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 1 / 4 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 1 / 4 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 1 / 4 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. (c) 2024 The Royal College of Radiologists. Published by Elsevier Ltd. All rights are reserved, including those for text and data mining, AI training, and similar technologies.