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BACKGROUND: Pan-FGFR inhibitors, targeting FGFR1-3 or FGFR1-4, are FDA-approved for FGFR2-driven cholangiocarcinoma. However, acquired resistance and dose-limiting toxicities from systemic FGFR inhibition constrain efficacy. Lirafugratinib (RLY-4008), a first-in-class FGFR2-selective inhibitor with activity against resistance-associated FGFR2 kinase domain mutations, shows promise in patients with FGFR2-altered solid tumors (ReFocus trial, NCT04526106). Defining acquired resistance mechanisms to selective FGFR2 targeting is essential for therapeutic development.METHODS: ctDNA samples from 28 patients treated with lirafugratinib (16 FGFR inhibitor-naïve, 12 FGFR inhibitor-refractory) were analyzed using targeted next-generation sequencing. Genomic alterations observed were compared to prior studies of pan-FGFR inhibitor resistance and validated in preclinical models.RESULTS: Polyclonal FGFR2 kinase domain mutations and RTK-MAPK bypass alterations emerged as common lirafugratinib resistance mechanisms in the FGFR inhibitor-naïve context (8/16 and 9/16 patients, respectively). Resistance profiles differed markedly from pan-FGFR inhibitors, with decreased FGFR2 V565F/L and N550H/K mutations, increased M538I and L618F mutations, and more frequent RTK-MAPK bypass alterations. The variant allele fraction was typically higher for FGFR2 kinase domain mutations, consistent with these alterations serving as primary resistance drivers. Preclinical studies confirmed differential sensitivity of these FGFR2 mutations to lirafugratinib. Importantly, lirafugratinib demonstrated clinical efficacy in the FGFR inhibitor-refractory setting, with ctDNA dynamics showing resolution of multiple FGFR2 mutations and persistence or emergence of others.CONCLUSIONS: Lirafugratinib retains activity against multiple mutations that confer clinical resistance to pan-FGFR inhibitors. However, diverse resistance mechanisms, including various kinase domain mutations and RTK-MAPK bypass alterations, remain challenges in the treatment of FGFR2-altered tumors, even with selective FGFR2 kinase inhibition.