Clinical Trial

. 2022 Nov 2;24(11):1935-1949.

doi: 10.1093/neuonc/noac116.

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

Michael Lim¹, Michael Weller², Ahmed Idbaih³, Joachim Steinbach^{4

5}, Gaetano Finocchiaro⁶, Raju R Raval⁷, George Ansstas⁸, Joachim Baehring⁹, Jennie W Taylor¹⁰, Jerome Honnorat¹¹, Kevin Petrecca¹², Filip De Vos¹³, Antje Wick¹⁴, Ashley Sumrall¹⁵, Solmaz Sahebjam¹⁶, Ingo K Mellinghoff¹⁷, Masashi Kinoshita¹⁸, Mustimbo Roberts¹⁹, Ruta Slepetis¹⁹, Deepti Warad¹⁹, David Leung¹⁹, Michelle Lee²⁰, David A Reardon²¹, Antonio Omuro^{9

17}

Affiliations

¹ Department of Neurosurgery, Stanford University School of Medicine, Palo Alto, California, USA.
² Department of Neurology and Brain Tumor Center, University Hospital and University of Zurich, Zurich, Switzerland.
³ Sorbonne Université, Institut du Cerveau-Paris Brain Institute-ICM, Inserm, CNRS, AP-HP, Hôpital Universitaire La Pitié Salpêtrière, Paris, France.
⁴ Frankfurt Cancer Institute, Goethe University, Frankfurt, Germany.
⁵ Institute of Neurooncology, Goethe University Hospital, Frankfurt, Germany.
⁶ Unit of Molecular Neuro-Oncology, Neurological Institute C. Besta, Milan, Italy.
⁷ Translational Therapeutics Program, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA.
⁸ Department of Medicine, Oncology Division, Washington University Medical School, St. Louis, Missouri, USA.
⁹ Department of Neurology, Yale University School of Medicine, New Haven, Connecticut, USA.
¹⁰ Departments of Neurology and Neurological Surgery, University of California San Francisco, San Francisco, California, USA.
¹¹ Neuro-Oncology Department, Hospices Civils de Lyon, SynatAc Team, Institute MeLis, INSERM U1314/CNRS UMR 5284, Université de Lyon, Université Claude Bernard Lyon 1, Lyon, France.
¹² Department of Neurology and Neurosurgery, Brain Tumour Research Centre, Montreal Neurological Institute-Hospital, McGill University, Montreal, Quebec, Canada.
¹³ Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
¹⁴ Neurology Clinic, University of Heidelberg, National Center for Tumor Diseases, Heidelberg, Germany.
¹⁵ Neuro-Oncology Department, Levine Cancer Institute, Charlotte, North Carolina, USA.
¹⁶ Moffitt Cancer Center, University of South Florida, Tampa, Florida, USA.
¹⁷ Department of Neurology and Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
¹⁸ Department of Neurosurgery, Kanazawa University, Ishikawa, Japan.
¹⁹ Bristol Myers Squibb, Princeton, New Jersey, USA.
²⁰ Syneos Health, Morrisville, North Carolina, USA.
²¹ Center for Neuro-Oncology, Dana-Farber/Harvard Cancer Center, Boston, Massachusetts, USA.

PMID: 35511454
PMCID: PMC9629431
DOI: 10.1093/neuonc/noac116

Clinical Trial

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

Michael Lim et al. Neuro Oncol. 2022.

. 2022 Nov 2;24(11):1935-1949.

doi: 10.1093/neuonc/noac116.

Authors

Affiliations

¹ Department of Neurosurgery, Stanford University School of Medicine, Palo Alto, California, USA.
² Department of Neurology and Brain Tumor Center, University Hospital and University of Zurich, Zurich, Switzerland.
³ Sorbonne Université, Institut du Cerveau-Paris Brain Institute-ICM, Inserm, CNRS, AP-HP, Hôpital Universitaire La Pitié Salpêtrière, Paris, France.
⁴ Frankfurt Cancer Institute, Goethe University, Frankfurt, Germany.
⁵ Institute of Neurooncology, Goethe University Hospital, Frankfurt, Germany.
⁶ Unit of Molecular Neuro-Oncology, Neurological Institute C. Besta, Milan, Italy.
⁷ Translational Therapeutics Program, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA.
⁸ Department of Medicine, Oncology Division, Washington University Medical School, St. Louis, Missouri, USA.
⁹ Department of Neurology, Yale University School of Medicine, New Haven, Connecticut, USA.
¹⁰ Departments of Neurology and Neurological Surgery, University of California San Francisco, San Francisco, California, USA.
¹¹ Neuro-Oncology Department, Hospices Civils de Lyon, SynatAc Team, Institute MeLis, INSERM U1314/CNRS UMR 5284, Université de Lyon, Université Claude Bernard Lyon 1, Lyon, France.
¹² Department of Neurology and Neurosurgery, Brain Tumour Research Centre, Montreal Neurological Institute-Hospital, McGill University, Montreal, Quebec, Canada.
¹³ Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
¹⁴ Neurology Clinic, University of Heidelberg, National Center for Tumor Diseases, Heidelberg, Germany.
¹⁵ Neuro-Oncology Department, Levine Cancer Institute, Charlotte, North Carolina, USA.
¹⁶ Moffitt Cancer Center, University of South Florida, Tampa, Florida, USA.
¹⁷ Department of Neurology and Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
¹⁸ Department of Neurosurgery, Kanazawa University, Ishikawa, Japan.
¹⁹ Bristol Myers Squibb, Princeton, New Jersey, USA.
²⁰ Syneos Health, Morrisville, North Carolina, USA.
²¹ Center for Neuro-Oncology, Dana-Farber/Harvard Cancer Center, Boston, Massachusetts, USA.

PMID: 35511454
PMCID: PMC9629431
DOI: 10.1093/neuonc/noac116

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.

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Figures

**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.

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

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

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