Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study.
Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study.
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DOI：
10.1016/s0140-6736(15)00817-x
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发表时间：
2016-03-05
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影响因子：
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通讯作者：
RAD001 in Advanced Neuroendocrine Tumours, Fourth Trial (RADIANT-4) Study Group
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作者：
Yao JC;Fazio N;Singh S;Buzzoni R;Carnaghi C;Wolin E;Tomasek J;Raderer M;Lahner H;Voi M;Pacaud LB;Rouyrre N;Sachs C;Valle JW;Fave GD;Van Cutsem E;Tesselaar M;Shimada Y;Oh DY;Strosberg J;Kulke MH;Pavel ME;RAD001 in Advanced Neuroendocrine Tumours, Fourth Trial (RADIANT-4) Study Group
对进行性肺或胃肠道神经内分泌肿瘤患者有效的全身治疗是有限的。我们的目的是评估依维莫司在该患者群体中的有效性和安全性。RADIANT-4是一项随机、双盲、安慰剂对照的3期研究，纳入了来自全球25个国家97个中心的晚期、进行性、高分化、无功能肺或胃肠道神经内分泌肿瘤患者。符合条件的患者以2:1的比例随机分配至依维莫司10mg /天或安慰剂，均给予支持治疗。根据肿瘤来源、运动状态和既往生长抑素类似物治疗对患者进行分层。主要终点是通过中心放射学检查评估的无进展生存期。总生存期是一个关键的次要终点。该试验已在ClinicalTrials.gov注册，注册号为NCT01524783。2012年4月至2013年8月，共纳入302例患者，其中依维莫司10 mg/天组205例，安慰剂组97例。依维莫司组的中位无进展生存期为11.0个月（95%可信区间[CI]， 9.2-13.3），安慰剂组的中位无进展生存期为3.9个月（95% CI, 3.6-7.4）。依维莫司与估计进展或死亡风险降低52%相关（风险比[HR]， 0.48; 95% CI, 0.35-0.67; p<0.00001）。虽然统计学上不显着，但在第一次预先计划的中期总生存分析中观察到生存改善的趋势（HR, 0.64; 95% CI: 0.40, 1.05；单侧p=0.037；统计学显著性边界，0.0002）。3级或4级药物相关不良事件（依维莫司vs安慰剂）相对少见，包括口炎（9% vs 0）、腹泻（7% vs 2%）、感染（7% vs 0）、贫血（4% vs 1%）、疲劳（4% vs 1%）和高血糖（4% vs 0）。依维莫司治疗与进展性肺或胃肠道神经内分泌肿瘤患者的无进展生存期显著改善相关。安全性研究结果与依维莫司已知的副作用相符。
Effective systemic therapies for patients with progressive neuroendocrine tumours of lung or gastrointestinal tract are limited. We aimed to assess the efficacy and safety of everolimus in this patient population. In RADIANT-4, a randomised, double-blind, placebo-controlled, phase 3 study, patients with advanced, progressive, well-differentiated, nonfunctional lung or gastrointestinal neuroendocrine tumours were enrolled from 97 centres in 25 countries worldwide. Eligible patients were randomised in a 2:1 ratio to everolimus 10 mg/day or placebo, both with supportive care. Patients were stratified by tumour origin, performance status, and prior somatostatin analogue treatment. The primary endpoint was progression-free survival assessed by central radiology review. Overall survival was a key secondary endpoint. This trial is registered with ClinicalTrials.gov, number NCT01524783. From April 2012 to August 2013, a total of 302 patients were enrolled, of whom, 205 were allocated to everolimus 10 mg/day and 97 to placebo. Median progression-free survival was 11.0 months (95% confidence interval [CI], 9.2–13.3) in the everolimus arm and 3.9 months (95% CI, 3.6–7.4) in the placebo arm. Everolimus was associated with a 52% reduction in the estimated risk of progression or death (hazard ratio [HR], 0.48; 95% CI, 0.35–0.67; p<0.00001). Although statistically not significant, a trend towards improved survival was observed in the first pre-planned interim overall survival analysis (HR, 0.64; 95% CI: 0.40, 1.05; one-sided p=0.037; boundary for statistical significance, 0.0002). Grade 3 or 4 drug-related adverse events (everolimus vs placebo) were relatively infrequent and included stomatitis (9% vs 0), diarrhoea (7% vs 2%), infections (7% vs 0), anaemia (4% vs 1%), fatigue (4% vs 1%), and hyperglycaemia (4% vs 0). Treatment with everolimus was associated with significant improvement in progression-free survival in patients with progressive lung or gastrointestinal neuroendocrine tumours. The safety findings were consistent with the known side effect profile of everolimus.