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.
Bibliographical noteFunding Information:
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 benefit with nivolumab was independent of PD-L1 positivity. The efficacy of nivolumab is of particular note in this heavily pretreated patient population, in whom approximately 80% of patients who were randomly assigned had received three or more previous treatment regimens. Relative to previous data from pivotal phase 3 trials 9,11,13,27 that support current standards of care for patients with chemotherapy-refractory advanced gastric or gastro-oesophageal junction cancer, the results from our trial show a clinically significant survival benefit with nivolumab in a heavily pretreated patient population. Although comparison across trials is limited due to differences in lines of therapy, the enrolled patient population, and treatment type, the HR for overall survival in our trial indicated that nivolumab had greater superiority relative to placebo in heavily pretreated patients compared with the observed survival benefits of second-line chemotherapy, second-line ramucirumab, or third-line apatinib. 9,11,13,27 In this study population of patients who had been heavily pretreated, nivolumab resulted in an absolute survival benefit of 1·1 months in median overall survival over placebo, which is numerically similar to the absolute survival benefits of second-line ramucirumab or chemotherapy. Furthermore, clear separation of the nivolumab and placebo overall survival curves occurred over time that was sustained beyond 1 year, suggesting a durable overall survival benefit with nivolumab. In comparison, data from phase 3 trials 9,11,13,27 of chemotherapy or VEGFR-2–targeting drugs do not show a sustained survival benefit. Our study shows that nivolumab has a statistically significant and clinically meaningful benefit in patients who have been treated with two or more previous lines of chemotherapy. In the planned overall survival analyses, the HR estimates for nivolumab versus placebo were less than 1·0 across across most baseline characteristic subgroups. Similar survival benefits with nivolumab were observed in patients regardless of primary tumour site (gastric vs gastro-oesophageal junction), Lauren classification (diffuse vs intestinal), or PD-L1 positivity (<1% vs ≥1%). Nivolumab had superior overall survival in patients who had been treated with two, three, or four or more lines of previous therapy—most commonly chemotherapy—although the CIs were wide and crossed 1·0 for two and three previous regimens ( figure 3 ). Despite the p interaction value being significant for number of previous regimens × treatment ( appendix ), we did not observe a qualitative interaction when considering the results of the subgroup analysis and interaction analysis. After the start of our study, the anti-angiogenic VEGFR-2–targeting antibody ramucirumab was established as a standard-of-care option in patients with advanced gastric or gastro-oesophageal junction cancer following failure of chemotherapy, and only 11% of patients had previous exposure to ramucirumab in the nivolumab group. An exploratory, post-hoc subgroup analysis of overall survival indicated benefit with nivolumab regardless of previous ramucirumab treatment. These results show that the benefit with nivolumab is observed across most patient subgroups and is present regardless of line of treatment or previous ramucirumab therapy. The safety profile of nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer was manageable and similar to that reported in patients with other advanced solid tumours. 16–19 No new safety signals were observed. The equivalent proportions of patients with all-cause adverse events, all-cause serious adverse events, and treatment-related adverse events leading to treatment discontinuation or death between the two groups suggest that the treatment-related adverse events reported in patients receiving nivolumab could be partly attributed to underlying illness in these heavily pretreated patients. In this study, clear clinical benefits with nivolumab were shown in a heavily pretreated patient population unselected for PD-L1-expressing tumours. Biomarker analyses might help to better indicate which patients are most likely to benefit from nivolumab. Although the collection of tumour samples was challenging in this heavily pretreated population, tumour samples from approximately 40% (n=192) of patients were retrospectively assessed for PD-L1 tumour expression. Exploratory analyses according to PD-L1 positivity in these patients suggest an overall survival benefit regardless of PD-L1 expression status, with HRs for overall survival favouring nivolumab over placebo across PD-L1-positive and PD-L1-negative patient groups. However, caution should be taken when interpreting these results considering the small sample size of the PD-L1-positive subgroup. Additional investigations with these tumour tissues are planned because of the importance of biomarker identification for selecting optimum patients and overcoming resistance. According to The Cancer Genome Atlas (TCGA) research network, molecular subtypes might also represent additional potential predictors of nivolumab response. TCGA has categorised gastric cancer into four molecular subtypes: Epstein-Barr virus-positive, high microsatellite instability, genomically stable, and chromosomally instable. 28 Epstein-Barr virus-positive tumours are associated with high PD-L1 tumour expression, and tumours with high microsatellite instability have been associated with high response rates to immunotherapies in other solid tumours, 28,29 suggesting that these gastric cancer subtypes might be particularly responsive to anti-PD-1 therapy. Tumour mutation burden has also been evaluated as a predictor of response to PD-1 blockade, with patients with higher mutational loads showing a greater likelihood of response. 30 However, TCGA subtypes and tumour mutation burden among patients enrolled in this study are unknown. Differential outcomes have been observed in studies of Asian and non-Asian patients with advanced gastric cancer receiving chemotherapy or VEGF-targeting drugs. 