Dabogratinib (TYRA-300), an FGFR3 Isoform-Selective Inhibitor: Preclinical and Initial Clinical Evidence of Antitumor Activity.

Despite recent advances in the treatment of fibroblast growth factor receptor 3 (FGFR3)-altered metastatic urothelial carcinoma, there is no approved precision therapy that selectively targets FGFR3 while sparing other FGFR isoforms. Dabogratinib (TYRA-300)-a rationally designed selective FGFR3 inhibitor-was evaluated in vitro and in vivo. We also report three patient cases from the ongoing first-in-human, phase I/II SURF301 study (NCT05544552). Dabogratinib elicited a dose-dependent reduction in downstream signaling across three bladder cancer cell lines harboring an FGFR3 fusion, mutation, or gatekeeper resistance mutation. In a xenograft model driven by an FGFR3S249C-activating mutation, dabogratinib treatment resulted in dose-dependent tumor growth inhibition with tumor regression observed at the highest doses. These preclinical findings are supported by the three case reports from the SURF301 study, which demonstrate early clinical activity in patients with advanced metastatic urothelial carcinoma with an FGFR3 fusion or activating mutation.