Background: Efficacy of the anti-PD -1 agents has been demonstrated in metastatic melanoma in phase I-III trials. During the development of these trials there was no optimal duration of treatment identified. Trials stopped therapy due to unacceptable side effects, investigator’s choice, at a specific time point typically at 24 months of therapy or at disease progression. Clinical reports suggest that stopping treatment early due to toxicity may not adversely impact efficacy. In addition, there is evidence that retreatment with immunotherapy may be clinically effective. Unnecessary long term therapy may result in a higher risk of toxicity, diminished quality of life (QoL) and will impact the cost-effectiveness of the therapy. We hypothesize that treatment to maximum tumour response will result in non-inferior overall survival with better QoL, less toxicity and lower cost than continuous therapy. Methods: This is a large, simple randomized phase III trial evaluating the duration of anti-PD-1 therapy in metastatic/unresectable melanoma. Consenting patients must be eligible to receive anti- PD-1 inhibitor as standard of care. Patients are randomized 1:1 to either standard 24 months of therapy in the absence of disease progression versus treatment until maximum tumour response (MTR) with retreatment at the time of progression. MTR is determined by at least two radiologic measurements three months apart. Eligibility criteria are broad to reflect a “real world” patient population. Data collection is streamlined to focus on key endpoints. The primary endpoint is overall survival. Secondary endpoints are PFS, response rate, adverse event rate, health related QoL and economic analysis. Patients are stratified based on line of therapy, stage of disease, BRAF status, LDH level, prior use of adjuvant therapy, anti-PD -1 inhibitor selected and the presence of CNS metastases. The trial will enroll 550 patients with 275 in each arm. It is expected that accrual will last 5.5 years. Currently 78 patients have been enrolled. Clinical trial information: NCT02821013.