Background: PD-1 monotherapy as the first line stand treatment for advanced melanoma yields an objective response rate (ORR) of < 20% in AM. Although multiple clinical trials are ongoing testing TMZ/APA, TMZ/PD-1 and APA/PD-1 combo therapies in AM, the reported ORR (range 17-23.8%) are far from satisfactory. We therefore conducted a phase II study of CAM/APA/TMZ combo in this subtype aiming for improved efficacy. Methods: We performed a single center, single arm phase II study (NCT04397770) testing the efficacy and safety of CAM/APA/TMZ combo as first-line therapy in pts with advanced AM. The primary endpoint was ORR per RECIST1.1, secondary endpoints included progression free survival (PFS), disease control rate (DCR), overall survival (OS), and safety. All pts received iv CAM (200mg q2w), iv TMZ (200mg/m2 d1-5, q4w) and po APA (250mg qd) until disease progression or intolerable toxicity. Results: By Jan 2022, fifty pts were enrolled (48 evaluable), the median follow-up was 12.1 mo (IQR 8.4-14.5). Thirty-one pts achieved CR/PR as the best response (including 1 CR and 30 PR), the ORR was 64.6% (95% CI 49.4-77.4%). The DCR was 95.8% (95%CI, 84.6-99.3%). Both the median PFS and OS was not reached (NR); 6-mo and 12-mo PFS rate was 81.7% (95%CI 71.6-93.3%) and 62.9% (95%CI 48.4-81.7%), respectively; 12-mo OS rate was 82.3% (95%CI 68.2-99.2%). The incidence of treatment-related adverse events (TRAEs) was 94% (47/50). Of 50 patients, the most common grade ≥3 TRAEs included γ-glutamyl transferase elevation (24.0%), direct bilirubin elevation (22.0%), aspartase transaminase elevation (20.0%), alanine transaminase elevation (16.0%), and hypertriglyceridemia (14.0%). No treatment-related deaths occurred. Conclusions: The CAM/APA/TMZ combination demonstrated promising efficacy as the first-line treatment for pts with advanced AM, and was generally well tolerated. Phase III randomized control trial is warranted. Clinical trial information: NCT04397770.