First-line PD-1/PD-L1 inhibitors plus chemotherapy versus chemotherapy alone for advanced esophageal and gastroesophageal junction adenocarcinoma: a systematic review and meta-analysis of randomized controlled trials.

Background: Immune checkpoint inhibitors (ICIs) combined with chemotherapy have become the first-line treatment for advanced or metastatic esophageal adenocarcinoma (EAC)/gastroesophageal junction adenocarcinoma (GEJC). The aim is to explore the safety and efficacy of ICI and a potential biomarker. Methods: As of August 2025, we comprehensively reviewed the literature on clinical randomized controlled trials (RCTs) by searching keywords, such as "esophageal adenocarcinoma", "gastroesophageal junction cancer", or "immunotherapy" across multiple databases (including Embase, Cochrane, Scopus, PubMed, Web of Science and the Clinical Trial Registries, as well as abstracts from the American Society of Clinical Oncology, European Society of Medical Oncology and other international tumor conferences). Two authors independently screened the studies, extracted the relevant data, and used RevMan 5.3 software and related evaluation tools for the statistical analysis and risk and quality evaluations, respectively. The primary outcomes of the study were overall survival (OS) and progression-free survival (PFS), which were estimated by calculating the hazard ratio (HR) and confidence interval (CI). The secondary outcomes were the objective response rate (ORR), and incidence of adverse events (AEs). Results: In total, seven studies, comprising 7,043 patients with advanced EAC/GEJC, were included in the meta-analysis. We compared the efficacy of immunotherapy combined with chemotherapy, and chemotherapy alone. Immunotherapy combined with chemotherapy significantly improved the survival rate of the patients, significantly prolonging their OS (HR =0.80, 95% CI: 0.76-0.85, P<0.001; I2=0%). The PFS (HR =0.75, 95% CI: 0.71-0.80, P<0.001; I2=0%) and ORR of these patients also improved significantly. The incidence of AEs was higher in the immunotherapy combined with chemotherapy patients than the chemotherapy alone patients, but the overall range was controllable. The magnitude of the treatment benefit from immunotherapy combined with chemotherapy was positively correlated with the combined positive score (CPS), with greater efficacy observed in patients with higher CPS levels. Conclusions: Immunotherapy combined with chemotherapy significantly improved the survival benefit of patients with advanced EAC/GEJC, better controlled disease progression, and had controllable AEs.