Gastric cancer is the fifth most common cancer and the third leading cause of cancer deaths annually, worldwide.1 Although the highest incidence of gastric cancer is observed in eastern Asian countries such as Japan and Korea,2 outcomes for patients in such countries have been improved because of proactive screening programmes and the use of extensive surgery in localised cases.3, 4 Platinum compounds plus fluoropyrimidines are the most common first-line treatment for patients with advanced or metastatic gastric cancer, as recommended by the European Society for Medical Oncology, Japanese Gastric Cancer Association, National Comprehensive Cancer Network, and the Asian resource-stratified treatment guidelines.5, 6, 7, 8 For patients with disease refractory to first-line chemotherapy, treatment options include docetaxel, paclitaxel, or irinotecan monotherapy,9, 10, 11, 12 or the anti-vascular endothelial growth factor receptor 2 (VEGFR-2) antibody ramucirumab alone or in combination with paclitaxel.13, 14 However, nearly all patients with advanced disease continue to have disease progression following treatment.9, 11, 13, 14 At present, no standard third-line therapy is available for patients with advanced gastric cancer and failure of two or more lines of chemotherapy that have been recommended by international treatment guidelines or that have been supported by randomised, prospective clinical trials.5, 6, 7, 8 Thus, an urgent need exists to develop new treatment options for patients with advanced gastric or gastro-oesophageal junction cancer.
Research in context
Evidence before this study
New treatment options, such as immunotherapies, are needed for patients with chemotherapy-refractory advanced gastric or gastro-oesophageal junction cancer to improve survival. We searched PubMed for English language articles between Jan 31, 2012, and Jan 31, 2017, using the search terms “advanced gastric cancer,” “chemotherapy-refractory,” and “programmed death-1 inhibitor OR PD-1 inhibitor” for trials of immunotherapies in patients with advanced gastric or gastro-oesophageal junction cancer. Meta-analysis references and review articles were excluded. Previous reports of immune checkpoint inhibitors in patients with advanced gastric or gastro-oesophageal junction cancer were found from the gastric cohort of the phase 1/2 CheckMate 032 trial of nivolumab and the gastric cohort of the phase 1 KEYNOTE-012 trial of pembrolizumab. These studies showed preliminary antitumour effects of nivolumab in patients with or without PD-L1–positive tumours, and antitumour effects of pembrolizumab in patients with PD-L1–positive tumours.
Added value of the study
This is the first report from a phase 3 study of an immune checkpoint inhibitor in patients with advanced gastric or gastro-oesophageal junction cancer. This placebo-controlled study shows a significant survival advantage with nivolumab compared with placebo in patients who have heavily pretreated advanced gastric or gastro-oesophageal junction cancer.
Implications of all the available evidence
The results of this study show that nivolumab is a safe and effective treatment in patients with advanced gastric or gastro-oesophageal junction cancer after failure of two or more lines of previous chemotherapy. These findings suggest that nivolumab could be a standard-of-care treatment option and support ongoing assessment of nivolumab, alone and in combination with other treatments in earlier lines of therapy, in patients with advanced gastric or gastro-oesophageal junction cancer.
Immune checkpoint inhibitors enhance antitumour T-cell activity through the inhibition of immune checkpoints such as the programmed death-1 (PD-1) receptor.15 In multiple solid tumour types, immune checkpoint inhibitors show reduced toxicity and improved survival compared with standard treatment options and are associated with durable responses in some patients.16, 17, 18, 19 Immune checkpoint inhibitors might provide benefits in patients with advanced gastric or gastro-oesophageal junction cancer because of the high mutational burden and overexpression of immune checkpoint proteins associated with these cancers. Programmed death-1 ligand 1 (PD-L1) expression, which is associated with depth of invasion, tumour size, lymph node metastasis, and a shorter median survival, has been reported in 25–65% of gastric cancers.20, 21, 22
Data from two trials23, 24 show preliminary efficacy of anti-PD-1 therapy in patients with chemotherapy-refractory advanced gastric or gastro-oesophageal junction cancer. The gastric cohort of the phase 1/2 CheckMate 032 trial23 showed clinical benefits of nivolumab, a fully human IgG4 monoclonal antibody inhibitor of PD-1, alone or in combination with ipilimumab, a fully human IgG1 monoclonal antibody inhibitor of cytotoxic T-lymphocyte–associated protein-4 (CTLA-4), in patients with chemotherapy-refractory advanced gastric or gastro-oesophageal junction cancer. In the gastric cohort of the phase 1 KEYNOTE-012 study,24 the anti-PD-1 antibody pembrolizumab had antitumour activity in patients with PD-L1–positive advanced gastric or gastro-oesophageal junction cancer.
The ONO-4538-12, ATTRACTION-2 study was designed to investigate the efficacy and safety of nivolumab, in heavily pretreated patients unselected for PD-L1 tumour expression.