Discontinuation of BRAF/MEK inhibitor therapy after long-lasting response: Clinical outcomes in advanced melanoma

Background BRAF and MEK inhibitors (BRAFi/MEKi) induce high response rates and rapid tumor regression in BRAF-mutated metastatic melanoma. While responses last around 12 months, ≈ 24 % of patients in clinical trials achieve progression-free survival (PFS) beyond 3 years. The impact of discontinuing therapy after long-lasting responses remains incompletely characterized. Methods We conducted a retrospective nationwide cohort study using the Danish Metastatic Melanoma Database (DAMMED), to include patients with metastatic melanoma treated with BRAFi/MEKi for ≥ 2 years from 2014 to 2022. Survival outcomes were assessed using Kaplan-Meier analyses and the log-rank test. Results 1367 patients initiated treatment with BRAFi/MEKi, 97 received therapy ≥ 2 years, and 37 patients discontinued treatment in the absence of disease progression between 2 and 3.5 years from treatment initiation. Among patients who discontinued, median overall survival was 125 months and median PFS post-discontinuation 14 months. After median follow-up of 49 months post-discontinuation, 24 of 37 patients (65 %) progressed, with 67 % who progressed within 12 months. Of those who progressed, 19 were reinduced with BRAFi/MEKi, achieving a 79 % response rate; mPFS post-reinduction was 25 months (median follow-up 29.4 months). Conclusion In this nationwide real-world cohort of patients with melanoma receiving prolonged BRAFi/MEKi treatment, a notable proportion of patients who discontinued treatment without progression became long-term survivors. Progression after discontinuation typically occurred within the first year, with BRAFi/MEKi-reinduction being highly effective. Treatment discontinuation could be a viable strategy for selected patients, provided close follow-up and prompt reinitiation upon progression. Identifying clinical or molecular features predictive of sustained tumor control remains essential.