Treatment of advanced biliary tract cancers: from chemotherapy to targeted agents

Abstract

Biliary tract cancers (BTCs) are usually diagnosed at an advanced stage and have a dismal prognosis. The treatment of advanced disease is mainly based on systemic chemotherapy, which is demonstrated to improve survival in the first- and second-line setting. Following the results of phase III clinical trials, the combination of cisplatin and gemcitabine is the regimen of choice in the frontline, while 5-fluorouracil plus oxaliplatin is considered the standard after first-line progression in unselected patients. Recent advances in molecular biology have unravelled the molecular heterogeneity of BTCs and identified patient subgroups harbouring unique molecular aberrations such as isocitrate dehydrogenase (IDH) mutations and fibroblast growth factor receptor (FGFR) fusions that can be targeted by specific agents. This knowledge has opened the way to personalised medicine in BTCs. Molecules targeting IDH and FGFR are currently approved for the treatment of advanced, refractory, intrahepatic cholangiocarcinoma. Beyond targeted therapies, novel combinatorial approaches that target the immune microenvironment and the crosstalk between cancer and stroma are being explored based on strong preclinical rationale. This review discusses the current therapeutic opportunities for the management of patients with advanced BTCs and provides an overview of the promising new strategies on the horizon with a particular focus on ongoing clinical trials.