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BRAF突变黑色素瘤患者连续或间歇性抑制BRAF和MEK的2期随机试验
作者:小柯机器人 发布时间:2020/10/11 21:23:24

美国加州大学旧金山分校Alain P. Algazi等研究人员完成BRAF突变黑色素瘤患者连续或间歇性抑制BRAF和MEK的2期随机试验。相关论文于2020年10月5日在线发表于国际学术期刊《自然—医学》。

研究人员进行了S1320(一项随机开放标签2期临床试验(NCT02196181)),以评估BRAF抑制剂dabrafenib和MEK抑制剂曲美替尼的间歇给药是否能改善转移性和不可切除BRAFV600黑色素瘤患者的无进展生存期。在全国68个学术和社区站点中招募了患者。所有患者均在8周的引入期内接受了连续的dabrafenib和曲美替尼治疗,之后,非进展性肿瘤患者被随机分配为连续或间歇用药,疗程为3周和5周。该试验已经完成累积,将206名基线特征相似的患者按1:1比例随机分配到两个研究组(105例为连续给药,101例为间歇给药)。
 
与间歇给药相比,连续给药在随机化后无进展生存率方面具有统计学上的显著改善(中位9.0个月对5.5个月,P = 0.064,预先指定的双面α= 0.2)。因此,与最初的假设相反,间歇给药不能改善患者的无进展生存期。两组之间的次级结局无差异,包括总体生存率和与治疗相关的毒性反应的总体发生率。
 
据悉,临床前模型表明,在黑色素瘤中阻断致癌BRAFV600时,间歇性BRAF抑制剂治疗可能会延迟获得性耐药。
 
附:英文原文

Title: Continuous versus intermittent BRAF and MEK inhibition in patients with BRAF -mutated melanoma: a randomized phase 2 trial

Author: Alain P. Algazi, Megan Othus, Adil I. Daud, Roger S. Lo, Janice M. Mehnert, Thach-Giao Truong, Robert Conry, Kari Kendra, Gary C. Doolittle, Joseph I. Clark, Michael J. Messino, Dennis F. Moore, Christopher Lao, Bryan A. Faller, Rangaswamy Govindarajan, Amy Harker-Murray, Luke Dreisbach, James Moon, Kenneth F. Grossmann, Antoni Ribas

Issue&Volume: 2020-10-05

Abstract: Preclinical modeling suggests that intermittent BRAF inhibitor therapy may delay acquired resistance when blocking oncogenic BRAFV600 in melanoma1,2. We conducted S1320, a randomized, open-label, phase 2 clinical trial (NCT02196181) evaluating whether intermittent dosing of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib improves progression-free survival in patients with metastatic and unresectable BRAFV600 melanoma. Patients were enrolled at 68 academic and community sites nationally. All patients received continuous dabrafenib and trametinib during an 8-week lead-in period, after which patients with non-progressing tumors were randomized to either continuous or intermittent dosing of both drugs on a 3-week-off, 5-week-on schedule. The trial has completed accrual and 206 patients with similar baseline characteristics were randomized 1:1 to the two study arms (105 to continuous dosing, 101 to intermittent dosing). Continuous dosing yielded a statistically significant improvement in post-randomization progression-free survival compared with intermittent dosing (median 9.0 months versus 5.5 months, P = 0.064, pre-specified two-sided α = 0.2). Therefore, contrary to the initial hypothesis, intermittent dosing did not improve progression-free survival in patients. There were no differences in the secondary outcomes, including overall survival and the overall incidence of treatment-associated toxicity, between the two groups. The randomized phase 2 trial S1320 comparing different dosing schedules of BRAF/MEK inhibitor combination in BRAF-mutated advanced melanoma shows intermittent therapy does not result in superior progression-free survival in patients.

DOI: 10.1038/s41591-020-1060-8

Source: https://www.nature.com/articles/s41591-020-1060-8

期刊信息

Nature Medicine:《自然—医学》,创刊于1995年。隶属于施普林格·自然出版集团,最新IF:30.641
官方网址:https://www.nature.com/nm/
投稿链接:https://mts-nmed.nature.com/cgi-bin/main.plex