Background: In patients (pts) with advanced, metastatic melanoma (aMM) anti-PD-1 monotherapy and anti-PD-1/anti-CTLA-4 combination regimens yield durable responses, yet the optimal therapy duration remains unclear. Most prospective studies have treated responding pts for at least 2 years unless there has been a prohibitive treatment related adverse event (TRAE). Durable treatment-free survival has been observed in pts where anti-PD-1 therapy is discontinued after short courses due to TRAEs. Biomarkers are needed to define which pts may safely discontinue anti-PD-1 therapy in order to reduce financial toxicity and risk of late TRAEs, and to improve quality of life. ¹⁸FDG-PET/CT scan and tumor biopsy may better assess for active residual disease and identify pts who can safely discontinue treatment. A retrospective study at G-LCCC demonstrated responding pts with aMM who elected to discontinue their anti-PD-1 therapy (median treatment duration 12 months) after a negative PET/CT scan and/or tumor biopsy had event free survival (EFS) of 95% at 3 years (Gibney et al JITC 2021). We hypothesize that pts with disease control by CT scan after 12 months on anti-PD-1 therapy can be safely discontinued from treatment if no hypermetabolic activity on PET/CT scan or negative biopsy for active disease. Methods: EA6192 is a multicenter phase II study to evaluate the EFS after discontinuation of anti-PD-1-based therapy in aMM pts with PET/CT scan and/or biopsy that is negative for active disease. Pts with unresectable stage IIIB-IV aMM treated with nivolumab/ipilimumab (nivo/ipi), nivo, pembrolizumab (pembro), or pembro/ipi are eligible. Pts with uveal melanoma are excluded. Pts must receive 52 weeks of therapy, have disease control (CR, PR or SD by imRECIST) and no prohibitive TRAEs. Eligible pts undergo screening including ¹⁸FDG-PET/CT scan at 52 weeks (+/- 2 weeks) from start of anti-PD-1 therapy. Pts with hypermetabolic tumor site(s) undergo biopsy. Pts with non-hypermetabolic PET/CT scan or negative biopsy are assigned to Arm A and are monitored off active treatment. Pts with hypermetabolic PET/CT scan and positive or non-feasible biopsy are assigned to Arm B and remain on active treatment for another 48 weeks. Restaging scans are performed every 12 weeks. Arm B pts with disease control undergo a second PET/CT scan and biopsy, and then are monitored off active treatment. 150 patients are planned for accrual. The primary objective is to accurately define the 12-month EFS rate of Arm A, distinguishing between the null and alternative hypotheses of 12-month EFS rate of 88% and 95% with 92% power and one-sided type 1 error rate of 0.072. Secondary and exploratory objectives include assessment of pathologic response, EFS for Arm B, overall survival, incidence of late TRAEs, and correlative biomarker studies. This study is actively enrolling pts. Clinical trial information: NCT04462406.