Background: In recent years, the treatment landscape for advanced MEL has evolved with approval of an anti-CTLA-4 antibody (IPI), BRAF/MEK inhibitors and anti-programmed death-1 (PD-1) antibodies (NIVO and pembrolizumab). In a phase III study with pts previously treated with IPI, NIVO had an objective response rate of 32% (vs 11% with chemotherapy) and a manageable safety profile. Anti-PD-1 antibodies have been associated with select adverse events (AEs; i.e., those with a potential immunologic etiology), most of which resolve using established safety management guidelines. However, further safety information would be desirable in pts who progressed after prior IPI, particularly in pt subgroups that were under-represented in previous studies. Consequently, this phase II trial will assess the safety of NIVO in a large population of European pts with stage III or IV MEL progressing after prior IPI treatment, including a separate prospective cohort of pts with ECOG performance status (PS) 2. Methods: Eligible pts are ≥ 18 years of age, have histologically confirmed malignant stage III (unresectable) or stage IV MEL, have ECOG PS 0–1 (Cohort 1) or 2 (Cohort 2), were previously treated regardless of BRAF mutation status and have evaluable RECIST v1.1-defined disease progression. Pts will be treated with NIVO 3 mg/kg every 2 weeks (Q2W) until progression or unacceptable toxicities for a maximum of 24 months. Safety assessments will be performed Q2W in Cohort 1 and Q1W in Cohort 2. Tumor assessments will begin at week 12. The primary objectives are to determine the rate and frequency of high-grade (CTCAE v4.0 grade 3 or higher), treatment-related, select AEs. Secondary objectives are to characterize the outcome (grade of resolution; duration of AE-specific treatment) of high-grade, select AEs and to estimate overall survival and investigator-assessed best overall response. Approximately 1,800 pts will be enrolled across Europe, including a maximum of 300 pts with ECOG PS 2. Clinical trial registration number: NCT02156804. Clinical trial information: NCT02156804