A randomized phase 2, single-blind study of temozolomide (TMZ) and radiotherapy (RT) combined with nivolumab or placebo (PBO) in newly diagnosed adult patients (pts) with tumor O6-methylguanine DNA methyltransferase (MGMT)-methylated glioblastoma (GBM)—CheckMate-548

Background

GBM, the most common adult primary brain tumor, has an aggressive clinical course and a poor prognosis. Approximately 40% of pts with GBM have tumors with a methylated MGMT gene promoter, which is associated with DNA repair. In these pts, TMZ may induce DNA damage and cell death due to silencing of the MGMT promoter, a mechanism potentially augmented by combination with checkpoint inhibitors. Nivolumab, a fully human IgG4 monoclonal antibody to the programmed death-1 receptor, has demonstrated overall survival (OS) benefit in the treatment of metastatic melanoma, non-small cell lung cancer, and advanced renal cell carcinoma. CheckMate-548 (NCT02667587) is a phase 2, randomized, single-blind study evaluating the efficacy and safety of TMZ/RT —> TMZ with nivolumab or PBO in pts with newly diagnosed MGMT-methylated GBM. In a companion phase 3 trial (CheckMate-498; NCT02617589), eligible pts with MGMT-unmethylated tumors (N = 550) will be randomized to receive nivolumab + RT followed by nivolumab, or TMZ/RT —> TMZ, with OS as the primary endpoint.

Trial design

Eligibility criteria include newly diagnosed, histologically confirmed supratentorial GBM in pts aged ≥18 years with Karnofsky performance status ≥70, and a tumor test result that shows a MGMT methylated, partially methylated, or indeterminate methylation type. Pts previously treated for GBM other than by resection and those with recurrent or secondary GBM are ineligible. Approximately 320 pts, stratified by partial or complete resection, will be randomized 1:1 to receive TMZ/RT —> TMZ in combination with nivolumab or PBO. Treatment will continue until disease progression or unacceptable toxicity. The primary objective is OS in pts treated with TMZ/RT —> TMZ and nivolumab versus TMZ/RT —> TMZ and PBO; the secondary objective is progression-free survival. Select exploratory objectives include safety, biomarker analyses, and neurocognitive outcomes. In the follow-up period, safety and tolerability, tumor progression, and survival will be evaluated.

Clinical trial identification

Legal entity responsible for the study

Bristol-Myers Squibb

Funding

Bristol-Myers Squibb

Disclosure

M. Weller: Has received research funding and/or honoraria from Celldex, ICT, Isarna, Magforce, MSD, Merck SG, Novocure, Northwestern Bio, Pfizer, Roche, Teva, Acceleron Pharma, Bayer. G. Vlahovic: Received research funding, honoraria, provided consulting or advisory services, or had travel, accommodations, or other expenses paid or reimbursed by Genentech, Pfizer, Hospira, or Bristol-Meyers Squibb. A.A. Brandes: Has had travel, accommodations, or other expenses paid or reimbursed by Roche

R. Zwirtes: Is an employee of Bristol-Myers Squibb who sponsored this study. K. Tatsuoka: Is an employee of Bristol-Myers Squibb who sponsored this study, and has patents, royalties, or other intellectual property interests related to GlaxoSmithKline. A.F. Carpentier: Has provided consulting services for Bristol-Myers Squibb. D.A. Reardon: Received research funding, honoraria, or provided consulting for Cavion, Genentech/Roche, Merck, Momenta, Novartis, Novocure, Regeron, Stemline Ther, BMS, Inovio, Juno Ther, Celldex, Oxigene, Celldex, Incyte, Midatech, Monteris Medical, Abbvie. M. van den Bent: Provided consulting or advisory services, or received research funding from Cavion, Roche, Merck, Serono, Actelion, Abbvie, Celldex, Amgen, Blue Earth Diagnostics, Novocure, Novartis, and Bristol-Myers Squibb. All other authors have declared no conflicts of interest.