Background: KEYNOTE-006 (NCT01866319) established superiority of pembro over ipi in advanced melanoma. We provide 4-y outcomes, long-term data for pts who completed 2 y pembro, and data for second course. Methods: Eligible pts (N = 834) were randomly assigned 1:1:1 to receive pembro 10 mg/kg Q2W, pembro 10 mg/kg Q3W, or ipi 3 mg/kg Q3W for 4 doses. Treatment was continued for 2 y (pembro only; completed defined as ≥94 weeks of pembro and discontinued with at least SD) or until disease progression, intolerable toxicity, or pt/investigator decision to discontinue. End points were OS and ORR per irRC by investigator review. Upon PD, eligible pts could receive an additional 1 y pembro. Results: At data cutoff (Dec 4, 2017), median follow-up was 45.9 mo (range, 0.3-50.0). 4-y OS rate was 42% in the pooled pembro arms (n = 556) and 34% in the ipi arm (n = 278); ORR was 42% and 17%. Median DOR was NR for pembro (range, 1.0+ to 46.1+ mo) or ipi (1.1+ to 45.6+ mo); 62% pembro- and 59% ipi-treated pts had a response lasting ≥42 mo. In treatment-naive pts, 4-y OS rates were 44% in the pooled pembro arms (n = 368) and 36% in the ipi arm (n = 181); ORR was 47% and 17%. Median DOR was NR for pembro (range, 1.6+ to 46.0+ mo) or ipi (1.1+ to 42.2+ mo); 65% pembro- and 68% ipi-treated pts had a response lasting ≥42 mo. Of 556 pts, 103 (19%) completed the protocol-specified 2-y pembro (28 CR, 65 PR, 10 SD). Median follow-up was 20.3 mo after pembro completion; 89 (86%) pts did not progress and 14 pts had PD (prior response 2 CR, 9 PR, 3 SD). Eight pts (prior response 3 CR [including 1 pt who discontinued early with CR and then progressed], 4 PR, and 1 SD) received second-course pembro but 3 discontinued (1 each due to PD, interstitial pneumonia, and infection). Median duration of second-course pembro was 9.7 mo; BOR was 1 CR, 1 PR, 5 SD, and 1 PD. 1 pt with SD had subsequent PD. 5 pts had a TRAE during second-course pembro; there were no grade 3/4 TRAEs or deaths. Conclusions: Pembro provides durable antitumor activity in treatment-naive or -experienced pts with advanced melanoma. Of pts who completed 2 y pembro, 86% were progression free at 20 mo. Pembro is safe and provides additional antitumor activity as second-course treatment. Clinical trial information: NCT01866319