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Background Approximately 50% of melanomas have BRAF mutations, which drive the proliferation and survival of tumor cells via constitutive activation of the MAPK pathway. BRAF inhibitors (BRAFi) ± MEK inhibitors (MEKi) may be used to treat advanced BRAF V600-mutant melanoma as first-line therapy or after progression on anti-PD-1 therapy. However, prior treatment with BRAF-directed therapy can diminish the efficacy of subsequent treatment with anti-PD-1 therapy. Vusolimogene oderparepvec (RP1; an HSV-1-based oncolytic immunotherapy) combined with nivolumab demonstrated clinically meaningful, durable antitumor activity (objective response rate [ORR], 32.9% by RECIST 1.1; median duration of response [DOR], 33.7 months) in patients with melanoma and confirmed progression on prior anti-PD-1 therapy. Here we report the impact of prior BRAFi/MEKi therapy on the efficacy of RP1 plus nivolumab.Methods Patients with melanoma and confirmed progression on anti-PD-1 ± anti-CTLA-4 therapy for ≥8 weeks as the last prior treatment were enrolled. Prior treatment with BRAFi ± MEKi therapy was allowed for BRAF V600 mutation-positive melanoma. RP1 was given intratumorally at 1×106 PFU/mL initially, then at 1×107 PFU/mL Q2W (≤7 doses) with intravenous nivolumab (240 mg), followed by nivolumab alone (240 mg Q2W or 480 mg Q4W) for up to 2 years. This post hoc analysis evaluated ORR, DOR, and progression-free survival (PFS) by RECIST 1.1 per independent review, and overall survival (OS) in patients with BRAF-mutant melanoma, stratified by prior BRAFi treatment (data cutoff: March 8, 2024).Results Of 140 enrolled patients, 53 had BRAF-mutant melanoma, including 16 (30.2%) who had received BRAFi/MEKi prior to anti-PD-1 therapy (BRAFi-exposed) and 37 (69.8%) who were BRAFi-naïve. The confirmed ORR was 12.5% in the BRAFi-exposed group vs 43.2% in the BRAFi-naïve group (table 1). Median DOR was 3.9 months in the BRAFi-exposed group vs 33.7 months in the BRAFi-naïve group. Median PFS was 1.9 months in the BRAFi-exposed group vs 5.6 months in the BRAFi-naïve group; the 12-month PFS rate was 13.3% vs 40.4%, respectively. The 12-month OS was 71.4% in BRAFi-exposed patients and 85.9% in BRAFi-naïve patients. Fifteen of the 37 BRAFi-naïve patients were subsequently treated with BRAFi ± MEKi for a median of 13.9 months with an ORR of 66.7%.Conclusions In patients with advanced BRAF-mutant melanoma that progressed on prior anti-PD-1 therapy, RP1 plus nivolumab appeared to be more effective in BRAFi-naïve patients. This finding is consistent with literature showing that BRAF-directed therapy leads to cross-resistance to subsequent immunotherapy.Trial Registration ClinicalTrials.gov NCT03767348Ethics Approval The study was conducted in accordance with the ethical principles originating from the Declaration of Helsinki and was approved by the institutional review board/ethics committee at each participating site. Written informed consent was obtained from all patients prior to the conduct of any study-related procedures.Abstract 611 Table 1Efficacy by prior BRAFi/MEKi treatmentCR, complete response; NR, not reached; PD, progressive disease; PR, partial response; SD, stable disease.