Immunotherapy in advanced gastric cancer

Metastatic gastroesophageal adenocarcinoma is a disease with a poor prognosis whose survival did not exceed twelve months until recently. Long limited to conventional cytotoxic chemo-therapy protocols, the therapeutic arsenal has been expanded in recent years with the advent of new molecules. In this evolving therapeutic landscape, immunotherapy has also been developed in metastatic gastric cancer. After initial therapeutic trials with mixed or even negative results, immunotherapy was able to make a breakthrough with the checkmate 649 phase III trial demonstrating a significant survival improvement by adding nivolumab to a first-line chemotherapy by XELOX or FOLFOX. The survival benefit provided by nivolumab was greater for patients with tumor CPS > 5 (or even > 10), whereas it was almost inexistant for tumor CPS < 5 (or even < 10). Based on this study, a UE approval was obtained from EMA for tumors with a CPS > 5. For HER2-positive metastatic gastric cancer, promising results have been obtained by combination of chemotherapy with anti-HER2 and immunotherapy, and these therapeutic approaches are currently assessed in phase III trials. The variation in the therapeutic response obtained by immunotherapy supposes the existence of molecular subgroups more or less sensitive to these immune checkpoint inhibitors. Some biomarkers have been identified as predictors of response to immunotherapy, such as microsatellite instability, which is probably the most robust of them, but also tumor mutational burden, lymphoplasmacytic infiltration, or EBV tumor positive.