Purpose: New therapies for glioblastoma are needed, especially MGMT-unmethylated (uMGMT) disease. NRG Oncology BN002 (phase I) demonstrated safety and suggested efficacy of ipilimumab (ipi) with nivolumab (nivo) in newly diagnosed glioblastoma, leading to this phase II/III trial.
Methods: Adults with newly diagnosed uMGMT glioblastoma and Karnofsky performance status (KPS) ≥70 were randomly assigned to radiotherapy with either immunotherapy (ipi and nivo) or temozolomide (TMZ), stratified by recursive partitioning analysis (RPA) class and intention to use tumor treating fields. With 95% power to detect a hazard ratio (HR) ≤0.58 for progression-free survival (PFS) at a one-sided significance level (P) of .15, superior PFS with immunotherapy in phase II would lead to phase III overall survival (OS) testing. Corticosteroids were disallowed when starting immunotherapy. Diagnosis, biomarkers, and PFS were centrally assessed.
Results: One hundred fifty-nine participants were randomly assigned (79 immunotherapy and 80 TMZ). Arms were well balanced for age (median 60 years, range, 28-79), sex (male n = 105, 66%), KPS (90-100 n = 97, 61%), resection extent (gross total, n = 103, 65%), and RPA class (III, n = 16, 10%; IV, n = 116, 73%; V, n = 27, 17%). A preplanned analysis of phase II data conducted after 100 centrally determined PFS events showed no significant PFS improvement for ipi and nivo versus TMZ (median 7.7 months v 8.5 months, HR, 1.47 [70% CI, 1.19 to 1.83]; one-sided P = .96 [95% CI, 0.98 to 2.2]). OS is immature (>50% alive) but with no observed difference between arms (median approximately 13 months each, HR, 0.95 [95% CI, 0.61 to 1.49]; P = .36).
Conclusion: Ipi and nivo did not improve PFS among patients with newly diagnosed uMGMT glioblastoma versus TMZ. Accrual closed permanently; the trial will not proceed to phase III. No new safety signals were identified. Molecular correlative analyses and survival follow-up are ongoing.
Trial registration: ClinicalTrials.gov NCT04396860.