接受单药达布拉非尼治疗的 BRAF V600 突变型转移性黑色素瘤患者的长期结局：来自 2 期和 3 期临床试验的分析。
Long-term outcomes in patients with BRAF V600-mutant metastatic melanoma receiving dabrafenib monotherapy: Analysis from phase 2 and 3 clinical trials.
机构信息
University Hospital Schleswig-Holstein, Kiel, Germany.
Istituto Nazionale Tumori IRCCS Fondazione "G. Pascale," Naples, Italy.
出版信息
Eur J Cancer. 2020 Jan;125:114-120. doi: 10.1016/j.ejca.2019.10.033.
BACKGROUND
Previous analyses of BREAK-2 and BREAK-3 showed that durable outcomes lasting ≥3 years are achievable with dabrafenib in some patients with BRAF V600-mutant metastatic melanoma (MM); however, additional follow-up is needed to fully characterise the long-term impact of dabrafenib in these patients.
METHODS
BREAK-2 was a single-arm phase 2 study evaluating dabrafenib in treatment-naive or previously treated BRAF V600E/K-mutant MM. BREAK-3, a randomised (3:1) phase 3 study, assessed dabrafenib versus dacarbazine in previously untreated unresectable or metastatic BRAF V600E-mutant melanoma. Five-year analyses were performed.
RESULTS
All BREAK-2 patients (N = 92 [V600E, n = 76; V600K, n = 16]) discontinued treatment by the data cutoff. Median follow-up was 13.0 months. In BRAF V600E patients, 5-year progression-free survival (PFS) and overall survival (OS) were 11% and 20%, respectively. Subsequent immunotherapy was received by 22% of patients. In BREAK-3, median follow-up was 17.0 and 12.0 months in the dabrafenib (n = 187) and dacarbazine (n = 63) arms, respectively. Thirty-seven patients (59%) receiving dacarbazine crossed over to dabrafenib following disease progression as per protocol. Five-year PFS was 12% in the dabrafenib arm; all dacarbazine-arm patients progressed or were censored by 5 years. Dabrafenib improved PFS versus dacarbazine, regardless of baseline lactate dehydrogenase levels. Five-year OS rates were 24% and 22% in the dabrafenib and dacarbazine arms, respectively. Subsequent therapy in each arm included anti-CTLA-4 (dabrafenib [24%] and dacarbazine [24%]) and/or anti-PD-1 (8% and 2%) treatment. No new safety signals were observed.
CONCLUSIONS AND RELEVANCE
These data, representing extended follow-up for dabrafenib monotherapy, demonstrate that durable benefit lasting ≥5 years is achievable in a subset of patients.
TRIAL REGISTRATION
ClinicalTrials.gov (BREAK-2, NCT01153763; BREAK-3, NCT01227889).
背景
先前对 BREAK-2 和 BREAK-3 的分析表明，达拉非尼可使部分 BRAF V600 突变转移性黑色素瘤（MM）患者获得持续 ≥3 年的持久缓解；然而，仍需进一步随访以充分评估达拉非尼在这些患者中的长期影响。
方法
BREAK-2 是一项单臂、2 期研究，评估达拉非尼在初治或既往治疗的 BRAF V600E/K 突变 MM 患者中的疗效。BREAK-3 是一项随机（3:1）3 期研究，评估达拉非尼对比达卡巴嗪在初治不可切除或转移性 BRAF V600E 突变黑色素瘤患者中的疗效。本研究进行了 5 年分析。
结果
所有 BREAK-2 患者（N=92 [V600E，n=76；V600K，n=16]）均在数据截止前停止治疗。中位随访时间为 13.0 个月。在 BRAF V600E 患者中，5 年无进展生存期（PFS）和总生存期（OS）分别为 11%和 20%。随后有 22%的患者接受了免疫治疗。BREAK-3 中，达拉非尼组（n=187）和达卡巴嗪组（n=63）的中位随访时间分别为 17.0 和 12.0 个月。根据方案，37 名（59%）接受达卡巴嗪治疗的患者疾病进展后交叉至达拉非尼治疗。达拉非尼组的 5 年 PFS 为 12%；所有达卡巴嗪组患者在 5 年内均进展或失访。与达卡巴嗪相比，达拉非尼可改善 PFS，且无论基线乳酸脱氢酶水平如何。达拉非尼组和达卡巴嗪组的 5 年 OS 率分别为 24%和 22%。每个治疗组中均包括抗 CTLA-4（达拉非尼[24%]和达卡巴嗪[24%]）和/或抗 PD-1（8%和 2%）治疗。未观察到新的安全性信号。
结论和相关性
这些数据代表了达拉非尼单药治疗的扩展随访，表明在一部分患者中可获得持续 ≥5 年的持久缓解。
试验注册
ClinicalTrials.gov（BREAK-2，NCT01153763；BREAK-3，NCT01227889）。
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