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》。
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
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.