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Lomustine-temozolomide combination therapy versus standard temozolomide therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter (CeTeG/NOA-09): a randomised, open-label, phase 3 trial

Ulrich Herrlinger, Theophilos Tzaridis, Frederic Mack, Joachim Peter Steinbach, Uwe Schlegel, Michael Sabel, Peter Hau, Rolf-Dieter Kortmann, Dietmar Krex, Oliver Grauer, Roland Goldbrunner, Oliver Schnell, Oliver Bähr, Martin Uhl, Clemens Seidel, Ghazaleh Tabatabai, Thomas Kowalski, Florian Ringel, Friederike Schmidt-Graf, Bogdana Suchorska, Stefanie Brehmer, Astrid Weyerbrock, Miriam Renovanz, Lars Bullinger, Norbert Galldiks, Peter Vajkoczy, Martin Misch, Hartmut Vatter, Moritz Stuplich, Niklas Schäfer, Sied Kebir, Johannes Weller, Christina Schaub, Walter Stummer, Jörg-Christian Tonn, Matthias Simon, Vera C Keil, Michael Nelles, Horst Urbach, Martin Coenen, Wolfgang Wick, Michael Weller, Rolf Fimmers, Matthias Schmid, Elke Hattingen, Torsten Pietsch, Christoph Coch, Martin Glas & Neurooncology Working Group Of The German Cancer Society

abstract

BACKGROUND
There is an urgent need for more effective therapies for glioblastoma. Data from a previous unrandomised phase 2 trial suggested that lomustine-temozolomide plus radiotherapy might be superior to temozolomide chemoradiotherapy in newly diagnosed glioblastoma with methylation of the MGMT promoter. In the CeTeG/NOA-09 trial, we aimed to further investigate the effect of lomustine-temozolomide therapy in the setting of a randomised phase 3 trial.

METHODS
In this open-label, randomised, phase 3 trial, we enrolled patients from 17 German university hospitals who were aged 18-70 years, with newly diagnosed glioblastoma with methylated MGMT promoter, and a Karnofsky Performance Score of 70% and higher. Patients were randomly assigned (1:1) with a predefined SAS-generated randomisation list to standard temozolomide chemoradiotherapy (75 mg/m per day concomitant to radiotherapy [59-60 Gy] followed by six courses of temozolomide 150-200 mg/m per day on the first 5 days of the 4-week course) or to up to six courses of lomustine (100 mg/m on day 1) plus temozolomide (100-200 mg/m per day on days 2-6 of the 6-week course) in addition to radiotherapy (59-60 Gy). Because of the different schedules, patients and physicians were not masked to treatment groups. The primary endpoint was overall survival in the modified intention-to-treat population, comprising all randomly assigned patients who started their allocated chemotherapy. The prespecified test for overall survival differences was a log-rank test stratified for centre and recursive partitioning analysis class. The trial is registered with ClinicalTrials.gov, number NCT01149109.

FINDINGS
Between June 17, 2011, and April 8, 2014, 141 patients were randomly assigned to the treatment groups; 129 patients (63 in the temozolomide and 66 in the lomustine-temozolomide group) constituted the modified intention-to-treat population. Median overall survival was improved from 31·4 months (95% CI 27·7-47·1) with temozolomide to 48·1 months (32·6 months-not assessable) with lomustine-temozolomide (hazard ratio [HR] 0·60, 95% CI 0·35-1·03; p=0·0492 for log-rank analysis). A significant overall survival difference between groups was also found in a secondary analysis of the intention-to-treat population (n=141, HR 0·60, 95% CI 0·35-1·03; p=0·0432 for log-rank analysis). Adverse events of grade 3 or higher were observed in 32 (51%) of 63 patients in the temozolomide group and 39 (59%) of 66 patients in the lomustine-temozolomide group. There were no treatment-related deaths.

INTERPRETATION
Our results suggest that lomustine-temozolomide chemotherapy might improve survival compared with temozolomide standard therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter. The findings should be interpreted with caution, owing to the small size of the trial.

FUNDING
German Federal Ministry of Education and Research.
   
citation Herrlinger U, Tzaridis T, Mack F, Steinbach J P, Schlegel U, Sabel M, Hau P, Kortmann R D, Krex D, Grauer O, Goldbrunner R, Schnell O, Bähr O, Uhl M, Seidel C, Tabatabai G, Kowalski T, Ringel F, Schmidt-Graf F, Suchorska B, Brehmer S, Weyerbrock A, Renovanz M, Bullinger L, Galldiks N, Vajkoczy P, Misch M, Vatter H, Stuplich M, Schäfer N, Kebir S, Weller J, Schaub C, Stummer W, Tonn J C, Simon M, Keil V C, Nelles M, Urbach H, Coenen M, Wick W, Weller M, Fimmers R, Schmid M, Hattingen E, Pietsch T, Coch C, Glas M, Neurooncology Working Group of the German Cancer Society . Lomustine-temozolomide combination therapy versus standard temozolomide therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter (CeTeG/NOA-09): a randomised, open-label, phase 3 trial. Lancet 2019; 393:678-688.
   
type journal paper/review (English)
date of publishing 14-02-2019
journal title Lancet (393/10172)
ISSN electronic 1474-547X
pages 678-688
PubMed 30782343
DOI 10.1016/S0140-6736(18)31791-4