論文No1113

 

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

 

James C Yao, Nicola Fazio, Simron Singh, Roberto Buzzoni, Carlo Carnaghi, Edward Wolin, Jiri Tomasek, Markus Raderer, Harald Lahner, Maurizio Voi, Lida Bubuteishvili Pacaud, Nicolas Rouyrre, Carolin Sachs, Juan W Valle, Gianfranco Delle Fave, Eric Van Cutsem, Margot Tesselaar, Yasuhiro Shimada, Do-Youn Oh, Jonathan Strosberg, Matthew H Kulke, Marianne E Pavel, RAD001 in Advanced Neuroendocrine Tumours, Fourth Trial (RADIANT-4) Study Group

 

Lancet 2016; 387: 968-977

 

<背景>

進行性神経内分泌腫瘍(肺、消化器)に有効な治療はほとんどない。

我々はこの疾患に対するエベロリムスの有効性、安全性を評価した。

 

<方法>

ランダム化二重盲検プラセボコントロールの第3相試験のRADIANT-4は、18歳以上の成人で進行性高分化非機能性神経内分泌腫瘍(肺あるいは消化管原発)を25か国95施設で登録した。

評価可能患者を2:1でエベロリムス10mg/日経口投与かプラセボに割り付け、両群とも支持療法を行った。

腫瘍の原発巣、PS、ソマトスタチンアナログによる全治療の有無で層別化した。

患者、評価者、研究のスポンサーは割り付けがわからないようにした。

主要エンドポイントは無増悪生存期間(PFS)で、中央で放射線科医が判断し、ITT解析を行った。

全生存期間(OS)はセカンドエンドポイントである。

この試験はClinicalTrials.gov, number NCT01524783で登録された。

 

<結果>

2012年4月から2013年8月まで、302名が登録され、205名がエベロリムス、97名がプラセボに割り付けられた。

平均PFSはエベロリムス群で11.0月(95% CI, 9.2-13.3)、プラセボ群で3.9月(95% CI, 3.6-7.4)であった。

エベロリムスは進行あるいは死亡リスクを52%低下させた(ハザード比0.48, 95%CI 0.35-0.67, p<0.0001)。

統計的に有意ではなかったが、OSはエベロリムス群で死亡リスク減少傾向であった(ハザード比0.64,95%CI 0.40-1.05, p=0.037、統計的有意は0.0002と設定)。

グレード3,4の副作用はまれで、口内炎(エベロリムス群で202名中18名(9%)、プラセボ群0名)、下痢(15名(7%) vs 2(2%))、感染(14名(7%) vs 0名)、貧血(8名(4%) vs 1名(1%))、倦怠感(7名(3%) vs 1名(1%)),高血糖(7名(3%) vs 0名)であった。

 

<感想>

神経内分泌腫瘍は予後不良で希少疾患です。

エベロリムスは肺、消化管の原発巣を問わずPFSを延長し、

副作用も許容範囲だったようです。

 


Background

Effective systemic therapies for patients with advanced, progressive neuroendocrine tumours of the lung or gastrointestinal tract are scarce. We aimed to assess the efficacy and safety of everolimus compared with placebo in this patient population.

Methods

In the randomised, double-blind, placebo-controlled, phase 3 RADIANT-4 trial, adult patients (aged ≥18 years) with advanced, progressive, well-differentiated, non-functional neuroendocrine tumours of lung or gastrointestinal origin were enrolled from 97 centres in 25 countries worldwide. Eligible patients were randomly assigned in a 2:1 ratio by an interactive voice response system to receive everolimus 10 mg per day orally or identical placebo, both with supportive care. Patients were stratified by tumour origin, performance status, and previous somatostatin analogue treatment. Patients, investigators, and the study sponsor were masked to treatment assignment. The primary endpoint was progression-free survival assessed by central radiology review, analysed by intention to treat. Overall survival was a key secondary endpoint. This trial is registered with ClinicalTrials.gov, number NCT01524783.

Findings

Between April 3, 2012, and Aug 23, 2013, a total of 302 patients were enrolled, of whom 205 were allocated to everolimus 10 mg per day and 97 to placebo. Median progression-free survival was 11·0 months (95% CI 9·2–13·3) in the everolimus group and 3·9 months (3·6–7·4) in the placebo group. 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 not statistically significant, the results of the first pre-planned interim overall survival analysis indicated that everolimus might be associated with a reduction in the risk of death (HR 0·64 [95% CI 0·40–1·05], one-sided p=0·037, whereas the boundary for statistical significance was 0·0002). Grade 3 or 4 drug-related adverse events were infrequent and included stomatitis (in 18 [9%] of 202 patients in the everolimus group vs 0 of 98 in the placebo group), diarrhoea (15 [7%] vs 2 [2%]), infections (14 [7%] vs 0), anaemia (8 [4%] vs 1 [1%]), fatigue (7 [3%] vs 1 [1%]), and hyperglycaemia (7 [3%] vs 0).

Interpretation

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. Everolimus is the first targeted agent to show robust anti-tumour activity with acceptable tolerability across a broad range of neuroendocrine tumours, including those arising from the pancreas, lung, and gastrointestinal tract.