PD-1/PD-L1 Inhibitors in Combination With Chemo or as Monotherapy vs. Chemotherapy Alone in Advanced, Unresectable HER2-Negative Gastric, Gastroesophageal Junction, and Esophageal Adenocarcinoma: A Meta-Analysis

Aims: Advanced gastroesophageal cancers are still associated with poor outcomes. We aim to study PD-1/PD-L1 inhibitors in phase III clinical trials that have compared them to chemotherapy in gastric, gastroesophageal junction (GEJ), and esophageal adenocarcinoma. Materials and methods: On March 28, 2024, we searched: PubMed, Embase, Cochrane Library, Web of Science, Scopus, and ClinicalTrials.gov. We only included randomized clinical trials for PD-1/PD-L1 inhibitors alone or with chemo vs chemotherapy in advanced gastric, GEJ, or esophageal adenocarcinoma. The primary endpoints were overall survival and progression-free survival. A subgroup analysis was conducted for the following variables: treatment line, type of intervention, age group, gender, ECOG Performance Status, combined positive scores (CPS), microsatellite instability (MSI) status, liver metastasis, and primary tumor location. Results: Only 10 out of 8,942 articles were included, involving 6,782 patients. PD-1/PD-L1 inhibitors showed a significant improvement in the overall survival compared to chemotherapy alone (hazard ratio (HR): 0.86, 95% CI: 0.80–0.93; p = 0.0002). Combining PD-1/PD-L1 inhibitors with chemotherapy significantly improved overall and progression-free survival compared to monotherapy (combined therapy HR 0.80; p < 0.00001 vs. monotherapy HR 0.98; p = 0.77). CPS ≥1 had an HR of 0.78 (95% CI: 0.73–0.84; p < 0.00001), CPS ≥10 had an HR of 0.67 (95% CI: 0.59–0.76; p < 0.00001), and MSI-high status had an HR of 0.35 (95% CI: 0.24–0.52; p < 0.00001). Esophageal adenocarcinoma, reported in three trials, did not show significant improvement in the overall survival (HR 0.89; 95% CI: 0.69–1.14; p = 0.37). Conclusion: PD-1/PD-L1 inhibitors have significantly improved overall survival, and combining them with chemotherapy is more effective than monotherapy. Both CPS ≥10 and MSI-H showed an added benefit to overall survival and should be included in biomarker investigations. Clinical trials are needed for second-line treatments and esophageal adenocarcinoma.