Site-Specific Genomic Markers Associated with Outcomes of PD-1 Blockade in Gastric and Esophagogastric Junction Cancer: Analysis of Japan’s C-CAT Registry

BACKGROUND: Only a minority of patients with advanced gastric cancer (GC) or esophagogastric junction (EGJ) adenocarcinoma derive durable benefit from anti-programmed cell death 1 (PD-1) therapy. However, reliable biomarkers for real-world clinical decision-making remain limited. OBJECTIVE: To identify tumor site-specific genomic alterations associated with outcomes of nivolumab monotherapy in a nationwide real-world cohort. METHODS: We conducted a retrospective nationwide analysis using Japan's Center for Cancer Genomics and Advanced Therapeutics (C-CAT) registry, including patients with GC and EGJ cancer adenocarcinoma treated with nivolumab monotherapy (July 2019-April 2024). Primary endpoints were time to treatment failure (TTF) and overall survival (OS), defined as the interval from nivolumab initiation to death from any cause; objective response rate (ORR) was secondary. Gene-level alteration indicators were derived from vendor-reported tumor-only panel calls across multiple platforms and filtered for clonal hematopoiesis of indeterminate potential (CHIP)-like variants (variant allele frequency < 0.05). Multivariable models adjusted for age and sex were fitted separately for GC and EGJ cancer. Variant pathogenicity was based on available panel annotations; therefore, gene-level results should be interpreted as exploratory findings. RESULTS: Among 798 patients with GC and 114 patients with EGJ cancer adenocarcinoma, median TTF/OS/ORR were 3.98 months/20.2 months/11.7% in GC and 4.80 months/24.7 months/14.9% in EGJ cancer adenocarcinoma. In GC, ASXL1 mutation remained independently associated with longer TTF (hazard ratio [HR] 0.59, 95% confidence interval [CI] 0.37-0.94) after adjustment and CHIP filtering. For OS, microsatellite instability-high [MSI-H] (HR 0.16, 95% CI 0.04-0.70) and FANCG (HR 0.37, 95% CI 0.16-0.87) were associated with longer OS, whereas CDH1 (HR 1.51, 95% CI 1.10-2.05) was associated with shorter OS. In EGJ cancer adenocarcinoma, NTRK1 mutation correlated with longer TTF (HR 0.31, 95% CI 0.10-0.98) and MUTYH with shorter OS (HR 5.68, 95% CI 2.04-15.81), both exploratory. CONCLUSIONS: In this large Japanese real-world cohort, genomic associations with nivolumab outcomes differed by tumor site. In gastric cancer, ASXL1 mutation was associated with prolonged treatment benefit under PD-1 blockade, while CDH1 and FANCG showed exploratory associations with OS. These findings warrant further validation in prospective and platform-controlled analyses.