Activity of KIN-3248, a next-generation pan-FGFR inhibitor, against acquired FGFR-gatekeeper and molecular-brake drug resistance mutations.

Abstract

461 Background: Oncogenic FGFR (FGFR1, FGFR2, FGFR3, and FGFR4) gene alterations are observed in approximately 7% of all human cancers and present as point mutations, small intragenic deletions, genomic amplifications, or chromosomal rearrangements/ gene fusions. FGFR2 gene fusions and FGFR3 activating alterations are predicted oncogenic drivers in 10-20% of cholangiocarcinoma and 20-35% of urothelial cancers, respectively. While currently approved FGFR inhibitors (e.g., erdafitinib, pemigatinib, infigratinib) and those in development (e.g., futibatinib) provide clinical benefit in these cancer indications, disease progression typically occurs within 6-8 months of starting treatment and is often associated with the emergence of on-target resistance mutations within the FGFR kinase domain. KIN-3248 is a next-generation, irreversible, small molecule, pan-FGFR inhibitor designed to target clinically relevant primary FGFR driver alterations and secondary resistance mutations, including FGFR2 and FGFR3 gatekeeper, molecular brake, and activation loop mutations. Methods: KIN-3248 was evaluated across wild-type FGFR family members and clinically relevant fusions and kinase domain resistance mutations in vitro. In addition, KIN-3248 activity was assessed in FGFR-driven and FGFR inhibitor-resistant human gastrointestinal xenograft tumor models. Results: KIN-3248 exhibited low nanomolar biochemical potency against wild-type FGFR family members as well as mutants associated with resistance to FGFR inhibitors (IC50 3.9 – 24.1 nM). Consistently, KIN-3248 was active in human FGFR2-PHGDH fusion-positive CCLP-1 and FGFR2-OPTN fusion-positive ICC13-7 cholangiocarcinoma cell lines engineered to express wild-type or clinically relevant gatekeeper, molecular brake, and activation loop mutant alleles (EC50 2.4 – 9.9 nM). Lastly, KIN-3248 led to dose-dependent tumor growth inhibition and regressions in FGFR inhibitor-resistant, patient-derived gastric cancer and cholangiocarcinoma models harboring secondary FGFR2 kinase domain mutations. This efficacy was accompanied by both pharmacodynamic biomarker modulation, downstream pathway inhibition, and apoptotic cell death across models in vitro and in vivo. Conclusions: KIN-3248 is a next-generation, irreversible, orally available, small molecule pan-FGFR inhibitor that overcomes clinically observed secondary mutations in FGFR2 and FGFR3 known to drive resistance to both reversible and irreversible FGFR inhibitors and associated with disease progression. Its highly-selective, potent and broad-spectrum activity against mutations in both the FGFR2 and FGFR3 kinase domains – including gatekeeper, molecular brake, and activation loop alterations – is unique among FGFR inhibitors and has the potential to extend the clinical response of cancer patients with FGFR-altered tumors.