14,31–33 A 2015 retrospective analysis 34 evaluated expression profiles of more than 1000 gastric adenocarcinomas from Asian and non-Asian cohorts. Immune and inflammation signatures were differentially expressed between the two cohorts. Tumours from non-Asian patients were associated with enrichment of tumour-infiltrating T cells and T-cell gene expression signatures, including CTLA-4 signalling. These data suggest that non-Asian patients might have stronger immune signatures than Asian patients, and are likely to have similar, if not better, responses to immuno-oncology drugs. Additionally, available evidence suggests that anti-PD-1 therapies have clinical benefit in non-Asian patients with advanced gastric cancer. In the gastric cohort of the KEYNOTE-12 study, 24 the immune checkpoint inhibitor pembrolizumab had similar clinical benefits in Asian and non-Asian patients with PD-L1–positive advanced gastric or gastro-oesophageal junction cancer. Furthermore, findings from the gastric cohort of the phase 1/2 CheckMate 032 study, 23 which has enrolled patients with advanced gastric, oesophageal, or gastro-oesophageal junction cancer treated with one or more previous chemotherapy regimens in North America and Europe, similarly showed antitumour activity with nivolumab (12% of patients had an objective response; 12-month overall survival of 39%). These data suggest that nivolumab also has clinical benefits in non-Asian patients with advanced gastric or gastro-oesophageal junction cancer. One limitation of our study was the absence of data about patient quality of life. Although patient-reported outcomes on quality of life are not available, the incidence of severe treatment-related adverse events was low and symptomatic adverse events were observed equally in both groups, indicating that these events were likely due to the disease and not study treatment. We speculate that nivolumab toxicities might have little effect on patient quality of life, and its efficacy might contribute to improvements in quality of life. In conclusion, nivolumab is the first immune checkpoint inhibitor to show efficacy in patients with advanced gastric or gastro-oesophageal junction cancer in a large phase 3 study. In heavily pretreated patients for whom no current standard of care therapy is available, nivolumab treatment resulted in clinically meaningful improvements in survival. The proportion of patients who achieved overall survival with nivolumab was greater than that with placebo at 12 months, with early and durable responses to nivolumab observed in some patients. These data indicate that nivolumab could become standard of care for these heavily pretreated patients and support ongoing evaluation of nivolumab in earlier lines of treatment in patients with advanced gastric or gastro-oesophageal junction cancer. Contributors NB, Y-KK, and L-TC conceived and designed the study. All authors gathered the data. Y-KK, NB, and L-TC analysed and interpreted the data. All authors were involved in development, review, and approval of the manuscript. NB, Y-KK, and L-TC were responsible for the final decision to submit for publication. Declaration of interests Y-KK has served as a consultant for Eli Lilly and Company, ImClone, Taiho Pharmaceutical, Daehwa Pharmaceutical, LSK Biopharma, Ono Pharmaceutical, Roche/Genentech, and Novartis; and received grants from Bayer, Novartis, Daehwa Pharmaceutical, LSK Biopharma, and Roche outside of the submitted work. NB received honoraria from Ono Pharmaceutical, Bristol-Myers Squibb, Merck Serono, AstraZeneca, and Chugai Pharmaceutical during the conduct of this study. TS received grants and personal fees from Yakult Honsha, Chugai Pharmaceutical, and Eli Lilly; personal fees from Merck Serono, Bristol-Myers Squibb, Takeda Pharmaceutical, Bayer, Taiho Pharmaceutical, and Takara Bio; and grants from Ono Pharmaceutical, outside the submitted work. KK received grants from Ono Pharmaceutical during the conduct of the study; and received grants from Shionogi, MSD, and Merck Serono, outside the submitted work. J-SC received advisory board and investigator fees from Ono Pharmaceutical during the conduct of this study. KMu received grants from Ono Pharmaceutical, MSD, Daiichi Sankyo, Kyowa Hakko Kirin, Shionogi Pharmaceutical, and Gilead Sciences; and personal fees from Taiho Pharmaceutical, Takeda Pharmaceutical, Chugai Pharmaceutical, Merck Serono, Eli Lilly and Company, and Yakult Honsha, during the conduct of the study. TY received grants and personal fees from Chugai Pharmaceutical, Yakult Honsha, and Taiho Pharmaceutical; and personal fees from Abbott, Eli Lilly, Taiho Pharmaceutical, Ono Pharmaceutical, MSD, Takeda Pharmaceutical, Novartis, Covidien, Johnson and Johnson, Olympus, and Nihon Kayaku, outside the submitted work. TT received grants from Ono Pharmaceutical during the conduct of this study. K-WL's institution (Seoul National University Bundang Hospital) received grants from Ono Pharmaceutical, during the conduct of the study. YH received advisory fees from Ono Pharmaceutical, Sumitomo Dainippon, Chugai Roche, and Taiho Pharmaceutical, outside the submitted work. L-TC received honoraria from Ono Pharmaceutical and Bristol-Myers Squibb during the conduct of this study; received honoraria from Eli Lilly, MSD, PharmaEngine, Merrimack, TTY Biopharm, Syncore, Five Prime, Novartis, and Pfizer, outside the submitted work; and both of his institutions received research funding from Novartis, GlaxoSmithKline, Merck Serono, TTY Biopharm, Syncore, and Polaris, outside the submitted work. M-HR, YC, HCC, WKK, K-HY, SCO, L-YB, JGK, KC, D-YO, KMi, JYC, and MT declare no competing interests. Acknowledgments This study was funded by Ono Pharmaceutical (Osaka, Japan) and Bristol-Myers Squibb (Princeton, NJ, USA). We thank Satoshi Morita (Kyoto University Graduate School of Medicine) and Naokazu Gion (Ono Pharmaceutical) for providing statistical support, the project leader Mitsunobu Tanimoto (Ono Pharmaceutical), the medical director Hironobu Minami (Kobe University Graduate School of Medicine), and the medical monitors Yoshinobu Namba and Yoshinori Hirashima (Ono Pharmaceutical). We thank the the Independent Data Monitoring Committee (Wataru Ichikawa [Showa University Fujigaoka Hospital], Yuichi Ando [Nagoya University Hospital], and Koji Oba [University of Tokyo]) for their role in this trial. We also thank the patients and their families, and the investigators and research staff at all study sites. Editorial assistance was provided by Jonathan Morgan (Chrysalis Medical Communications), and was funded by Bristol-Myers Squibb.
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