Recent advances in the treatment of FGFR-altered cholangiocarcinoma

Cholangiocarcinoma (CCA) is a rare, highly lethal biliary malignancy comprising intrahepatic (iCCA), perihilar (pCCA), and distal (dCCA) subtypes, with a rising global incidence. Surgery is the only curative option, yet most patients present with advanced disease, making systemic therapy the mainstay. Molecular profiling has revealed marked heterogeneity, and fibroblast growth factor receptor 2 (FGFR2) fusions in iCCA represent one of the most actionable targets.

An extensive literature search was performed in PubMed/MEDLINE, Embase, and ClinicalTrials.gov to identify preclinical studies, clinical research, and clinical trials evaluating FGFR inhibitor therapy in CCA. This review summarizes FGFR signaling biology, the prevalence and diagnostic challenges of FGFR2 fusions, and clinical evidence for FGFR inhibitors. Resistance mechanisms, diagnostic strategies, toxicity profiles, and ongoing trials are also reviewed.

FGFR inhibitors are transitioning from experimental to established targeted options, underscoring the need for routine molecular profiling and optimized fusion detection. Key challenges include overcoming resistance, refining patient selection, and defining the role of FGFR inhibition in combination strategies and earlier-line or perioperative settings. Further evidence is needed to clarify long-term clinical benefit in FGFR2-altered CCA.