Combined BRAF and MEK Inhibition versus BRAF Inhibition Alone in Melanoma
Combined BRAF and MEK Inhibition versus BRAF Inhibition Alone in Melanoma
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DOI：
10.1056/nejmoa1406037
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发表时间：
2014-11-13
影响因子：
158.5
通讯作者：
Flaherty, K.
中科院分区：
文献类型：
--
作者：
Long, G. V.;Stroyakovskiy, D.;Flaherty, K.
背景：与单独抑制BRAF相比，BRAF和MEK联合抑制可延缓BRAF V600E或V600K突变黑色素瘤患者的耐药出现并降低毒性作用。方法：在这项3期试验中，我们随机分配了423例先前未接受治疗的BRAF V600E或V600K突变的IIIC期或IV期不可切除黑色素瘤患者，接受达非尼（150mg口服，每日2次）和曲美替尼（2mg口服，每日1次）或达非尼和安慰剂的联合治疗。主要终点为无进展生存期。次要终点包括总生存期、反应率、反应持续时间和安全性。进行了预先计划的中期总生存分析。结果达非尼-曲美替尼组的中位无进展生存期为9.3个月，单药组的中位无进展生存期为8.8个月（达非尼-曲美替尼组进展或死亡的风险比为0.75；95%可信区间[CI]， 0.57 ~ 0.99; P = 0.03）。达非尼-曲美替尼组总有效率为67%，达非尼单用组为51% （P = 0.002）。6个月时，达非尼-曲美替尼组的中期总生存率为93%，单独达非尼组的中期总生存率为85%（死亡风险比为0.63；95% CI为0.42 ~ 0.94;P = 0.02）。然而，没有越过指定的疗效停止边界（双侧P = 0.00028）。两组的不良事件发生率相似，尽管达非尼-曲美替尼组发生了更多的剂量调整。达非尼-曲美替尼组皮肤鳞状细胞癌的发生率低于仅达非尼组（2%对9%），而达非尼-曲美替尼组出现发热的患者更多（51%对28%），且更严重（3级，6%对2%）。结论：与单用达非尼相比，达非尼联合曲美替尼可提高先前未经治疗的BRAF V600E或V600K突变转移性黑色素瘤患者的无进展生存率。
BACKGROUNDCombined BRAF and MEK inhibition, as compared with BRAF inhibition alone, delays the emergence of resistance and reduces toxic effects in patients who have melanoma with BRAF V600E or V600K mutations.METHODSIn this phase 3 trial, we randomly assigned 423 previously untreated patients who had unresectable stage IIIC or stage IV melanoma with a BRAF V600E or V600K mutation to receive a combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily) or dabrafenib and placebo. The primary end point was progression-free survival. Secondary end points included overall survival, response rate, response duration, and safety. A preplanned interim overall survival analysis was conducted.RESULTSThe median progression-free survival was 9.3 months in the dabrafenib-trametinib group and 8.8 months in the dabrafenib-only group (hazard ratio for progression or death in the dabrafenib-trametinib group, 0.75; 95% confidence interval [CI], 0.57 to 0.99; P = 0.03). The overall response rate was 67% in the dabrafenib-trametinib group and 51% in the dabrafenib-only group (P = 0.002). At 6 months, the interim overall survival rate was 93% with dabrafenib-trametinib and 85% with dabrafenib alone (hazard ratio for death, 0.63; 95% CI, 0.42 to 0.94; P = 0.02). However, a specified efficacy-stopping boundary (two-sided P = 0.00028) was not crossed. Rates of adverse events were similar in the two groups, although more dose modifications occurred in the dabrafenib-trametinib group. The rate of cutaneous squamous-cell carcinoma was lower in the dabrafenib-trametinib group than in the dabrafenib-only group (2% vs. 9%), whereas pyrexia occurred in more patients (51% vs. 28%) and was more often severe (grade 3, 6% vs. 2%) in the dabrafenib-trametinib group.CONCLUSIONSA combination of dabrafenib and trametinib, as compared with dabrafenib alone, improved the rate of progression-free survival in previously untreated patients who had metastatic melanoma with BRAF V600E or V600K mutations.