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Clinical Trial
. 2023 Jan 5;25(1):123-134.
doi: 10.1093/neuonc/noac099.

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

Antonio Omuro  1   2 , Alba A Brandes  3 , Antoine F Carpentier  4 , Ahmed Idbaih  5 , David A Reardon  6 , Timothy Cloughesy  7 , Ashley Sumrall  8 , Joachim Baehring  1 , Martin van den Bent  9 , Oliver Bähr  10 , Giuseppe Lombardi  11 , Paul Mulholland  12 , Ghazaleh Tabatabai  13 , Ulrik Lassen  14 , Juan Manuel Sepulveda  15 , Mustafa Khasraw  16 , Elodie Vauleon  17 , Yoshihiro Muragaki  18 , Anna Maria Di Giacomo  19 , Nicholas Butowski  20 , Patrick Roth  21 , Xiaozhong Qian  22 , Alex Z Fu  22 , Yanfang Liu  22 , Von Potter  22 , Alexandros-Georgios Chalamandaris  23 , Kay Tatsuoka  22 , Michael Lim  24 , Michael Weller  21
Affiliations
Clinical Trial

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

Antonio Omuro et al. Neuro Oncol. .

Abstract

Background: Addition of temozolomide (TMZ) to radiotherapy (RT) improves overall survival (OS) in patients with glioblastoma (GBM), but previous studies suggest that patients with tumors harboring an unmethylated MGMT promoter derive minimal benefit. The aim of this open-label, phase III CheckMate 498 study was to evaluate the efficacy of nivolumab (NIVO) + RT compared with TMZ + RT in newly diagnosed GBM with unmethylated MGMT promoter.

Methods: Patients were randomized 1:1 to standard RT (60 Gy) + NIVO (240 mg every 2 weeks for eight cycles, then 480 mg every 4 weeks) or RT + TMZ (75 mg/m2 daily during RT and 150-200 mg/m2/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 (mOS) was 13.4 months (95% CI, 12.6 to 14.3) with NIVO + RT and 14.9 months (95% CI, 13.3 to 16.1) with TMZ + RT (hazard ratio [HR], 1.31; 95% CI, 1.09 to 1.58; P = .0037). Median progression-free survival was 6.0 months (95% CI, 5.7 to 6.2) with NIVO + RT and 6.2 months (95% CI, 5.9 to 6.7) with TMZ + RT (HR, 1.38; 95% CI, 1.15 to 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 mOS 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 the standard of care for GBM.ClinicalTrials.gov NCT02617589.

Keywords: newly diagnosed glioblastoma; nivolumab; radiotherapy; temozolomide; unmethylated MGMT.

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Figures

Fig. 1
Fig. 1
Trial profile. aThe majority of the nonrandomized population was excluded due to methylation status (cutoff, ratio of the gene copy numbers of methylated MGMT to control (β-actin) × 1000 < 2).
Fig. 2
Fig. 2
OS and PFS in all patients. (A) Shows the number of events, median OS, and the Kaplan-Meier curve for OS in all patients treated with nivolumab plus radiotherapy or temozolomide plus radiotherapy. (B) Shows the number of events, median PFS, and the Kaplan-Meier curve for PFS per investigator assessment in patients treated with nivolumab plus radiotherapy or temozolomide plus radiotherapy. Symbols indicate censored observations. Hazard ratios and 95% CIs were estimated using a Cox proportional hazards model. OS, overall survival; PFS, progression-free survival.
Fig. 3
Fig. 3
Overall survival in prespecified patient subgroups defined by baseline clinical characteristics. This figure shows a forest plot of unstratified hazard ratios for death in the analysis of treatment effect in prespecified patient subgroups according to baseline characteristics.
See this image and copyright information in PMC

Comment in

  • The road we travel.
    Nabors B. Nabors B. Neuro Oncol. 2023 Jan 5;25(1):135-136. doi: 10.1093/neuonc/noac235. Neuro Oncol. 2023. PMID: 36219132 Free PMC article. No abstract available.

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