Institute Gustave Roussy, Paris, France.
Lancet Oncol. 2013 Jul;14(8):733-40. doi: 10.1016/S1470-2045(13)70237-7. Epub 2013 Jun 2.
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.
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.
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).
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.
AstraZeneca.
50%的转移性黑色素瘤患者其肿瘤存在 BRAF 突变，这些患者的预后较差。MEK1/2 抑制剂 selumetinib 在 BRAF 突变型黑色素瘤患者和临床前模型中与化疗联合应用时显示出抗肿瘤活性。本研究旨在通过比较 selumetinib 联合达卡巴嗪与单独使用达卡巴嗪来寻找疗效改善的信号。
这项双盲、随机、安慰剂对照的 2 期研究调查了 selumetinib 联合达卡巴嗪与安慰剂联合达卡巴嗪作为 18 岁以上组织学或细胞学证实的晚期 BRAF 突变性皮肤或未知原发性黑色素瘤患者的一线治疗。患者通过中央交互式语音应答系统（1:1 比例，4 个块大小）随机分配接受口服 selumetinib（75mg，每日 2 次，21 天为一个周期）或安慰剂；所有患者均接受静脉注射达卡巴嗪（1000mg/m2，21 天周期的第 1 天）。患者、研究者和研究团队对所分配的治疗方案均不知情。主要终点是通过意向治疗分析的总生存期。这项研究在 ClinicalTrials.gov 上注册，NCT00936221。
2009 年 7 月 20 日至 2010 年 4 月 8 日期间，91 例患者被随机分配接受达卡巴嗪联合 selumetinib（n=45）或安慰剂（n=46）治疗。两组的总生存期无显著差异（selumetinib 联合达卡巴嗪组的中位生存期为 13.9 个月，95%CI 10.2-15.6，安慰剂联合达卡巴嗪组为 10.5 个月，9.6-14.7；风险比[HR]0.93，95%CI 0.67-1.28，单侧 p=0.39）。然而，selumetinib 联合达卡巴嗪组的无进展生存期明显优于安慰剂联合达卡巴嗪组（HR 0.63，95%CI 0.47-0.84，单侧 p=0.021），中位无进展生存期分别为 5.6 个月（95%CI 4.9-5.9）和 3.0 个月（2.8-4.6）。最常见的不良事件包括恶心（44 例接受 selumetinib 治疗的患者中有 28 例[64%]，45 例接受安慰剂治疗的患者中有 25 例[56%]）、痤疮样皮炎（23 例[52%]，1 例[2%]）、腹泻（21 例[48%]，13 例[29%]）、呕吐（21 例[48%]，15 例[33%]）和外周水肿（19 例[43%]，3 例[7%]）。最常见的 3-4 级不良事件是中性粒细胞减少症（selumetinib 联合达卡巴嗪组 6 例[14%]，安慰剂联合达卡巴嗪组 4 例[9%]）。
selumetinib 联合达卡巴嗪在 BRAF 突变型皮肤或未知原发性黑色素瘤患者中显示出临床活性，与安慰剂联合达卡巴嗪组相比，无进展生存期显著改善，但总生存期无显著变化。这种联合治疗的耐受性通常与单药治疗的安全性一致。
阿斯利康。
