This phase I study evaluated the combination of fianlimab (a human LAG-3 monoclonal antibody) and cemiplimab (an anti-PD-1 antibody) in patients with advanced melanoma. The primary objective was to assess the preliminary antitumor activity, measured by objective response rate (ORR) and progression-free survival (PFS). The study enrolled 113 patients across four expansion cohorts, including those with no previous anti-PD-1 therapy and those with previous adjuvant therapy. The combination therapy demonstrated high clinical activity, with an ORR of 61.2% and a median PFS of 13.3 months. The safety profile was generally comparable to that of single-agent cemiplimab and other anti-PD-1 monotherapies, with a higher rate of adrenal insufficiency observed. The study also showed promising results in patients with poor prognosis features, such as elevated lactate dehydrogenase (LDH) levels and hepatic metastases. These findings suggest that the combination of fianlimab and cemiplimab may represent a future treatment option for advanced melanoma, warranting further clinical development.This phase I study evaluated the combination of fianlimab (a human LAG-3 monoclonal antibody) and cemiplimab (an anti-PD-1 antibody) in patients with advanced melanoma. The primary objective was to assess the preliminary antitumor activity, measured by objective response rate (ORR) and progression-free survival (PFS). The study enrolled 113 patients across four expansion cohorts, including those with no previous anti-PD-1 therapy and those with previous adjuvant therapy. The combination therapy demonstrated high clinical activity, with an ORR of 61.2% and a median PFS of 13.3 months. The safety profile was generally comparable to that of single-agent cemiplimab and other anti-PD-1 monotherapies, with a higher rate of adrenal insufficiency observed. The study also showed promising results in patients with poor prognosis features, such as elevated lactate dehydrogenase (LDH) levels and hepatic metastases. These findings suggest that the combination of fianlimab and cemiplimab may represent a future treatment option for advanced melanoma, warranting further clinical development.