MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study
MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study
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DOI：
10.1016/s1470-2045(13)70024-x
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发表时间：
2013-03-01
期刊：
影响因子：
51.1
通讯作者：
Dummer, Reinhard
中科院分区：
文献类型：
--
作者：
Ascierto, Paolo A.;Schadendorf, Dirk;Dummer, Reinhard
携带Val600 BRAF突变的黑色素瘤患者可从BRAF抑制剂治疗中获益。然而，对于BRAF野生型肿瘤患者，包括NRAS突变患者，没有靶向治疗。我们的目的是评估使用MEK 162，小分子MEK 1/2抑制剂，在NRAS突变或Val600 BRAF突变的晚期melanoma. Methods患者在我们的开放标签，非随机，2期研究，我们分配NRAS突变或BRAF突变的晚期黑色素瘤患者的突变状态的基础上，三个治疗组之一。患者在欧洲和美国的大学医院或私人癌症中心入组。这三只手臂分别是：对于NRAS突变的黑色素瘤，每天两次MEK162 45 mg，对于BRAF突变的黑色素瘤，每天两次MEK162 45 mg，对于BRAF突变的黑色素瘤，每天两次MEK162 60 mg。允许既往接受BRAF抑制剂治疗，但不允许既往接受MEK抑制剂治疗。主要终点是客观缓解（即完全缓解或确认的部分缓解）的患者比例。我们报告了45 mg组的数据。我们评估了所有接受至少一剂MEK 162的患者和可评估反应的患者（有两次可用的CT扫描）的临床活性。该研究在www.example.com注册，编号NCT01320085，目前正在招募更多的NRAS突变患者（基于方案修订）。截至2012年2月29日（数据截止日期），中位随访时间为3.3个月（范围0.6 - 8.7; IQR 2.2 - 5.0）。无患者完全缓解。30例NRAS突变黑色素瘤患者中有6例（20%）有部分缓解（3例已确认），41例BRAF突变黑色素瘤患者中有8例（20%）有部分缓解（2例已确认）。最常见的不良事件是痤疮样皮炎（18例[60%] NRAS突变黑色素瘤患者和15例[37%] BRAF突变黑色素瘤患者），皮疹（6例[20%]和16例[39%]），外周水肿（10例[33%]和14例[34%]）、面部水肿（9例[30%]和7例[17%]）、腹泻（8例[27%]和15例[37%]）和肌酸磷酸激酶升高（11例[37%]和9例[22%]）。肌酸磷酸激酶升高是最常见的3 - 4级不良事件（7例[23%]和7例[17%]）。4例患者发生严重不良事件（每组2例），包括腹泻、脱水、痤疮样皮炎、全身状况恶化、心率不齐、不适和小肠穿孔。据我们所知，MEK162是第一个在NRAS突变黑色素瘤患者中显示活性的靶向治疗，可能为几乎没有有效治疗的癌症提供新的选择。
Background Patients with melanoma harbouring Val600 BRAF mutations benefit from treatment with BRAF inhibitors. However, no targeted treatments exist for patients with BRAF wild-type tumours, including those with NRAS mutations. We aimed to assess the use of MEK162, a small-molecule MEK1/2 inhibitor, in patients with NRAS-mutated or Val600 BRAF-mutated advanced melanoma.Methods In our open-label, non-randomised, phase 2 study, we assigned patients with NRAS-mutated or BRAF-mutated advanced melanoma to one of three treatment arms on the basis of mutation status. Patients were enrolled at university hospitals or private cancer centres in Europe and the USA. The three arms were: twice-daily MEK162 45 mg for NRAS-mutated melanoma, twice-daily MEK162 45 mg for BRAF-mutated melanoma, and twice-daily MEK162 60 mg for BRAF-mutated melanoma. Previous treatment with BRAF inhibitors was permitted, but previous MEK inhibitor therapy was not allowed. The primary endpoint was the proportion of patients who had an objective response (ie, a complete response or confirmed partial response). We report data for the 45 mg groups. We assessed clinical activity in all patients who received at least one dose of MEK162 and in patients assessable for response (with two available CT scans). This study is registered with ClinicalTrials.gov, number NCT01320085, and is currently recruiting additional patients with NRAS mutations (based on a protocol amendment).Findings Between March 31, 2011, and Jan 17, 2012, we enrolled 71 patients who received at least one dose of MEK162 45 mg. By Feb 29, 2012 (data cutoff), median follow-up was 3.3 months (range 0.6-8.7; IQR 2.2-5.0). No patients had a complete response. Six (20%) of 30 patients with NRAS-mutated melanoma had a partial response (three confirmed) as did eight (20%) of 41 patients with BRAF-mutated melanoma (two confirmed). The most frequent adverse events were acneiform dermatitis (18 [60%] patients with NRAS-mutated melanoma and 15 [37%] patients with the BRAF-mutated melanoma), rash (six [20%] and 16 [39%]), peripheral oedema (ten [33%] and 14 [34%]), facial oedema (nine [30%] and seven [17%]), diarrhoea (eight [27%] and 15 [37%]), and creatine phosphokinase increases (11 [37%] and nine [22%]). Increased creatine phosphokinase was the most common grade 3-4 adverse event (seven [23%] and seven [17%]). Four patients had serious adverse events (two per arm), which included diarrhoea, dehydration, acneiform dermatitis, general physical deterioration, irregular heart rate, malaise, and small intestinal perforation. No deaths occurred from treatment-related causes.Interpretation To our knowledge, MEK162 is the first targeted therapy to show activity in patients with NRAS-mutated melanoma and might off er a new option for a cancer with few effective treatments.