Role of Nivolumab in the Management of First-Line Unresectable Advanced or Recurrent Gastric Cancer in Combination with Chemotherapy: Lessons from the Japanese Experience

Abstract

Recently, immune checkpoint inhibitor (ICI), such as anti-programmed cell death-1 (PD-1) or programmed cell death ligand-1 (PD-L1) monoclonal antibodies, has provided clinical benefits in various cancer types including advanced gastric cancer (AGC). Nivolumab, a monoclonal anti-PD-1 antibody, firstly showed an improvement in the overall survival (OS) in patients with AGC in the ATTRACTION-2 trial. Recently, chemotherapy plus nivolumab, as a first-line treatment for AGC, showed both OS and progression-free survival (PFS) benefits in patients with PD-L1 combined positive score (CPS) ≥5 in the global CheckMate-649 trial, and demonstrated PFS benefit irrespective of CPS status in the Asian ATTRACTION-4 trial. Based on these results, chemotherapy plus nivolumab in a first-line treatment was approved worldwide. However, the approval requirements and recommendations are different according to the approval agent or country. Thus, this review summarized the clinical trials of chemotherapy plus anti-PD1 antibody as a first-line treatment and focused on the role of nivolumab combined with chemotherapy mainly from the viewpoint of the Japanese experience.

Updated Immunotherapy for Gastric Cancer

“…In the AVAGAST trial conducted more than a decade ago, the frequency of patients who received chemotherapy after disease progression varied widely, similar to these four recent clinical trials (64–68% in the Asian trial vs. 33–54% in the global trial) [ 38 ]. Moreover, 14% of patients in the KEYNOTE-062 trial and 9% of patients in the Checkmate 649 trial received immunotherapy in the control arm, whereas 27% of patients in the ATTRACTION-4 trial received immunotherapy [ 39 ]. These differences in primary sites, multiple lines of treatment, and tumor volume at diagnosis, as well as the widespread use of gastrointestinal endoscopy in Asian counties, may contribute to the longer prognosis of Asian patients.…”

Interpretation of PD-L1 expression in gastric cancer: summary of a consensus meeting of Korean gastrointestinal pathologists

“…Among these, the CheckMate-649 trial demonstrated the efficacy of nivolumab (a PD-1 binding immune checkpoint inhibitor) in combination with chemotherapy as a first-line treatment for human epidermal growth factor receptor 2 (HER2)–negative advanced or metastatic GC [ 3 ]. Currently, nivolumab plus chemotherapy is the standard first-line treatment for advanced or metastatic GC [ 3 , 9 , 11 ].…”

“…Additional results showed significant improvement in overall survival and progression-free survival in patients with PD-L1 CPS ≥1 and all randomly assigned patients [ 3 ]. However, approval and recommendations for nivolumab differ according to the country or approval agency [ 11 ]. In Korea, nivolumab reimbursement for GC treatment is restricted to patients with PD-L1 CPS ≥5.…”