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 III 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/m2 once daily during RT, then 150-200 mg/m2 once daily on 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.

Keywords: MGMT promoter; PD-L1; glioblastoma; nivolumab; temozolomide.

Fig. 1

Progression-free survival in all patients. Number of events, median PFS, and the Kaplan-Meier curve for PFS per blinded independent central review (A) and investigator (B) assessment. Symbols indicate censored observations. Abbreviations: HR, hazard ratio; PFS, progression-free survival; RT, radiotherapy; TMZ, temozolomide.

Fig. 2.

Overall survival in all patients and patients without baseline corticosteroids. Number of events, median OS, and the Kaplan-Meier curve for OS in all patients (A) and in patients without baseline corticosteroid use (B). Symbols indicate censored observations. Abbreviations: OS, overall survival; RT, radiotherapy; TMZ, temozolomide.

Fig. 3

Progression-free survival and overall survival by PD-L1 expression. Number of events, median PFS, and Kaplan-Meier curves for PFS in all patients with baseline PD-L1 expression ≥1% (A) and <1% (B). Number of events, median OS, and Kaplan-Meier curves for OS in all patients with baseline PD-L1 expression ≥1% (C) and <1% (D). Symbols indicate censored observations. Abbreviations: BICR, blinded independent central review; OS, overall survival; PD-L1, programmed death-1 ligand 1; PFS, progression-free survival; RT, radiotherapy; TMZ, temozolomide.

Fig. 4a

Progression-free survival and overall survival in prespecified patient subgroups defined by baseline clinical characteristics. Forest plots of unstratified hazard ratios for progression per blinded independent central review (A) or death (B) in the analysis of treatment effect in prespecified patient subgroups according to baseline characteristics. Abbreviations: CRF, case report form; HR, hazard ratio; RPA, recursive partitioning analysis; RT, radiotherapy; TMZ, temozolomide.

Fig. 4a

Progression-free survival and overall survival in prespecified patient subgroups defined by baseline clinical characteristics. Forest plots of unstratified hazard ratios for progression per blinded independent central review (A) or death (B) in the analysis of treatment effect in prespecified patient subgroups according to baseline characteristics. Abbreviations: CRF, case report form; HR, hazard ratio; RPA, recursive partitioning analysis; RT, radiotherapy; TMZ, temozolomide.