TYRA-200: Potent Against FGFR2 Fusions, Molecular Brake Mutations and Gatekeeper Resistance

Background: Approved pan-FGFR (fibroblast growth factor receptor) inhibitors and those in late-stage clinical development (pemigatinib, infigratinib, and futibatinib) have demonstrated a clinical benefit in metastatic FGFR2-fusion or rearranged intrahepatic cholangiocarcinoma (ICC). However, inhibition of emerging polyclonal on-target acquired resistance mutations remains a critical unmet need. TYRA-200 is an FGFR1/2/3 inhibitor that was designed to specifically address these clinically observed acquired resistance mutations within the kinase domain of FGFR2. A significant therapeutic benefit may be achieved from this precision approach for FGFR2-driven cancers. Materials and Methods: TYRA-200 was evaluated in enzymatic assays and cell lines driven by FGFR2 fusions and mutations. in vivo tumor growth inhibition with TYRA-200 was tested in several FGFR2-driven models. Results: In enzymatic assays, TYRA-200 maintained potent inhibition for the gatekeeper mutants V565L/F and the molecular brake mutants N550D/H/ K and E566A. Cellular potency for these mutants was confirmed in a panel of Ba/F3 cell lines expressing wild type FGFR2 and variants N550 K, V565F, V565I, K660E and K660N. Additionally, TYRA-200 maintained potency in vitro in an endometrial cancer cell line AN3CA, which harbors the molecular brake mutation N550 K. in vivo tumor regressions were achieved in both the AN3CA and Ba/F3 FGFR2 V565F models. In the AN3CA xenograft model 80% tumor regression was achieved, while in the Ba/F3 FGFR2 V565F allograft model, a 64% tumor regression was seen, whereas tumor regression was not observed with futibatinib. Conclusions: TYRA-200 is currently under development for FGFR2-altered advanced solid tumors, including ICC. Importantly, the data demonstrates that TYRA-200 retains potency across multiple resistance mutations which emerge during therapy, including gatekeeper and molecular brake mutations. Conflict of interest: Ownership: Tyra Biosciences shareholders.