Embracing the New Era of Immunotherapy in Gastric Cancer Treatment

Abstract

Advanced gastric cancer still presents a grim outlook, typically yielding a median survival rate of approximately 12 to 15 months. Recently, immune checkpoint inhibitors have emerged as a promising standard treatment for various malignancies, including advanced gastric cancer. They have shown significant clinical advantages in certain patient groups. In this comprehensive review, we delve into the current landscape of immunotherapy in gastric cancer. Our focus centers on elucidating the molecular and immunological characteristics, identifying relevant biomarkers, scrutinizing major clinical trials, and exploring innovative immunotherapeutic approaches. Immune checkpoint inhibitors (ICIs), exemplified by anti-programmed cell death-1 (PD-1) or programmed cell death ligand-1 (PD-L1) monoclonal antibodies, have extended survival rates across various malignancies, including advanced gastric cancer (AGC). Notably, Nivolumab, a monoclonal anti-PD-1 antibody, demonstrated enhanced overall survival in AGC patients as a later-line therapy in the ATTRACTION-2 study, and when combined with chemotherapy as a first-line treatment in the global CheckMate-649 study. Another monoclonal anti-PD-1 antibody, Pembrolizumab, exhibited promising single-agent efficacy in tumors characterized by high microsatellite instability or a high tumor mutational burden. Additionally, the recent KEYNOTE-811 study showcased a significant increase in response rates when Pembrolizumab was used in conjunction with trastuzumab and chemotherapy for HER2-positive AGC. These groundbreaking findings have led to the integration of ICIs into the standard treatment regimen for AGC patients. Consequently, pivotal clinical trials have culminated in the approval of three distinct anti-PD-1 antibodies for AGC treatment: Nivolumab in combination with chemotherapy as a first-line option, or Nivolumab monotherapy for third- or later-line treatment in Asian countries; Pembrolizumab for previously treated microsatellite instability-high (MSI-H) or tumor mutational burden-high AGC, as well as 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.