Biomarker‐based long‐term safety and efficacy of PD ‐1/ PD ‐ L1 inhibitors combined with chemotherapy in advanced gastroesophageal carcinomas: A systematic review and meta‐analysis

Abstract Advanced gastroesophageal cancers often have poor survival rates even with chemotherapy. We aim to study the long‐term safety and efficacy of combining PD‐1/PD‐L1 inhibitors with chemotherapy, incorporating biomarker analysis and recent Phase III trial data. Data from eight phase III trials (from inception to 2025, comprising 5668 patients) was combined in this PRISMA‐guided meta‐analysis. Overall survival (OS), objective response rate (ORR), progression‐free survival (PFS), and grade ≥3 adverse events were among the outcomes. Random‐effects models were employed for statistical synthesis, and I 2 was used to assess the heterogeneity. Cochrane RoB 2.0 was used to evaluate the risk of bias. Compared to chemotherapy alone, the combined regimen significantly improved overall survival (HR: 0.79; 95% CI: 0.75–0.83; p < .0001), progression‐free survival (HR: 0.73; 95% CI: 0.68–0.78; p < .00001), and objective response rate (OR: 1.60; 95% CI: 1.44–1.78; p < .0001). The CPS ≥10 subgroups showed the greatest benefits (OS HR, 0.66; PFS HR, 0.63; p < .0001). Although manageable, grade ≥3 adverse events (OR, 1.37; 95% CI: 1.20–1.56) and immune‐related toxicities (OR: 3.44; 95% CI: 2.91–4.08) were more common with ICIs. The OS advantage was greatest for MSI‐high tumors (HR: 0.54; p < .04), but was not significant for esophageal cancers (HR: 0.88; p < .18). With long‐lasting improvements in survival and manageable toxicity, PD‐1/PD‐L1 inhibitors in combination with chemotherapy constitute the first‐line standard for advanced gastric/GEJ malignancies. Immune checkpoint inhibitors show a higher incidence of adverse events, and clinicians should balance efficacy against adverse event risk.