Background: Co-blockade of LAG-3 improves the effectiveness of anti-PD-1 treatment (Tx) in advanced melanoma (Mel) patients (pts). We previously reported high clinical activity of the combination immunotherapy of anti-LAG-3 (fianlimab) and anti-PD-1 (cemiplimab) in pts (N = 80) with anti–PD-1/PD-ligand (L)1-naïve advanced Mel enrolled in two expansion phase 1 cohorts. The objective response rate (ORR) (N = 80) and disease control rate (DCR) was 63.8% and 80.0%, respectively with median duration of response (mDOR) not reached (NR). Factors associated with poor prognosis include elevated lactate dehydrogenase (LDH) levels and sites of metastases, including liver or other visceral organs (M1c). Here we present updated efficacy data in poor prognosis pts from three phase 1 advanced Mel expansion cohorts: cohort 6 and 15 of anti-PD-(L)1/systemic Tx-naïve pts and cohort 16 of pts previously exposed to adjuvant (adj) or neo-adj systemic Tx including anti-PD-1. Methods: Pts with advanced Mel (excluding uveal Mel) were treated with fianlimab 1600 mg + cemiplimab 350 mg intravenously every 3 weeks for 12 months (+ additional 12 months if clinically indicated). Tumor measurements were assessed by RECIST 1.1 every 6 weeks for 24 weeks, then every 9 weeks. Results: 40 pts each in cohort 6 and 15, and 18 pts in cohort 16 (total N = 98) were enrolled and treated with fianlimab + cemiplimab as of 01 Nov 2022 data cutoff. In the adj/neo-adj setting, 23.5% of pts had received prior systemic Tx for Mel including 15.3% with prior exposure to immune checkpoint inhibitors (iCPIs). Median follow up was 12.6 months and median Tx duration was 32.9 weeks. ORR among all 98 pts and in 15 pts with prior iCPIs was 61.2% and 60.0%, respectively. In pts with LDH > upper limit of normal (ULN) (N = 32, 32.7%), ORR, DCR, and mDOR were 53.1%, 71.9%, and NR (95% CI, 7.4– not estimated [NE]), respectively, and median progression-free survival (mPFS) was 11.8 months (95% CI, 3.7–NE). In pts with liver mets at baseline (BL) (N = 21, 21.4%), ORR, DCR, and mDOR were 42.9%, 57.1%, and 9.0 months (95% CI, 2.8–NE), respectively, and mPFS was 4.2 months (95% CI, 1.2–NE). In pts with any M1c disease and LDH > ULN at BL (N = 17, 17.3%), ORR, DCR, mDOR were 35.3%, 58.8%, and NR (95% CI, 5.7–NE), respectively, and mPFS was 7.1 months (95% CI, 1.2–NE). Overall, 43.9% and 32.7% of pts reported grade ≥3 Tx-emergent adverse events (TEAEs) and serious TEAEs. Correlative biomarkers analyses are in progress and will be included in the presentation. Conclusions: The combination of fianlimab and cemiplimab showed high activity in pts with advanced Mel and poor prognosis features at BL. The ORR and DCR observed in these subgroups compare positively with the available data for approved combinations of iCPIs in the same clinical setting. A phase 3 trial (NCT05352672) of fianlimab + cemiplimab in Tx-naïve advanced Mel pts is ongoing. Clinical trial information: NCT03005782.