Background: Previous reports have demonstrated that treatment (Tx) with anti-LAG-3 Ab fianlimab + anti-PD-1 Ab cemiplimab had a 63.8% ORR across two separate cohorts of advanced PD-(L)1 naïve metastatic melanoma (Mel) patients (pts). The benefit the fianlimab + cemiplimab combination in pts exposed to prior anti-PD-1 Tx as adjuvant (adj) Tx is unknown. Here we present phase 1 safety and clinical activity data from pts with advanced Mel including those who received prior adj systemic Tx. Methods: Three separate expansion cohorts of adult pts with unresectable or metastatic Mel (excluding uveal Mel) who were anti–PD-(L)1 Tx-naïve for advanced disease were enrolled. All pts received fianlimab 1600 mg + cemiplimab 350 mg IV Q3W for 12 months (mos) (optional additional 12 mos if clinically indicated). Study enrollment closed in June 2022. Tumor measurements were performed every 6 weeks (wks) for 24 wks, then every 9 wks. Results: 98 pts were enrolled and treated with fianlimab + cemiplimab as of 01 Nov 2022 data cutoff. Median age was 68.0 years, 60.2% were male, and 89.8% were White. 2.0% of pts had received prior metastatic Tx (not anti–PD-(L)1) and 23.5% had received prior systemic Tx for Mel in the adj/neo-adj setting (disease-free interval > 6 mos), including 13.3% treated with an anti-PD-1 (nivolumab or pembrolizumab). Median follow up was 12.6 mos and median treatment duration was 32.9 wks. Grade ≥3 treatment-emergent adverse events (TEAEs), serious TEAEs, and immune-related AEs (irAEs) occurred in 43.9%, 32.7%, and 65.3% of pts, respectively. 16.3% of pts discontinued Tx due to a TEAE. Rates of irAEs were similar to anticipated rates for PD-1 monotherapy with the exception of adrenal insufficiency (AI) with 12.2% (all grades) and 4.1% (grade ≥3). RECIST 1.1-based investigator-assessed overall ORR was 61.2% (12 complete responses; 48 partial responses), with median DOR (mDOR) not reached [NR] (95% CI: 22.6– not estimated [NE]). KM estimation of median PFS (mPFS) was 15.3 (95% CI: 9.4–NE) mos. In pts with any prior adj Tx, ORR, mDOR, and mPFS was 60.9% (14/23), NR, and 13.3 mos, respectively. In pts with prior anti-PD-1 adj Tx, ORR, mDOR, and mPFS was 61.5% (8/13), NR, and 11.8 mos, respectively. Data from subgroup and correlative biomarker analyses, PK and immunogenicity will be included in the presentation. Conclusions: Fianlimab + cemiplimab in advanced Mel pts showed high clinical activity that compares favorably with other approved combinations of immune checkpoint inhibitors in the same clinical setting. This is the first indication that dual LAG-3 blockade can produce high level of activity with significant ORR in pts with advanced Mel post adj anti-PD-1 Tx. The safety profile of fianlimab + cemiplimab is similar to anti-PD-1 monotherapy with the exception of AI. A phase 3 trial (NCT05352672) of fianlimab + cemiplimab in Tx-naïve advanced Mel pts is ongoing. Clinical trial information: NCT03005782.