Nivolumab in Previously Untreated Melanoma without BRAF Mutation
Nivolumab in Previously Untreated Melanoma without BRAF Mutation
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DOI：
10.1056/nejmoa1412082
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发表时间：
2015-01-22
影响因子：
158.5
通讯作者：
Ascierto, Paolo A.
中科院分区：
文献类型：
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作者：
Robert, Caroline;Long, Georgina V.;Ascierto, Paolo A.
在一项涉及易普利姆单抗难治性转移性黑色素瘤患者的3期研究中，纳武单抗的客观反应率高于化疗。nivolumab在既往未经治疗的晚期黑色素瘤患者中的应用尚未在3期对照研究中进行测试。方法我们随机分配了418名既往未经治疗的转移性黑色素瘤患者，他们没有BRAF突变，接受nivolumab治疗。（剂量为每千克体重3 mg，每2周一次，达卡巴嗪匹配安慰剂，每3周一次）或达卡巴嗪（剂量为每平方米体表面积1000 mg，每3周一次，nivolumab匹配安慰剂每2周一次）。主要终点是总生存率，1年总生存率为72.9%，（95%置信区间[CI]，65.5 - 78.9），相比之下，达卡巴嗪组（95%CI，33.0至50.9）（死亡风险比，0.42; 99.79%CI，0.25至0.73; P < 0.001）。纳武利尤单抗组的中位无进展生存期为5.1个月，而达卡巴嗪组为2.2个月（死亡或疾病进展的风险比为0.43; 95%CI为0.34至0.56; P < 0.001）。纳武利尤单抗组的客观缓解率为40.0%（95%CI，33.3至47.0），而达卡巴嗪组为13.9%（95%CI，9.5至19.4）（比值比，4.06; P < 0.001）。在预先指定的亚组中观察到纳武利尤单抗相对于达卡巴嗪的生存获益，包括根据程序性死亡配体1（PD-L1）状态定义的亚组。与纳武利尤单抗相关的常见不良事件包括疲劳、瘙痒和恶心。药物相关的3级或4级不良事件发生在11.7%的患者与nivolumab治疗和17.6%的dacarbazine.CONCLUSIONSNivolumab与总生存期和无进展生存期的显着改善，与达卡巴嗪相比，在以前未经治疗的转移性黑色素瘤患者没有BRAF突变。
BACKGROUNDNivolumab was associated with higher rates of objective response than chemotherapy in a phase 3 study involving patients with ipilimumab-refractory metastatic melanoma. The use of nivolumab in previously untreated patients with advanced melanoma has not been tested in a phase 3 controlled study.METHODSWe randomly assigned 418 previously untreated patients who had metastatic melanoma without a BRAF mutation to receive nivolumab (at a dose of 3 mg per kilogram of body weight every 2 weeks and dacarbazine-matched placebo every 3 weeks) or dacarbazine (at a dose of 1000 mg per square meter of body-surface area every 3 weeks and nivolumab-matched placebo every 2 weeks). The primary end point was overall survival.RESULTSAt 1 year, the overall rate of survival was 72.9% (95% confidence interval [CI], 65.5 to 78.9) in the nivolumab group, as compared with 42.1% (95% CI, 33.0 to 50.9) in the dacarbazine group (hazard ratio for death, 0.42; 99.79% CI, 0.25 to 0.73; P < 0.001). The median progression-free survival was 5.1 months in the nivolumab group versus 2.2 months in the dacarbazine group (hazard ratio for death or progression of disease, 0.43; 95% CI, 0.34 to 0.56; P < 0.001). The objective response rate was 40.0% (95% CI, 33.3 to 47.0) in the nivolumab group versus 13.9% (95% CI, 9.5 to 19.4) in the dacarbazine group (odds ratio, 4.06; P < 0.001). The survival benefit with nivolumab versus dacarbazine was observed across prespecified subgroups, including subgroups defined by status regarding the programmed death ligand 1 (PD-L1). Common adverse events associated with nivolumab included fatigue, pruritus, and nausea. Drug-related adverse events of grade 3 or 4 occurred in 11.7% of the patients treated with nivolumab and 17.6% of those treated with dacarbazine.CONCLUSIONSNivolumab was associated with significant improvements in overall survival and progression-free survival, as compared with dacarbazine, among previously untreated patients who had metastatic melanoma without a BRAF mutation.