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Lancet Oncol., Published Online January 11, 2022 | https://doi.org/10.1016/S1470-2045(21)00692-6 Nivolumab plus chemotherapy versus placebo plus chemotherapy in patients with HER2-negative, untreated, unresectable advanced or recurrent gastric or gastrooesophageal junction cancer (ATTRACTION-4): a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial

Prof Yoon-Koo Kang MD^a, Prof Li-Tzong Chen MD^b,c, Prof Min-Hee Ryu MD^a, Prof Do-Youn Oh MD^d,e, Sang Cheul Oh MD^f, Prof Hyun Cheol Chung MD^g, Prof Keun-Wook Lee MD^h, Takeshi Omori MDⁱ, Kohei Shitara MD^j, Prof Shinichi Sakuramoto MD^k, Prof Ik-Joo Chung MD^l, Kensei Yamaguchi MD^m, Ken Kato MDⁿ, Prof Sun Jin Sym MD^o, Shigenori Kadowaki MD^p, Kunihiro Tsuji MD^q, Jen-Shi Chen MD^r, Li-Yuan Bai MD^s, Sung-Yong Oh MD^t, Yasuhiro Choda MD^u, Hisateru Yasui MD^v, Kentaro Takeuchi MSc^w, Yoshinori Hirashima MD^w, Shunsuke Hagihara MSc^x, Narikazu Boku MD^n,*

^aDepartment of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
^bNational Institute of Cancer Research, National Health Research Institutes, and National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
^cKaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
^dDepartment of Internal Medicine, Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
^eIntegrated Major in Innovative Medical Science, Seoul National University Graduate School, Seoul, Korea
^fDivision of Hematology and Oncology, Department of Internal Medicine, College of Medicine, Korea University, Seoul, South Korea
^gDivision of Medical Oncology, Yonsei Cancer Center, Song-Dang Institute for Cancer Research, Yonsei University College of Medicine, Yonsei University Health System, Seoul, South Korea
^hDivision of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea
ⁱDepartment of Gastroenterological Surgery, Osaka International Cancer Institute, Osaka, Japan
^jDepartment of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
^kDepartment of Gastroenterological Surgery, Saitama Medical University International Medical Center, Hidaka, Japan
^lDepartment of Hematology-Oncology, Chonnam National University Hwasun Hospital, Chonnam National University College of Medicine, Hwasun, South Korea
^mDepartment of Gastroenterological Chemotherapy, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
ⁿDivision of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
^oDepartment of Internal Medicine, Division of Medical Oncology, Gachon University Gil Medical Center, Incheon, South Korea
^pDepartment of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan
^qDepartment of Medical Oncology, Ishikawa Prefectural Central Hospital, Kanazawa, Japan
^rDivision of Hematology and Oncology, Department of Internal Medicine, Linkou Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan
^sDivision of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, and China Medical University, Taichung, Taiwan
^tDepartment of Hemato-Oncology, Dong-a University Hospital, Busan, South Korea
^uDepartment of Surgery, Hiroshima Citizens Hospital, Hiroshima, Japan
^vDepartment of Medical Oncology, Kobe City Medical Center General Hospital, Hyogo, Japan
^wDepartment of Oncology Clinical Development Planning, Ono Pharmaceutical, Osaka, Japan
^xDepartment of Statistical Analysis, Ono Pharmaceutical, Osaka, Japan

^*Corresponding author.

Abstract

Background
The additive or synergistic sustained antitumour effect of immune checkpoint inhibitors in combination with oxaliplatin-based chemotherapy has previously been reported. We investigated the efficacy of nivolumab plus oxaliplatin-based chemotherapy versus placebo plus oxaliplatin-based chemotherapy as first-line therapy for patients with HER2-negative, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer.

Methods
We did a randomised, multicentre, double-blind, placebo-controlled, phase 2–3 trial (ATTRACTION-4) at 130 centres (hospitals, cancer centres, and medical centres) across Japan, South Korea, and Taiwan. We enrolled patients aged 20 years and older with previously untreated (except for neoadjuvant or adjuvant chemotherapy completed ≥180 days before recurrence), HER2-negative, unresectable, advanced or recurrent gastric or gastro-oesophageal junction cancer (regardless of PD-L1 expression), at least one measurable lesion per Response Evaluation Criteria in Solid Tumours guidelines (version 1.1), and a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients were randomly assigned (1:1) to chemotherapy every 3 weeks (intravenous oxaliplatin 130 mg/m² on day 1 plus either oral S-1 40 mg/m² [SOX] or oral capecitabine 1000 mg/m² [CAPOX], twice daily on days 1–14), in addition to either 360 mg nivolumab intravenously every 3 weeks (nivolumab plus chemotherapy group) or placebo (placebo plus chemotherapy group). Randomisation was done using an interactive web response system with block sizes of four and stratified by intensity of PD-L1 expression, ECOG performance status score, disease status, and geographical region. Patients, investigators, and the study sponsor were masked to treatment assignment. The primary endpoints were centrally assessed progression-free survival and overall survival in the intention-to-treat population, which included all randomly assigned patients. Safety was assessed in all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov, NCT02746796. Trial recruitment is complete and follow-up is ongoing.

Findings
Between March 23, 2017, and May 10, 2018, 724 patients were randomly assigned to treatment: 362 patients to the nivolumab plus chemotherapy group and 362 to the placebo plus chemotherapy group. At the time of data cutoff on Oct 31, 2018, with a median follow-up of 11·6 months (IQR 8·7–14·1), median progression-free survival at a prespecified interim analysis was 10·45 months (95% CI 8·44–14·75) in the nivolumab plus chemotherapy group and 8·34 months (6·97–9·40) in the placebo plus chemotherapy group (hazard ratio [HR] 0·68; 98·51% CI 0·51–0·90; p=0·0007). At the time of data cutoff on Jan 31, 2020, with a median follow-up of 26·6 months (IQR 24·1–29·0), median overall survival at the final analysis was 17·45 months (95% CI 15·67–20·83) in the nivolumab plus chemotherapy group and 17·15 months (15·18–19·65) in the placebo plus chemotherapy group (HR 0·90; 95% CI 0·75–1·08; p=0·26). The most common treatment-related grade 3–4 adverse events were neutrophil count decreased (71 [20%] of 359 patients in the nivolumab plus chemotherapy group vs 57 [16%] of 358 patients in the placebo plus chemotherapy group) and platelet count decreased (34 [9%] vs 33 [9%]). Treatment-related serious adverse events of any grade were observed in 88 (25%) patients in the nivolumab plus chemotherapy group and in 51 (14%) in the placebo plus chemotherapy group, of which the most common was decreased appetite (18 [5%] vs ten [3%]). Six treatment-related deaths occurred: three in the nivolumab plus chemotherapy group (one each of febrile neutropenia, hepatic failure, and sudden death) and three in the placebo plus chemotherapy group (one each of sepsis, haemolytic anaemia, and interstitial lung disease).

Interpretation
Nivolumab combined with oxaliplatin-based chemotherapy significantly improved progression-free survival, but not overall survival, in Asian patients with untreated, HER2-negative, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer, and could potentially be a new first-line treatment option for these patients.

논문정보

형식Research article
게재일2022년 01월 (BRIC 등록일 2022-01-19)
연구진국내+국외 연구진
분야 생명과학 > 노화/암생물학

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