Brose Marcia S, Cabanillas Maria E, Cohen Ezra E W, Wirth Lori J, Riehl Todd, Yue Huibin, Sherman Steven I, Sherman Eric J
Department of Otorhinolaryngology: Head and Neck Surgery, and Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Lancet Oncol. 2016 Sep;17(9):1272-82. doi: 10.1016/S1470-2045(16)30166-8. Epub 2016 Jul 23.
About half of patients with papillary thyroid cancer have tumours with activating BRAF(V600E) mutations. Vemurafenib, an oncogenic BRAF kinase inhibitor approved for BRAF-positive melanoma, showed clinical benefit in three patients with BRAF(V600E)-positive papillary thyroid cancer in a phase 1 trial. We aimed to establish the activity of vemurafenib in patients with BRAF(V600E)-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 BRAF(V600E) 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, BRAF(V600E)-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.
F Hoffmann-La Roche.
约半数甲状腺乳头状癌患者的肿瘤存在激活型BRAF（V600E）突变。维莫非尼是一种已被批准用于BRAF阳性黑色素瘤的致癌性BRAF激酶抑制剂，在一项1期试验中，3例BRAF（V600E）阳性甲状腺乳头状癌患者显示出临床获益。我们旨在确定维莫非尼对BRAF（V600E）阳性甲状腺乳头状癌患者的疗效。
我们在全球10个学术中心和医院开展了一项开放标签、非随机的2期试验，纳入年龄在18岁及以上、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且BRAF（V600E）突变阳性的患者。参与者要么从未接受过靶向VEGFR的多激酶抑制剂治疗（队列1），要么曾接受过VEGFR多激酶抑制剂治疗（队列2）。患者口服维莫非尼960mg，每日两次。主要终点是队列1中研究者评估的最佳总体缓解（在相隔4周或更长时间的两次评估中得到确认）。计划分析的最短中位随访时间为15个月（数据截止于2014年4月18日），并在安全性、意向性治疗和符合方案人群中进行分析。该试验已结束，在ClinicalTrials.gov注册，编号为NCT01286753。
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有26例，队列2有25例。队列1的中位随访时间为18.8个月（四分位间距14.2 - 26.0），队列
