Background: Standard MAPK-targeted therapy (tx) for pts with BRAF MT MM involves combined BRAF and MEK inhibition with high efficacy in advanced melanoma, but durability of response is limited by acquired resistance. One combination, dabrafenib and trametinib (DT), was shown to be less effective in the frontline setting than combined immune checkpoint inhibition (ICI) but did achieve a 48% objective response rate (ORR) after ICI. (Atkins et al., JCO 2022) Preclinical data show that targeting mediators of apoptosis improves response and survival with BRAF-targeted tx. Navitoclax (N) is a BH3-mimetic that inhibits BCL-2, BCL-xL, and BCL-W. We previously demonstrated the safety of DTN in patients with BRAF MT solid tumors in a phase I trial. This randomized phase II study compared DTN to DT. (NCT01989585). Methods: Pts with BRAF MT MM were randomized 1:1 to either DT (standard dosing D 150 mg BID and T 2 mg QD) or DTN (standard DT plus N 225 mg QD) and stratified by maximal tumor burden (RECIST 1.1 sum of diameter of target lesions ≥ 100 mm or < 100 mm). The target sample size was 50 evaluable pts (25 per arm). Prior ICI, but not prior BRAF targeted therapy, was permitted. The co-primary endpoints were to estimate complete response (CR) rate for DTN compared to historic controls and to assess maximal tumor shrinkage of pts treated with DTN vs DT. Secondary endpoints included ORR, progression-free survival (PFS) and overall survival (OS). Results: Fifty-six pts were enrolled and 50 treated (25 DTN, 25 DT) from 1/11/19 – 3/25/22 at 13 sites. Seventeen pts (68%) in each arm received prior ICI. The ORR was 84% for DTN and 80% for DT. The CR rate for DTN was 20% and 15% for DT; this met pre-specified criteria for success of the primary CR endpoint. There was no difference in the maximal tumor shrinkage in pts treated with DTN vs DT. With median follow up of 25.9 months (mo), there was a trend for improved OS with DTN vs DT (median 36 vs 25 mo, log-rank p = 0.07). In the stratification cohort of 37 pts (74%) with smaller baseline tumor burden, there was a statistically significant improvement in OS among pts receiving DTN (log-rank p = 0.05), with two-year estimates of OS of 78% (95% CI: 0.46 to 0.93) for DTN and 57% (95% CI: 0.29 to 0.77) for DT. There was no difference in PFS between the two groups. The most common treatment-related toxicities ( > 50% of pts) were nausea (36), diarrhea (31), fatigue (30), fever (28), and vomiting (27), which were not different in pts treated with DTN vs DT. Conclusions: In pts with BRAF MT MM, DTN was associated with a CR rate of 20% and ORR of 84%. There was a trend for improved OS in pts treated with DTN compared to DT; the difference in OS was significant in pts with smaller tumor burden. The DTN regimen may be considered for further exploration in the post-ICI setting. Updated data on survival and translational studies will be presented. Clinical trial information: NCT01989585.