Department of Dermatology, University of Essen, Essen Department of Dermatology, University of Würzburg, Würzburg
Department of Dermatology, University of Mainz, Mainz.
Ann Oncol. 2015 Mar;26(3):573-82. doi: 10.1093/annonc/mdu573. Epub 2014 Dec 18.
Kinase inhibitors targeting the BRAF V600 mutation have become standard in the treatment of metastatic melanoma. Albeit in wide clinical use, the patterns associated with therapy outcome are not fully elucidated. The present study was aimed to identify predictive factors of therapy response and survival under the BRAF inhibitor vemurafenib.
This multicenter retrospective study analyzed patient, tumor, and pretreatment characteristics collected in BRAF V600-mutated stage IV melanoma patients before single-agent therapy with the BRAF inhibitor vemurafenib.
A total of 300 patients from 14 centers were included into this study with a median follow-up time of 13.0 months. Median progression-free survival (PFS) was 5.1 months; median overall survival (OS) was 7.6 months. Best response under vemurafenib was associated with serum lactate dehydrogenase (LDH; ≤ versus >upper normal limit; P = 0.0000001), Eastern Cooperative Oncology Group (ECOG) overall performance status (OPS) (0 versus ≥ 1; P = 0.00089), and BRAF mutation subtype (V600E versus V600K; P = 0.016). Multivariate analysis identified ECOG OPS ≥ 1 [hazard ratio (HR) = 1.88; P = 0.00005], immunotherapy pretreatment (HR = 0.53; P = 0.0067), elevated serum LDH (HR = 1.45; P = 0.012), age >55 years (HR = 0.72; P = 0.019), and chemotherapy pretreatment (HR = 1.39; P = 0.036) as independent predictors of PFS. For OS, elevated serum LDH (HR = 1.99; P = 0.00012), ECOG OPS ≥ 1 (HR = 1.90; P = 0.00063), age >55 years (HR = 0.65; P = 0.011), kinase inhibitor pretreatment (HR = 1.86; P = 0.014), immunotherapy pretreatment (HR = 0.57; P = 0.025), chemotherapy pretreatment (HR = 2.17; P = 0.039), and male gender (HR = 0.70; 95% confidence interval 0.50-0.98; P = 0.039) were found as predictors.
Our data demonstrate that the type of pretreatment strongly influences the outcome of vemurafenib therapy, with a precedent immunotherapy showing a positive, and a prior chemotherapy and kinase inhibitors showing a negative impact on survival, respectively. Moreover, we show that the patient's OPS, serum LDH, age, and gender independently impact vemurafenib therapy outcome. These findings should be taken into account for the future design of therapy sequencing in BRAF V600 mutation-positive melanoma patients.
针对 BRAF V600 突变的激酶抑制剂已成为转移性黑色素瘤治疗的标准方法。尽管在广泛的临床应用中，但与治疗结果相关的模式尚未完全阐明。本研究旨在确定 BRAF 抑制剂 vemurafenib 治疗下的治疗反应和生存的预测因素。
这项多中心回顾性研究分析了在 BRAF V600 突变的 IV 期黑色素瘤患者接受 BRAF 抑制剂 vemurafenib 单药治疗之前收集的患者、肿瘤和预处理特征。
本研究共纳入了来自 14 个中心的 300 例患者，中位随访时间为 13.0 个月。中位无进展生存期（PFS）为 5.1 个月；中位总生存期（OS）为 7.6 个月。vemurafenib 治疗的最佳反应与血清乳酸脱氢酶（LDH；≤与>正常上限；P = 0.0000001）、东部合作肿瘤学组（ECOG）总体表现状态（OPS）（0 与≥1；P = 0.00089）和 BRAF 突变亚型（V600E 与 V600K；P = 0.016）有关。多变量分析确定 ECOG OPS ≥ 1 [风险比（HR）= 1.88；P = 0.00005]、免疫治疗预处理（HR = 0.53；P = 0.0067）、血清 LDH 升高（HR = 1.45；P = 0.012）、年龄>55 岁（HR = 0.72；P = 0.019）和化疗预处理（HR = 1.39；P = 0.036）是 PFS 的独立预测因素。对于 OS，血清 LDH 升高（HR = 1.99；P = 0.00012）、ECOG OPS ≥ 1（HR = 1.90；P = 0.00063）、年龄>55 岁（HR = 0.65；P = 0.011）、激酶抑制剂预处理（HR = 1.86；P = 0.014）、免疫治疗预处理（HR = 0.57；P = 0.025）、化疗预处理（HR = 2.17；P = 0.039）和男性（HR = 0.70；95%置信区间 0.50-0.98；P = 0.039）是生存的预测因素。
我们的数据表明，预处理的类型强烈影响 vemurafenib 治疗的结果，先前的免疫治疗显示出积极的影响，而先前的化疗和激酶抑制剂则显示出对生存的负面影响。此外，我们表明患者的 OPS、血清 LDH、年龄和性别独立影响 vemurafenib 治疗结果。这些发现应在未来 BRAF V600 突变阳性黑色素瘤患者的治疗方案设计中加以考虑。
