Cholangiocarcinoma: the quest for a second-line systemic treatment.

Biliary tract cancers (BTC) are a heterogeneous group of epithelial neoplasms, with a poor prognosis. Advanced BTC remains a challenging, non-curable disease. Gemcitabine plus platinum chemotherapy is the standard of care as first-line (L1) therapy in this setting. Beyond failure of L1, available evidence to guide therapeutic decisions is scarce. Data from phase III studies are lacking and there is no validated strategy to date. In this review, we provide an overview of the systemic therapeutic options that can be proposed and unsolved questions in the management of patients with advanced BTC in the second-line (L2) setting. Criteria to select which patients should receive L2 therapy are ill defined and reliable prognostic tools and models to help estimate individual patient survival at the beginning of L2 are needed. Chemotherapy, mainly fluoropyrimidine-based yields modest survival results. There is insufficient evidence level to recommend a specific L2 chemotherapy regimen, and anti-epidermal growth factor receptor and antiangiogenic agents failed to demonstrate any survival improvement in a non-selected patient population. In recent years, knowledge about BTC molecular heterogeneity has considerably increased with the advent of high-throughput genomic and transcriptomic analyses, opening new avenues for targeted therapies. Patients with BTC may be particularly good candidates for biomarker-driven therapy in clinical practice. Among the ongoing developments, targeting of FGFR and IDH mutations and immune therapies hold many promises for the next future. In future L2 clinical trials, patients should be carefully characterized and stratified according to prognostic factors, disease subtype, and genetic drivers.