Associations of Clinical and Molecular Characteristics with the Response to Immune Checkpoint Blockade in Advanced Gastric Cancers

PURPOSE: Immunotherapy provides a new treatment option for advanced gastric cancer (AGC). This study aims to explore the response markers of immunotherapy in AGCs. METHODS: Next-generation sequencing was performed on 44 AGC patients who received immune checkpoint inhibitors and the associations between their outcomes after combination immunotherapy, and the clinicopathological/molecular characteristics were analyzed. RESULTS: The current study cohort had a median progression-free survival (PFS) of 5.9 months, an overall survival (OS) of 12.1 months, and an objective response rate (ORR) of 36.4%. Through multivariable analysis of the clinical characteristics, primary tumor resection (HR = 2.66, 95% CI: 1.06–6.70, p=0.037) and increased proportion of lymphocytes after combination immunotherapy (HR = 0.40, 95% CI: 0.16–0.99, p=0.048) were revealed as independent predictors for patient outcomes. All the 18 patients who underwent genetic profiling were microsatellite-stable with a median TMB of four mutations per Mb. ATM alterations, PI3K pathway mutations, increased TMB, and positive PD-L1 expression were associated with the increased trend of PFS and ORR. According to the combination of baseline lymphocyte count, ATM mutation, TMB status, and PD-L1 expression, patients were stratified into higher- and lower-risk groups, with the lower-risk group showing improved PFS (HR = 4.7e−10, 95% CI: 0–inf, p=0.02) and ORR (75% vs. 0%, p=0.007). CONCLUSION: Several highly relevant potential biomarkers predictive of immunotherapy response in AGC patients have been identified in this research.