KEYNOTE-022 part 3: a randomized, double-blind, phase 2 study of pembrolizumab, dabrafenib, and trametinib in BRAF-mutant melanoma.
KEYNOTE-022 part 3: a randomized, double-blind, phase 2 study of pembrolizumab, dabrafenib, and trametinib in BRAF-mutant melanoma.
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DOI：
10.1136/jitc-2020-001806
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发表时间：
2020-12
影响因子：
10.9
通讯作者：
KEYNOTE-022 international team
中科院分区：
文献类型：
--
作者：
Ferrucci PF;Di Giacomo AM;Del Vecchio M;Atkinson V;Schmidt H;Schachter J;Queirolo P;Long GV;Stephens R;Svane IM;Lotem M;Abu-Amna M;Gasal E;Ghori R;Diede SJ;Croydon ES;Ribas A;Ascierto PA;KEYNOTE-022 international team
在KEYNOTE-022研究中，与安慰剂联合达拉非尼和曲美替尼（双联）相比，帕博利珠单抗联合达拉非尼和曲美替尼（三联）改善了无进展生存期（PFS），但未达到统计学显著性。报告了PFS、缓解持续时间（DOR）和总生存期（OS）的成熟结果。KEYNOTE-022的双盲、2期部分招募了来自7个国家22个研究中心的既往未经治疗的BRAF V600 E/K突变晚期黑色素瘤患者。患者以1：1的比例随机分配至静脉注射派姆单抗（200 mg，每3周一次）或安慰剂+达拉非尼（150 mg，口服，每天两次）和曲美替尼（2 mg，口服，每天一次）。主要终点为PFS。次要终点为客观缓解率、DOR和OS。在意向治疗人群中评估疗效，并在接受至少一剂研究药物的所有患者中评估安全性。方案中未规定该分析。在2015年11月30日至2017年4月24日期间，120例患者被随机分配至三联（n=60）或双联（n=60）治疗。在36.6个月的随访中，三联体治疗的中位PFS为16.9个月（95% CI 11.3至27.9），二联体治疗为10.7个月（95% CI 7.2至16.8）（HR 0.53; 95% CI 0.34至0.83）。三联体和二联体的24个月PFS分别为41.0%（95% CI 27.4%至54.2%）和16.3%（95% CI 8.1%至27.1%）;中位DOR分别为25.1个月（95% CI 14.1至未达到）和12.1个月（95% CI 6.0至15.7）。三联治疗未达到中位OS，双联体治疗为26.3个月（HR 0.64; 95% CI 0.38 - 1.06）。三联体和二联体的24个月OS分别为63.0%（95% CI 49.4%-73.9%）和51.7%（95% CI 38.4%-63.4%）。接受三联治疗的35例患者（58%，包括1例死亡）和接受双联治疗的15例患者（25%）发生了3-5级治疗相关不良事件（TRAE）。在BRAF V600 E/K突变晚期黑色素瘤中，帕博利珠单抗联合达拉非尼和曲美替尼大幅改善了PFS、DOR和OS，同时TRAE的发生率更高。这些结果的解释受到分析的事后性质的限制。
In the KEYNOTE-022 study, pembrolizumab with dabrafenib and trametinib (triplet) improved progression-free survival (PFS) versus placebo with dabrafenib and trametinib (doublet) without reaching statistical significance. Mature results on PFS, duration of response (DOR), and overall survival (OS) are reported. The double-blind, phase 2 part of KEYNOTE-022 enrolled patients with previously untreated BRAF V600E/K-mutated advanced melanoma from 22 sites in seven countries. Patients were randomly assigned 1:1 to intravenous pembrolizumab (200 mg every 3 weeks) or placebo plus dabrafenib (150 mg orally two times per day) and trametinib (2 mg orally one time a day). Primary endpoint was PFS. Secondary endpoints were objective response rate, DOR, and OS. Efficacy was assessed in the intention-to-treat population, and safety was assessed in all patients who received at least one dose of study drug. This analysis was not specified in the protocol. Between November 30, 2015 and April 24, 2017, 120 patients were randomly assigned to triplet (n=60) or doublet (n=60) therapy. With 36.6 months of follow-up, median PFS was 16.9 months (95% CI 11.3 to 27.9) with triplet and 10.7 months (95% CI 7.2 to 16.8) with doublet (HR 0.53; 95% CI 0.34 to 0.83). With triplet and doublet, respectively, PFS at 24 months was 41.0% (95% CI 27.4% to 54.2%) and 16.3% (95% CI 8.1% to 27.1%); median DOR was 25.1 months (95% CI 14.1 to not reached) and 12.1 months (95% CI 6.0 to 15.7), respectively. Median OS was not reached with triplet and was 26.3 months with doublet (HR 0.64; 95% CI 0.38 to 1.06). With triplet and doublet, respectively, OS at 24 months was 63.0% (95% CI 49.4% to 73.9%) and 51.7% (95% CI 38.4% to 63.4%). Grade 3–5 treatment-related adverse events (TRAEs) occurred in 35 patients (58%, including one death) receiving triplet and 15 patients (25%) receiving doublet. In BRAF V600E/K-mutant advanced melanoma, pembrolizumab plus dabrafenib and trametinib substantially improved PFS, DOR, and OS with a higher incidence of TRAEs. Interpretation of these results is limited by the post hoc nature of the analysis.
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