Efficacy hierarchy and absolute survival benefit of first-line immunotherapy in advanced gastric cancer: a meta-analysis and pooled survival analysis.

While immune checkpoint inhibitors (ICIs) have revolutionized first-line treatment for advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma, outcomes across phase III trials remained heterogeneous. This study aimed to determine the efficacy and safety of ICI plus chemotherapy, and to define a clinically meaningful PD-L1 expression threshold through a meta-analysis. We systematically searched PubMed, Embase, and Cochrane for phase III randomized controlled trials (up to November 2025) comparing ICI-chemotherapy combinations against chemotherapy alone in patients with advanced gastric or GEJ adenocarcinoma. The combined hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) were calculated using a random-effects model. Safety was assessed through the combined risk ratio (RR) of grade ≥3 adverse events (AEs) and serious adverse events (SAEs). Eight trials involving 7,127 patients with previously untreated, HER2-negative, advanced gastric or GEJ adenocarcinoma were included. The pooled analysis showed a significant improvement in OS (HR = 0.79) and PFS (HR = 0.71) with immunochemotherapy versus chemotherapy alone. Immunochemotherapy was associated with longer median OS (14.4 vs 12.6 months) and PFS (7.3 vs 6.2 months). Treatment benefit increased with higher PD-L1 combined positive score (CPS): OS HRs were 0.90 (CPS < 1), 0.76 (CPS ≥ 1), 0.74 (CPS ≥ 5), and 0.65 (CPS ≥ 10). Combination therapy modestly increased grade ≥3 AEs (RR = 1.16) and SAEs (RR = 1.54) compared with chemotherapy alone. Our results supported the strategy of first-line immunochemotherapy, which significantly prolongs OS and PFS in advanced gastric and GEJ adenocarcinoma with manageable toxicity. https://www.crd.york.ac.uk/PROSPERO/view/CRD420251180445, identifier CRD420251180445.