Programmed Cell Death Protein 1 Blockade Elicits Ongoing Remission in 2 Cases of Refractory Epstein-Barr Virus-Associated Metastatic Gastric Carcinoma

Over the last decade immunotherapy has revolutionized oncological treatment of malignancies across all entities including gastric cancer. The programmed cell death protein 1 (PD-1) inhibitor pembrolizumab has demonstrated durable responses and survival benefit in distinct patient subgroups with advanced gastric cancer. In 2017, pembrolizumab monotherapy was approved by the U.S. Food and Drug Administration (FDA) for the treatment of refractory metastatic gastric cancer overexpressing PD-L1, as well as for refractory advanced tumors with deficient DNA mismatch repair/microsatellite instability (dMMR/MSI) or high tumor mutational burden (TMB-H). However, several biomarker unselected studies have reported only limited single-agent immunotherapeutic efficacy. Thus, the identification of predictive biomarkers to select patient subgroups who are most eligible for immunotherapy is of particular importance. A growing number of studies consider Epstein-Barr virus associated gastric cancer (EBVaGC) as a molecularly distinct and immunogenic subtype which might be particularly sensitive to immune checkpoint inhibition.Here we present two cases of heavily pretreated patients with refractory, metastatic EBVaGC, who experienced a significant and sustained response to monotherapy with the PD-1 checkpoint inhibitor pembrolizumab.Comprehensive genetic testing for predictive biomarkers (e.g. PD-L1, MSI/dMMR, tTMB, EBV) to identify patient subgroups most eligible for immunotherapy is of particular importance in advanced gastric cancer, especially in patients that are refractory to conventional chemotherapy.