A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas
A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas
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DOI：
10.1038/sj.bjc.6603419
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发表时间：
2006-11-06
影响因子：
8.8
通讯作者：
Siu, L. L.
中科院分区：
文献类型：
--
作者：
Duran, I.;Kortmansky, J.;Siu, L. L.
神经内分泌肿瘤的标准细胞毒性治疗与有限的活性和显著的毒性有关。一项II期研究旨在评估替西罗莫司在晚期神经内分泌癌（NEC）患者中的疗效、安全性和药效学。37例晚期进展性NEC患者接受每周一次25 mg替西罗莫司静脉给药。评估患者的肿瘤缓解、至进展时间（TTP）、总生存期（OS）和不良事件（AE）。22个档案标本，以及13对肿瘤活检标本获得的治疗前和2周后的替西罗莫司进行了评估潜在的预测和相关的标志物。意向治疗反应率为5.6%（95%CI 0.6-18.7%），中位TTP 6个月和1年OS率为71.5%。所有级别中最常见的药物相关AE（患者百分比）为：疲乏（78%）、高血糖症（69%）和皮疹/脱屑（64%）。替西罗莫司能有效抑制S6的磷酸化（P=0.02）。较高的pmTOR（磷酸化哺乳动物雷帕霉素靶蛋白）基线水平（P=0.01）预测更好的反应。治疗后pAKT升高（P=0.041）和pmTOR降低（P=0.048）与TTP升高相关。替西罗莫司似乎没有什么活性，不需要在晚期NEC中进行进一步的单药评价。药效学分析显示有效的mTOR通路下调。
Standard cytotoxic treatments for neuroendocrine tumours have been associated with limited activity and remarkable toxicity. A phase II study was designed to evaluate the efficacy, safety and pharmacodynamics of temsirolimus in patients with advanced neuroendocrine carcinoma (NEC). Thirty-seven patients with advanced progressive NEC received intravenous weekly doses of 25 mg of temsirolimus. Patients were evaluated for tumour response, time to progression (TTP), overall survival (OS) and adverse events (AE). Twenty-two archival specimens, as well as 13 paired tumour biopsies obtained pretreatment and after 2 weeks of temsirolimus were assessed for potential predictive and correlative markers. The intent-to-treat response rate was 5.6% (95% CI 0.6-18.7%), median TTP 6 months and 1-year OS rate 71.5%. The most frequent drug-related AE of all grades as percentage of patients were: fatigue (78%), hyperglycaemia (69%) and rash/desquamation (64%). Temsirolimus effectively inhibited the phosphorylation of S6 (P=0.02). Higher baseline levels of pmTOR (phosphorylated mammalian target of rapamycin) (P=0.01) predicted for a better response. Increases in pAKT (P=0.041) and decreases in pmTOR (P=0.048) after treatment were associated with an increased TTP. Temsirolimus appears to have little activity and does not warrant further single-agent evaluation in advanced NEC. Pharmacodynamic analysis revealed effective mTOR pathway downregulation.