First-Line Chemotherapy Regimens for Unresectable Locally Advanced or Metastatic Biliary Tract Cancer

Importance: Biliary tract cancers (BTCs) are aggressive malignant neoplasms with a dismal prognosis. Recent advancements, including immunotherapy and targeted therapies, have expanded therapeutic options, yet head-to-head comparisons between regimens remain limited. Objective: To conduct a comprehensive network meta-analyses (NMA) to include latest advances in BTC therapy to guide clinical practice. Data Sources: PubMed, Embase, and Cochrane Central were searched for randomized clinical trials (RCT) from 2000 to 2024, with manual updates through August 2025 and conference abstracts and ClinicalTrials.gov screened. Study Selection: Phase 2 to 3 RCTs of unresectable, locally advanced, or metastatic BTC reporting progression-free survival (PFS) or overall survival (OS) were eligible. Data Extraction and Synthesis: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guideline was followed. Two reviewers independently extracted data, resolving discrepancies with a third. Data were pooled with a fixed-effect model. Main Outcomes and Measures: Primary outcomes were PFS and OS; secondary outcomes included objective response rate (ORR) and grade 3 to 4 adverse events. Results: This systematic review and bayesian NMA synthesized data from 33 RCTs involving 7303 patients (median [IQR] age, 64 [63-65] years; 3704 [51.5%] male). Compared with gemcitabine plus cisplatin (GC), GC plus sintilimab plus anlotinib (hazard ratio [HR], 0.47; 95% CI, 0.28-0.80), GC plus S-1 (HR, 0.75; 95% CI, 0.59-0.97), and GC plus durvalumab (HR, 0.80; 95% CI, 0.66-0.97) were associated with highest PFS benefits. Capecitabine plus oxaliplatin (HR, 0.64; 95% CI, 0.44-0.92), GC plus durvalumab (HR, 0.71; 95% CI, 0.61-0.84), and gemcitabine plus oxaliplatin (GO) (HR, 0.78; 95% CI, 0.63-0.96) were associated with improved OS. ORR was highest with GC plus S-1 (odds ratio [OR], 4.13; 95% CI, 2.20-7.70), GC plus cediranib (OR, 3.20; 95% CI, 1.40-7.20), and GC plus durvalumab (OR, 1.60; 95% CI, 1.10-2.28) compared with GC. Toxicity profiles showed no significant hematological differences between regimens, but nonhematological risks varied. Overall, GC plus durvalumab, GC plus S-1, GO plus panitumumab, and GO plus cetuximab showed the greatest consistency in the surface under the cumulative ranking curve value for PFS, OS, ORR, and safety. Conclusions and relevance: This NMA establishes GC plus durvalumab and GC plus S-1 as potential leading first-line options for advanced BTC due to a consistent clear benefit in PFS, OS, ORR, and safety. This study also establishes that GC remains among the top regimens, as most other therapy lacked a clear superior benefit or were associated with worse PFS or OS compared with GC.