Abstract 1439: In vivo characterization of a selective FGFR2 inhibitor with potency against gatekeeper and molecular brake mutations

Abstract

Abstract Fibroblast growth factor receptor (FGFR) mutations, fusions, and rearrangements have been linked to the pathogenesis of multiple tumor types. FGFR2 alterations have emerged as oncogenic drivers across a variety of tumor types, including cholangiocarcinoma, lung, endometrial, and uterine cancer. Approved FGFR inhibitors have demonstrated responses in patients that harbor FGFR genetic alterations but show reduced activity in patients with gatekeeper and molecular brake mutations. In addition, pan-FGFR inhibitors are associated with dose-limiting hyperphosphatemia linked to the inhibition of FGFR1. To address these issues, a novel series of reversible FGFR2 inhibitors with activity against clinically relevant mutations and selectivity over FGFR1 has been identified. The inhibition of FGFR2 phosphorylation in engineered cell lines demonstrated activity toward wild-type FGFR2, molecular brake mutations N549H/K, and gatekeeper mutations V564I/F/L. Selectivity of these inhibitors against FGFR1 and the broader kinome could lead to fewer dose limiting toxicities compared to approved FGFR inhibitors. Additionally, maintaining potency against molecular brake and gatekeeper mutations may result in significantly improved clinical response. In vivo characterization to be presented includes dose escalating rodent pharmacokinetics (PK), second species PK, and pharmacodynamics (PD) in tumor bearing mice. Most importantly, efficacy in a mouse tumor xenograft model at a dose that does not show elevated plasma phosphorus levels in the rat hyperphosphatemia model will be presented. Herein, the in vitro and in vivo characterization of a representative selective reversible FGFR2 inhibitor is described. Citation Format: John Fischer, Karyn Bouhana, Mark Chicarelli, Brad Fell, Jennifer Fulton, Anna Guarnieri, Leyla Haygood, Ravi Jalluri, Amber Johnson, Brent Mclean, Max Mejia, Rob Rieger, John Robinson, Mareli Rodriguez, Francis Sullivan, Yang Wang, Shannon Winski, YeYun Zhou. In vivo characterization of a selective FGFR2 inhibitor with potency against gatekeeper and molecular brake mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1439.