Temozolomide and Radiotherapy versus Radiotherapy Alone in Patients with Glioblastoma, IDH-wildtype: Post Hoc Analysis of the EORTC Randomized Phase III CATNON Trial

C. Mircea S. Tesileanu, Marc Sanson, Wolfgang Wick, Alba A. Brandes, Paul M. Clement, Sara C. Erridge, Michael A. Vogelbaum, Anna K. Nowak, Jean Francois Baurain, Warren P. Mason, Helen Wheeler, Olivier L. Chinot, Sanjeev Gill, Matthew Griffin, Leland Rogers, Walter Taal, Roberta Rudà, Michael Weller, Catherine McBain, Myra E. Van LindeKenneth Aldape, Robert B. Jenkins, Johan M. Kros, Pieter Wesseling, Andreas Von Deimling, Youri Hoogstrate, Iris De Heer, Peggy N. Atmodimedjo, Hendrikus J. Dubbink, Rutger W.W. Brouwer, Wilfred F.J. Van IJcken, Kin Jip Cheung, Vassilis Golfinopoulos, Brigitta G. Baumert, Thierry Gorlia, Pim J. French, Martin J. Van Den Bent*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Purpose: In a post hoc analysis of the CATNON trial (NCT00626990), we explored whether adding temozolomide to radiotherapy improves outcome in patients with IDH1/2 wildtype (wt) anaplastic astrocytomas with molecular features of glioblastoma [redesignated as glioblastoma, isocitrate dehydrogenase- wildtype (IDH-wt) in the 2021 World Health Organization (WHO) classification of central nervous system tumors]. Patients and Methods: From the randomized phase III CATNON study examining the addition of adjuvant and concurrent temozolomide to radiotherapy in anaplastic astrocytomas, we selected a subgroup of IDH1/2wt and H3F3Awt tumors with presence of TERT promoter mutations and/or EGFR amplifications and/or combined gain of chromosome 7 and loss of chromosome 10. Molecular abnormalities including MGMT promoter methylation status were determined by next-generation sequencing, DNA methylation profiling, and SNaPshot analysis. Results: Of the 751 patients entered in the CATNON study, 670 had fully molecularly characterized tumors. A total of 159 of these tumors met the WHO 2021 molecular criteria for glioblastoma, IDH-wt. Of these patients, 47 received radiotherapy only and 112 received a combination of radiotherapy and temozolomide. There was no added effect of temozolomide on either overall survival [HR, 1.19; 95% confidence interval (CI), 0.82-1.71] or progression-free survival (HR, 0.87; 95% CI, 0.61-1.24). MGMT promoter methylation was prognostic for overall survival, but was not predictive for outcome to temozolomide treatment either with respect to overall survival or progression-free survival. Conclusions: In this cohort of patients with glioblastoma, IDH-wt temozolomide treatment did not add benefit beyond that observed from radiotherapy, regardless of MGMT promoter status. These findings require a new well-powered prospective clinical study to explore the efficacy of temozolomide treatment in this patient population.

Original languageEnglish
Pages (from-to)2527-2535
Number of pages9
JournalClinical Cancer Research
Volume28
Issue number12
DOIs
Publication statusPublished - 15 Jun 2022

Bibliographical note

Funding Information:
M. Sanson reports grants and other support from AstraZeneca, as well as personal fees from Genenta, Orion, and Mundi Pharma outside the submitted work. W. Wick reports non-financial support from Apogenix, Pfizer, and Roche; personal fees from Enterome; and other support from AstraZeneca, Mundipharma, and Bayer outside the submitted work. P.M. Clement reports personal fees and non-financial support from MSD during the conduct of the study. P.M. Clement also reports personal fees and non-financial support from BMS and Bayer; personal fees from Merck, Takeda, Rakuten, and Leo; non-financial support from Teva; and grants and non-financial support from AstraZeneca outside the submitted work. M.A. Vogelbaum reports grants from Oncosynergy, Celgene, and Denovo; grants and other support from Infuseon Therapeutics; and personal fees from Chimerix outside the submitted work. A.K. Nowak reports grants and personal fees from AstraZeneca and Douglas Pharmaceuticals, as well as personal fees from Seagen, Trizell, Bristol Myers Squibb, and PharmAbcine outside the submitted work. M. Weller reports grants and personal fees from Apogenix; grants from MSD, Merck (EMD), and Quercis; and personal fees from Philogen, BMS, Medac, Nerviano, Novartis, Orbus, and Y-mAbs outside the submitted work. H.J. Dubbink reports personal fees from AbbVie, Bayer, Janssen, Lilly, and Pfizer; grants and personal fees from AstraZeneca and Merck; and nonfinancial support from Illumina outside the submitted work. B.G. Baumert reports personal fees and non-financial support from SAMO (Swiss Academy of Multidisciplinary Oncology) and Roche outside the submitted work. P.J. French reports personal fees from Aurikamed outside the submitted work. M.J. van den Bent reports grants from Dutch Cancer Society, UK Brain Tumor Society, Strijd van Salland, and Schering Plough/MSD during the conduct of the study, as well as personal fees from AGIOS, Boehringer, AstraZeneca, Carthera, Karyopharm, and Genenta outside the submitted work. No disclosures were reported by the other authors.

Funding Information:
This study was funded by Merck, Sharp & Dohme (MSD) formerly Schering-Plough by an educational grant, and by the provision of temozolomide. The clinical study was also supported by the NRG (grants U10CA180868 and U10CA180822), Cancer Research UK grant CRUK/07/028, and Cancer Australia (project grants 1026842 and 1078655). The molecular study was funded by grant GN-000577 from The Brain Tumour Charity, grant 10685 from the Dutch Cancer Society, and financial support from the Vereniging Heino “Strijd van Salland.” We thank our patients and their relatives for their willingness to participate to this study. We also thank all sites and their staff for contributing to this study. We further acknowledge the support of this study by the staff at the EORTC Headquarters, Brussels, Belgium; the NRG Oncology (formerly the Radiation Therapy Oncology Group) staff at the American College of Radiology; the staff at the Australian National Health and Medical Research Council (NHMRC) Clinical Trials Centre (COGNO Coordinating Centre); and the staff at MRC Clinical Trials Unit, London, United Kingdom.

Publisher Copyright:
©2022 American Association for Cancer Research.

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