Department of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Moscow Research Institute of Pediatrics and Pediatric Surgery, Moscow, Russia.
Lancet Oncol. 2014 Dec;15(13):1513-1520. doi: 10.1016/S1470-2045(14)70489-9. Epub 2014 Nov 10.
In the EXIST-1 trial, initiated on Aug 10, 2009, more than 35% of patients with subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex had at least 50% reduction in SEGA volume after 9·6 months of treatment with everolimus. In this Article, we report interim data (up to Jan 11, 2013) to support longer-term tolerability and efficacy of everolimus from the continuing 4-year extension phase of EXIST-1.
We assessed data from a prospective, open-label extension of a multicentre, phase 3, randomised, double-blind, placebo-controlled study in patients with tuberous sclerosis complex who had SEGA that was growing and needed treatment. In this extension study, we included all patients who had been assigned everolimus during the double-blind, randomised phase of the trial and those patients who crossed over from the placebo group to receive everolimus during the randomised phase or at the start of the extension phase. All patients received oral everolimus at a starting dose of 4·5 mg/m(2) per day. Everolimus dose was subsequently adjusted subject to tolerability to attain blood trough concentrations of 5-15 ng/mL. An independent central radiology review team assessed SEGA response (at least a 50% reduction from baseline in total volume of all target SEGAs; the primary endpoint) by MRI at 12, 24, and 48 weeks, then every year thereafter in all patients who received at least one dose of everolimus. This study was registered with ClinicalTrials.gov, number NCT00789828.
Of the original 117 randomly assigned patients, 111 were given everolimus between Aug 20, 2009, and Jan 11, 2013 (date of data cutoff); we included these patients in our longer-term analysis. Median duration of everolimus exposure was 29·3 months (IQR 19·4-33·8). Median follow-up was 28·3 months (IQR 19·3-33·0). 54 (49%) patients had a response of 50% or greater reduction in SEGA volume (95% CI 39·0-58·3), and duration of response was between 2·1 and 31·1 months (median not reached). SEGA volume was reduced by 50% or more in 39 (37%) of 105 patients at 24 weeks, 48 (46%) of 104 patients at 48 weeks, 36 (47%) of 76 patients at 96 weeks, and 11 (38%) of 29 patients at 144 weeks. Stomatitis (48 [43%] patients) and mouth ulceration (33 [30%] patients) were the most frequent treatment-related adverse events; infections were the most commonly reported treatment-related serious adverse event, occurring in 15 (14%) patients. 35 (32%) patients reported treatment-related grade 3 or 4 adverse events, the most common of which were stomatitis (nine [8%]) and pneumonia (nine [8%]). 18 (16%) patients had treatment-related serious adverse events. Six (5%) patients withdrew because of adverse events.
These results support the longer-term use of everolimus in patients who have few treatment options and who need continued treatment for tuberous sclerosis complex and its varied manifestations. Reduction or stabilisation of tumour volume with everolimus will hopefully provide long-term clinical benefit in patients with SEGA.
Novartis Pharmaceuticals.
在 2009 年 8 月 10 日启动的 EXIST-1 试验中，超过 35%的伴结节性硬化症的室管膜下巨细胞星形细胞瘤（SEGA）患者在接受依维莫司治疗 9.6 个月后，SEGA 体积至少减少了 50%。在本文中，我们报告了 EXIST-1 持续 4 年扩展阶段的中期数据（截至 2013 年 1 月 11 日），以支持依维莫司更长期的耐受性和疗效。
我们评估了一项多中心、3 期、随机、双盲、安慰剂对照研究的前瞻性、开放标签扩展数据，该研究纳入了有生长性且需要治疗的结节性硬化症伴 SEGA 的患者。在这项扩展研究中，我们纳入了试验双盲随机阶段接受依维莫司治疗的所有患者，以及在随机阶段或扩展阶段开始时从安慰剂组交叉接受依维莫司治疗的患者。所有患者均接受起始剂量为 4.5mg/m²/天的口服依维莫司。随后根据耐受性调整依维莫司剂量，以达到血药谷浓度 5-15ng/ml。一个独立的中心放射学审查小组通过 MRI 评估 SEGA 反应（所有目标 SEGA 的总体积减少至少 50%；主要终点），在所有接受至少一剂依维莫司的患者中，在 12、24 和 48 周时进行评估，此后每年评估一次。这项研究在 ClinicalTrials.gov 上注册，编号为 NCT00789828。
在最初随机分配的 117 名患者中，有 111 名患者在 2009 年 8 月 20 日至 2013 年 1 月 11 日期间（数据截止日期）接受了依维莫司治疗；我们将这些患者纳入了我们的长期分析。依维莫司暴露的中位持续时间为 29.3 个月（IQR 19.4-33.8）。中位随访时间为 28.3 个月（IQR 19.3-33.0）。54 名（49%）患者 SEGA 体积减少 50%或更多（95%CI 39.0-58.3），反应持续时间为 2.1-31.1 个月（中位数未达到）。在 24 周时，105 名患者中有 39 名（37%）、48 周时 104 名患者中有 48 名（46%）、96 周时 76 名患者中有 36 名（47%）、144 周时 29 名患者中有 11 名（38%）的 SEGA 体积减少了 50%或更多。最常见的治疗相关不良事件是口腔炎（48 [43%]例）和口腔溃疡（33 [30%]例）；感染是最常见的治疗相关严重不良事件，发生在 15 名（14%）患者中。35 名（32%）名患者报告了与治疗相关的 3 级或 4 级不良事件，其中最常见的是口腔炎（9 [8%]例）和肺炎（9 [8%]例）。18 名（16%）患者发生了与治疗相关的严重不良事件。6 名（5%）患者因不良事件退出。
这些结果支持在治疗选择有限且需要继续治疗结节性硬化症及其各种表现的患者中使用依维莫司进行长期治疗。依维莫司可减少或稳定肿瘤体积，有望为 SEGA 患者带来长期的临床获益。
诺华制药公司。
