Meeting
2014 ASCO Annual Meeting
MGMT promoter methylation as a prognostic biomarker for benefit from dose-intensified temozolomide rechallenge in progressive glioblastoma: First results from the randomized phase II DIRECTOR trial.
Authors
Ghazaleh Tabatabai
Department of Neurology, University Hospital Zurich, Zurich, Switzerland
Ghazaleh Tabatabai , Wolfgang Wick , Joachim Peter Steinbach , Antje Wick , Oliver Schnell , Peter Hau , Ulrich Herrlinger , Michael Sabel , Hans-Georg Wirsching , Ralf Ketter , Oliver Baehr , Michael Platten , Joerg Tonn , Johannes Huesing , Guido Reifenberger , Michael Weller
Organizations
Department of Neurology, University Hospital Zurich, Zurich, Switzerland, Neurooncology, University of Heidelberg Medical Center, Heidelberg, Germany, Senckenberg Institute of Neurooncology, Frankfurt, Germany, Department of Neurooncology, University Hospital Heidelberg, Heidelberg, Germany, Department of Neurosurgery, University Hospital Munich LMU, Munich, Germany, Department of Neurology and Wilhelm Sander NeuroOncology Unit, University Hospital Regensburg, Regensburg, Germany, Division of Clinical Neurooncology, Department of Neurology and Center of Integrated Oncology Cologne/Bonn, University of Bonn, Bonn, Germany, Department of Neurosurgery, University Hospital Düsseldorf, Düsseldorf, Germany, Department of Neurosurgery, University Hospital Homburg, Homburg, Germany, Dr. Senckenberg Institute of Neurooncology, Frankfurt, Germany, Department of Neurosurgery, LMU Munich, Munich, Germany, Coordination Centre for Clinical Trials (KKS), Heidelberg University Hospital, Heidelberg, Germany, Institute of Neuropathology, University of Duesseldorf, Duesseldorf, Germany, University Hospital Zurich, Zurich, Switzerland
Research Funding
Pharmaceutical/Biotech Company
Background: Rechallenge with temozolomide (TMZ) at first progression of glioblastoma after radiotherapy with concomitant and maintenance temozolomide (TMZ/RT→TMZ) has been studied in retrospective and single-arm prospective studies, applying TMZ continuously or using 7/14 or 21/28 days schedules. Progression-free survival rates have been in the range of 10-30% without any major prognostic impact of O6-methylguanine DNA methyltransferase (MGMT). Methods: Glioblastoma patients at first progression after TMZ/RT→TMZ and at least 2 maintenance TMZ cycles were randomized to Arm A (one week on (150 mg/sqm TMZ per day) / one week off) or to Arm B (three weeks on (100 mg/sqm TMZ per day) / one week off). The primary end point was median time to treatment failure defined as progression, premature (< 12 months) TMZ discontinuation for toxicity, or death from any cause; 166 patients were deemed necessary to show a meaningful difference between arms. Results: Because of withdrawal of support, the trial was prematurely closed to accrual after 105 patients.The outcomes in Arm A and Arm B for the primary endpoint of median time to treatment failure (56 days [95% CI 55-98] vs. 59.5 days [95% CI 56-105]) and for overall survival (OS) (298 days [95% CI 202-395] vs. 322 days, [95% CI 246-356]) were similar. These endpoints differed, however, by MGMT promoter methylation status, which was informative for all patients. Median time to treatment failure in patients with MGMT-methylated tumors was 98 days [95% CI 56-223] vs. 56 days [95% CI 56-60] in MGMT-unmethylated glioblastoma. PFS-6 was 39.7% vs. 6.9% with vs. without MGMT promoter methylation; OS with MGMT-methylated glioblastoma was 382 days [95% CI 300-531] vs. 241 days [95% CI 191-313] in MGMT-unmethylated glioblastoma. Hematological toxicity > grade 3 was similar (27% Arm A vs. 30.7% Arm B). Conclusions: TMZ rechallenge is an active treatment for MGMT promoter-methylated glioblastoma progressive after standard therapy. The best TMZ regimen remains to be defined. Alternative strategies are warranted for patients with progressive MGMT-unmethylated glioblastoma. Clinical trial information: NCT00941460.
Disclaimer
This material on this page is ©2024 American Society of Clinical Oncology, all rights reserved. Licensing available upon request. For more information, please contact licensing@asco.org
Abstract Details
Session Type
Poster Highlights Session
Session Title
Central Nervous System Tumors
Track
Central Nervous System Tumors
Sub Track
Central Nervous System Tumors
Clinical Trial Registration Number
NCT00941460
Citation
J Clin Oncol 32:5s, 2014 (suppl; abstr 2015)
DOI
10.1200/jco.2014.32.15_suppl.2015
Abstract #
2015
Poster Bd #
5
Abstract Disclosures
Similar Abstracts
Abstract
2023 ASCO Annual Meeting
A randomised phase II multicentre study of ipilimumab with temozolomide vs temozolomide alone after surgery and chemoradiotherapy in patients with recently diagnosed glioblastoma: Ipi-Glio.
First Author: Paul James Mulholland
Abstract
2022 ASCO Annual Meeting
Bortezomib sensitization of recurrent glioblastoma with unmethylated MGMT promoter to temozolomide, a phase II study (NCT03643549).
First Author: Dorota Goplen
Abstract
2023 ASCO Annual Meeting
Final analysis of 2-THE-TOP: A phase 2 study of TTFields (Optune) plus pembrolizumab plus maintenance temozolomide (TMZ) in patients with newly diagnosed glioblastoma.
First Author: David D. Tran
Abstract
2022 ASCO Annual Meeting
Phase II multicentric Italian trial on repositioning of the antipsychotic drug chlorpromazine and its combination with temozolomide in patients with MGMT unmethylated glioblastoma: The RACTAC trial.
First Author: Giuseppe Lombardi