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Ref Type Abstract
PMID
Authors E. Allen A. Balcer D. Bensen T. Burn I. Hoffman R. Hudkins S. Iyer M. Neal K. Nelson C. Occhino P. Patel J. Starrett R. Swanson Q. Ye
Title TYRA-200: Potent Against FGFR2 Fusions, Molecular Brake Mutations and Gatekeeper Resistance
URL https://www.ejcancer.com/article/S0959-8049(22)00846-2/fulltext
Abstract Text 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.

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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-200 TYRA-200 9 1
Drug Name Trade Name Synonyms Drug Classes Drug Description
TYRA-200 TYRA 200|TYRA200 FGFR1 Inhibitor 28 FGFR2 Inhibitor 23 FGFR3 Inhibitor 19 TYRA-200 is an FGFR1/2/3 inhibitor with activity against acquired resistance mutations, which potentially inhibits tumor growth (Eur J Cancer 2022 Vol 174, Supp 1:S16).
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
FGFR2 N550K Advanced Solid Tumor predicted - sensitive TYRA-200 Preclinical - Cell culture Actionable In a preclinical study, TYRA-200 inhibited FGFR2 N550K in an in vitro assay and demonstrated activity in cells expressing FGFR2 N550K in culture (Eur J Cancer 2022 Vol 174, Supp 1:S16). detail...
FGFR2 V565L Advanced Solid Tumor predicted - sensitive TYRA-200 Preclinical - Biochemical Actionable In a preclinical study, TYRA-200 inhibited FGFR2 V565L in an in vitro assay (Eur J Cancer 2022 Vol 174, Supp 1:S16). detail...
FGFR2 N550K endometrial cancer predicted - sensitive TYRA-200 Preclinical - Cell line xenograft Actionable In a preclinical study, TYRA-200 demonstrated activity in an endometrial cancer cell line harboring FGFR2 N550K in culture and treatment resulted in 80% tumor regression in a cell line xenograft model (Eur J Cancer 2022 Vol 174, Supp 1:S16). detail...
FGFR2 E566A Advanced Solid Tumor predicted - sensitive TYRA-200 Preclinical - Biochemical Actionable In a preclinical study, TYRA-200 inhibited FGFR2 E566A in an in vitro assay (Eur J Cancer 2022 Vol 174, Supp 1:S16). detail...
FGFR2 V565I Advanced Solid Tumor predicted - sensitive TYRA-200 Preclinical - Cell culture Actionable In a preclinical study, TYRA-200 demonstrated activity in cells expressing FGFR2 V565I in culture (Eur J Cancer 2022 Vol 174, Supp 1:S16). detail...
FGFR2 K660E Advanced Solid Tumor predicted - sensitive TYRA-200 Preclinical - Cell culture Actionable In a preclinical study, TYRA-200 demonstrated activity in cells expressing FGFR2 K660E in culture (Eur J Cancer 2022 Vol 174, Supp 1:S16). detail...
FGFR2 K660N Advanced Solid Tumor predicted - sensitive TYRA-200 Preclinical - Cell culture Actionable In a preclinical study, TYRA-200 demonstrated activity in cells expressing FGFR2 K660N in culture (Eur J Cancer 2022 Vol 174, Supp 1:S16). detail...
FGFR2 N550H Advanced Solid Tumor predicted - sensitive TYRA-200 Preclinical - Biochemical Actionable In a preclinical study, TYRA-200 inhibited FGFR2 N550H in an in vitro assay (Eur J Cancer 2022 Vol 174, Supp 1:S16). detail...
FGFR2 V565F Advanced Solid Tumor predicted - sensitive TYRA-200 Preclinical Actionable In a preclinical study, TYRA-200 inhibited FGFR2 V565F in an in vitro assay, demonstrated activity in cells expressing FGFR2 V565F in culture, and induced 64% tumor growth regression in an allograft model (Eur J Cancer 2022 Vol 174, Supp 1:S16). detail...