Phase III trial of chemoradiotherapy with temozolomide plus nivolumab or placebo for newly diagnosed glioblastoma with methylated MGMT promoter PMID: 35511454

Target-related Cytokines

2026-09-23

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

Neuro Oncol. 2022 Nov 2;24(11):1935-1949. doi: 10.1093/neuonc/noac116.

Michael Lim ¹ , Michael Weller ² , Ahmed Idbaih ³ , Joachim Steinbach ⁴ ⁵ , Gaetano Finocchiaro ⁶ , Raju R Raval ⁷ , George Ansstas ⁸ , Joachim Baehring ⁹ , Jennie W Taylor ¹⁰ , Jerome Honnorat ¹¹ , Kevin Petrecca ¹² , Filip De Vos ¹³ , Antje Wick ¹⁴ , Ashley Sumrall ¹⁵ , Solmaz Sahebjam ¹⁶ , Ingo K Mellinghoff ¹⁷ , Masashi Kinoshita ¹⁸ , Mustimbo Roberts ¹⁹ , Ruta Slepetis ¹⁹ , Deepti Warad ¹⁹ , David Leung ¹⁹ , Michelle Lee ²⁰ , David A Reardon ²¹ , 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.

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.