Systemic Therapy for Advanced Biliary Tract Cancers in 2026: Current Standard of Care and Emerging Therapeutic Strategies.

Biliary tract cancers (BTCs)-including cholangiocarcinoma and gallbladder cancer-are increasing in incidence worldwide and carry a poor prognosis, constituting a growing global health burden. Early-stage disease can be potentially cured with surgical resection; however, the majority present with advanced disease, and palliative systemic therapy is the mainstay of treatment. In the first-line setting, gemcitabine plus cisplatin (GemCis) chemotherapy served as the long-standing standard of care; subsequently, TOPAZ-1 and KEYNOTE-966 established GemCis plus durvalumab or pembrolizumab as the current standard. For patients who progressed after frontline therapy and lack actionable alterations, fluoropyrimidine plus oxaliplatin and fluoropyrimidine plus liposomal irinotecan are recommended second-line options, supported by ABC-06 and NIFTY, respectively. Several targeted agents have demonstrated clinically meaningful efficacy in phase 2-3 trials and are recommended as subsequent-line therapy for biomarker-selected disease, including FGFR2 gene rearrangements, IDH1 mutations, and HER2 amplification. Although recent advances have improved clinical outcomes in patients with advanced BTC, median overall survival remains around 1 year, underscoring the need for further therapeutic innovation. This review provides a comprehensive overview of the current standards of care and highlights emerging therapeutic strategies for advanced BTC.