Selumetinib plus dacarbazine versus placebo plus dacarbazine as first-line treatment for BRAF-mutant metastatic melanoma: a phase 2 double-blind randomised study
Selumetinib plus dacarbazine versus placebo plus dacarbazine as first-line treatment for BRAF-mutant metastatic melanoma: a phase 2 double-blind randomised study
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DOI：
10.1016/s1470-2045(13)70237-7
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发表时间：
2013-07-01
期刊：
影响因子：
51.1
通讯作者：
Middleton, Mark R.
中科院分区：
文献类型：
--
作者：
Robert, Caroline;Dummer, Reinhard;Middleton, Mark R.
背景转移性黑色素瘤患者，50%的肿瘤携带BRAF突变，预后不良。Selumetinib是一种MEK 1/2抑制剂，在BRAF突变型黑色素瘤患者和临床前模型中与化疗联合使用时显示出抗肿瘤活性。本研究的目的是寻找改善疗效的信号，通过比较组合的司美替尼和达卡巴嗪与dacarbazine.Methods这双盲，随机，安慰剂对照的2期研究调查司美替尼+达卡巴嗪与安慰剂+达卡巴嗪作为一线治疗的患者年龄大于18岁，组织学或细胞学证实的晚期BRAF突变皮肤或未知的原发性黑色素瘤。通过中央交互式语音应答系统（1：1比例，区组大小4）将患者随机分配到口服司美替尼（75 mg，每日两次，21天为一个周期）或安慰剂组;所有患者均接受静脉注射达卡巴嗪（1000 mg/m2，21天为一个周期的第1天）。患者、研究者和研究团队均对分配的治疗设盲。主要终点是通过意向治疗分析的总生存率。该研究在ClinicalTrials.gov注册，NCT 00936221。结果在2009年7月20日至2010年4月8日期间，91名患者被随机分配接受达卡巴嗪联合司美替尼（n=45）或安慰剂（n=46）。两组的总生存期无显著差异（司美替尼+达卡巴嗪组的中位生存期为13.9个月，80% CI 10.2-15.6，安慰剂+达卡巴嗪组为10.5个月，9.6-14.7;风险比[HR] 0.93，80% CI 0.67-1.28，单侧p=0.39）。然而，司美替尼+达卡巴嗪组与安慰剂+达卡巴嗪组相比，无进展生存期显著改善（HR 0.63，80% CI 0.47-0.84，单侧p=0.021），中位时间分别为5.6个月（80% CI 4.9-5.9）和3.0个月（2.8-4.6）。最常见的不良反应包括恶心（司美替尼组28/44例[64%] vs安慰剂组25/45例[56%]），痤疮样皮炎（23例[52%] vs 1例[2%]）、腹泻（21例[48%] vs 13例[29%]）、呕吐（21例[48%] vs 15例[33%]）和外周水肿（19例[43%] vs 3例[7%]）。最常见的3-4级不良事件是中性粒细胞减少症（司美替尼加达卡巴嗪组中的六名[14%]患者对安慰剂加达卡巴嗪组中的四名[9%]患者）。解释司美替尼加达卡巴嗪在患有BRAF突变皮肤或未知原发性黑素瘤的患者中显示临床活性，反映为与安慰剂加达卡巴嗪组相比在无进展生存期方面的显著益处，尽管没有注意到总存活率的显著变化。该联合治疗的耐受性通常与单药治疗的安全性特征一致。
Background Patients with metastatic melanoma, 50% of whose tumours harbour a BRAF mutation, have a poor prognosis. Selumetinib, a MEK1/2 inhibitor, has shown antitumour activity in patients with BRAF-mutant melanoma and in preclinical models when combined with chemotherapy. This study was designed to look for a signal of improved efficacy by comparing the combination of selumetinib and dacarbazine with dacarbazine alone.Methods This double-blind, randomised, placebo-controlled phase 2 study investigated selumetinib plus dacarbazine versus placebo plus dacarbazine as first-line treatment in patients older than 18 years with histologically or cytologically confirmed advanced BRAF-mutant cutaneous or unknown primary melanoma. Patients were randomly assigned by central interactive voice response system (1:1 ratio, block size four) to take either oral selumetinib (75 mg twice daily in a 21-day cycle) or placebo; all patients received intravenous dacarbazine (1000 mg/m(2) on day 1 of a 21-day cycle). Patients, investigators, and the study team were masked to the treatment assigned. The primary endpoint was overall survival analysed by intention to treat. This study is registered at ClinicalTrials.gov, NCT00936221.Findings Between July 20, 2009, and April 8, 2010, 91 patients were randomly assigned to receive dacarbazine in combination with selumetinib (n=45) or placebo (n=46). Overall survival did not differ significantly between groups (median 13.9 months, 80% CI 10.2-15.6, in the selumetinib plus dacarbazine group and 10.5 months, 9.6-14.7, in the placebo plus dacarbazine group; hazard ratio [HR] 0.93, 80% CI 0.67-1.28, one-sided p=0.39). However, progression-free survival was significantly improved in the selumetinib plus dacarbazine group versus the placebo plus dacarbazine group (HR 0.63, 80% CI 0.47-0.84, one-sided p=0.021), with a median of 5.6 months (80% CI 4.9-5.9) versus 3.0 months (2.8-4.6), respectively. The most frequent adverse events included nausea (28 [64%] of 44 patients on selumetinib vs 25 [56%] of 45 on placebo), acneiform dermatitis (23 [52%] vs one [2%]), diarrhoea (21 [48%] vs 13 [29%]), vomiting (21 [48%] vs 15 [33%]), and peripheral oedema (19 [43%] vs three [7%]). The most common grade 3-4 adverse event was neutropenia (six [14%] patients in the selumetinib plus dacarbazine group vs four [9%] in the placebo plus dacarbazine group).Interpretation Selumetinib plus dacarbazine showed clinical activity in patients with BRAF-mutant cutaneous or unknown primary melanoma, reflected by a significant benefit in progression-free survival compared with placebo plus dacarbazine group, although no significant change in overall survival was noted. The tolerability of this combination was generally consistent with monotherapy safety profiles.