Systemic treatment of advanced biliary tract cancers: moving from ‘all-comers’ to precision medicine

Biliary tract cancers (BTC) are a diverse group of aggressive malignancies with a growing global prevalence and a persistently poor prognosis. Over the past decade, substantial evolution in systemic therapy has transformed the therapeutic landscape for advanced disease. Gemcitabine–cisplatin remains the mainstay of first-line treatment, but the incorporation of immune checkpoint inhibitors — most notably durvalumab and pembrolizumab — has set new standards of care, providing long-term survival benefits across BTC subtypes. In later lines of treatment, the benefit of cytotoxic chemotherapy is modest, though FOLFOX and liposomal irinotecan combinations can offer limited improvements in selected patients. Alongside these incremental advances, major progress has beendriven by molecularly targeted therapies. Actionable genomic alterations, including FGFR2 fusions, IDH1 mutations, HER2 amplification, BRAF V600E mutations, NTRK fusions, and rare KRAS G12C alterations, enable the use of highly effective tumour-agnostic or tumour-specific agents. Next-generation sequencing, ideally incorporating both DNA and RNA profiling, is therefore essential in the modern management of BTC. Locoregional therapies, including selective internal radiation therapy (SIRT) and hepatic arterial infusion (HAI), may enhance tumour control further and occasionally enable secondary resection, particularly in cases of liver-limited intrahepatic cholangiocarcinoma. Continued advances in biomarker-driven therapy and an improved understanding of resistance mechanisms and multimodal integration will be crucial in achieving meaningful survival improvements in this challenging disease.