Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229-3039, USA.
Lancet. 2013 Mar 9;381(9869):817-24. doi: 10.1016/S0140-6736(12)61767-X.
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.
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.
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<0·0001). The most common adverse events in the everolimus and placebo groups were stomatitis (48% [38 of 79], 8% [3 of 39], respectively), nasopharyngitis (24% [19 of 79] and 31% [12 of 39]), and acne-like skin lesions (22% [17 of 79] and 5% [2 of 39]).
Everolimus reduced angiomyolipoma volume with an acceptable safety profile, suggesting it could be a potential treatment for angiomyolipomas associated with tuberous sclerosis.
Novartis Pharmaceuticals.
血管平滑肌脂肪瘤是与哺乳动物雷帕霉素靶蛋白（mTOR）组成性激活相关的生长缓慢的肿瘤，在结节性硬化症和散发性淋巴管平滑肌瘤病患者中很常见。这些肿瘤的隐匿性生长使患者易发生严重并发症，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。我们比较了依维莫司和安慰剂治疗结节性硬化症或散发性淋巴管平滑肌瘤病相关血管平滑肌脂肪瘤患者的血管平滑肌脂肪瘤反应率。
在这项双盲、安慰剂对照、3 期临床试验中，年龄在 18 岁或以上的患者至少有一个 3 cm 或以上最长直径的血管平滑肌脂肪瘤（通过影像学评估定义），并明确诊断为结节性硬化症或散发性淋巴管平滑肌瘤病，他们以 2:1 的比例，使用交互式网络反应系统随机分配，接受每天口服依维莫司 10 mg 或安慰剂。主要疗效终点是与基线相比，确认的血管平滑肌脂肪瘤反应率至少为靶血管平滑肌脂肪瘤总体积减少 50%的患者比例。本研究在 ClinicalTrials.gov 注册号为 NCT00790400。
来自 11 个国家 24 个中心的 118 名患者（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 名患者正在接受双盲治疗；停药的两个主要原因是疾病进展（9 名安慰剂患者），随后是不良事件（2 名依维莫司患者；4 名安慰剂患者）。依维莫司的血管平滑肌脂肪瘤反应率为 42%（79 例中的 33 例[95%CI 31-53%]），安慰剂为 0%（39 例中的 0 例[0-9%]）（反应率差异 42%[24-58%]；单侧 Cochran-Mantel-Haenszel 检验 p<0.0001）。依维莫司组和安慰剂组最常见的不良事件分别为口腔炎（48%[79 例中的 38 例]和 8%[39 例中的 3 例]）、鼻咽炎（24%[79 例中的 19 例]和 31%[39 例中的 12 例]）和痤疮样皮肤损伤（22%[79 例中的 17 例]和 5%[39 例中的 2 例]）。
依维莫司降低了血管平滑肌脂肪瘤的体积，安全性可接受，这表明它可能成为治疗与结节性硬化症相关的血管平滑肌脂肪瘤的一种潜在治疗方法。
诺华制药公司。
