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Abstract Background Unresectable advanced or recurrent gastric and gastroesophageal junction (GC/GEJ) cancers carry poor prognoses, and several programmed death-1 (PD-1) inhibitors have shown clinical activity. However, no head-to-head trial has compared their relative efficacy and safety. This network meta-analysis aimed to evaluate and rank PD-1–based regimens in this setting. Methods A systematic review of PubMed, Embase, CENTRAL, Web of Science, and Google Scholar through August 10, 2025, identified randomized controlled trials enrolling adults with unresectable advanced or recurrent GC/GEJ cancer. Primary outcomes were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), treatment-related adverse events (TRAEs), and grade ≥ 3 TRAEs. A Bayesian random-effects network meta-analysis generated mean differences (MDs) or odds ratios (ORs) with 95% confidence intervals (CIs) and calculated surface under the cumulative ranking curve (SUCRA) values. Results Nineteen trials (n = 9,460) were included. Nivolumab monotherapy ranked first for OS (SUCRA 98.3%) and PFS (97.6%), and improved OS versus control (HR 0.59, 95% CI 0.50–0.69). Sintilimab plus chemotherapy ranked highly for OS and PFS (SUCRA 53.9% and 70.9%) and reduced PFS risk versus pembrolizumab monotherapy (HR 0.53, 95% CI 0.35–0.82). Nivolumab plus chemotherapy also improved OS versus control (HR 0.79, 95% CI 0.68–0.92) and PFS versus pembrolizumab monotherapy (HR 0.55, 95% CI 0.42–0.72). Nivolumab monotherapy yielded the highest ORR and DCR (SUCRA 99.9% and 95.2%) but the lowest safety ranking for grade ≥ 3 TRAEs (SUCRA 7.1%). Pembrolizumab monotherapy showed the most favorable safety (SUCRA 100% for grade ≥ 3 TRAEs) but the lowest efficacy across PFS, ORR, and DCR. Across agents, PD-1 inhibitor–chemotherapy combinations reduced progression or death versus control without increasing severe toxicity. Conclusion Chemoimmunotherapy should be prioritized as first-line therapy for unresectable advanced or recurrent GC/GEJ cancer, with nivolumab-based combinations offering the most favorable efficacy-safety balance. Nivolumab monotherapy provides the strongest tumor response and survival ranking but requires vigilant toxicity management. These comparative rankings can inform individualized regimen selection.
Wang et al. (Fri,) studied this question.