Comparative efficacy and safety of targeted therapeutics or immunotherapy agents combined with chemotherapy as first-line treatment for advanced biliary tract cancer: a systematic review and network meta-analysis.

BACKGROUND: Although durvalumab or pembrolizumab combined with gemcitabine plus cisplatin (GC) remains the standard first-line therapy, novel targeted agents and immunotherapies integrated with chemotherapy have demonstrated promising efficacy. However, the crosswise comparison between each regimen is rare. Therefore, we comparative the efficacy and safety of targeted therapeutics or immunotherapy agents combined with chemotherapy as first-line treatment for advanced biliary tract cancer. METHODS: We included 18 randomized controlled trials (RCTs) meeting selection criteria to evaluate first-line targeted/immunotherapy-chemotherapy combinations for advanced BTC. Among them, 15 RCTs were analyzed via Bayesian network meta-analysis (NMA) for the average group, while 6 RCTs were used for pairwise meta-analyses of molecular subgroups, with three studies contributing to both analyses. Outcomes included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and serious adverse events (SAEs). Subgroup analyses were performed for KRAS wild-type and PD-L1-positive populations. RESULTS: Durvalumab (HR 0.76, 95% CI 0.64-0.91) and pembrolizumab (HR 0.83, 95% CI 0.72-0.95) combined with GC significantly improved OS versus chemotherapy alone, with comparable SAE rates. Sintilimab plus anlotinib and GC achieved the best PFS (HR 0.47, 95% CI 0.28-0.80), though OS benefits were nonsignificant. EGFR inhibitors prolonged PFS in KRAS wild-type patients (HR 0.72, 95% CI 0.52-0.98). Bintrafusp alfa and cetuximab showed higher SAE risks (OR 2.26 and 1.95, respectively). CONCLUSION: Our findings directly inform clinical guidelines, address gaps in current therapeutic decision-making. Durvalumab or pembrolizumab combined with GC are optimal first-line regimens for advanced BTC, balancing survival benefits and safety. Sintilimab plus anlotinib combined with GC demonstrates superior PFS but requires further validation. While EGFR inhibitors plus chemotherapy demonstrate potential in KRAS wild-type patients, confirmation in large-scale RCTs is required. PD-L1 expression may represent a promising predictive biomarker for response to PD-1 inhibitor therapy.