Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial
Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial
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DOI：
10.1016/s1470-2045(14)70420-6
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发表时间：
2014-10-01
期刊：
影响因子：
51.1
通讯作者：
Ohtsu, Atsushi
中科院分区：
文献类型：
--
作者：
Wilke, Hansjochen;Muro, Kei;Ohtsu, Atsushi
背景VEGFR-2在胃癌发病机制和进展中发挥作用。我们评估是否ramucirumab，单克隆抗体VEGFR-2拮抗剂，与紫杉醇联合治疗，将增加总生存率在以前接受治疗的晚期胃癌患者相比，安慰剂加paclitaxel.Methods这个随机，安慰剂对照，双盲，3期试验在170个中心在北美和南美，欧洲，亚洲和澳大利亚的27个国家。年龄≥ 18岁的晚期胃或胃食管交界处腺癌患者，在一线化疗（铂类+氟嘧啶+或不含蒽环类）或化疗后4个月内疾病进展，通过集中交互式语音或网络应答系统以1：1的比例随机分配，在28天周期的第1天和第15天静脉注射雷莫芦单抗8 mg/kg或安慰剂，在第1天、第8天和第15天静脉注射紫杉醇80 mg/m2。采用排列区组随机化，按地理区域、一线治疗进展时间和疾病可测量性分层。主要终点是总生存期。疗效分析按意向治疗进行，安全性分析包括所有接受至少一次研究药物治疗的患者。该试验已在ClinicalTrials.gov注册，编号NCT 01170663，并已完成;仍在接受治疗的患者处于扩展阶段。结果2010年12月23日至2012年9月23日期间，665名患者被随机分配至治疗组--330名患者接受雷莫芦单抗加紫杉醇治疗，335名患者接受安慰剂加紫杉醇治疗。雷莫芦单抗+紫杉醇组的总生存期显著长于安慰剂+紫杉醇组（中位9.6个月[95% CI 8.5-10.8] vs 7.4个月[95% CI 6.3-8.4]，风险比0.807 [95% CI 0.678-0.962]; p=0.017）。雷莫芦单抗+紫杉醇组与安慰剂+紫杉醇组相比，超过5%的患者发生的3级或以上不良事件包括中性粒细胞减少症（133/327 [41%] vs 62/329 [19%]），白细胞减少症（57 [17%] vs 22 [7%]）、高血压（46 [14%] vs 8 [2%]）、疲乏（39 [12%] vs 18 [5%]）、贫血（30 [9%] vs 34 [10%]）和腹痛（20 [6%] vs 11 [3%]）。两组中3级或以上发热性中性粒细胞减少症的发生率均较低（10例[3%] vs 8例[2%]）。解释与安慰剂加紫杉醇相比，雷莫芦单抗与紫杉醇联合治疗显着提高了总生存期，可以被视为新的标准晚期胃癌患者的二线治疗。
Background VEGFR-2 has a role in gastric cancer pathogenesis and progression. We assessed whether ramucirumab, a monoclonal antibody VEGFR-2 antagonist, in combination with paclitaxel would increase overall survival in patients previously treated for advanced gastric cancer compared with placebo plus paclitaxel.Methods This randomised, placebo-controlled, double-blind, phase 3 trial was done at 170 centres in 27 countries in North and South America, Europe, Asia, and Australia. Patients aged 18 years or older with advanced gastric or gastro-oesophageal junction adenocarcinoma and disease progression on or within 4 months after first-line chemotherapy (platinum plus fluoropyrimidine with or without an anthracycline) were randomly assigned with a centralised interactive voice or web-response system in a 1:1 ratio to receive ramucirumab 8 mg/kg or placebo intravenously on days 1 and 15, plus paclitaxel 80 mg/m(2) intravenously on days 1, 8, and 15 of a 28-day cycle. A permuted block randomisation, stratified by geographic region, time to progression on first-line therapy, and disease measurability, was used. The primary endpoint was overall survival. Efficacy analysis was by intention to treat, and safety analysis included all patients who received at least one treatment with study drug. This trial is registered with ClinicalTrials.gov, number NCT01170663, and has been completed; patients who are still receiving treatment are in the extension phase.Findings Between Dec 23, 2010, and Sept 23, 2012, 665 patients were randomly assigned to treatment-330 to ramucirumab plus paclitaxel and 335 to placebo plus paclitaxel. Overall survival was significantly longer in the ramucirumab plus paclitaxel group than in the placebo plus paclitaxel group (median 9.6 months [95% CI 8.5-10.8] vs 7.4 months [95% CI 6.3-8.4], hazard ratio 0.807 [95% CI 0.678-0.962]; p=0.017). Grade 3 or higher adverse events that occurred in more than 5% of patients in the ramucirumab plus paclitaxel group versus placebo plus paclitaxel included neutropenia (133 [41%] of 327 vs 62 [19%] of 329), leucopenia (57 [17%] vs 22 [7%]), hypertension (46 [14%] vs eight [2%]), fatigue (39 [12%] vs 18 [5%]), anaemia (30 [9%] vs 34 [10%]), and abdominal pain (20 [6%] vs 11 [3%]). The incidence of grade 3 or higher febrile neutropenia was low in both groups (ten [3%] vs eight [2%]).Interpretation The combination of ramucirumab with paclitaxel significantly increases overall survival compared with placebo plus paclitaxel, and could be regarded as a new standard second-line treatment for patients with advanced gastric cancer.