Background: Brain metastasis develops in approximately 50% of pts with metastatic MEL. In these pts, progressive brain disease is the major cause of tumor-related death (median overall survival [OS] after diagnosis, 4 months). NIVO (a fully human IgG4 PD-1 immune checkpoint inhibitor antibody) and IPI (a fully human IgG1 CTLA-4 immune checkpoint inhibitor antibody) are each approved as monotherapy for advanced MEL. In a phase II study, IPI showed activity in some pts with advanced MEL and brain metastases. Building upon the success of that study, this open-label, multi-site, US, phase II study is the first to evaluate NIVO combined with IPI followed by NIVO monotherapy for pts with MEL metastatic to the brain. It is anticipated that approximately 50% of enrolled pts will have had prior stereotactic radiotherapy (SRT). Methods: Pts ≥ 18 years of age with MEL measurable in extracranial sites and with asymptomatic brain metastases are eligible. Pts with a history of leptomeningeal involvement, a history of whole brain irradiation, autoimmune disease or corticosteroid use will be excluded. Pts will receive NIVO 1 mg/kg combined with IPI 3 mg/kg every three weeks (Q3W; 4 doses), followed by NIVO monotherapy 3 mg/kg Q2W until progression or unacceptable toxicity. SRT for progression of a single central nervous system (CNS) lesion will be permitted. The primary objective is to assess the CNS clinical benefit rate (CBR; complete response + partial response + stable disease [SD] ≥ 6 months) per protocol-defined response criteria; this endpoint was selected based on its relevance in this population and ability to capture both objective response and durable SD. Secondary objectives are to assess extracranial CBR per RECIST v1.1; global CBR (CNS plus extracranial) per RECIST v1.1 with modifications; CNS, extracranial and global CBR per immune-related response criteria; OS and safety. Exploratory correlates are also planned. An estimated 110 pts will be enrolled. Clinical trial registration number: NCT02320058. Clinical trial information: NCT02320058