Personalized Therapy in Advanced Cholangiocarcinoma: Contemporary Treatment Approaches and Future Directions.

Cholangiocarcinoma (CCA) includes a heterogeneous group of malignancies arising from the biliary epithelium, anatomically classified into intrahepatic, perihilar, and distal disease, with subtype-specific molecular features and treatment implications. Intrahepatic CCA is further subclassified into small- and large-duct variants. Most patients present with advanced, unresectable disease, and 5-year survival rates remain poor. For over a decade, gemcitabine-cisplatin (Gem-Cis) combination chemotherapy was the only established first-line standard of care. More recently, the addition of immune checkpoint inhibitors (IO), durvalumab and pembrolizumab, to Gem-Cis in the TOPAZ-1 and KEYNOTE-966 trials, respectively, improved overall survival, establishing chemoimmunotherapy as the new first-line therapy. Given the high prevalence of actionable alterations in CCA, comprehensive molecular profiling has become indispensable for second-line treatment selection and front-line clinical trial eligibility. FGFR2 fusions, IDH1 mutations, and HER2 amplification are among the most relevant, with several targeted agents now available in the second-line setting. Despite this progress, most patients exhaust treatment options within the first year, highlighting the need for further therapeutic advances. Emerging strategies include novel targeted agents, antibody-drug conjugates, locoregional approaches for liver-limited disease, and circulating tumor DNA monitoring for real-time treatment adaptation. The immunosuppressive tumor microenvironment and the absence of reliable predictive biomarkers for IO response remain key challenges that ongoing research aims to address. This review summarizes current evidence for the management of advanced CCA, focusing on molecular profiling, treatment sequencing, and emerging therapies.