9529 Background: The mitogen-activated protein kinase (MAPK) pathway can be activated by alternative driver mutations in BRAFV600/ NRASQ61R/K/L wild-type (wt) melanoma. MEK-inhibitor monotherapy has activity in BRAFV600/ NRASQ61R/K/L wt melanoma, but is associated with considerate skin toxicity. Skin toxicity associated with the MEK-inhibitor trametinib (T) can be effectively mitigated by adding a low dose (50 mg BID) of the BRAF-inhibitor dabrafenib (LD-D) (Awada et al. Ann Oncol 2020). Methods: This two-stage, single-center phase 2 trial investigated T 2 mg QD in patients (pts) with advanced BRAFV600/ NRASQ61R/K/L wt melanoma who previously progressed on treatment with checkpoint inhibitors. In case of dose-limiting T-related skin toxicity, LD-D (50 mg BID) was added to T (pre-amend). The trial was amended in June 2019 to administer T upfront with LD-D (post-amend). Objective response rate (ORR, by RECIST v1.1) served as the primary endpoint. A Simon’s two-stage optimal design was used (p0 0.10; p1 0.30; alpha 0.05; power 0.80): in case of > 1 OR in the first 10 pts, 19 additional pts would be included in stage 2. The trial is considered positive if > 5 OR are observed. Results: As of February 9, 2021, 16 pts (3 pre-amend; 13 post-amend) were included (median age 56.5; male 56.3%; stage IIIB 6.3%, IV-M1a-c 68.8%, IV-M1d 25.0%; ECOG performance status 0-1 93.8%; normal lactate dehydrogenase 56.3%). Median duration of follow-up is 17.9 weeks (wks; range 1.9-90.1). The ORR in 14 evaluable pts is 42.9% (5 confirmed and 1 unconfirmed partial response), the disease control rate is 71.4%. Four OR are ongoing after a median follow-up of 8.0 wks (range 0.0-77.0), 2 responding pts progressed on therapy after respectively 16.6 and 24.0 wks. Four out of 6 OR are observed in pts with MAPK-pathway activating mutations (3 class II BRAF and 1 GNAQ mutation). Eight pts (50.0%) have progressed (median progression-free survival 16.4 wks [95% confidence interval [CI] 6.9-25.9]); 4 pts (25.0%) have died (median overall survival 54.7 wks [95% CI 37.6-71.8]). Adverse events (AE) are observed in all pts (grade [G] 3-4 9 [56.3%]). Two pre-amend pts added on LD-D due to dose-limiting T-related skin toxicity; no clinically relevant T-related skin toxicity was observed post-amend with the upfront addition of LD-D. The most frequent AE were creatine kinase increase (G1-2 11 [68.8%]; G3-4 1 [6.3%]), and anemia and acneiform rash (both G1-2 7 [43.8%]; G3-4 0). Therapy was temporarily interrupted due to AE in 11 pts (68.8%) and permanently interrupted in 1 pt (6.3%) due to recurrent pneumonitis. Conclusions: In this two-stage phase 2 trial, T plus LD-D was found to have promising antitumor activity and acceptable toxicity in pts with advanced pretreated BRAFV600/ NRASQ61R/K/L wt melanoma, especially in the presence of identifiable somatic MAPK-pathway activating mutations. Clinical trial information: NCT04059224.