Chemoimmunotherapy and targeted therapy in biliary tract cancer: current evidence and future directions

Biliary tract cancer (BTC) is an uncommon, heterogeneous malignancy with increasing incidence and mortality. Most patients present with advanced disease, which limits curative treatment options and contributes to a poor prognosis. Recent advances in molecular profiling and immuno-oncology have substantially reshaped the therapeutic landscape of BTC by providing deeper insight into its molecular and immunological features. In particular, the incorporation of immune checkpoint inhibitors, such as durvalumab and pembrolizumab, into first-line gemcitabine-cisplatin therapy has demonstrated clinically meaningful survival benefits. Phase III trials, including TOPAZ-1 and KEYNOTE-966, reported significant improvements in overall survival and progression-free survival compared with gemcitabine-cisplatin alone, establishing chemoimmunotherapy as a new standard of care for advanced BTC. The advent of targeted therapies has further expanded treatment options. Agents directed against fibroblast growth factor receptor 2 (FGFR2) fusions, isocitrate dehydrogenase 1 (IDH1) mutations, and human epidermal growth factor receptor 2 (HER2) overexpression have enabled precision-based approaches for patients harboring actionable molecular alterations. These developments highlight the critical role of comprehensive molecular profiling in guiding individualized treatment strategies. Despite these advances, important challenges remain, largely because of the relative rarity of BTC and the inherent limitations of small, heterogeneous study populations. Future research should prioritize large-scale, multicenter, prospective trials to optimize therapeutic sequencing and combination strategies. Furthermore, the routine integration of next-generation sequencing into clinical practice is essential to fully realize the potential of molecularly tailored therapies. This review summarizes the latest evidence on immunotherapy and targeted therapy for BTC and discusses their clinical implications for improving patient outcomes.