加州大学洛杉矶分校和琼森综合癌症中心Antoni Ribas研究小组取得一项新成果，他们试验了达巴芬尼、曲美替尼和派姆单抗或安慰剂治疗BRAF突变黑色素瘤。这一研究成果发表在2019年出版的国际学术期刊《Nature Medicine》上。

课题组人进行了一项随机2期试验(NCT02130466)，其中治疗初期BRAFV600E/ K突变的晚期黑色素瘤患者接受BRAF抑制剂达帕菲尼和MEK抑制剂曲美替尼以及PD -1阻断抗体派姆单抗 (三重组;n=60)或安慰剂(双重组;n = 60)。三联组无进展生存的主要终点16.0个月与双联组10.3个月相比有数值上的改善(危险比0.66;P = 0.043);然而，该试验并没有达到预期的效益，在统计上有显著的改善。中位反应持续时间为18.7个月(95%置信区间，10.122.1)和12.5个月(95%置信区间，6.014.1);据估计，59.8和27.8%的三重和双重治疗的反应持续时间超过18个月。

三联疗法和双联疗法35级治疗相关不良事件发生率分别为58.3%和26.7%，最常见的不良事件为发热、转氨酶升高和皮疹。一名接受三重治疗的病人死于肺炎。综上所述，与达帕菲尼、曲美替尼和派姆单抗的三药治疗相比，达帕菲尼、曲美替尼和安慰剂的双药治疗在无进展生存期和反应时间上更长，3/4级不良事件发生率更高。研究人员表示，程序性死亡1 (PD-1)阻断剂可增强BRAF和MEK1联合抑制诱导的抗肿瘤反应的持久性。

附：英文原文

Title: Dabrafenib, trametinib and pembrolizumab or placebo in BRAF -mutant melanoma

Author: Paolo Antonio Ascierto, Pier Francesco Ferrucci, Rosalie Fisher, Michele Del Vecchio, Victoria Atkinson, Henrik Schmidt, Jacob Schachter, Paola Queirolo, Georgina V. Long, Anna Maria Di Giacomo, Inge Marie Svane, Michal Lotem, Gil Bar-Sela, Felix Couture, Bijoyesh Mookerjee, Razi Ghori, Nageatte Ibrahim, Blanca Homet Moreno, Antoni Ribas

Issue&Volume: Volume 25 Issue 6，June 2019

Abstract: Blocking programmed death 1 (PD-1) may enhance the durability of anti-tumor responses that are induced by the combined inhibition of BRAF and MEK1. Here we performed a randomized phase 2 trial (NCT02130466), in which patients with treatment-naive BRAFV600E/K-mutant, advanced melanoma received the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib together with the PD-1-blocking antibody pembrolizumab (triplet; n=60) or placebo (doublet; n=60). The primary end point of progression-free survival was numerically improved in the triplet group16.0monthscompared with 10.3months in the doublet group (hazard ratio, 0.66; P=0.043); however, the trial did not reach the planned benefit for a statistically significant improvement. Median duration of response was 18.7months (95% confidence interval, 10.122.1) and 12.5months (95%confidence interval, 6.014.1); 59.8 and 27.8% of responses were estimated to have lasted for more than 18 months for triplet and doublet treatment, respectively. Grade 35 treatment-related adverse events occurred in 58.3 and 26.7% of patients treated with triplet and doublet therapies, respectively, which were most commonly fever, increased transaminase levels and rash. One patient who received triplet therapy died of pneumonitis. In summary, triplet therapy with dabrafenib, trametinib and pembrolizumab conferred numerically longer progression-free survival and duration of response with a higher rate of grade 3/4 adverse events compared with the doublet therapy of dabrafenib, trametinib and placebo.

DOI: 10.1038/s41591-019-0448-9

Source:https://www.nature.com/articles/s41591-019-0448-9