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    Original Investigation
    Gastroenterology and Hepatology
    August 2, 2019

    Effect of First-line S-1 Plus Oxaliplatin With or Without Ramucirumab Followed by Paclitaxel Plus Ramucirumab on Advanced Gastric Cancer in East Asia: The Phase 2 RAINSTORM Randomized Clinical Trial

    Author Affiliations
    • 1Department of Gastrointestinal Surgery, Kanagawa Cancer Center Hospital, Yokohama, Japan
    • 2currently affiliated with Department of Gastric Surgery, National Cancer Center Hospital, Tokyo, Japan
    • 3Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan
    • 4Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
    • 5Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea
    • 6Department of Oncology, Asan Medical Center, University of Ulsan, Seoul, South Korea
    • 7Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea
    • 8Osaka University Graduate School of Medicine, Osaka, Japan
    • 9currently affiliated with Osaka International Cancer Institute, Osaka, Japan
    • 10The Cancer Institute Hospital of the Japanese Foundation of Cancer Research, Tokyo, Japan
    • 11Keio University School of Medicine, Tokyo, Japan
    • 12Chiba Cancer Center, Chiba, Japan
    • 13currently affiliated with Oita University Faculty of Medicine, Oita, Japan
    • 14Graduate School of Medicine, Gifu University, Gifu, Japan
    • 15Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
    • 16Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
    • 17Division of Hematology and Oncology, China Medical University Hospital, China Medical University, Taichung, Taiwan
    • 18Eli Lilly Japan KK, Kobe, Japan
    JAMA Netw Open. 2019;2(8):e198243. doi:10.1001/jamanetworkopen.2019.8243
    Key Points español 中文 (chinese)

    Question  Does the addition of ramucirumab to S-1 and oxaliplatin improve progression-free survival in patients with metastatic gastric or gastroesophageal junction adenocarcinoma in the first-line setting?

    Findings  In this phase 2 randomized clinical trial of 189 East Asian patients with metastatic gastric or gastroesophageal junction adenocarcinoma, median progression-free survival was not prolonged in the ramucirumab plus S-1 and oxaliplatin arm compared with the placebo plus S-1 and oxaliplatin arm (6.34 vs 6.74 months).

    Meaning  Addition of ramucirumab to first-line S-1 and oxaliplatin treatment did not improve progression-free survival, suggesting that the efficacy of ramucirumab in the second-line setting may not be applicable to the first-line setting when combined with fluoropyrimidine and platinum chemotherapy.

    Abstract

    Importance  Ramucirumab, a human IgG 1 antibody against vascular endothelial growth factor receptor 2, has been shown to improve progression-free survival and overall survival in patients with advanced gastric cancer in the second-line setting.

    Objective  To compare progression-free survival for S-1 and oxaliplatin plus ramucirumab with that for S-1 and oxaliplatin plus placebo in patients with advanced gastric cancer.

    Design, Setting, and Participants  This phase 2, double-blind randomized clinical trial (RAINSTORM [First-line S-1 Plus Oxaliplatin With or Without Ramucirumab Followed by Paclitaxel Plus Ramucirumab in Patients With Advanced Gastric Cancer]) was conducted from October 12, 2015, to April 11, 2018, at 36 sites in Japan, South Korea, and Taiwan. Participants were chemotherapy-naive patients (n = 189) with metastatic gastric or gastroesophageal adenocarcinoma. Analyses of the full analysis set and safety population were conducted between November 27, 2017, and June 4, 2018.

    Interventions  Patients randomized to the ramucirumab plus S-1 and oxaliplatin arm received S-1, 80 to 120 mg/d twice daily, on days 1 to 14 and oxaliplatin, 100 mg/m2, on day 1 with ramucirumab, 8 mg/kg, on days 1 and 8 in part A (21-day cycle). Patients randomized to the placebo plus S-1 and oxaliplatin arm received the same S-1 and oxaliplatin dosage as well as placebo on days 1 and 8 in part A. Eligible patients received second-line paclitaxel, 80 mg/m2, on days 1, 8, and 15 and ramucirumab, 8 mg/kg, on days 1 and 15 in part B (28-day cycle).

    Main Outcomes and Measures  The primary end point was progression-free survival, analyzed using the stratified log-rank test; the hazard ratio (HR) was estimated using the stratified Cox proportional hazards regression model. Secondary end points included overall survival and adverse events.

    Results  In total, 189 patients were randomized and received treatment: 96 to the ramucirumab plus S-1 and oxaliplatin arm and 93 to the placebo plus S-1 and oxaliplatin arm. Among the 189 patients, 121 (64.0%) were male, and the median (range) age was 62.0 (26-84) years. Median progression-free survival was not prolonged in the ramucirumab plus S-1 and oxaliplatin arm compared with the placebo plus S-1 and oxaliplatin arm (6.34 [80% CI, 5.65-6.93] vs 6.74 [80% CI, 5.75-7.13] months; HR, 1.07; 80% CI, 0.86-1.33; P = .70). Median overall survival was 14.65 (80% CI, 12.39-15.67) months in the ramucirumab plus S-1 and oxaliplatin arm and 14.26 (80% CI, 13.83-17.31) months in the placebo plus S-1 and oxaliplatin arm (HR, 1.11; 80% CI, 0.89-1.40; P = .55). The most commonly reported grade 3 or higher treatment-emergent adverse events in the ramucirumab plus S-1 and oxaliplatin arm in part A were decreased neutrophil count (14 patients [14.6%]), hypertension (10 patients [10.4%]), and anemia (10 patients [10.4%]).

    Conclusions and Relevance  In this randomized clinical trial, the addition of ramucirumab to first-line S-1 and oxaliplatin treatment did not prolong progression-free survival or overall survival compared with S-1 and oxaliplatin alone among East Asian patients with advanced gastric cancer; no new safety signals for ramucirumab were identified.

    Trial Registration  ClinicalTrials.gov identifier: NCT02539225

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