Kinnate Biopharma Inc. announced the presentation of updates from preclinical studies evaluating its Fibroblast Growth Factor Receptor (FGFR) inhibitor candidate, KIN-3248. These findings will be presented during a poster session at the ASCO Gastrointestinal Cancers Symposium taking place in San Francisco, January 20-22, 2022. KIN-3248, a next-generation, irreversible, small molecule pan-FGFR inhibitor, was developed to address both primary FGFR2 and FGFR3 oncogenic alterations and those predicted to drive acquired resistance to current FGFR-targeted therapies, including gatekeeper, molecular brake, and activation loop mutations observed in cancers such as intrahepatic cholangiocarcinoma (ICC) and other gastrointestinal cancers.

The Investigational New Drug application for KIN-3248 was cleared by the U.S. Food and Drug Administration on January 18, 2022, and Kinnate anticipates the initiation of a Phase 1 trial of KIN-3248 in the first half of 2022. Oncogenic FGFR (FGFR1, FGFR2, FGFR3, and FGFR4) gene alterations are observed in approximately 7% of all human cancers. FGFR2 gene fusions and FGFR3 activating alterations are predicted oncogenic drivers in approximately 10-20% of cholangiocarcinoma and 20-35% of urothelial cancers, respectively.

While currently approved FGFR inhibitors provide clinical benefit to these cancer patients, disease progression typically occurs within several months of starting treatment and is often associated with the emergence of on-target resistance mutations within the FGFR kinase domain. KIN-3248 has been evaluated across wild-type FGFR family members and clinically relevant fusions and kinase domain resistance mutations in vitro. In addition, KIN-3248 activity has been assessed in FGFR-driven and FGFR inhibitor-resistant human gastrointestinal xenograft tumor models.

Data to be presented shows that KIN-3248 exhibited low nanomolar biochemical potency against wild-type FGFR kinase family members as well as mutations associated with resistance to FGFR inhibitors (IC50 3.9 – 24.3 nM). In preclinical studies, KIN-3248 has consistently shown to be 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, with a less than 5-fold difference in mutant to wild-type EC50 values. KIN-3248 has also led to tumor growth inhibition and regressions in cancer cell line- and patient-derived xenograft models harboring distinct secondary FGFR2 kinase domain resistance mutations, including gatekeeper and molecular brake mutations.

This efficacy was accompanied by robust FGFR pathway inhibition and underscores how KIN-3248 is poised to overcome on-target resistance in patients that often present with multiple FGFR kinase domain mutations.