From chemotherapy to molecular targeted therapy in advanced biliary tract cancer

Biliary tract cancers are a rare and lethal group of malignancies arising from the gallbladder or intra- or extrahepatic bile ducts. Despite advances in management, prognosis for unresectable disease remains dismal. In recent years, chemoimmunotherapy has superseded chemotherapy alone in first-line treatment of advanced biliary tract cancer with modest improvements in overall survival. The high frequency of somatic mutations, particularly in intrahepatic cholangiocarcinoma, has opened the door to an increasing number of matched targeted therapies, with fibroblast growth factor receptor (FGFR), isocitrate dehydrogenase 1 (IDH1), and human epidermal growth factor receptor 2 (HER2)-directed therapies now approved for second-line treatment of advanced biliary tract cancers, and RET, BRAF, and neurotrophic receptor tyrosine kinase (NTRK)-directed treatments available via tumour-agnostic approvals. Key to ongoing progress, including the probable shift in matched targeted therapies into the first-line setting, will be the uptake of upfront and broad molecular testing to maximise therapeutic options, identify and recruit suitable patients to large clinical trials, and ultimately improve patient outcomes. Here, we discuss in detail current and emerging systemic therapies for biliary tract cancers and future directions.