Vemurafenib in patients with BRAF(V600E)-positive metastatic or unresectable papillary thyroid cancer refractory to radioactive iodine: a non-randomised, multicentre, open-label, phase 2 trial.
Vemurafenib in patients with BRAF(V600E)-positive metastatic or unresectable papillary thyroid cancer refractory to radioactive iodine: a non-randomised, multicentre, open-label, phase 2 trial.
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DOI：
10.1016/s1470-2045(16)30166-8
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发表时间：
2016-09
期刊：
影响因子：
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通讯作者：
Sherman EJ
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文献类型：
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作者：
Brose MS;Cabanillas ME;Cohen EE;Wirth LJ;Riehl T;Yue H;Sherman SI;Sherman EJ
大约一半的甲状腺乳头状癌患者患有BRAFV 600 E突变。Vemurafenib是一种被批准用于BRAF阳性黑色素瘤的致癌BRAF激酶抑制剂，在1期试验中在3例BRAFV 600 E阳性乳头状甲状腺癌患者中显示出临床获益。我们的目的是确定vemurafenib在BRAFV 600 E阳性甲状腺乳头状癌患者中的活性。我们在全球10个学术中心和医院进行了一项开放标签、非随机、II期试验，患者年龄≥ 18岁，经组织学证实为放射性碘难治性复发性或转移性甲状腺乳头状癌，BRAFV 600 E突变阳性。参与者从未接受过靶向VEGFR的多激酶抑制剂（队列1）或既往接受过VEGFR多激酶抑制剂治疗（队列2）。患者接受维罗非尼960 mg口服，每日两次。主要终点是队列1中的评估者评估的最佳总体缓解（在间隔4周或更长时间的两次评估中确认）。分析计划至少进行15个月的中位随访（数据截止日期为2014年4月18日），并在安全性、意向治疗和符合方案人群中进行。本试验已关闭，并在ClinicalTrials.gov上注册，编号为NCT 01286753。2011年6月23日至2013年1月15日期间，51例患者入组研究，队列1中26例，队列2中25例。队列1的中位随访时间为18.8个月（IQR 14.2 - 26.0），队列2为12.0个月（6.7 - 20.3）。队列1的26例患者中有10例记录到部分缓解（最佳总体缓解率为38.5%，95% CI 20.2 - 59.4）。队列1中26例患者中的17例（65%）和队列2中25例患者中的17例（68%）记录了3级或4级不良事件;最常见的3级和4级不良事件是皮肤鳞状细胞癌（队列1中7例[27% ]，队列2中5例[20% ]）、淋巴细胞减少症（每个队列中2例[8% ]）和γ-谷氨酰转移酶升高（队列1中1例[4% ]，队列2中3例[12% ]）。队列2中有2例患者死于不良事件，1例死于呼吸困难，1例死于多器官衰竭，但均与治疗无关。队列1中26例患者中的16例（62%）和队列2中25例患者中的17例（68%）报告了严重不良事件。Vemurafenib在从未接受过多激酶抑制剂治疗的放射性碘难治性进行性BRAFV 600 E阳性甲状腺乳头状癌患者中显示出抗肿瘤活性。因此，这种药物代表了这些患者的潜在新治疗选择。
About half of patients with papillary thyroid cancer have tumours with activating BRAFV600E mutations. Vemurafenib, an oncogenic BRAF kinase inhibitor approved for BRAF-positive melanoma, showed clinical benefit in three patients with BRAFV600E-positive papillary thyroid cancer in a phase 1 trial. We aimed to establish the activity of vemurafenib in patients with BRAFV600E-positive papillary thyroid cancer. We did an open-label, non-randomised, phase 2 trial at ten academic centres and hospitals worldwide in patients aged 18 years or older with histologically confirmed recurrent or metastatic papillary thyroid cancer refractory to radioactive iodine and positive for the BRAFV600E mutation. Participants either had never received a multikinase inhibitor targeting VEGFR (cohort 1) or had been treated previously with a VEGFR multikinase inhibitor (cohort 2). Patients received vemurafenib 960 mg orally twice daily. The primary endpoint was investigator-assessed best overall response in cohort 1 (confirmed on two assessments 4 weeks or longer apart). Analyses were planned to have a minimum median follow-up of 15 months (data cutoff April 18, 2014) and were done in safety, intention-to-treat, and per-protocol populations. This trial is closed and is registered at ClinicalTrials.gov, number NCT01286753. Between June 23, 2011, and Jan 15, 2013, 51 patients were enrolled to the study, 26 in cohort 1 and 25 in cohort 2. Median duration of follow-up was 18·8 months (IQR 14·2–26·0) in cohort 1 and 12·0 months (6·7–20·3) in cohort 2. Partial responses were recorded in ten of 26 patients in cohort 1 (best overall response 38·5%, 95% CI 20·2–59·4). Grade 3 or 4 adverse events were recorded in 17 (65%) of 26 patients in cohort 1 and 17 (68%) of 25 patients in cohort 2; the most common grade 3 and 4 adverse events were squamous cell carcinoma of the skin (seven [27% ] in cohort 1, five [20% ] in cohort 2), lymphopenia (two [8% ] in each cohort), and increased γ-glutamyltransferase (one [4% ] in cohort 1, three [12% ] in cohort 2). Two individuals in cohort 2 died due to adverse events, one from dyspnoea and one from multiorgan failure, but neither was treatment related. Serious adverse events were reported for 16 (62%) of 26 patients in cohort 1 and 17 (68%) of 25 patients in cohort 2. Vemurafenib showed antitumour activity in patients with progressive, BRAFV600E-positive papillary thyroid cancer refractory to radioactive iodine who had never been treated with a multikinase inhibitor. As such, this agent represents a potential new treatment option for these patients.