A large systematic review and Bayesian network meta-analysis published in JAMA Network Open provides a comprehensive comparison of first-line systemic therapies for unresectable locally advanced or metastatic biliary tract cancers, a group of malignancies associated with poor prognosis and limited treatment options. By synthesising data across multiple randomised trials, the study offers an updated view of treatment options in an increasingly complex therapeutic landscape.
The analysis included 33 randomised clinical trials comprising more than 7,300 patients, evaluating a range of chemotherapy backbones in combination with immunotherapy or targeted agents. Historically, gemcitabine plus cisplatin has been the standard first-line treatment in advanced biliary tract cancer; however, recent therapeutic advances have introduced multiple combination strategies, creating uncertainty around optimal regimen selection.
CLINICAL SUMMARY
What was examined
A systematic review and Bayesian network meta-analysis of 33 randomised trials evaluating first-line systemic therapies for unresectable locally advanced or metastatic biliary tract cancer.
Key findings
- Several regimens ranked favourably in network analyses across selected outcomes, including gemcitabine–cisplatin plus durvalumab and gemcitabine–cisplatin plus S-1.
- Multiple combination strategies were associated with improved overall and progression-free survival in indirect comparisons versus gemcitabine–cisplatin alone.
- Rates of grade 3–4 haematological toxicity were broadly comparable among more favourably ranked regimens.
Clinical implications
- First-line treatment of advanced biliary tract cancer is evolving toward an expanding range of combination options, with varying levels of evidence.
- Immunotherapy-containing regimens, particularly gemcitabine–cisplatin plus durvalumab, are supported as a contemporary standard of care.e
- Treatment selection may increasingly depend on patient factors, tumour biology, and access to targeted or immune-based therapies.
Across outcomes including progression-free survival, overall survival, and objective response rate, several regimens ranked more favourably within the network analysis, although results varied depending on the endpoint assessed. Combinations such as gemcitabine and cisplatin plus durvalumab and gemcitabine and cisplatin plus S-1 were among those associated with improved outcomes in indirect comparisons. Some targeted therapy combinations demonstrated variable efficacy, but a consistent survival benefit has not been established.
Notably, gemcitabine and cisplatin plus durvalumab, which has already been incorporated into clinical practice following phase 3 evidence, remained among the more favourably ranked regimens, supporting its role as a contemporary standard of care.
At the same time, the findings suggest an expanding range of combination approaches, with differing levels of supporting evidence and potential applicability depending on patient and disease characteristics.
Featured Event
In terms of survival outcomes, several regimens were associated with improved overall survival in indirect comparisons relative to gemcitabine and cisplatin alone. Similarly, progression-free survival benefits were observed with some combination strategies, particularly those incorporating immunotherapy or additional cytotoxic agents. However, the authors emphasise that these findings are based on indirect comparisons and should be interpreted with caution.
Importantly, these efficacy signals did not appear to be accompanied by substantial increases in toxicity. The more favourably ranked regimens demonstrated broadly comparable rates of grade 3–4 haematological adverse events, suggesting that combination approaches may be feasible in appropriately selected patients.
The authors note that, despite these findings, direct head-to-head comparisons between many regimens remain limited, and the results should be interpreted within the constraints inherent to network meta-analysis. Nevertheless, the study provides a valuable synthesis of current evidence and highlights the growing role of combination strategies, particularly those incorporating immunotherapy, in the first-line treatment of advanced biliary tract cancers.
Overall, these findings reflect a shift away from a single standard regimen toward a more nuanced treatment landscape, where regimen selection may increasingly be guided by tumour biology, patient characteristics, and access to targeted or immune-based therapies.
Paper: Elemosho A, Blair AB, Angez M, et al. First-Line Chemotherapy Regimens for Unresectable Locally Advanced or Metastatic Biliary Tract Cancer: A Systematic Review and Bayesian Network Meta-Analysis. JAMA Netw Open. 2026;9(4):e266849. doi:10.1001/jamanetworkopen.2026.6849 Access online here.
