Background: GBM, the most common primary brain tumor in adults, has an aggressive clinical course and a median survival of 15–18 months in clinical trial populations. Approximately 40% of pts with GBM have tumors with an MGMT-methylated promoter, which is associated with sensitivity to TMZ. New treatment options for pts with GBM are desirable, particularly for those with MGMT-unmethylated GBM, as TMZ efficacy is historically marginal in this population. Nivolumab, a fully human IgG4 monoclonal antibody to the programmed death-1 receptor, has shown clinical activity and increased survival in pts with metastatic melanoma, non–small-cell lung cancer, and renal cell carcinoma. CheckMate-498 (NCT02617589) is a phase 3 study designed to compare overall survival (OS) of nivolumab or TMZ, each in combination with RT, in pts with newly diagnosed MGMT-unmethylated GBM. In a companion phase 2 trial (CheckMate-548; NCT02667587), eligible pts with MGMT-methylated tumors (N = 320) will be randomized to RT + TMZ + nivolumab vs RT + TMZ + placebo, with OS as the primary objective. Methods: Eligibility criteria include newly diagnosed, histologically confirmed, MGMT-unmethylated (centrally confirmed) GBM in pts aged ≥ 18 years with Karnofsky performance status ≥ 70. Pts with prior treatment for GBM and recurrent or secondary GBM are ineligible. Approximately 550 pts will be randomized to receive nivolumab + RT followed by nivolumab, or TMZ + RT followed by TMZ. Treatment will continue until progression or unacceptable toxicity. The primary objective is to compare OS with nivolumab + RT vs TMZ + RT; secondary objectives include progression-free survival and 2-year survival rate. Exploratory objectives include safety, biomarker analyses, and neurocognitive outcomes. Patients will be followed for safety and tolerability, tumor progression, and survival. At least 397 events, with an interim analysis after ≥ 298 events, will provide 90% power to detect a hazard ratio of < 0.72. Clinical trial information: NCT02617589