Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label, randomised, phase 3 trial
Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label, randomised, phase 3 trial
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DOI：
10.1016/s1470-2045(17)30180-8
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发表时间：
2017-04-01
期刊：
影响因子：
51.1
通讯作者：
Flaherty, Keith
中科院分区：
文献类型：
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作者：
Dummer, Reinhard;Schadendorf, Dirk;Flaherty, Keith
背景：尽管免疫疗法已经出现，但目前还没有针对NRAS突变型黑色素瘤的既定疗法。我们的目的是评估的MEK抑制剂比尼替尼与达卡巴嗪的疗效和安全性与先进的NRAS突变melanoma.Methods患者是一个正在进行的，随机的，开放标签的3期研究在26个国家的118家医院。晚期、不可切除、美国癌症联合委员会IIIC期或IV期NRAS突变型黑色素瘤患者，既往未接受过治疗或在既往免疫治疗期间或之后进展，随机（2：1）接受binimetinib 45 mg口服每日2次或达卡巴嗪1000 mg/m2静脉注射每3周一次。随机化按分期、体能状态和既往免疫治疗分层。主要终点是在意向治疗人群中通过设盲中心审查评估的无进展生存期。在安全性人群中进行安全性分析，包括接受至少一次研究药物给药和一次基线后安全性评估的所有患者。该研究注册于ClinicalTrials.gov，编号NCT 01763164和EudraCT，编号2012-003593- 51。结果在2013年8月19日至2015年4月28日期间，402名患者入组并随机分配，269名接受比尼替尼治疗，133名接受达卡巴嗪治疗。中位随访时间为1.7个月（IQR 1.4-4.1）。Binimetinib组的中位无进展生存期为2.8个月（95%CI 2.8-3.6），达卡巴嗪组为1.5个月（1.5-1.7）（风险比0.62 [95%CI 0.47-0.80];单侧p< 0.001）。两组中至少5%的安全性人群患者发生的3-4级不良事件为肌酸磷酸激酶升高（比尼替尼组269例患者中52例[19%] vs达卡巴嗪组114例患者中无），高血压（20例[7%] vs 2例[2%]）、贫血（5例[2%] vs 6例[5%]）和中性粒细胞减少症（2例[1%] vs 10例[9%]）。严重不良事件（所有级别）发生在91（34%）比尼替尼组和25（22%）达卡巴嗪组patients.Interpretation比尼替尼改善无进展生存期与达卡巴嗪相比，是可以耐受的。比尼美替尼可能代表免疫治疗失败后NRAS突变黑色素瘤患者的一种新治疗选择。
Background There are no established therapies specific for NRAS-mutant melanoma despite the emergence of immunotherapy. We aimed to assess the efficacy and safety of the MEK inhibitor binimetinib versus that of dacarbazine in patients with advanced NRAS-mutant melanoma.Methods NEMO is an ongoing, randomised, open-label phase 3 study done at 118 hospitals in 26 countries. Patients with advanced, unresectable, American Joint Committee on Cancer stage IIIC or stage IV NRAS-mutant melanoma who were previously untreated or had progressed on or after previous immunotherapy were randomised (2: 1) to receive either binimetinib 45 mg orally twice daily or dacarbazine 1000 mg/m 2 intravenously every 3 weeks. Randomisation was stratified by stage, performance status, and previous immunotherapy. The primary endpoint was progression-free survival assessed by blinded central review in the intention-to-treat population. Safety analyses were done in the safety population, consisting of all patients who received at least one study drug dose and one post-baseline safety assessment. This study is registered with ClinicalTrials.gov, number NCT01763164 and with EudraCT, number 2012-003593-51.Findings Between Aug 19, 2013, and April 28, 2015, 402 patients were enrolled and randomly assigned, 269 to binimetinib and 133 to dacarbazine. Median follow-up was 1.7 months (IQR 1.4-4.1). Median progression-free survival was 2.8 months (95% CI 2.8-3.6) in the binimetinib group and 1.5 months (1.5-1.7) in the dacarbazine group (hazard ratio 0.62 [95% CI 0.47-0.80]; one-sided p< 0.001). Grade 3-4 adverse events seen in at least 5% of patients the safety population in either group were increased creatine phosphokinase (52 [19%] of 269 patients in the binimetinib group vs none of 114 in the dacarbazine group), hypertension (20 [7%] vs two [2%]), anaemia (five [2%] vs six [5%]), and neutropenia (two [1%] vs ten [9%]). Serious adverse events (all grades) occurred in 91 (34%) patients in the binimetinib group and 25 (22%) patients in the dacarbazine group.Interpretation Binimetinib improved progression-free survival compared with dacarbazine and was tolerable. Binimetinib might represent a new treatment option for patients with NRAS-mutant melanoma after failure of immunotherapy.