DOC-MEK：多西他赛联合或不联合塞来替尼治疗野生型 BRAF 晚期黑色素瘤的双盲随机 II 期试验。

DOC-MEK: a double-blind randomized phase II trial of docetaxel with or without selumetinib in wild-type BRAF advanced melanoma.

机构信息

Department of Oncology, Oxford University Hospitals NHS Trust, Oxford.

出版信息

Ann Oncol. 2014 May;25(5):968-74. doi: 10.1093/annonc/mdu054. Epub 2014 Feb 24.

DOI:10.1093/annonc/mdu054

PMID:24567366

Abstract

BACKGROUND

Treatment options for wild-type BRAF melanoma patients remain limited. Selumetinib, a MEK 1/2 inhibitor, suppresses pERK levels independent of BRAF and NRAS mutation status, and combination with docetaxel has demonstrated synergy in xenograft models. The aim of this study was to assess the efficacy and safety of selumetinib plus docetaxel as first-line treatment in patients with wild-type BRAF advanced melanoma.

PATIENTS AND METHODS

In this double-blind multicentre phase II trial patients with wild-type BRAF melanoma were randomized (1:1) to docetaxel with selumetinib or placebo. Docetaxel 75 mg/m(2) was administered intravenously every 3 weeks up to six cycles. Selumetinib 75 mg or placebo was given orally twice daily until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS). Tumour NRAS mutation status was analysed retrospectively and correlated with treatment outcomes.

RESULTS

Eighty-three patients were randomized to docetaxel plus selumetinib (n = 41) or docetaxel plus placebo (n = 42). The PFS hazard ratio (HR) (selumetinib:placebo) was 0.75 [90% confidence interval (CI) 0.50-1.14; P = 0.130], with a median PFS of 4.23 months (90% CI 3.63-6.90) for docetaxel plus selumetinib and 3.93 months (90% CI 2.07-4.16) for docetaxel alone. There was no significant difference in overall survival. The objective response rate was 32% with selumetinib versus 14% with placebo (P = 0.059). In a retrospective subset analysis, NRAS mutation status did not affect significantly upon clinical outcomes in either arm. The combination of docetaxel and selumetinib could be administered effectively to patients with metastatic melanoma, although the combination was less well tolerated than docetaxel alone.

CONCLUSIONS

The combination of docetaxel with selumetinib showed no significant improvement in PFS compared with docetaxel alone, although more patients showed a response to combination therapy. We found no evidence to support using tumour NRAS mutation as a basis for selecting patients for combined MEK inhibitor and chemotherapy.

CLINICAL TRIAL

DOC-MEK (EudraCT no: 2009-018153-23).

摘要

背景

野生型 BRAF 黑色素瘤患者的治疗选择仍然有限。Selumetinib，一种 MEK1/2 抑制剂，可抑制 pERK 水平，与 BRAF 和 NRAS 突变状态无关，与多西紫杉醇联合使用在异种移植模型中显示出协同作用。本研究旨在评估 selumetinib 联合多西紫杉醇作为野生型 BRAF 晚期黑色素瘤患者一线治疗的疗效和安全性。

患者和方法

在这项双盲多中心 II 期试验中，野生型 BRAF 黑色素瘤患者按 1:1 随机分为多西紫杉醇联合 selumetinib 或安慰剂组。多西紫杉醇 75mg/m2 静脉滴注，每 3 周一次，最多 6 个周期。Selumetinib 75mg 或安慰剂每天口服两次，直到疾病进展或不可接受的毒性。主要终点是无进展生存期（PFS）。回顾性分析肿瘤 NRAS 突变状态，并与治疗结果相关联。

结果

83 例患者随机分为多西紫杉醇联合 selumetinib（n=41）或多西紫杉醇联合安慰剂（n=42）组。PFS 风险比（HR）（selumetinib：安慰剂）为 0.75[90%置信区间（CI）0.50-1.14；P=0.130]，多西紫杉醇联合 selumetinib 的中位 PFS 为 4.23 个月（90%CI 3.63-6.90），多西紫杉醇单药治疗为 3.93 个月（90%CI 2.07-4.16）。总生存期无显著差异。Selumetinib 的客观缓解率为 32%，安慰剂为 14%（P=0.059）。在回顾性亚组分析中，NRAS 突变状态在两个治疗组的临床结局中均无显著影响。多西紫杉醇联合 selumetinib 可有效用于转移性黑色素瘤患者，但联合治疗的耐受性较单药多西紫杉醇差。