Combination Immunotherapy for Pancreatic Cancer: A Systematic Review and Meta-Analysis

Abstract Background Pancreatic cancer remains one of the most treatment-resistant malignancies, with limited survival benefits achieved using standard therapies. Immunotherapy has transformed treatment in several cancers, yet its clinical efficacy in pancreatic cancer remains uncertain, particularly in the context of combination regimens. This systematic review and meta-analysis evaluated the impact of combination immunotherapy on survival outcomes in pancreatic cancer and identified study-level factors contributing to variability in effect sizes. Methods A comprehensive search was conducted across PubMed, MEDLINE, Cochrane Library, ClinicalTrials.gov, and Epistemonikos through March 2025. Eligible studies included clinical trials reporting hazard ratios (HRs) for overall survival (OS) or progression-free survival (PFS) in pancreatic cancer treated with combination immunotherapy. Random-effects meta-analyses were performed using the REML estimator with Hartung-Knapp adjustment. Moderator analyses and publication bias assessments were also conducted. Results Eleven trials met inclusion criteria. After excluding three outliers, the pooled HR for OS indicated a significant survival benefit for combination immunotherapy (HR = 0.77, 95% CI: 0.66-0.90, p < 0.001), with no residual heterogeneity (I² = 0%). PFS analysis showed high heterogeneity (I² = 95.5%) and no significant pooled effect (HR = 2.87, 95% CI: 0.92-8.92). Trial phase emerged as a significant moderator, with later-phase trials showing more favorable outcomes. Funnel plot asymmetry and Egger's test suggested potential publication bias, though adjusted estimates remained robust. Conclusions Combination immunotherapy shows promise in improving overall survival in pancreatic cancer, particularly in later-phase trials. However, variability in PFS outcomes and limited biomarker data underscore the need for biomarker-driven trials and standardized reporting. Key messages • Combination immunotherapy significantly improves overall survival in pancreatic cancer, particularly in later-phase trials, highlighting its promise as a strategy for this treatment-resistant disease. • High variability in PFS outcomes and limited biomarker data underscore the need for biomarker-driven trials and standardized reporting to improve treatment precision and patient selection.