Abstract CT013: SWOG S1320: Improved progression-free survival with continuous compared to intermittent dosing with dabrafenib and trametinib in patients with BRAF mutated melanoma

Abstract

Abstract Background: BRAF and MEK inhibitors yield objective responses in the majority of BRAFV600E/K mutant melanoma patients, but acquired resistance limits response durations. Preclinical data suggests that intermittent dosing of these agents may delay acquired resistance by deselecting tumor cells that grow optimally in the presence of these agents. S1320 is a randomized phase 2 clinical trial designed to determine whether intermittent versus continuous dosing of dabrafenib and trametinib improves progression-free survival (PFS) in patients with advanced BRAFV600E/K melanoma. Methods: All patients received continuous dabrafenib and trametinib for 8-weeks after which non-progressing patients were randomized to receive either continuous treatment or intermittent dosing of both drugs on a 3-week-off, 5-week-on schedule. Unscheduled treatment interruptions of both drugs for > 14 days were not permitted. Responses were assessed using RECIST v1.1 at 8-week intervals scheduled to coincide with on-treatment periods for patients on the intermittent dosing arm. Adverse events were assessed using CTCAE v4 monthly. The design assumed exponential PFS with a median of 9.4 months using continuous dosing, 206 eligible patients and 156 PFS events. It had 90% power with a two-sided α = 0.2 to detect a change to a median with an a priori hypothesis that intermittent dosing would improve the median PFS to 14.1 months using a Cox model stratified by the randomization stratification factors. Results: 242 patients were treated and 206 patients without disease progression after 8 weeks were randomized, 105 to continuous and 101 to intermittent treatment. 70% of patients had not previously received immune checkpoint inhibitors. There were no significant differences between groups in terms of baseline patient characteristics. The median PFS was statistically significantly longer, 9.0 months from randomization, with continuous dosing vs. 5.5 months from randomization with intermittent dosing (p = 0.064). There was no difference in overall survival between groups (median OS = 29.2 months in both arms p = 0.93) at a median follow up of 2 years. 77% of patient treated continuously discontinued treatment due to disease progression vs. 84% treated intermittently (p = 0.34). Conclusions: Continuous dosing with the BRAF and MEK inhibitors dabrafenib and trametinib yields superior PFS compared with intermittent dosing. Support: NIH/NCI grants CA180888, CA180819, CA180820 Citation Format: Alain Algazi, Megan Othus, Adil Daud, Roger Lo, Janice Mehnert, Thach-Giao Truong, Robert Conry, Kari Kendra, Gary Doolittle, Joseph I. Clark, Michael Messino, Dennis F. Moore, Christopher Lao, Bryan A. Faller, Rangaswamy Govindarajan, Amy Harker-Murray, Luke Dreisbach, James Moon, Kenneth Grossman, Antoni Ribas. SWOG S1320: Improved progression-free survival with continuous compared to intermittent dosing with dabrafenib and trametinib in patients with BRAF mutated melanoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT013.