Abstract 4729: The reversible and selective FGFR2/3 inhibitor CGT4859 has superior target coverage of resistance mutations missed by leading FGFR inhibitors

Abstract FGFR2 and FGFR3 alterations are oncogenic events across many solid tumors, often through chromosomal fusion or activating mutations. FGFR2 translocations are prevalent in intrahepatic cholangiocarcinoma, while FGFR3 mutations and fusions are prevalent in bladder cancer. Both indications have approved pan-FGFR inhibitors that demonstrate responses in patients that harbor these genetic alterations, however, responses are short-lived or show reduced activity in patients with on-target resistance mutations. In addition, efficacy of these agents has been hampered by inhibition of FGFR1, which leads to dose-limiting hyperphosphatemia. To address these issues, we present our clinical candidate CGT4859, a novel reversible FGFR2/3 inhibitor with activity against clinically relevant mutations and >140-fold selectivity over FGFR1. In vivo characterization of CGT4859 demonstrates robust efficacy in target-altered models at tolerated doses. Together, these data demonstrate CGT4859 as a potential best-in-class FGFR1-sparing pan-mutant FGFR2/3 inhibitor. Citation Format: John Fischer, Karyn Bouhana, Richard Brizendine, Mark Chicarelli, Brad Fell, Jennifer Fulton, Anna Guarnieri, Leyla Haygood, Ravi Jalluri, Amber Johnson, Keith Koch, Erika Koslov-Davino, Macedonio J. Mejia, Rob Rieger, John Robinson, Mareli Rodriguez, Francis Sullivan, Yang Wang, Shannon Winski, Silas Wood, Yeyun Zhou. The reversible and selective FGFR2/3 inhibitor CGT4859 has superior target coverage of resistance mutations missed by leading FGFR inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4729.