Abstract
Simple SummaryAdvanced gastric cancer remains a malignancy with a poor prognosis, with a median survival of about 12–15 months. In recent years, immune checkpoint inhibitors have emerged as a new standard of care for several malignancies, including advanced gastric cancer, and have demonstrated good clinical benefit in some populations. In this review paper, we describe the current status of immunotherapy in gastric cancer, with a focus on molecular and immunological profiles, biomarkers, major clinical trials, and novel immunotherapies.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.
Highlights
Gastric cancer is the fourth leading cause of cancer death in the world and the fifth most common malignant tumor [1]
objective response rate (ORR) was lower with nivolumab plus ipilimumab versus chemotherapy (27% vs. 47% in combined positive score (CPS) ≥ 5, 23% vs. 47% in all randomized populations), duration of response was longer in both CPS ≥ 5
These results have changed the standard of care in the first-line setting for advanced unresectable or recurrent gastric cancer (AGC)
Summary
Gastric cancer is the fourth leading cause of cancer death in the world and the fifth most common malignant tumor [1]. Combination regimens, including a fluoropyrimidine and a platinum agent (plus trastuzumab as an anti HER2 monoclonal antibody for HER2positive cases) at first-line and paclitaxel with or without ramucirumab at second-line, are standard treatment for advanced unresectable or recurrent gastric cancer (AGC). Immune checkpoint inhibitors (ICIs) have emerged as new standard treatment in several malignancies, including AGC with favorable clinical benefit in some populations [6,7,8,9,10]. Drug Administration (FDA) in combination with trastuzumab, first-line chemotherapy for patients with HER2 positive AGC [13] Another anti-PD-1 antibody, nivolumab, showed a survival benefit in third-line or subsequent treatment in an Asian patient population irrespective of PD-L1 expression (ATTRACTION-2) or in first-line treatment combined with standard cytotoxic agents (CheckMate-649) [14,15]. We will discuss current status of immunotherapy for gastric cancer (Figure 1), including molecular and immunological profiles, pivotal clinical trials of ICIs with related biomarkers, and investigational immunotherapy
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