Dabrafenib plus trametinib in patients with BRAFV600E-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm, multicentre basket trial
Dabrafenib plus trametinib in patients with BRAFV600E-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm, multicentre basket trial
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DOI：
10.1016/s1470-2045(20)30321-1
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发表时间：
2020-09-01
期刊：
影响因子：
51.1
通讯作者：
Wainberg, Zev A.
中科院分区：
文献类型：
--
作者：
Subbiah, Vivek;Lassen, Ulrik;Wainberg, Zev A.
背景：吉西他滨为主的化疗进展后胆管癌患者急需有效的治疗方法。在5%的胆道肿瘤中发现了BRAF基因的突变。达普拉非尼和曲美替尼的组合在几种BRAFV(600e)突变的癌症中显示出活性。我们的目的是评估达普拉非尼和曲美替尼联合治疗BRAF(V600E)突变胆道癌患者的活性和安全性。方法这项研究是正在进行的针对BRAF(V600E)突变罕见癌症患者的开放标签、单臂、多中心、罕见肿瘤学不可知性研究(ROAR)篮子试验的一部分。如果患者年龄在18岁或以上，患有BRAF(V600E)突变、无法切除、转移、局部晚期或复发的胆道癌，东部合作肿瘤组的表现状态为0-2，并曾接受过系统治疗，则有资格参加胆道癌队列。所有患者均口服达普拉非尼150 mg，每日2次，曲美替尼2 mg，每日1次，直至病情进展或治疗不耐受。主要终点是总体应答率，这是由意向治疗可评估人群中实体肿瘤版本1.1中的反应评估标准确定的，该标准包括所有登记的患者，无论他们接受的治疗是可评估的(即，病情进展、开始新的抗癌治疗、撤回同意、死亡、病情稳定6周或更长时间、或有两次或更多基线后评估)。Roar试验在ClinicalTrials.gov注册，NCT02034110。这些结果是基于一项中期分析；这项研究是积极的，但不是招募。2014年3月12日至2018年7月18日的发现，43名BRAFV600E突变的胆道癌患者进入了这项研究，并可进行评估。中位随访时间为10个月(IQR6-15)。43名患者中有22名(51%，95%可信区间36-67)获得了研究者评估的总体反应。43名患者中有20名(47%，95%可信区间31-62)获得了独立的评价者评估的总体反应。最常见的3级或更严重的不良事件是5例(12%)患者的伽马-谷氨酰转移酶升高。17例(40%)患者发生严重不良事件，9例(21%)发生与治疗相关的严重不良事件，其中最常见的是发热(8例[19%])。没有与治疗相关的死亡报告。释义达普拉非尼联合曲美替尼治疗BRAF(V600E)突变胆道癌患者显示出良好的疗效，且安全性可控。胆道癌患者应考虑常规检测BRAF(V600E)突变。版权所有(C)2020爱思唯尔有限公司。保留所有权利。
Background Effective treatments for patients with cholangiocarcinoma after progression on gemcitabine-based chemotherapy are urgently needed. Mutations in the BRAF gene have been found in 5% of biliary tract tumours. The combination of dabrafenib and trametinib has shown activity in several BRAFV(600E)-mutated cancers. We aimed to assess the activity and safety of dabrafenib and trametinib combination therapy in patients with BRAFV600E-mutated biliary tract cancer.Methods This study is part of an ongoing, phase 2, open-label, single-arm, multicentre, Rare Oncology Agnostic Research (ROAR) basket trial in patients with BRAF(V600E)-mutated rare cancers. Patients were eligible for the biliary tract cancer cohort if they were aged 18 years or older, had BRAF(V600E)-mutated, unresectable, metastatic, locally advanced, or recurrent biliary tract cancer, an Eastern Cooperative Oncology Group performance status of 0-2, and had received previous systemic treatment. All patients were treated with oral dabrafenib 150 mg twice daily and oral trametinib 2 mg once daily until disease progression or intolerance of treatment. The primary endpoint was the overall response rate, which was determined by Response Evaluation Criteria in Solid Tumors version 1.1 in the intention-to-treat evaluable population, which comprised all enrolled patients regardless of receiving treatment who were evaluable (ie, had progression, began a new anticancer treatment, withdrew consent, died, had stable disease for 6 weeks or longer, or had two or more post-baseline assessments). The ROAR trial is registered with ClinicalTrials.gov, NCT02034110. These results are based on an interim analysis; the study is active but not recruiting.Findings Between March 12, 2014, and July 18, 2018, 43 patients with BRAFV600E-mutated biliary tract cancer were enrolled to the study and were evaluable. Median follow-up was 10 months (IQR 6-15). An investigator-assessed overall response was achieved by 22 (51%, 95% CI 36-67) of 43 patients. An independent reviewer-assessed overall response was achieved by 20 (47%, 95% CI 31-62) of 43 patients. The most common grade 3 or worse adverse event was increased gamma-glutamyltransferase in five (12%) patients. 17 (40%) patients had serious adverse events and nine (21%) had treatment-related serious adverse events, the most frequent of which was pyrexia (eight [19%]). No treatment-related deaths were reported.Interpretation Dabrafenib plus trametinib combination treatment showed promising activity in patients with BRAF(V600E)-mutated biliary tract cancer, with a manageable safety profile. Routine testing for BRAF(V600E) mutations should be considered in patients with biliary tract cancer. Copyright (C) 2020 Elsevier Ltd. All rights reserved.