This review covers the evolving systemic therapy landscape of biliary tract cancer (BTC), including cholangiocarcinoma, gallbladder cancer, and ampullary cancer, with a focus on chemo-immunotherapy as first-line standard of care and precision oncology strategies targeting FGFR2 fusions, IDH1 mutations, HER2 alterations, and tumour-agnostic biomarkers (BRAF V600E, MSI-H/dMMR, RET/NTRK/NRG1 fusions).
Chemo-immunotherapy (CisGem + durvalumab or pembrolizumab) is now first-line standard of care; approved targeted agents include pemigatinib (ORR 37%, mPFS 7.0 mo, mOS 17.5 mo) and futibatinib (ORR 42%, mPFS 9.0 mo, mOS 21.7 mo) for FGFR2 fusion+ iCCA, ivosidenib for IDH1-mutant CCA (mOS 10.3 mo vs. 7.5 mo placebo, crossover-adjusted HR 0.49), and zanidatamab for HER2 IHC3+ BTC (ORR 41.3%, mOS 15.5 mo); lirafugratinib shows promising next-gen FGFR2 selectivity (ORR 47%, mPFS 11.3 mo, mOS 22.8 mo).
- All targeted therapy approvals are in previously treated patients only; no first-line phase III targeted therapy trial has completed successfully (three closed early due to low accrual). - Biomarker testing is heterogeneous and incompletely standardised, with up to 25% of tissue samples failing NGS; no BTC-specific HER2 IHC scoring system exists. - This is a narrative review without systematic methods or meta-analysis; cross-trial comparisons are confounded by differing patient populations and the potential prognostic effect of molecular subtypes.
All patients with advanced BTC should receive hybrid-capture DNA/RNA NGS at diagnosis to identify actionable alterations (FGFR2 fusions, IDH1 mutations, HER2 status, and tumour-agnostic targets) before second-line therapy decisions are made. In the absence of a targetable alteration, CisGem plus durvalumab or pembrolizumab is first-line standard of care; when actionable alterations are found, approved targeted agents should be prioritised over second-line chemotherapy.
Explore related topics
