Molecularly Guided Therapy and the Tumor Microenvironment in Advanced Cholangiocarcinoma: Current Evidence and Emerging Strategies Targeting FGFR2, HER2, and IDH1 with Pemigatinib, Zanidatamab, and Ivosidenib

Cholangiocarcinoma (CCA) remains an aggressive malignancy characterized by late-stage diagnosis, substantial molecular heterogeneity, and limited therapeutic options. Advances in molecular characterization have identified actionable alterations and expanded systemic treatment beyond conventional cytotoxic chemotherapy. This review examines three clinically relevant and mechanistically distinct targeted strategies in advanced CCA. Pemigatinib, a selective fibroblast growth factor receptor 1–3 (FGFR1–3) inhibitor, targets oncogenic signaling driven by FGFR2 fusions or rearrangements, which occur predominantly in intrahepatic CCA. Zanidatamab, a bispecific human epidermal growth factor receptor 2 (HER2)-directed antibody targeting two extracellular HER2 domains, provides a therapeutic approach for HER2-positive biliary tract cancers (BTCs). Ivosidenib, a selective inhibitor of mutant isocitrate dehydrogenase 1 (IDH1m), suppresses production of the oncometabolite D-2-hydroxyglutarate and targets the associated metabolic and epigenetic dysregulation in IDH1-mutant CCA. The review integrates the molecular rationale and pivotal clinical evidence supporting these therapies with their safety profiles, mechanisms of acquired resistance, biomarker selection, and therapeutic positioning. Particular attention is given to tumor heterogeneity and the tumor microenvironment as determinants of treatment response and resistance, as well as to emerging strategies involving next-generation inhibitors, antibody–drug conjugates, immunotherapy, rational combinations, and longitudinal molecular monitoring. Collectively, the clinical development of pemigatinib, zanidatamab, and ivosidenib demonstrates the therapeutic value of matching actionable molecular alterations with mechanism-based treatments, while highlighting the need to overcome resistance and optimize treatment sequencing to achieve more durable benefit in advanced CCA.