Roswell Park Cancer Institute, Buffalo, New York.
University of California, Los Angeles.
JAMA Oncol. 2020 Aug 1;6(8):1256-1264. doi: 10.1001/jamaoncol.2020.2288.
The optimal sequencing of immune checkpoint inhibitors and targeted therapy for BRAF V600E/K-mutant melanoma is not well established.
To assess the association of BRAF wild-type (WT) or BRAF V600E/K-mutant status and BRAF inhibitor (BRAFi) with or without MEK inhibitor (MEKi) therapy with response to pembrolizumab.
DESIGN, SETTING, AND PARTICIPANTS: This study is a post hoc subgroup analysis of pooled data from 3 multinational, multisite studies: KEYNOTE-001 (data cutoff September 1, 2017), KEYNOTE-002 (data cutoff May 30, 2018), and KEYNOTE-006 (data cutoff December 4, 2017). Patients included in this analysis were adults with advanced melanoma and known BRAF V600E/K tumor status who had received pembrolizumab.
Patients received pembrolizumab in dosages of 2 mg/kg every 3 weeks, 10 mg/kg every 2 weeks, or 10 mg/kg every 3 weeks.
End points were objective response rate (ORR) and progression-free survival (PFS) assessed by Response Evaluation Criteria in Solid Tumors, version 1.1, and overall survival (OS). Objective response rates, 4-year PFS, and OS rates were compared in the following patient subgroups: BRAF WT vs BRAF V600E/K-mutant melanoma and BRAF V600E/K-mutant melanoma with vs without previous treatment with BRAFi with or without MEKi therapy.
The overall study population (N = 1558) included 944 men (60.6%) and 614 women (39.4%). The mean (SD) age was 60.0 years (14.0). The ORR was 38.3% (596/1558), 4-year PFS rate was 22.0%, and 4-year OS rate was 36.9%. For patients with BRAF WT (n = 1124) and BRAF V600E/K-mutant melanoma (n = 434), ORR was 39.8% (n = 447) and 34.3% (n = 149), 4-year PFS rate was 22.9% and 19.8%, and 4-year OS rate was 37.5% and 35.1%, respectively. Patients with BRAF V600E/K-mutant melanoma who had (n = 271) vs had not (n = 163) previously received BRAFi with or without MEKi therapy had baseline characteristics with worse prognosis; ORR was 28.4% (n = 77) and 44.2% (n = 72), 4-year PFS rate was 15.2% and 27.8%, and 4-year OS rate was 26.9% and 49.3%, respectively.
Results of this subgroup analysis support the use of pembrolizumab for treatment of advanced melanoma regardless of BRAF V600E/K mutation status or receipt of prior BRAFi with or without MEKi therapy.
BRAF V600E/K 突变型黑色素瘤的免疫检查点抑制剂和靶向治疗的最佳序贯治疗尚未得到很好的确定。
评估 BRAF 野生型（WT）或 BRAF V600E/K 突变状态以及 BRAF 抑制剂（BRAFi）联合或不联合 MEK 抑制剂（MEKi）治疗与 pembrolizumab 应答的相关性。
设计、地点和参与者：这是来自 3 项多中心、多地点研究的汇总数据的事后亚组分析：KEYNOTE-001（数据截止日期 2017 年 9 月 1 日）、KEYNOTE-002（数据截止日期 2018 年 5 月 30 日）和 KEYNOTE-006（数据截止日期 2017 年 12 月 4 日）。本分析纳入的患者为接受 pembrolizumab 治疗的晚期黑色素瘤且已知 BRAF V600E/K 肿瘤状态的成年人。
患者接受 pembrolizumab 治疗，剂量分别为 2 mg/kg 每 3 周、10 mg/kg 每 2 周或 10 mg/kg 每 3 周。
终点为根据实体瘤反应评价标准，第 1.1 版评估的客观缓解率（ORR）和无进展生存期（PFS）以及总生存期（OS）。在以下患者亚组中比较了客观缓解率、4 年 PFS 和 OS 率：BRAF WT 与 BRAF V600E/K 突变型黑色素瘤以及 BRAF V600E/K 突变型黑色素瘤伴或不伴先前接受 BRAFi 联合或不联合 MEKi 治疗。
总体研究人群（N=1558）包括 944 名男性（60.6%）和 614 名女性（39.4%）。平均（SD）年龄为 60.0 岁（14.0）。ORR 为 38.3%（596/1558），4 年 PFS 率为 22.0%，4 年 OS 率为 36.9%。对于 BRAF WT（n=1124）和 BRAF V600E/K 突变型黑色素瘤（n=434）患者，ORR 分别为 39.8%（n=447）和 34.3%（n=149），4 年 PFS 率分别为 22.9%和 19.8%，4 年 OS 率分别为 37.5%和 35.1%。先前接受过 BRAFi 联合或不联合 MEKi 治疗（n=271）和未接受过（n=163）的 BRAF V600E/K 突变型黑色素瘤患者具有预后较差的基线特征；ORR 分别为 28.4%（n=77）和 44.2%（n=72），4 年 PFS 率分别为 15.2%和 27.8%，4 年 OS 率分别为 26.9%和 49.3%。
这项亚组分析的结果支持使用 pembrolizumab 治疗晚期黑色素瘤，无论 BRAF V600E/K 突变状态或先前是否接受过 BRAFi 联合或不联合 MEKi 治疗。
