达拉非尼治疗 BRAF 突变型转移性黑色素瘤：一项多中心、开放标签、III 期随机对照临床试验。

Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial.

机构信息

University Hospital, Schleswig-Holstein, Department of Dermatology, Kiel, Germany.

出版信息

Lancet. 2012 Jul 28;380(9839):358-65. doi: 10.1016/S0140-6736(12)60868-X. Epub 2012 Jun 25.

DOI:10.1016/S0140-6736(12)60868-X

PMID:22735384

Abstract

BACKGROUND

Dabrafenib, an inhibitor of mutated BRAF, has clinical activity with a manageable safety profile in studies of phase 1 and 2 in patients with BRAF(V600)-mutated metastatic melanoma. We studied the efficacy of dabrafenib in patients with BRAF(V600E)-mutated metastatic melanoma.

METHODS

We enrolled patients in this open-label phase 3 trial between Dec 23, 2010, and Sept 1, 2011. This report is based on a data cutoff date of Dec 19, 2011. Patients aged 18 years or older with previously untreated, stage IV or unresectable stage III BRAF(V600E) mutation-positive melanoma were randomly assigned (3:1) to receive dabrafenib (150 mg twice daily, orally) or dacarbazine (1000 mg/m(2) intravenously every 3 weeks). Patients were stratified according to American Joint Committee on Cancer stage (unresectable III+IVM1a+IVM1b vs IVM1c). The primary endpoint was investigator-assessed progression-free survival and was analysed by intention to treat; safety was assessed per protocol. This study is registered with ClinicalTrials.gov, number NCT01227889.

FINDINGS

Of the 733 patients screened, 250 were randomly assigned to receive either dabrafenib (187 patients) or dacarbazine (63 patients). Median progression-free survival was 5·1 months for dabrafenib and 2·7 months for dacarbazine, with a hazard ratio (HR) of 0·30 (95% CI 0·18-0·51; p<0·0001). At data cutoff, 107 (57%) patients in the dabrafenib group and 14 (22%) in the dacarbazine group remained on randomised treatment. Treatment-related adverse events (grade 2 or higher) occurred in 100 (53%) of the 187 patients who received dabrafenib and in 26 (44%) of the 59 patients who received dacarbazine. The most common adverse events with dabrafenib were skin-related toxic effects, fever, fatigue, arthralgia, and headache. The most common adverse events with dacarbazine were nausea, vomiting, neutropenia, fatigue, and asthenia. Grade 3-4 adverse events were uncommon in both groups.

INTERPRETATION

Dabrafenib significantly improved progression-free survival compared with dacarbazine.

FUNDING

GlaxoSmithKline.

摘要

背景

在 BRAF(V600)-突变型转移性黑色素瘤患者的 1 期和 2 期研究中，BRAF 突变抑制剂 dabrafenib 具有临床活性，且安全性可管理。我们研究了 dabrafenib 在 BRAF(V600E)-突变型转移性黑色素瘤患者中的疗效。

方法

我们于 2010 年 12 月 23 日至 2011 年 9 月 1 日期间开展了这项开放性 3 期试验，纳入患者，并将其随机分配（3:1）接受 dabrafenib（每日两次，每次 150mg，口服）或达卡巴嗪（每 3 周静脉注射 1000mg/m2）。患者为未经治疗的 IV 期或不可切除的 III 期 BRAF(V600E)突变阳性黑色素瘤，年龄为 18 岁或以上。患者根据美国癌症联合委员会分期（不可切除的 III+IVM1a+IVM1b 与 IVM1c）进行分层。主要终点是研究者评估的无进展生存期，按意向治疗进行分析；安全性按方案评估。该研究在 ClinicalTrials.gov 注册，编号为 NCT01227889。

结果

在 733 例筛查患者中，有 250 例患者被随机分配接受 dabrafenib（187 例）或达卡巴嗪（63 例）治疗。dabrafenib 组和达卡巴嗪组的中位无进展生存期分别为 5.1 个月和 2.7 个月，风险比（HR）为 0.30（95%CI 0.18-0.51;p<0.0001）。截止数据分析时，dabrafenib 组有 107 例（57%）患者和达卡巴嗪组有 14 例（22%）患者仍在接受随机治疗。接受 dabrafenib 治疗的 187 例患者中有 100 例（53%）和接受达卡巴嗪治疗的 59 例患者中有 26 例（44%）发生治疗相关不良事件（≥2 级）。接受 dabrafenib 治疗的患者最常见的不良事件是皮肤相关的毒性作用、发热、疲劳、关节痛和头痛。接受达卡巴嗪治疗的患者最常见的不良事件是恶心、呕吐、中性粒细胞减少、疲劳和乏力。两组均少见 3-4 级不良事件。