Phase III trial of chemoradiotherapy with temozolomide plus nivolumab or placebo for newly diagnosed glioblastoma with methylated MGMT promoter

Abstract

Background Nearly all patients with newly diagnosed glioblastoma experience recurrence following standard-of-care radiotherapy (RT) + temozolomide (TMZ). The purpose of the phase 3 randomized CheckMate 548 study was to evaluate RT+TMZ combined with the immune checkpoint inhibitor nivolumab (NIVO) or placebo (PBO) in patients with newly diagnosed glioblastoma with methylated MGMT promoter (NCT02667587). Methods Patients (N=716) were randomized 1:1 to NIVO [(240 mg every 2 weeks ×8, then 480 mg every 4 weeks) + RT (60 Gy over 6 weeks) + TMZ (75 mg/m 2 once daily during RT, then 150-200 mg/m 2 once daily days 1-5 of every 28-day cycle ×6)] or PBO+RT+TMZ following the same regimen. The primary endpoints were progression-free survival (PFS) and overall survival (OS) in patients without baseline corticosteroids and in all randomized patients. Results As of December 22, 2020, median (m)PFS (blinded independent central review) was 10.6 months (95% CI, 8.9-11.8) with NIVO+RT+TMZ vs 10.3 months (95% CI, 9.7-12.5) with PBO+RT+TMZ (HR, 1.1; 95% CI, 0.9-1.3) and mOS was 28.9 months (95% CI, 24.4-31.6) vs 32.1 months (95% CI, 29.4-33.8), respectively (HR, 1.1; 95% CI, 0.9-1.3). In patients without baseline corticosteroids, mOS was 31.3 months (95% CI, 28.6-34.8) with NIVO+RT+TMZ vs 33.0 months (95% CI, 31.0-35.1) with PBO+RT+TMZ (HR, 1.1; 95% CI, 0.9-1.4). Grade 3/4 treatment-related adverse event rates were 52.4% vs 33.6%, respectively. Conclusions NIVO added to RT+TMZ did not improve survival in patients with newly diagnosed glioblastoma with methylated or indeterminate MGMT promoter. No new safety signals were observed.

Novel macrophage-related gene prognostic index for glioblastoma associated with M2 macrophages and T cell dysfunction

“…Given that the overall response rate of GBM to ICI remains dismal, it is crucial to determine who will benefit from the therapy. Several studies are devoted to develop biomarkers related to the prognosis and treatment effecacy of GBM from a tumor ontology or TME perspective, but the results are not yet satisfactory ( 48 ). Recent transcriptome-based achievements in immunophenotyping of gliomas and transcriptomic characterization of macrophage polarization provide the basis for screening genetic metrics of clinical implication from TAMs.…”

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).…”

Next Steps for Immunotherapy in Glioblastoma

“…Subsequently, two large phase 3 trials investigated the role of nivolumab in newly diagnosed GBM. In the CheckMate 548 trial, the addition of nivolumab to radiotherapy and temozolomide did not improve OS (mOS 28.9 vs. 32.1 months in nivolumab vs. placebo group, respectively, HR 1.10) or PFS (10.6 months vs. 10.3 months, HR 1.1) in newly diagnosed GBM patients with methylated/indeterminate MGMT promotor [ 4 ]. 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.…”

“…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.…”