Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial
Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial
复制标题
DOI：
10.1016/s0140-6736(13)61719-5
复制
发表时间：
2014-01-04
期刊：
影响因子：
168.9
通讯作者：
Tabernero, Josep
中科院分区：
文献类型：
--
作者：
Fuchs, Charles S.;Tomasek, Jiri;Tabernero, Josep
背景血管内皮生长因子（VEGF）及其受体2（VEGFR-2）介导的信号转导和血管生成在胃癌的发生、发展中起重要作用。我们的目的是评估是否ramucirumab，单克隆抗体VEGFR-2拮抗剂，延长生存期的晚期gastric cancer.Methods患者，我们做了一个国际，随机，双盲，安慰剂对照，3期临床试验2009年10月6日至2012年1月26日，在119个中心，在北美，中美洲和南美洲，欧洲，亚洲，澳大利亚和非洲的29个国家。通过中央交互式语音应答系统，随机分配（2：1）年龄为24-87岁的晚期胃或胃食管交界处腺癌患者，在一线含铂或含氟嘧啶化疗后疾病进展，接受最佳支持治疗加雷莫芦单抗8 mg/kg或安慰剂，每2周一次静脉注射。研究申办者、受试者和研究者对治疗分配设盲。主要终点是总生存期。该试验在ClinicalTrials.gov注册，编号NCT 00917384。结果355名患者被分配接受雷莫芦单抗（n=238）或安慰剂（n=117）。雷莫芦单抗组患者的中位总生存期为5.2个月（IQR 2.3-9.9），安慰剂组为3.8个月（1.7-7.1）（风险比[HR] 0.776，95% CI 0.603-0.998; p=0.047）。在对其他预后因素进行多变量校正后，雷莫芦单抗的生存获益保持不变（多变量HR 0.774，0.605-0.991; p=0.042）。雷莫芦单抗组的高血压发生率高于安慰剂组（38 [16%] vs 9 [8%]），而其他不良事件的发生率在两组之间基本相似（223 [94%] vs 101 [88%]）。雷莫芦单抗组中的五例（2%）死亡和安慰剂组中的两例（2%）死亡被认为与研究药物有关。解释雷莫芦单抗是第一种作为单一药物给予的生物治疗，对一线化疗后进展的晚期胃或胃食管交界处腺癌患者具有生存益处。我们的研究结果验证了VEGFR-2信号传导作为进展期胃癌的重要治疗靶点。
Background Vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2)-mediated signalling and angiogenesis can contribute to the pathogenesis and progression of gastric cancer. We aimed to assess whether ramucirumab, a monoclonal antibody VEGFR-2 antagonist, prolonged survival in patients with advanced gastric cancer.Methods We did an international, randomised, double-blind, placebo-controlled, phase 3 trial between Oct 6, 2009, and Jan 26, 2012, at 119 centres in 29 countries in North America, Central and South America, Europe, Asia, Australia, and Africa. Patients aged 24-87 years with advanced gastric or gastro-oesophageal junction adenocarcinoma and disease progression after first-line platinum-containing or fluoropyrimidine-containing chemotherapy were randomly assigned (2: 1), via a central interactive voice-response system, to receive best supportive care plus either ramucirumab 8 mg/kg or placebo, intravenously once every 2 weeks. The study sponsor, participants, and investigators were masked to treatment assignment. The primary endpoint was overall survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00917384.Findings 355 patients were assigned to receive ramucirumab (n=238) or placebo (n=117). Median overall survival was 5.2 months (IQR 2.3-9.9) in patients in the ramucirumab group and 3.8 months (1.7-7.1) in those in the placebo group (hazard ratio [HR] 0.776, 95% CI 0.603-0.998; p=0.047). The survival benefit with ramucirumab remained unchanged after multivariable adjustment for other prognostic factors (multivariable HR 0.774, 0.605-0.991; p=0.042). Rates of hypertension were higher in the ramucirumab group than in the placebo group (38 [16%] vs nine [8%]), whereas rates of other adverse events were mostly similar between groups (223 [94%] vs 101 [88%]). Five (2%) deaths in the ramucirumab group and two (2%) in the placebo group were considered to be related to study drug.Interpretation Ramucirumab is the first biological treatment given as a single drug that has survival benefits in patients with advanced gastric or gastro-oesophageal junction adenocarcinoma progressing after first-line chemotherapy. Our findings validate VEGFR-2 signalling as an important therapeutic target in advanced gastric cancer.