Background: Anti-PD1 alone and combined with anti-CTLA4 therapy has improved survival in pts with advanced melanoma. Optimal treatment duration has not been defined and it is unclear if survival is compromised when pts discontinue (DC) therapy. Methods: A single institution review of pts with advanced melanoma treated with nivolumab or pembrolizumab monotherapy (anti-PD1) or nivolumab plus ipilimumab (nivo-ipi) was performed. Response rate (RR; provider assessed), reason for treatment DC and survival were analyzed. Outcomes in pts after treatment DC with CT scan response, PET/CT and/or biopsy of residual disease was assessed. OTS in pts with disease control was defined from time of last anti-PD1 dose to time of subsequent systemic therapy or death. Results: Of 96 pts, 44 received anti-PD1 and 52 received nivo-ipi. Median age 64 yrs, 62% male, 95% ECOG 0-1, 73% stage M1c, 37% BRAF mutant, 39% elevated LDH, and 28% brain metastasis. Overall RR was 34% for anti-PD1 and 63% for nivo-ipi. Another 25% and 6% of pts had stable disease, respectively. Median overall survival (OS) was not reached, although survival was significantly greater with nivo-ipi (P = 0.007). At 24 months, 80% of nivo-ipi pts were alive vs 51% anti-PD1 pts. 41 pts with disease control DC treatment for toxicity (n = 21) or pt/provider choice (n = 20). Of the latter, 17 pts DC treatment after one year for partial/complete response on CT scan (n = 4), negative PET/CT scan (n = 9), and positive PET/CT with negative biopsy (n = 4). 3 pts DC treatment after 2 years for positive PET/CT and negative biopsy. Median OTS was not reached for either group (91% and 77% were event free at 18 months); median follow up was 13.5 and 27.5 months, respectively. In the pt/provider choice group, 1 pt had progressive disease (PD) managed surgically and 1 pt died from non-melanoma causes; none received further systemic treatment. In the toxicity group, 4 pts had PD requiring further systemic therapy. Conclusions: In our experience, superior OS was seen with nivo-ipi over anti-PD-1 alone. OTS appears durable in pts with disease control if treatment DC due to toxicity or pt/provider decision. PET/CT and biopsy may be an effective strategy for safe DC of therapy after 1 year. Further prospective study is warranted.