AbstractBackgroundProgrammed death‐ligand 1 (PD‐L1) is an important screening biomarker to select patients with gastric cancer (GC) for optimized treatment, including immune checkpoint inhibitors (ICI).MethodsIn this single‐institution retrospective cohort study, patients with metastatic GC with available PD‐L1 results between October 2019 and September 2021 were identified by reviewing their electronic medical records. Genomic data were obtained from the Samsung Medical Center Clinical Sequencing Platform.ResultsAmong the 399 patients, 276 (69%) had a PD‐L1 combined positive score (CPS) ≥1, 155 (39%) had a CPS between 1 and 5, and 121 (30%) had a CPS ≥5. Of the 121 patients with CPS ≥5, 28 (23%) had a known etiology for “inflamed tumor,” with Epstein–Barr virus (EBV) positivity (N = 11) or high tumor mutational burden (TMB) (N = 17), which included microsatellite instability (MSI) (N = 9). PD‐L1 CPS ≥5 was observed in 11/11 (100%) patients with EBV positivity, 9/12 (75%) patients with MSI, and 17/33 (52%) patients with high TMB. For the 108 patients who received ICI therapy, CPS ≥5 was the only predictor significantly associated with survival in multivariable analyses, including TMB, MSI, or EBV. Objective response rate (ORR) was 49% in patients with CPS ≥5, 30% in patients with 1 ≤ CPS <5, and 19% in patients with CPS <1. Among the 31 responders to ICI therapy, 27 (87%) had a CPS of ≥1. Mutations in TET2, IRS2, DOT1L, PTPRT, and LRP1B were associated with a higher ORR (63%–100%), whereas MDC1 mutations were associated with a low ORR (22%).ConclusionsPD‐L1 expression is an independent and sensitive biomarker for ICI therapy. Considering its significant association with several gene alterations, including PIK3CA mutations and MET amplification, combining ICI therapy with other targeted agents may be a promising therapeutic strategy for GC.