Background: Combination BRAF inhibitor (BRAFi) and MEK inhibitor (MEKi) therapy is a widely accepted treatment option for patients (pts) with BRAF-V600E mutant melanoma. Although effective, these combinations exhibit high rates of adverse events (AEs), with 44% - 66% requiring dose modification or interruption and up to 26% discontinuing due to AEs in the adjuvant setting. Enhanced tolerance to BRAFi/MEKi is expected to improve pts quality of life and potentially enhance clinical outcomes. Clinicians at Roswell Park Comprehensive Cancer Center (RPCCC) have implemented a dose escalation regimen upon initiation of BRAFi/MEKi in efforts to enhance the tolerance of these combinations for pts with BRAF-V600E mutant melanoma in the adjuvant and advanced setting. Here we present a retrospective analysis of the toxicity profiles and outcomes associated with this “ramp-up” approach. Methods: Pts presenting to RPCCC in Buffalo, NY for management of stage III or IV melanoma harboring BRAF-V600E mutations were retrospectively observed from 1/2012 to 12/2020. Pts starting BRAFi/MEKi combinations, regardless of prior lines of therapy, were included unless concurrently receiving immune checkpoint inhibition. The “ramp-up” regimen involves a 25% dose of BRAFi and 50% dose of MEKi, which is gradually increased over 4 weekly intervals until full dose is achieved. Pts started on full-dose BRAFi/MEKi were included as a comparison arm. Observations included 1) demographics, 2) treatment regimens and disruptions, 3) rate and severity of AEs, 4) outcomes including best overall response rates (ORR), progression-free survival (PFS) and overall survival (OS). Results: A total of 88 pts were analyzed (21 and 35 receiving “ramp-up” BRAFi/MEKi in the adjuvant and advanced (unresectable stage III or stage IV) setting, respectively, and 32 received full-dose (non-ramp-up) BRAFi/MEKi in the advanced setting). Demographics were similar except pts in the “ramp-up” cohorts were higher in average age (62.0 vs 56.0, p = 0.032) than pts starting at full-dose. Pts receiving adjuvant BRAFi/MEKi at “ramp-up” dosing exhibited a 4.8% (n = 1) rate of grade 3 or higher (Gr3+) AEs and 33.3% (n = 7) AE-related discontinuation rate (9.9 month average time to discontinuation). In the advanced setting, “ramp-up” vs full-dose treated pts exhibited Gr3+ AE rates of 25.7% (n = 9) vs 43.8% (n = 14; p = 0.197) and AE-related discontinuation rates of 34.4% (n = 12) vs 40.6% (n = 13; p = 0.592), respectively. Trends in overall AEs, ORR, PFS, and OS were similar to historical observations across all groups. Conclusions: This real-world analysis suggests that “ramp-up” incremental dosing of BRAFi/MEKi for pts with melanoma in the adjuvant and advanced setting may improve the tolerance and toxicity profiles of these agents without compromising their clinical efficacy, and may be of particular utility in pts with advanced age.