Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial
Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial
复制标题
DOI：
10.1016/s0140-6736(12)61767-x
复制
发表时间：
2013-03-09
期刊：
影响因子：
168.9
通讯作者：
Budde, Klemens
中科院分区：
文献类型：
--
作者：
Bissler, John J.;Kingswood, J. Christopher;Budde, Klemens
血管平滑肌脂肪瘤是一种生长缓慢的肿瘤，与哺乳动物雷帕霉素靶蛋白（mTOR）的组成性激活有关，常见于结节性硬化症和散发性淋巴管平滑肌瘤病患者。这些肿瘤的隐匿性生长使患者易于发生严重并发症，包括腹膜后出血和肾功能受损。依维莫司是一种雷帕霉素衍生物，通过作用于mTOR复合物1来抑制mTOR通路。我们比较了结节性硬化症或散发性淋巴管平滑肌瘤病相关的血管平滑肌脂肪瘤患者对依维莫司和安慰剂的血管平滑肌脂肪瘤反应率。年龄≥ 18岁且至少有一个血管平滑肌脂肪瘤最长直径≥ 3 cm的患者（通过放射学评估定义）和结节性硬化症或散发性淋巴管平滑肌瘤病的明确诊断的患者随机分配，在2：1时尚与使用交互式网络响应系统，接受口服依维莫司10 mg/天或安慰剂。主要疗效终点是确认血管平滑肌脂肪瘤缓解的患者比例，即靶血管平滑肌脂肪瘤总体积相对于基线至少减少50%。ClinicalTrials.gov结果来自11个国家24个中心的118例患者（中位年龄31.0岁; IQR 18.0-61.0）被随机分配接受依维莫司（n=79）或安慰剂（n=39）。在数据截止时，98名患者正在进行双盲治疗;中止的两个主要原因是疾病进展（9名安慰剂患者），其次是不良事件（2名依维莫司患者; 4名安慰剂患者）。血管平滑肌脂肪瘤缓解率依维莫司组为42%（33/79 [95%CI 31-53%]），安慰剂组为0%（0/39 [0-9%]）（缓解率差异为42% [24-58%];单侧Cochran-Mantel-Haenszel检验p
Background Angiomyolipomas are slow-growing tumours associated with constitutive activation of mammalian target of rapamycin (mTOR), and are common in patients with tuberous sclerosis complex and sporadic lymphangioleiomyomatosis. The insidious growth of these tumours predisposes patients to serious complications including retroperitoneal haemorrhage and impaired renal function. Everolimus, a rapamycin derivative, inhibits the mTOR pathway by acting on the mTOR complex 1. We compared the angiomyolipoma response rate on everolimus with placebo in patients with tuberous sclerosis or sporadic lymphanioleiomyomatosis-associated angiomyolipomata.Methods In this double-blind, placebo-controlled, phase 3 trial, patients aged 18 years or older with at least one angiomyolipoma 3 cm or larger in its longest diameter (defined by radiological assessment) and a definite diagnosis of tuberous sclerosis or sporadic lymphangioleiomyomatosis were randomly assigned, in a 2: 1 fashion with the use of an interactive web response system, to receive oral everolimus 10 mg per day or placebo. The primary efficacy endpoint was the proportion of patients with confirmed angiomyolipoma response of at least a 50% reduction in total volume of target angiomyolipomas relative to baseline. This study is registered with ClinicalTrials.gov number NCT00790400.Results 118 patients (median age 31.0 years; IQR 18.0-61.0) from 24 centres in 11 countries were randomly assigned to receive everolimus (n=79) or placebo (n=39). At the data cutoff, double-blind treatment was ongoing for 98 patients; two main reasons for discontination were disease progression (nine placebo patients) followed by adverse events (two everolimus patients; four placebo patients). The angiomyolipoma response rate was 42% (33 of 79 [95% CI 31-53%]) for everolimus and 0% (0 of 39 [0-9%]) for placebo (response rate difference 42% [24-58%]; one-sided Cochran-Mantel-Haenszel test p