and amplifications were found in 1.1%-2.6% and 1.4%-2.5%, respectively. Conclusions: Futibatinib had single agent activity of selected breast cancer PDX models. FGFR2 activating mutations and amplification may represent rare but promising therapeutic targets to FGFR inhibition. Citation Format: Turcin Saridogan, Argun Akcakanat, Ming Zhao, Kurt W. Evans, Erkan Yuca, Stephen Scott, Bryce P. Kirby, Xiaofeng Zheng, Senthil Damodaran, Funda Meric-Bernstam. Efficacy of futibatinib, an irreversible fibroblast growth factor receptor (FGFR) inhibitor, in breast cancer models with FGFR alterations [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-08-12.