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

  • 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.

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Author:Michael LimGND, Michael WellerORCiDGND, Ahmed IdbaihORCiD, Joachim Peter SteinbachORCiDGND, Gaetano FinocchiaroORCiD, Raju R, RavalORCiD, George AnsstasORCiD, Joachim BähringGND, Jennie W Taylor, Jerome HonnoratORCiD, Kevin PetreccaGND, Filip de VosORCiD, Antje WickORCiDGND, Ashley SumrallORCiD, Solmaz SahebjamORCiD, Ingo K. MellinghoffORCiD, Masashi KinoshitaORCiD, Mustimbo Roberts, Ruta Slepetis, Deepti Warad, David Leung, Michelle Lee, David A. ReardonGND, Antonio OmuroORCiD
URN:urn:nbn:de:hebis:30:3-633129
DOI:https://doi.org/10.1093/neuonc/noac116
ISSN:1523-5866
Parent Title (English):Neuro Oncology
Publisher:Oxford Univ. Press
Place of publication:Oxford
Document Type:Article
Language:English
Date of Publication (online):2022/05/02
Date of first Publication:2022/05/02
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2022/12/19
Tag:temozolomide
MGMT promoter; PD-L1; glioblastoma; nivolumab
Volume:24
Issue:11
Page Number:15
First Page:1935
Last Page:1949
Note:
Funding
This study was supported by Bristol Myers Squibb, Inc., Princeton, NJ, USA.

Conflict of interest statement. M. Lim received research support from Accuray, Arbor Pharmaceuticals, Biohaven, Bristol Myers Squibb, Kirin-Kyowa, Tocagen, and UroGen; received personal and consultant fees from Biohaven, Black Diamond Therapeutics, Century Therapeutics, Hemispherian, InCando, InCephalo Therapeutics, Insightec, Novocure, Noxxon, Pyramid Bio, Sanianoia, Stryker, VBI; and has shares in Egret Theraeutics. M.W. received other funding from Bristol Myers Squibb; grants from Merck (EMD), MSD, Novocure, and Quercis; and personal fees from AbbVie, Bristol Myers Squibb, Merck (EMD), MSD, Orbus, and Y-mAbs. A.I. received research grants from Carthera, Transgene, Sanofi, Air Liquide, Servier Pharmaceuticals, Nutritheragene; travel funding from Novocure, Carthera, and Leo Pharma; served on advisory boards for Leo Pharma and Novocure. J.S. received other funding from AbbVie; received personal fees from Medac, Med-Update, Novocure, Roche, and Seagen; and served on advisory boards for Novocure and Seagen. G.F. received other funding from Genenta. R.R.R. has nothing to disclose. G.A. has nothing to disclose. J.B. has served as a consultant for Bristol Myers Squibb. J.W.T. received grants from AbbVie, Agios, and Navio and personal fees from Medlink. J.H. has nothing to disclose. K.P. has nothing to disclose. F.D.V. received funding from Agios, Bristol Myers Squibb, Novartis, and Roche. A.W. has nothing to disclose. A.S. received grant funding from Kura Oncology and Exelixis; other funding from Bristol Myers Squibb, Novocure, Merck, Bayer, AbbVie, Oncoceutics, and Caris Life Sciences. S.S. received grant funding from Bristol Myers Squibb, Brooklyn Immunotherapeutics, and Merck; other funding from Boehringer Ingelheim, Eli Lilly, Merck; and personal fees from AbbVie. I.K.M. received research funding from Amgen, General Electric, Lilly, Kazia Therapeutics, and Servier Pharmaceuticals; other funding from Agios, Black Diamond Therapeutics, Debiopharm Group, Puma Biotechnology, Servier Pharmaceuticals, Voyager Therapeutics, DC Europa Ltd, Kazia Therapeutics, Novartis, Cardinal Health, Roche, Vigeo Therapeutics, Samus Therapeutics, Prelude Therapeutics, and AstraZeneca. M.K. has nothing to disclose. M.R. is an employee and received stocks from Bristol Myers Squibb. R.S. is an employee of Bristol Myers Squibb. D.W. is an employee of Bristol Myers Squibb. D.L. was an employee and received stocks from Bristol Myers Squibb. M. Lee is an employee of Bristol Myers Squibb. D.A.R. received other funding from Acerta Pharma, Agenus, Celldex, EMD Serono, Incyte, Inovio, Midatech, Omniox, and Tragara and personal fees from AbbVie, Advantagene, Agenus, Amgen, Bayer, Bristol Myers Squibb, Celldex, DelMar, EMD Serono, Genentech/Roche, Inovio, Merck, Merck KGaA, Monteris, Novocure, Oncorus, Oxigene, Regeneron, Stemline, and Taiho Oncology, Inc. A.O. has served as a consultant on ad hoc advisory boards for KIYATEC, Merck, Pyramid, and Ono Pharmaceutical Company Ltd, and has received grant funding from Agios, Arcus Biosciences, and Denovo.
Note:
Data Availability
The Bristol Myers Squibb policy on data sharing may be found at https://www.bms.com/researchers-and-partners/independent-research/data-sharing-request-process.html.
Institutes:Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - CC BY-NC - Namensnennung - Nicht kommerziell 4.0 International

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