Immune checkpoint inhibitors (ICIs) such as anti-programmed cell death-1 (PD-1) or programmed cell death ligand-1 (PD-L1)
monoclonal antibodies have prolonged survival in various types of
malignancies, including advanced
gastric cancer (AGC).
Nivolumab, a monoclonal anti-PD-1 antibody, showed an improvement in overall survival at a later-line
therapy in unselected AGC patients in the ATTRACTION-2 study or in combination with
chemotherapy as first-line
therapy in the global CheckMate-649 study. Another monoclonal anti-PD-1 antibody,
pembrolizumab, showed single agent activity in
tumors with high
microsatellite instability or high
tumor mutational burden. Furthermore, a recent KEYNOTE-811 study demonstrated significant improvement in response rate with
pembrolizumab combined with
trastuzumab and
chemotherapy for HER2-positive AGC. Based on these results, ICIs are now incorporated into standard treatment for AGC patients. As a result of pivotal clinical trials, three anti-PD-1
antibodies were approved for AGC:
nivolumab combined with
chemotherapy as first-line treatment or
nivolumab monotherapy as third- or later-line treatment in Asian countries;
pembrolizumab for previously treated
microsatellite instability-high (MSI-H) or
tumor mutational burden-high AGC, or
pembrolizumab combined with
trastuzumab and
chemotherapy for HER2-positive AGC in the United States; and
dostarlimab for previously treated MSI-H AGC in the United States. However, a substantial number of patients have showed resistance to ICIs, highlighting the importance of the better selection of patients or further combined
immunotherapy. This review focused on molecular and immunological profiles, pivotal clinical trials of ICIs with related
biomarkers, and investigational
immunotherapy for AGC.