Phase II Trial (BREAK-2) of the BRAF Inhibitor Dabrafenib (GSK2118436) in Patients With Metastatic Melanoma
Phase II Trial (BREAK-2) of the BRAF Inhibitor Dabrafenib (GSK2118436) in Patients With Metastatic Melanoma
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DOI：
10.1200/jco.2013.49.8691
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发表时间：
2013-09-10
影响因子：
45.3
通讯作者：
Trefzer, Uwe
中科院分区：
文献类型：
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作者：
Ascierto, Paolo A.;Minor, David;Trefzer, Uwe
目的达拉非尼（Dabrafenib，GSK 2118436）是一种突变型BRAF激酶的有效抑制剂。我们的多中心、单臂、II期研究评估了达拉非尼在BRAF（V600 E/K）突变阳性转移性黑色素瘤（mut（+）MM）中的安全性和临床活性。患者和方法组织学证实的IV期BRAF（V600 E/K）mut（+）MM患者接受口服达拉非尼150 mg每日两次，直至疾病进展、死亡或不可接受的不良事件（AE）。主要终点是BRAF（V600 E）mut（+）MM患者中评估者评估的总体缓解率。次要终点包括无进展生存期（PFS）和总生存期（OS）。探索性目标包括肿瘤特异性循环无细胞DNA（cfDNA）和肿瘤组织之间的BRAF突变状态的比较，cfDNA作为临床outcome.Results76例BRAF（V600 E）和16例BRAF（V600 K）突变（+）MM患者的预测因子的评价入组研究。在BRAF（V600 E）组中，45例患者（59%）确认缓解（95% CI，48.2 - 70.3），包括5例完全缓解患者（7%）。2例BRAF（V600 K）mut（+）MM患者（13%）确认部分缓解（95% CI，0 - 28.7）。在BRAF（V600 E）和BRAF（V600 K）组中，中位PFS分别为6.3个月和4.5个月，中位OS分别为13.1个月和12.9个月。最常见的AE为关节痛（33%）、角化过度（27%）和发热（24%）。总体而言，25例患者（27%）发生严重AE，9例患者（10%）发生鳞状细胞癌。结论达拉非尼治疗BRAF（V600 E）/K mut（+）MM患者耐受性好，临床疗效显著，cfDNA可作为BRAF（V600 E）/K mut（+）MM患者预后和疗效的指标。(C)2013年美国临床肿瘤学会
PurposeDabrafenib (GSK2118436) is a potent inhibitor of mutated BRAF kinase. Our multicenter, single-arm, phase II study assessed the safety and clinical activity of dabrafenib in BRAF(V600E/K) mutation-positive metastatic melanoma (mut(+) MM).Patients and MethodsHistologically confirmed patients with stage IV BRAF(V600E/K) mut(+) MM received oral dabrafenib 150 mg twice daily until disease progression, death, or unacceptable adverse events (AEs). The primary end point was investigator-assessed overall response rate in BRAF(V600E) mut(+) MM patients. Secondary end points included progression-free survival (PFS) and overall survival (OS). Exploratory objectives included the comparison of BRAF mutation status between tumor-specific circulating cell-free DNA (cfDNA) and tumor tissue, and the evaluation of cfDNA as a predictor of clinical outcome.ResultsSeventy-six patients with BRAF(V600E) and 16 patients with BRAF(V600K) mut(+) MM were enrolled onto the study. In the BRAF(V600E) group, 45 patients (59%) had a confirmed response (95% CI, 48.2 to 70.3), including five patients (7%) with complete responses. Two patients (13%) with BRAF(V600K) mut(+) MM had a confirmed partial response (95% CI, 0 to 28.7). In the BRAF(V600E) and BRAF(V600K) groups, median PFS was 6.3 months and 4.5 months, and median OS was 13.1 months and 12.9 months, respectively. The most common AEs were arthralgia (33%), hyperkeratosis (27%), and pyrexia (24%). Overall, 25 patients (27%) experienced a serious AE and nine patients (10%) had squamous cell carcinoma. Baseline cfDNA levels predicted response rate and PFS in BRAF(V600E) mut(+) MM patients.ConclusionDabrafenib was well tolerated and clinically active in patients with BRAF(V600E)/K mut(+) MM. cfDNA may be a useful prognostic and response marker in future studies. (C) 2013 by American Society of Clinical Oncology