Dual Immune Checkpoint Blockade Plus Radiotherapy Fails to Improve Outcomes Among Newly Diagnosed Patients With MGMT-Unmethylated Glioblastoma

According to results from a phase 2 trial, radiotherapy in addition to dual immune checkpoint blockade with ipilmumab and nivolumab failed to improve outcomes compared to radiotherapy plus single-agent temozolomide among newly diagnosed adult patients with O6-methylguanine-DNA-methyltransferase (MGMT)-unmethylated glioblastoma. 

MGMT-unmethylated glioblastoma is “more aggressive than methylated disease,” stated Andrew Lassman, MD, Herbert Irving Comprehensive Cancer Center, New York, New York, and coauthors. “Dual [immune checkpoint inhibitor] therapy has superior efficacy, with reasonable safety, over single agents in other solid tumors.” 

In this study, 159 patients with a Karnofsky performance status of ≥ 70 were randomized on a 1-to-1 basis to undergo radiotherapy with either ipilmumab plus nivolumab (n = 79) or temozolomide (n = 80). Patients were stratified based on recursive partitioning analysis class and intention to use tumor treating fields. Patients were not allowed to receive corticosteroids upon the start of immunotherapy. The primary end point was progression-free survival (PFS). A key secondary end point was overall survival (OS). 

At analysis, median PFS was 7.7 months in the ipilmumab plus nivolumab arm and 8.5 months in the temozolomide arm (hazard ratio [HR] 1.47; 95% confidence interval [CI], 0.98 to 2.2; P = .96). OS data were immature with > 50% of patients alive. Approximate median OS was 13 months in both treatment arms (HR 0.95; 95% CI, 0.61 to 1.49; P = .36). 

“[Ipilmumab plus nivolumab] did not improve PFS among patients with newly diagnosed [MGMT-unmethylated] glioblastoma versus [temozolomide]... the trial will not proceed to phase III,” concluded Dr Lassman et al. 

“While hope continues that immunotherapy in one [of] its manifestations will be useful for patients with glioblastoma, these data reaffirm the activity of [temozolomide] with radiation for primary resected disease,” added Journal of Clinical Oncology associate editor Robert Maki, MD, PhD, Memorial Sloan Kettering Cancer Center, New York, New York. 

Source:

Lassman AB, Polley MYC, Iwamoto FM, et al. Dual immune check point blockade in MGMT-unmethylated newly diagnosed glioblastoma: NRG Oncology BN007, a randomized phase II/III clinical trial. J Clin Oncol. Published online: August 8, 2025. doi: 10.1200/JCO-25-00618