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Lancet Gastroenterol. Hepatol., Jun 18 2024, S2468-1253(24)00156-0 | https://doi.org/10.1016/S2468-1253(24)00156-0 Adjuvant nivolumab plus chemotherapy versus placebo plus chemotherapy for stage III gastric or gastro-oesophageal junction cancer after gastrectomy with D2 or more extensive lymph-node dissection (ATTRACTION-5): a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial

Prof Yoon-Koo Kang MD ^a, Masanori Terashima MD ^b, Young-Woo Kim MD ^c, Prof Narikazu Boku MD ^d, Prof Hyun Cheol Chung MD ^e, Prof Jen-Shi Chen MD ^f, Jiafu Ji MD ^h, Ta-Sen Yeh MD ^g, Prof Li-Tzong Chen MD^i,j, Prof Min-Hee Ryu MD ^a, Jong Gwang Kim MD ^k, Takeshi Omori MD^l, Prof Sun Young Rha MD^e, Tae Yong Kim MD^m, Keun Won Ryu MD ^c, Prof Shinichi Sakuramoto MD ⁿ, Yasunori Nishida MD ^o, Norimasa Fukushima MD ^p, Takanobu Yamada MD ^q, Li-Yuan Bai MD ^r, Yoshinori Hirashima MD^s, Shunsuke Hagihara MSc ^s, Takashi Nakada BSc ^s, Mitsuru Sasako MD ^t

^aAsan Medical Center, College of Medicine, University of Ulsan, Seoul, South Korea

^bDivision of Gastric Surgery, Shizuoka Cancer Center, Shizuoka, Japan

^cSurgical Department, Center for Gastric Cancer, National Cancer Center, Goyang, South Korea

^dDepartment of Oncology and General Medicine, Institute of Medical Science, University of Tokyo Hospital, Tokyo, Japan

^eYonsei Cancer Center, Yonsei University Health System, Seoul, South Korea

^fDivision of Hematology and Oncology, Department of Internal Medicine, Linkou Chang Gung Memorial Hospital, Chang Gung University, Taoyuan City, Taiwan

^gDepartment of Surgery, Linkou Chang Gung Memorial Hospital, Chang Gung University, Taoyuan City, Taiwan

^hDepartment of Gastrointestinal Surgery, Beijing Cancer Hospital, Beijing, China

ⁱCentre for Cancer Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung City, Taiwan

^jDepartment of Internal Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan City, Taiwan

^kDepartment of Hemato-Oncology, Chilgok Hospital, Kyungpook National University, Daegu, South Korea

^lDepartment of Gastroenterological Surgery, Osaka International Cancer Institute, Osaka, Japan

^mOncology Department, Seoul National University Hospital, Seoul, South Korea

ⁿDepartment of Gastrointestinal Surgery, International Medical Center, Saitama Medical University, Saitama, Japan

^oDepartment of Gastrointestinal Surgery and Medical Oncology, Keiyukai Sapporo Hospital, Sapporo, Japan

^pDepartment of Surgery, Yamagata Prefectural Central Hospital, Yamagata, Japan

^qDepartment of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan

^rDivision of Hematology and Oncology, China Medical University Hospital, China Medical University, Taichung, Taiwan

^sOno Pharmaceutical, Osaka, Japan

^tDepartment of Surgery, Yodogawa Christian Hospital, Osaka, Japan

Correspondence to: Dr Mitsuru Sasako

Abstract

Background: In Asia, adjuvant chemotherapy after gastrectomy with D2 or more extensive lymph-node dissection is standard treatment for people with pathological stage III gastric or gastro-oesophageal junction (GEJ) cancer. We aimed to assess the efficacy and safety of adjuvant nivolumab plus chemotherapy versus placebo plus chemotherapy administered in this setting.

Methods: ATTRACTION-5 was a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial conducted at 96 hospitals in Japan, South Korea, Taiwan, and China. Eligible patients were aged between 20 years and 80 years with histologically confirmed pathological stage IIIA-C gastric or GEJ adenocarcinoma after gastrectomy with D2 or more extensive lymph-node dissection, with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 and available tumour tissue for PD-L1 expression analysis. Patients were randomly assigned (1:1) to receive either nivolumab plus chemotherapy or placebo plus chemotherapy via an interactive web-response system with block sizes of four. Investigational treatment, either nivolumab 360 mg or placebo, was administered intravenously for 30 min once every 3 weeks. Adjuvant chemotherapy was administered as either tegafur-gimeracil-oteracil (S-1) at an initial dose of 40 mg/m2 per dose orally twice per day for 28 consecutive days, followed by 14 days off per cycle, or capecitabine plus oxaliplatin consisting of an initial dose of intravenous oxaliplatin 130 mg/m2 for 2 h every 21 days and capecitabine 1000 mg/m2 per dose orally twice per day for 14 consecutive days, followed by 7 days off treatment. The primary endpoint was relapse-free survival by central assessment. The intention-to-treat population, consisting of all randomly assigned patients, was used for analysis of efficacy endpoints. The safety population, defined as patients who received at least one dose of trial drug, was used for analysis of safety endpoints. This trial is registered with ClinicalTrials.gov (NCT03006705) and is closed.

Findings: Between Feb 1, 2017, and Aug 15, 2019, 755 patients were randomly assigned to receive either adjuvant nivolumab plus chemotherapy (n=377) or adjuvant placebo plus chemotherapy (n=378). 267 (71%) of 377 patients in the nivolumab group and 263 (70%) of 378 patients in the placebo group were male; 110 (29%) of 377 patients in the nivolumab group and 115 (31%) of 378 patients in the placebo group were female. 745 patients received assigned treatment (371 in the nivolumab plus chemotherapy group; 374 in the placebo plus chemotherapy group), which was the safety population. Median time from first dose to data cutoff was 49·1 months (IQR 43·1-56·7). 3-year relapse-free survival was 68·4% (95% CI 63·0-73·2) in the nivolumab plus chemotherapy group and 65·3% (59·9-70·2) in the placebo plus chemotherapy group; the hazard ratio for relapse-free survival was 0·90 (95·72% CI 0·69-1·18; p=0·44). Treatment-related adverse events occurred in 366 (99%) of 371 patients in the nivolumab plus chemotherapy group and 364 (98%) of 374 patients in the placebo plus chemotherapy group. Discontinuation due to adverse events was more frequent in the nivolumab plus chemotherapy group (34 [9%] of 371 patients) than the placebo plus chemotherapy group (13 [4%] of 374 patients). The most common treatment-related adverse events were decreased appetite, nausea, diarrhoea, neutrophil count decreased, and peripheral sensory neuropathy.

Interpretation: The results of this trial do not support the addition of nivolumab to postoperative adjuvant therapy for patients with untreated, locally advanced, resectable gastric or GEJ cancer.

논문정보

형식Research article
게재일2024년 06월 (BRIC 등록일 2024-06-24)
연구진국내+국외 연구진
분야 생명과학 > 노화/암생물학

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