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BACKGROUND: Mutant IDH1 (mIDH1) defines a therapeutically-targetable subtype of intrahepatic cholangiocarcinoma (ICC), with the mIDH1 inhibitor ivosidenib approved for advanced disease. A subset of patients experiences prolonged disease stabilization, although the molecular basis for eventual progression remains poorly defined.EXPERIMENTAL DESIGN: We performed molecular profiling of matched baseline and post-progression circulating tumor DNA (ctDNA) samples from patients with mIDH1 ICC enrolled in the ClarIDHy phase III trial. Functional studies were conducted to characterize candidate resistance mechanisms.RESULTS: Longitudinal ctDNA analysis of 18 patients treated with ivosidenib for >6 months revealed emergent genomic alterations in multiple cases. Acquired mutations in MAPK-pathway genes (KRAS, NRAS, MAP2K1, NF1) were identified in five cases, with instances of concurrent alterations and/or high variant allele fractions (VAF). Additional candidate resistance events included a secondary IDH1 mutation and a hotspot IDH2 mutation, detected at low VAF in the same patient. Functional studies demonstrated that these IDH mutations conferred sustained 2-hydroxyglutarate (2HG) production and ivosidenib resistance, whereas MAPK activation blunted gene expression induced by ivosidenib plus interferon-γ, a key therapeutic output of mIDH1 inhibition. In parallel, baseline ctDNA profiling of 81 patients linked ARID1A mutations and elevated mIDH1 VAF to reduced clinical benefit.CONCLUSIONS: MAPK-pathway alterations represent a recurrent mechanism of resistance to mIDH1 inhibition in ICC, while emergent IDH1/IDH2 mutations appear infrequent. Functional data suggest that MAPK-mediated resistance may involve impaired IFN signaling. These results support MAPK-directed combination strategies and highlight the utility of ctDNA profiling to identify predictive and resistance biomarkers in mIDH1-driven ICC.