Impact of metastatic pattern and histologic subtype on PD-(L)1 inhibitor efficacy in HER2-negative advanced gastric and gastroesophageal cancer: a meta-analysis

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• Picked for Hematology (top studies of the week, 19 July 2026).
• Picked for Histology (top studies of the week, 19 July 2026).

Abstract

BACKGROUND: The therapeutic benefit of PD-(L)1 blockade in advanced gastric and gastroesophageal junction adenocarcinoma (GC/GEJ) may vary by niche and tumor biology. We conducted a meta-analysis to evaluate how metastatic site and Lauren histologic subtype influence survival outcomes in HER2-negative GC/GEJ treated with PD-(L)1 inhibitor-based chemoimmunotherapy. METHODS: A systematic PubMed, MEDLINE, and Embase search identified phase III randomized controlled trials published between 2021 and 2025 comparing IO plus platinum-fluoropyrimidine chemotherapy vs. chemotherapy alone in HER2-negative metastatic or unresectable GC/GEJ. Hazard ratios (HRs) for overall survival (OS) were pooled using random-effects models in the intention-to-treat (ITT) population and prespecified subgroups, including liver metastases (LM), peritoneal metastases (PM), Lauren histologic subtype, and PD-L1 expression assessed by combined positive score (CPS) or tumor area positivity score (TAPS). Between-study heterogeneity was assessed using the I² statistic, and analyses were conducted in R. RESULTS: Six global trials including 5, 410 patients (CHECKMATE 649, ATTRACTION-4, KEYNOTE-859, ORIENT-16, RATIONALE-305, AND GEMSTONE-303) were analyzed. Overall, IO plus CT significantly improved OS compared with CT alone (HR 0.79, 95% CI 0.75-0.84; p<0.001). Survival benefit was observed in patients with and without LM (HR 0.75 and 0.82), whereas patients with PM derived limited benefit (HR 0.93). Intestinal-type tumors achieved greater OS improvement than diffuse-type tumors (HR 0.78 vs 0.87). PD-L1 CPS ≥5 predicted superior OS benefit (HR 0.70). Grade ≥3 adverse events were infrequent and hematologic. CONCLUSION: First-line chemoimmunotherapy prolongs survival in HER2-negative GC/GEJ. Reduced benefit in diffuse-type and peritoneal disease underscores heterogeneity and supports site- and histology-specific strategies. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD420251174893.

Abstract as published, via PubMed.