Impact of metastatic sites and Lauren subtype on survival outcomes of first-line PD-1 inhibitors combined with chemotherapy in HER2-negative advanced gastric cancer: A meta-analysis.

393 Background: Multiple landmark phase III clinical trials demonstrated overall survival (OS) benefit when using PD-1 blockade plus chemotherapy (CT) compared to CT alone in patients with HER2-negative advanced gastric cancer (AGC). However, the magnitude of this benefit remains uncertain among those with peritoneal metastases (PM), liver metastases (LM), and differing Lauren histology subtypes where distinct tumor microenvironments may influence therapeutic response. Methods: A systematic review through PubMed identified eligible phase III randomized clinical trials from 2021 to 2025 comparing PD-1 inhibitors plus CT versus CT alone in HER2-negative AGC. We performed a PROSPERO registered meta-analysis per PRISMA 2020. Outcomes included OS overall with LM, PM, and Lauren histology subgroups. We derived logHR Hazard ratios (HRs) with 95% confidence intervals (CIs) which were pooled using R, and forest plots were generated. A random-effects model was utilized. Heterogeneity was assessed using the I 2 statistic. Results: Six eligible phase III studies (n = 5,410) were included in this meta-analysis. In the ITT population, patients with PM derived no significant OS benefit from PD-1 inhibitor plus CT (HR 0.93 0.78,1.11, p = 0.42; I² = 46.3%). Similarly, in patients with diffuse-type AGC, the OS benefit was attenuated, though still statistically significant (HR 0.83 0.74, 0.94, p=0.003; I² = 39.0%), compared with the overall OS benefit observed in the ITT cohort (HR 0.79 0.75,0.84, p < 0.001, I² = 0%). By contrast, OS benefit was consistent in patients with LM (HR 0.73 0.66,0.81, p < 0.001; I² = 14.4%), patients without LM (HR 0.79 0.73,0.86, p < 0.001; I² = 0%), patients without PM (HR 0.73 0.66,0.81, p < 0.001; I² = 0%), and those with intestinal-type AGC (HR 0.78 0.74,0.87, p < 0.001; I² = 0%). Between-study heterogeneity was absent in the overall cohort, low among patients with LM, absent in those without LM, moderate in patients with PM, absent in those without PM, moderate in patients with diffuse-type AGC, and absent in patients with intestinal-type AGC. In the PD-L1 positive subgroup, between-study heterogeneity was absent both in patients with or without liver metastases. Conclusions: PD-1 inhibitor plus CT improves OS in HER2-negative advanced gastric cancer, with consistent benefit in patients with and without LM and in intestinal-type disease. These results illustrate the presence of an immune-exclusive TME in AGC with PM with a reduced response to PD-1 inhibition.