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Ref Type Abstract
Authors J. Starrett E. Allen A.M. Balcer D.C. Bensen T. Burn I. Hoffman R.L. Hudkins S. Iyer M. Neal K. Nelson C. Occhino P. Patel R.V. Swanson Q. Ye
Title 462P TYRA-300: FGFR3 selective and gatekeeper agnostic
Abstract Text Background There is a critical unmet need for next generation targeted therapies with improved efficacy and tolerability for patients with metastatic urothelial carcinoma. Resistance to FGFR targeted therapies can be mediated by an acquired gatekeeper mutation, yet no approved therapies are available in this setting. TYRA-300 is an FGFR3-selective inhibitor agnostic to the gatekeeper mutation, with less hyperphosphatemia mediated by FGFR1 inhibition than pan-FGFR inhibitors in preclinical models. Methods TYRA-300 was evaluated in enzymatic assays and cell lines driven by FGFR3 fusions and mutations, as well as a CRISPR-engineered gatekeeper-mutant cell line. In vivo tumor growth inhibition with TYRA-300 was tested in several FGFR3-driven xenograft models. Results In enzymatic assays, TYRA-300 maintained potency against the gatekeeper mutants V555L/M, while approved pan-FGFR inhibitors lost at least 30-fold potency compared to wild-type IC50s. These data were confirmed in an FGFR3::TACC3 human bladder cancer cell line engineered to express the V555M gatekeeper mutation. TYRA-300 caused in vivo tumor regression in an FGFR3::TACC3 bladder cancer xenograft model as well as an FGFR3 S249C bladder cancer xenograft model when dosed either once or twice daily. In the FGFR3::TACC3-V555M xenograft model, a 77% inhibition of tumor growth was observed with TYRA-300 while a 12% tumor growth inhibition was observed with erdafitinib. TYRA-300 shows significant FGFR3 isoform selectively in a panel of Ba/F3 cell lines expressing FGFR1-4, in contrast to approved pan-FGFR inhibitors. In support of TYRA-300’s selectivity profile, a single oral dose of TYRA-300 did not substantially elevate phosphate levels in rats, while erdafitinib did increase phosphate. RNA sequencing analysis of in vitro and in vivo treated tumors identified potential biomarkers of activity that can be followed to assess TYRA-300 in future clinical studies. Conclusions TYRA-300 is currently under development for patients with FGFR3-altered urothelial carcinoma. TYRA-300 retains efficacy in the presence of a gatekeeper resistance mutation. Importantly, TYRA-300 is selective for FGFR3, and thus may limit toxicities observed with pan-FGFR inhibitors.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
TYRA-300 TYRA-300 1 1
Drug Name Trade Name Synonyms Drug Classes Drug Description
TYRA-300 TYRA300|TYRA 300 FGFR3 Inhibitor 19 TYRA-300 selectively inhibits FGFR3, potentially leading to decreased tumor growth (Annals of Oncology 33 (2022): S751).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR3 S249C urinary bladder cancer predicted - sensitive TYRA-300 Preclinical - Cell line xenograft Actionable In a preclinical study, TYRA-300 induced tumor regression a cell line xenograft model of bladder cancer harboring FGFR3 S249C (Annals of Oncology 33 (2022): S751). detail...