Efficacy and safety of PD-1 inhibitors in advanced gastric and gastroesophageal junction cancer: A meta-analysis

Advanced gastric/gastroesophageal junction cancer (G/GEJC) has a poor prognosis, with conventional chemotherapy offering limited survival benefits. Immune checkpoint inhibitors targeting programmed death-1 (PD-1) have revolutionized oncology, but their role in G/GEJC remains incompletely defined, particularly regarding efficacy across PD-L1 expression subgroups and safety in combination regimens. We conducted a systematic review and meta-analysis to evaluate PD-1 inhibitors as monotherapy or combined with chemotherapy in advanced G/GEJC, focusing on survival outcomes stratified by PD-L1 status and treatment-related toxicity. PubMed, Embase, Cochrane Library, Web of Science, Scopus, and ClinicalTrials.gov were searched (up to November 7, 2024) for randomized trials comparing PD-1 inhibitors ± chemotherapy to chemotherapy alone. Primary endpoints were overall survival (OS) and progression-free survival (PFS); secondary outcomes included treatment-related adverse events (TRAEs) and subgroup analyses (ECOG PS, MSI status, PD-L1 CPS). Among 20 studies (10,638 patients), PD-1 monotherapy significantly improved OS (HR = 0.70, 95%CI 0.65–0.75; P < 0.00001) but not PFS (P = 0.23). Combination therapy showed no OS/PFS benefit overall but demonstrated marked efficacy in PD-L1 CPS ≥ 10 (OS HR = 0.65, P < 0.0001; PFS HR = 0.61, P < 0.0001). Monotherapy reduced grade ≥ 3 TRAEs (OR = 0.44, P = 0.02), while combination therapy increased severe TRAEs (OR = 1.41, P < 0.00001) despite fewer all-grade events (OR = 0.77, P = 0.0009). PD-1 inhibitor monotherapy significantly extends OS in advanced G/GEJC, demonstrating a favorable safety profile. In contrast, the survival benefit of combination chemoimmunotherapy is restricted to patients with high PD-L1 expression (CPS ≥ 10), a subgroup that also experiences increased toxicity. These findings underscore PD-L1 CPS ≥ 10 as a crucial predictive biomarker for combination regimens and highlight the necessity of biomarker-driven strategies to optimize the efficacy and safety of immunotherapy in G/GEJC.