Michael Lim1, Michael Weller2, Ahmed Idbaih3, Joachim Steinbach4,5, 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 Omuro9,17. 1. Stanford University School of Medicine, Palo Alto, CA, 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. The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA. 8. Washington University Medical School, St Louis, MO, USA. 9. Yale University School of Medicine, New Haven, CT, USA. 10. Departments of Neurology and Neurological Surgery, University of California San Francisco, San Francisco, CA, 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. Brain Tumour Research Centre, Montreal Neurological Institute-Hospital, Department of Neurology and Neurosurgery, McGill University, Montreal, QC, 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. Levine Cancer Institute, Charlotte, NC, USA. 16. Moffitt Cancer Center, University of South Florida, Tampa, FL, USA. 17. Department of Neurology and Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 18. Department of Neurosurgery, Kanazawa University, Ishikawa, Japan. 19. Bristol Myers Squibb, Princeton, NJ, USA. 20. Syneos Health, Morrisville, NC, USA. 21. Dana-Farber/Harvard Cancer Center, Boston, MA, 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 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.
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.
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