Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial
Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial
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DOI：
10.1016/s0140-6736(15)60898-4
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发表时间：
2015-08-01
期刊：
影响因子：
168.9
通讯作者：
Flaherty, Keith
中科院分区：
文献类型：
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作者：
Long, Georgina V.;Stroyakovskiy, Daniil;Flaherty, Keith
背景之前，我们的一项研究表明，与达普拉非尼和安慰剂相比，达普拉非尼和曲美替尼联合应用可提高BRAF Val600Lys/Glu突变阳性转移性黑色素瘤患者的无进展生存率。这项研究继续评估总体生存的次要终点，我们在这篇文章中报道了这一点。方法我们在14个国家的113个地点进行了这项双盲阶段3研究。我们招募了以前未经治疗的BRAF Val600Glu或Val600Lys突变阳性、无法切除的IIIC期或IV期黑色素瘤患者。参与者被计算机随机(1：1)接受达普拉非尼(每天两次口服150毫克)和曲美替尼(每天一次2毫克)的组合，或者达普拉非尼和安慰剂的组合。主要终点是无进展存活率，总体存活率是次要终点。这项研究在ClinicalTrials.gov注册，编号NCT01584648。在2012年5月4日至2012年11月30日期间，我们筛选了947名患者，其中423人被随机分配接受达普拉非尼和曲美替尼治疗(n=211)或仅接受达普拉非尼治疗(n=212)。最终的数据截止日期是2015年1月12日，当时已有222名患者死亡。达普拉非尼组和曲美替尼组的中位总生存期为25.1月(95%CI19.2-未达到)，而单用组为18.7个月(15.2-23.7)(风险比[HR]0.71，95%CI0.55-0.92；p=0.0107)。达普拉非尼组和曲美替尼组1年和2年总存活率分别为74%和51%，而单用达普拉非尼组分别为68%和42%。达普拉非尼组和曲美替尼组的中位无进展生存期分别为11.0个月(95%可信区间8.0-13.9)和8.8个月(5.9-9.3)(HR0.67，95%可信区间0.53-0.84；p=0.0004；未经多次试验调整)。在服用达普拉非尼和曲美替尼的209名患者中，有181人(87%)发生了与治疗相关的不良事件，在服用达普拉非尼的211名患者中，有189人(90%)发生了与治疗相关的不良事件；最常见的是达普拉非尼和曲美替尼组的发热(108名患者，52%)和角化过度症(70名患者，33%)。达普拉非尼和曲美替尼组有67名患者(32%)发生了3级或4级的不良事件，单用组有66名患者(31%)发生了3级或4级不良事件。总体存活率的改善使达普拉非尼和曲美替尼联合治疗BRAF Val600突变阳性黑色素瘤成为标准的靶向治疗。评估达普拉非尼和曲美替尼与免疫疗法相结合的研究正在进行中。
Background Previously, a study of ours showed that the combination of dabrafenib and trametinib improves progression-free survival compared with dabrafenib and placebo in patients with BRAF Val600Lys/Glu mutation-positive metastatic melanoma. The study was continued to assess the secondary endpoint of overall survival, which we report in this Article.Methods We did this double-blind phase 3 study at 113 sites in 14 countries. We enrolled previously untreated patients with BRAF Val600Glu or Val600Lys mutation-positive unresectable stage IIIC or stage IV melanoma. Participants were computer-randomised (1:1) to receive a combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily), or dabrafenib and placebo. The primary endpoint was progression-free survival and overall survival was a secondary endpoint. This study is registered with ClinicalTrials.gov, number NCT01584648.Findings Between May 4, 2012, and Nov 30, 2012, we screened 947 patients for eligibility, of whom 423 were randomly assigned to receive dabrafenib and trametinib (n=211) or dabrafenib only (n=212). The final data cutoff was Jan 12, 2015, at which time 222 patients had died. Median overall survival was 25.1 months (95% CI 19.2-not reached) in the dabrafenib and trametinib group versus 18.7 months (15.2-23.7) in the dabrafenib only group (hazard ratio [HR] 0.71, 95% CI 0.55-0.92; p=0.0107). Overall survival was 74% at 1 year and 51% at 2 years in the dabrafenib and trametinib group versus 68% and 42%, respectively, in the dabrafenib only group. Based on 301 events, median progression-free survival was 11.0 months (95% CI 8.0-13.9) in the dabrafenib and trametinib group and 8.8 months (5.9-9.3) in the dabrafenib only group (HR 0.67, 95% CI 0.53-0.84; p=0.0004; unadjusted for multiple testing). Treatment-related adverse events occurred in 181 (87%) of 209 patients in the dabrafenib and trametinib group and 189 (90%) of 211 patients in the dabrafenib only group; the most common was pyrexia (108 patients, 52%) in the dabrafenib and trametinib group, and hyperkeratosis (70 patients, 33%) in the dabrafenib only group. Grade 3 or 4 adverse events occurred in 67 (32%) patients in the dabrafenib and trametinib group and 66 (31%) patients in the dabrafenib only group.Interpretation The improvement in overall survival establishes the combination of dabrafenib and trametinib as the standard targeted treatment for BRAF Val600 mutation-positive melanoma. Studies assessing dabrafenib and trametinib in combination with immunotherapies are ongoing.