Elsevier

The Lancet

Volume 390, Issue 10111, 2–8 December 2017, Pages 2461-2471
The Lancet

Articles
Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial

https://doi.org/10.1016/S0140-6736(17)31827-5Get rights and content

Summary

Background

Patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, two or more previous regimens of chemotherapy have a poor prognosis, and current guidelines do not recommend any specific treatments for these patients. We assessed the efficacy and safety of nivolumab, a fully human IgG4 monoclonal antibody inhibitor of programmed death-1 (PD-1), in patients with advanced gastric or gastro-oesophageal junction cancer who had been previously been treated with two or more chemotherapy regimens.

Methods

In this randomised, double-blind, placebo-controlled, phase 3 trial done at 49 clinical sites in Japan, South Korea, and Taiwan, eligible patients (aged ≥20 years with unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, standard therapy [including two or more previous chemotherapy regimens], with an Eastern Cooperative Oncology Group [ECOG] performance status of 0–1, and naive to anti-PD-1 therapy or other therapeutic antibodies and pharmacotherapies for the regulation of T cells) were recruited. Patients were randomly assigned (2:1) using an interactive web response system to receive 3 mg/kg nivolumab or placebo intravenously every 2 weeks, stratified by country, ECOG performance status, and number of organs with metastases. Study treatment was continued until progressive disease per investigator assessment or onset of toxicities requiring permanent discontinuation. Patients and investigators were masked to group assignment. The primary endpoint was overall survival in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study treatment. This study is ongoing but not recruiting new patients, and is registered with ClinicalTrials.gov, number NCT02267343.

Findings

Between Nov 4, 2014, and Feb 26, 2016, we randomly assigned 493 patients to receive nivolumab (n=330) or placebo (n=163). At the data cutoff (Aug 13, 2016), median follow-up in surviving patients was 8·87 months (IQR 6·57–12·37) in the nivolumab group and 8·59 months (5·65–11·37) in the placebo group. Median overall survival was 5·26 months (95% CI 4·60–6·37) in the nivolumab group and 4·14 months (3·42–4·86) in the placebo group (hazard ratio 0·63, 95% CI 0·51–0·78; p<0·0001). 12-month overall survival rates were 26·2% (95% CI 20·7–32·0) with nivolumab and 10·9% (6·2–17·0) with placebo. Grade 3 or 4 treatment-related adverse events occurred in 34 (10%) of 330 patients who received nivolumab and seven (4%) of 161 patients who received placebo; treatment-related adverse events led to death in five (2%) of 330 patients in the nivolumab group and two (1%) of 161 patients in the placebo group. No new safety signals were observed.

Interpretation

In this phase 3 study, the survival benefits indicate that nivolumab might be a new treatment option for heavily pretreated patients with advanced gastric or gastro-oesophageal junction cancer. Ongoing trials that include non-Asian patients are investigating nivolumab for advanced gastric or gastro-oesophageal junction cancer in various settings and earlier treatment lines.

Funding

Ono Pharmaceutical and Bristol-Myers Squibb.

Introduction

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.

Section snippets

Study design and patients

We did a randomised, double-blind, placebo-controlled, phase 3 trial at 49 clinical sites in Japan, South Korea, and Taiwan. Eligible patients were aged 20 years or older with unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer histologically confirmed to be adenocarcinoma refractory to, or intolerant of, standard therapy. Patients treated with two or more previous chemotherapy regimens in the advanced or recurrent setting were eligible, and had to have an Eastern

Results

Between Nov 4, 2014, and Feb 26, 2016, we screened 601 patients for eligibility, of whom 493 were randomly assigned (2:1) to receive nivolumab (n=330) or placebo (n=163; figure 1) at 49 study sites.

Baseline patient and disease characteristics were balanced across treatment groups (table 1). Tumour samples were obtained before the study from 134 (41%) of 330 patients in the nivolumab group and 62 (38%) of 163 patients in the placebo group. However, four samples from the nivolumab group were not

Discussion

This trial is the first randomised phase 3 study of an immune checkpoint inhibitor in patients with advanced gastric or gastro-oesophageal junction cancer. Patients treated with nivolumab had longer overall survival than patients treated with placebo, with early and durable responses and a manageable safety profile. The HR for survival was 0·63, and the proportion of patients with overall survival in the nivolumab group at 12 months was greater than that in the placebo group. The survival

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