Abstract Background: Immune checkpoint inhibitors (ICIs) have transformed the first-line management of advanced gastric and gastroesophageal junction adenocarcinoma. Several phase III trials have evaluated adding an ICI to chemotherapy, yet results have been heterogeneous. This study aimed to determine the efficacy and safety of first-line ICI plus chemotherapy versus chemotherapy alone and to define a clinically meaningful PD-L1 expression threshold through a systematic review and meta-analysis of randomized phase III trials. Methods: PubMed, Embase, and the Cochrane Registry of Clinical Controlled Trials were systematically searched up to September 2025. The studies included in this analysis were Phase III randomized controlled trials that compared immune checkpoint inhibitors (ICI) combined with chemotherapy to chemotherapy alone in the treatment of patients with advanced or metastatic gastric cancer or GEJ adenocarcinoma. The combined hazard ratios (HRs) and 95% confidence intervals (CIs) for overall survival (OS) and progression-free survival (PFS) were calculated using a random-effects model. Subgroup analyses were conducted based on the PD-L1 combined positive score (CPS), age, gender, ECOG performance status score (ECOG), geographical region, liver metastasis and tumor location. Safety was assessed through the combined hazard ratio (RR) of grade ≥3 adverse events (AEs) and serious adverse events (SAEs). Results: Eight phase III trials involving 7,127 patients with previously untreated, HER2-negative, advanced or metastatic gastric or GEJ adenocarcinoma were included. The pooled analysis showed significant improvement in OS (HR = 0.79, 95% CI 0.75-0.83) and PFS (HR = 0.71, 95% CI 0.65-0.79) with ICI plus chemotherapy versus chemotherapy alone. Treatment benefit increased with higher PD-L1 CPS: OS HRs were 0.90 (CPS 1), 0.76 (CPS ≥ 1), 0.75 (CPS ≥ 5), and 0.65 (CPS ≥ 10); similar trends were seen for PFS (0.87, 0.73, 0.65, 0.63, respectively). Efficacy was consistent across major subgroups (all interaction p 0.05). Combination therapy modestly increased grade ≥3 AEs (RR = 1.16, 95% CI 1.09-1.23) and SAEs (RR = 1.54, 95% CI 1.35-1.77) compared with chemotherapy alone. Conclusions: First-line ICI plus chemotherapy significantly prolongs OS and PFS in advanced gastric and GEJ adenocarcinoma, with manageable toxicity. The magnitude of benefit is mainly driven by PD-L1 expression, supporting CPS as a clinically meaningful biomarker for treatment selection. ICI-based combinations should be considered a new standard of care across clinically relevant subgroups. Citation Format: Jialun Lyu, Zhenzhen Zhang, Krishnapriya Thangaretnam, Md Obaidul Islam, Jason Tang, Sabine Denize, Nadeem Bhat, Shoumin Zhu, Heng Lu, Dunfa Peng, Wael El Rifai, Zheng Chen. PD-L1 expression-dependent efficacy of first-line immune checkpoint inhibitor plus chemotherapy in advanced gastric and gastroesophageal junction adenocarcinoma: A systematic review and meta-analysis of phase III trials abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6633.
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