Yoon-Koo Kang1, Narikazu Boku2, Taroh Satoh3, Min-Hee Ryu1, Yee Chao4, Ken Kato5, Hyun Cheol Chung6, Jen-Shi Chen7, Kei Muro8, Won Ki Kang9, Kun-Huei Yeh10, Takaki Yoshikawa11, Sang Cheul Oh12, Li-Yuan Bai13, Takao Tamura14, Keun-Wook Lee15, Yasuo Hamamoto16, Jong Gwang Kim17, Keisho Chin18, Do-Youn Oh19, Keiko Minashi20, Jae Yong Cho21, Masahiro Tsuda22, Li-Tzong Chen23. 1. Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea. 2. Division of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan. Electronic address: nboku@ncc.go.jp. 3. Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, Suita, Japan. 4. Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan. 5. Division of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan. 6. Division of Medical Oncology, Medical Oncology Yonsei Cancer Center, Song-Dang Institute for Cancer Research, Yonsei University College of Medicine, Yonsei University Health System, Seoul, South Korea. 7. Division of Hematology and Oncology, Department of Internal Medicine, Linkou Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan. 8. Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan. 9. Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. 10. Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan. 11. Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan. 12. Division of Hematology and Oncology, Department of Internal Medicine, College of Medicine, Korea University, Seoul, South Korea. 13. Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, China Medical University, Taichung, Taiwan. 14. Department of Medical Oncology, Faculty of Medicine, Kindai University, Osakasayama, Japan. 15. Division of Hematology and Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea. 16. Keio Cancer Center, Keio University School of Medicine, Tokyo, Japan. 17. Kyungpook National University School of Medicine, Daegu, South Korea. 18. Department of Gastroenterology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan. 19. Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea. 20. Department of Clinical Trial Promotion, Chiba Cancer Center, Chiba, Japan. 21. Department of Medical Oncology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea. 22. Department of Gastroenterological Oncology, Hyogo Cancer Center, Akashi, Japan. 23. National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan; National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan.
Abstract
BACKGROUND:Patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, two or more previous regimens ofchemotherapy 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.
RCT Entities:
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.
Authors: Charles S Fuchs; Toshihiko Doi; Raymond W Jang; Kei Muro; Taroh Satoh; Manuela Machado; Weijing Sun; Shadia I Jalal; Manish A Shah; Jean-Phillipe Metges; Marcelo Garrido; Talia Golan; Mario Mandala; Zev A Wainberg; Daniel V Catenacci; Atsushi Ohtsu; Kohei Shitara; Ravit Geva; Jonathan Bleeker; Andrew H Ko; Geoffrey Ku; Philip Philip; Peter C Enzinger; Yung-Jue Bang; Diane Levitan; Jiangdian Wang; Minori Rosales; Rita P Dalal; Harry H Yoon Journal: JAMA Oncol Date: 2018-05-10 Impact factor: 31.777