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, Peña Carol, Molnár István, Schlumberger Martin J
Department of Otorhinolaryngology: Head and Neck Surgery, and Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA, USA.
Royal Marsden Hospital, London, UK.
Lancet. 2014 Jul 26;384(9940):319-28. doi: 10.1016/S0140-6736(14)60421-9. Epub 2014 Apr 24.
Patients with radioactive iodine ((131)I)-refractory locally advanced or metastatic differentiated thyroid cancer have a poor prognosis because of the absence of effective treatment options. In this study, we assessed the efficacy and safety of orally administered sorafenib in the treatment of patients with this type of cancer.
In this multicentre, randomised, double-blind, placebo-controlled, phase 3 trial (DECISION), we investigated sorafenib (400 mg orally twice daily) in patients with radioactive iodine-refractory locally advanced or metastatic differentiated thyroid cancer that had progressed within the past 14 months. Adult patients (≥18 years of age) with this type of cancer were enrolled from 77 centres in 18 countries. To be eligible for inclusion, participants had to have at least one measurable lesion by CT or MRI according to Response Evaluation Criteria In Solid Tumors (RECIST); Eastern Cooperative Oncology Group performance status 0-2; adequate bone marrow, liver, and renal function; and serum thyroid-stimulating hormone concentration lower than 0·5 mIU/L. An interactive voice response system was used to randomly allocate participants in a 1:1 ratio to either sorafenib or matching placebo. Patients, investigators, and the study sponsor were masked to treatment assignment. The primary endpoint was progression-free survival, assessed every 8 weeks by central independent review. Analysis was by intention to treat. Patients in the placebo group could cross over to open-label sorafenib upon disease progression. Archival tumour tissue was examined for BRAF and RAS mutations, and serum thyroglobulin was measured at baseline and at each visit. This study is registered with ClinicalTrials.gov, number NCT00984282, and with the EU Clinical Trials Register, number EudraCT 2009-012007-25.
Patients were randomly allocated on a 1:1 basis to sorafenib or placebo. The intention-to-treat population comprised 417 patients (207 in the sorafenib group and 210 in the placebo group) and the safety population was 416 patients (207 in the sorafenib group and 209 in the placebo group). Median progression-free survival was significantly longer in the sorafenib group (10·8 months) than in the placebo group (5·8 months; hazard ratio [HR] 0·59, 95% CI 0·45-0·76; p<0·0001). Progression-free survival improved in all prespecified clinical and genetic biomarker subgroups, irrespective of mutation status. Adverse events occurred in 204 of 207 (98·6%) patients receiving sorafenib during the double-blind period and in 183 of 209 (87·6%) patients receiving placebo. Most adverse events were grade 1 or 2. The most frequent treatment-emergent adverse events in the sorafenib group were hand-foot skin reaction (76·3%), diarrhoea (68·6%), alopecia (67·1%), and rash or desquamation (50·2%).
Sorafenib significantly improved progression-free survival compared with placebo in patients with progressive radioactive iodine-refractory differentiated thyroid cancer. Adverse events were consistent with the known safety profile of sorafenib. These results suggest that sorafenib is a new treatment option for patients with progressive radioactive iodine-refractory differentiated thyroid cancer.
Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals (an Amgen subsidiary).
放射性碘（¹³¹I）难治性局部晚期或转移性分化型甲状腺癌患者因缺乏有效的治疗选择，预后较差。在本研究中，我们评估了口服索拉非尼治疗这类癌症患者的疗效和安全性。
在这项多中心、随机、双盲、安慰剂对照的3期试验（DECISION）中，我们研究了索拉非尼（每日口服两次，每次400 mg）用于治疗在过去14个月内病情进展的放射性碘难治性局部晚期或转移性分化型甲状腺癌患者。18个国家的77个中心招募了患有这类癌症的成年患者（≥18岁）。根据实体瘤疗效评价标准（RECIST），参与者必须有至少一个可通过CT或MRI测量的病灶；东部肿瘤协作组体能状态为0 - 2；骨髓、肝脏和肾功能良好；血清促甲状腺激素浓度低于0.5 mIU/L，才有资格入选。使用交互式语音应答系统以1:1的比例将参与者随机分配至索拉非尼组或匹配的安慰剂组。患者、研究者和研究申办者均对治疗分配不知情。主要终点是无进展生存期，每8周由中心独立审查进行评估。分析采用意向性分析。安慰剂组的患者在疾病进展时可交叉接受开放标签的索拉非尼治疗。对存档肿瘤组织检测BRAF和RAS突变，并在基线和每次访视时测量血清甲状腺球蛋白。本研究已在ClinicalTrials.gov注册，编号为NCT00984282，在欧盟临床试验注册中心注册编号为EudraCT 2009 - 012007 - 25。
患者按1:1的比例随机分配至索拉非尼组或安慰剂组。意向性分析人群包括417例患者（索拉非尼组207例，安慰剂组210例），安全性分析人群为416例患者（索拉非尼组207例，安慰剂组209例）。索拉非尼组的中位无进展生存期（10.8个月）显著长于安慰剂组（5.8个月；风险比[HR] 为0.59，95% CI为0.45 - 0.76；p < 0.0001）。在所有预先设定的临床和基因生物标志物亚组中，无论突变状态如何，无进展生存期均有所改善。在双盲期，接受索拉非尼治疗的207例患者中有204例（98.6%）发生不良事件，接受安慰剂治疗的209例患者中有183例（87.6%）发生不良事件。大多数不良事件为1级或2级。索拉非尼组最常见的治疗中出现的不良事件为手足皮肤反应（76.3%）、腹泻（68.6%）、脱发（67.1%）以及皮疹或脱屑（50.2%）。
与安慰剂相比，索拉非尼显著改善了放射性碘难治性进展期分化型甲状腺癌患者的无进展生存期。不良事件与索拉非尼已知的安全性特征相符。这些结果表明，索拉非尼是放射性碘难治性进展期分化型甲状腺癌患者的一种新的治疗选择。
拜耳医疗保健制药公司和安进公司旗下的Onyx制药公司。
