Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial.
Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial.
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DOI：
10.1016/s0140-6736(14)60421-9
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发表时间：
2014-07-26
期刊：
影响因子：
168.9
通讯作者：
Schlumberger, Martin J.
中科院分区：
文献类型：
--
作者：
Brose, Marcia S.;Nutting, Christopher M.;Jarzab, Barbara;Elisei, Rossella;Siena, Salvatore;Bastholt, Lars;de la Fouchardiere, Christelle;Pacini, Furio;Paschke, Ralf;Shong, Young Kee;Sherman, Steven I.;Smit, Johannes W. A.;Chung, John;Kappeler, Christian;Pena, Carol;Molnar, Istvan;Schlumberger, Martin J.
放射性碘（131 I，RAI）难治性局部晚期或转移性分化型甲状腺癌（DTC）患者由于缺乏有效的治疗选择，预后不良。这项多中心、随机（1：1）、双盲、安慰剂对照、III期研究（DECISION; NCT 00984282）在过去14个月内进展的RAI难治性局部晚期或转移性DTC患者中研究了索拉非尼（400 mg，口服，每日两次）。主要终点为中心独立审核的无进展生存期（PFS）。接受安慰剂治疗的患者可在进展时交叉至开放标签索拉非尼治疗。检查存档肿瘤组织的BRAF和RAS突变。在基线和每次访视时测量血清甲状腺球蛋白。共有417例患者随机分配至索拉非尼组（n=207）或安慰剂组（n=210）。与安慰剂相比，索拉非尼治疗显著改善了PFS（风险比，0.59; 95%置信区间，0.45 - 0.76; P<0.0001;中位数分别为10.8个月和5.8个月）。在所有预先指定的临床和遗传生物标志物亚组中均观察到PFS改善，无论突变状态如何。总生存期无统计学显著差异（风险比，0.80; 95%置信区间，0.54 - 1.19; P= 0.14）;尚未达到中位总生存期，150名（71%）接受安慰剂的患者在进展后交叉使用索拉非尼。应答率（全部部分应答）为12.2%（24/196;索拉非尼）和0.5%（1/201;安慰剂; p<0.0001）。安慰剂组中位甲状腺球蛋白水平升高，索拉非尼组中位甲状腺球蛋白水平降低，然后降低治疗反应。大多数不良事件为1级或2级。索拉非尼组最常见的治疗后出现的不良事件为手足皮肤反应（76.3%）、腹泻（68.6%）、脱发（67.1%）和皮疹/脱屑（50.2%）。与安慰剂相比，索拉非尼显著改善了进展性RAI难治性DTC患者的PFS。不良事件与已知的索拉非尼安全性特征一致。这些结果表明，索拉非尼代表了一种新的治疗选择，患者进行性RAI难治性DTC。
Patients with radioactive iodine (131I, RAI)-refractory locally advanced or metastatic differentiated thyroid cancer (DTC) have a poor prognosis due to the lack of effective treatment options. This multicentre, randomized (1:1), double-blind, placebo-controlled, phase 3 study (DECISION; NCT00984282) investigated sorafenib (400 mg orally twice-daily) in patients with RAI-refractory locally advanced or metastatic DTC progressing within the past 14 months. The primary endpoint was progression-free survival (PFS) by central independent review. Patients receiving placebo could crossover to open-label sorafenib upon progression. Archival tumour tissue was examined for BRAF and RAS mutations. Serum thyroglobulin was measured at baseline and each visit. A total of 417 patients were randomized to sorafenib (n=207) or placebo (n=210). Sorafenib treatment significantly improved PFS compared with placebo (hazard ratio, 0·59; 95% confidence interval, 0·45–0·76; P<0·0001; median 10·8 vs. 5·8 months, respectively). PFS improvement was seen in all pre-specified clinical and genetic biomarker subgroups irrespective of mutation status. There was no statistically significant difference in overall survival (hazard ratio, 0·80; 95% confidence interval, 0·54–1·19; P=0·14); median overall survival had not been reached and 150 (71%) patients receiving placebo crossed over to sorafenib upon progression. Response rates (all partial responses) were 12·2% (24/196; sorafenib) and 0·5% (1/201; placebo; p<0·0001). Median thyroglobulin levels increased in the placebo group, and decreased, then paralleled treatment responses in the sorafenib group. Most adverse events were grade 1 or 2. The most common treatment-emergent adverse events in the sorafenib arm were hand–foot skin reaction (76·3%), diarrhoea (68·6%), alopecia (67·1%), and rash/desquamation (50·2%). Sorafenib significantly improved PFS compared with placebo in patients with progressive RAI-refractory DTC. Adverse events were consistent with the known sorafenib safety profile. These results suggest that sorafenib represents a new treatment option for patients with progressive RAI-refractory DTC.