Radiotherapy combined with nivolumab or temozolomide for newly diagnosed glioblastoma with unmethylated MGMT promoter: An international randomized phase III trial

Abstract

BACKGROUND Addition of temozolomide (TMZ) to radiotherapy (RT) improves overall survival (OS) in glioblastoma, but previous studies suggest that patients with tumors harboring an unmethylated MGMT promoter derive minimal benefit. The aim of this open-label, phase 3 CheckMate 498 study was to evaluate the efficacy of nivolumab (NIVO)+RT compared with TMZ+RT in newly diagnosed glioblastoma with unmethylated MGMT promoter. METHODS Patients were randomized 1:1 to standard RT (60 Gy) + NIVO (240 mg every 2 weeks for 8 cycles, then 480 mg every 4 weeks) or RT+TMZ (75 mg/m 2 daily during RT and 150-200 mg/m 2/day 5/28 days during maintenance). The primary endpoint was OS. RESULTS A total of 560 patients were randomized, 280 to each arm. Median OS was 13.4 months (95% CI, 12.6-14.3) with NIVO+RT and 14.9 months (95% CI, 13.3-16.1) with TMZ+RT (hazard ratio [HR], 1.31; 95% CI, 1.09-1.58; P=0.0037). Median progression-free survival was 6.0 months (95% CI, 5.7-6.2) with NIVO+RT and 6.2 months (95% CI, 5.9-6.7) with TMZ+RT (HR, 1.38; 95% CI, 1.15-1.65). Response rates were 7.8% (9/116) with NIVO+RT and 7.2% (8/111) with TMZ+RT; grade 3/4 treatment-related adverse event (TRAE) rates were 21.9% and 25.1%, and any-grade serious TRAE rates were 17.3% and 7.6%, respectively. CONCLUSIONS The study did not meet the primary endpoint of improved OS; TMZ+RT demonstrated a longer median OS than NIVO+RT. No new safety signals were detected with NIVO in this study. The difference between the study treatment arms is consistent with the use of TMZ+RT as standard of care for glioblastoma.

Potential 18F-RGD PET/CT and DCE-MRI Imaging-Based Biomarkers for Postoperative Survival Prediction Among Patients With Newly Diagnosed Glioblastoma Treated With Bevacizumab and Chemoradiotherapy

“…Recently, immunocheckpoint inhibitors represented by PD•1 have been widely studied in glioblastoma. Series of phase III clinical trials displayed disappointing results of PD•1 in glioblastoma, including the OS of recurrent glioblastoma in CheckMate-143, OS of newly diagnosed MGMT•unmethylated glioblastoma, PFS of newly diagnosed MGMT•methylated glioblastoma (49)(50)(51). In addition, it's also worth to note that the efficacy of neoadjuvant was better than the adjuvant PD•1 therapy in recurrent glioblastoma (52).…”

Emerging systemic treatment options in meningioma

“…ICI targeting the programmed death receptor (ligand) 1 (PD-1/PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) axis are widely applied in solid malignancies such as melanoma, lung cancer, renal cell carcinoma, head and neck squamous cell carcinoma, among others. Whereas ICI have shown activity in asymptomatic patients with brain metastases [71][72][73][74], clinical trials have failed to show an overall benefit in primary CNS malignancies such as glioblastoma both in newly diagnosed disease as well as in the recurrent setting [75][76][77].…”

Next Steps for Immunotherapy in Glioblastoma

“…The companion phase 3 CheckMate 498 trial was designed to compare OS for new unmethylated MGMT glioblastoma patients treated with either nivolumab + RT vs. temozolomide + RT. Notably, this trial also did not meet its primary endpoint of prolonged survival (mOS = 13.4 months vs. 14.9 months, HR 1.31, p = 0.0037), and results favored the control arm [ 5 ]. The use of dual checkpoint blockade, PD-1, and CTLA-4, is currently undergoing investigation in the NRG Oncology cooperative group in a randomized phase 2/3 trial BN007 (NCT04396860), which has completed the phase 2 accrual.…”

“…Immunotherapeutic approaches, including vaccines, immune checkpoint inhibitors, or cell-based therapies, have proven remarkably successful in a host of non-central nervous system (CNS) malignancies [ 3 ]. Unfortunately, such gains in durable survival have yet to be observed across unselected patient populations with glioblastoma in the phase 3 trials thus far conducted [ 4 , 5 , 6 ]. A number of factors, both known and unknown, contribute to the lack of benefit from immunotherapy observed thus far.…”