Clinical Trial

. 2022 May 4;24(5):755-767.

doi: 10.1093/neuonc/noab243.

Trabectedin for recurrent WHO grade 2 or 3 meningioma: A randomized phase II study of the EORTC Brain Tumor Group (EORTC-1320-BTG)

Matthias Preusser¹, Antonio Silvani², Emilie Le Rhun^{3

4

5

6}, Riccardo Soffietti⁷, Giuseppe Lombardi⁸, Juan Manuel Sepulveda⁹, Petter Brandal¹⁰, Lucy Brazil¹¹, Alice Bonneville-Levard¹², Veronique Lorgis¹³, Elodie Vauleon¹⁴, Jacoline Bromberg¹⁵, Sara Erridge¹⁶, Alison Cameron¹⁷, Florence Lefranc¹⁸, Paul M Clement^{19

20}, Sarah Dumont²¹, Marc Sanson²², Charlotte Bronnimann^{23

24}, Carmen Balaná²⁵, Niklas Thon²⁶, Joanne Lewis²⁷, Maximilian J Mair¹, Philipp Sievers^{28

29}, Julia Furtner³⁰, Josef Pichler³¹, Jordi Bruna³², Francois Ducray^{33

34}, Jaap C Reijneveld^{35

36}, Christian Mawrin³⁷, Martin Bendszus³⁸, Christine Marosi¹, Vassilis Golfinopoulos³⁹, Corneel Coens³⁹, Thierry Gorlia³⁹, Michael Weller⁴⁰, Felix Sahm^{28

29}, Wolfgang Wick⁴¹

Affiliations

¹ Department of Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria.
² Department of Neuro-Oncology, IRCCS Fondazione Istituto Neurologico Carlo Besta, Milan, Italy.
³ University of Lille, U-1192, Lille, France.
⁴ Inserm, U-1192, Lille, France.
⁵ General and Stereotaxic Neurosurgery Service, CHU Lille, Lille, France.
⁶ Medical Oncology Department, Oscar Lambret Center, Lille, France.
⁷ Department of Neuro-Oncology, University and City of Health and Science Hospital, Turin, Italy.
⁸ Department of Oncology 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
⁹ Neurooncology Unit, Hospital Universitario 12 de Octubre, Madrid, Spain.
¹⁰ Department of Oncology, Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway.
¹¹ St Thomas' Hospital, London, UK.
¹² Centre Leon Berard, Lyon, France.
¹³ Department of Medical Oncology, Centre Georges François Leclerc, Dijon, France.
¹⁴ Department of Medical Oncology, Centre Eugene Marquis, Rennes, France.
¹⁵ Department of Neuro-Oncology, Erasmus MC University Medical Center Cancer Center, Rotterdam, the Netherlands.
¹⁶ Edinburgh Cancer Centre, Western General Hospital, Edinburgh, UK.
¹⁷ Bristol Cancer Institute, University Hospitals Bristol, Bristol, UK.
¹⁸ Department of Neurosurgery, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.
¹⁹ Department of Oncology, KU Leuven, Leuven, Belgium.
²⁰ Department of General Medical Oncology, Leuven Cancer Institute, UZ Leuven, Leuven, Belgium.
²¹ Medical Oncology Department, Institut Gustave-Roussy, Université Paris-Saclay, Villejuif, France.
²² Sorbonne Université, Inserm, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Service de Neurologie 2-Mazarin, Paris, France.
²³ Department of Medical Oncology, Bordeaux University Hospital-CHU, Bordeaux, France.
²⁴ University of Bordeaux, Bordeaux, France.
²⁵ Department of Medical Oncology, Catalan Institute of Oncology, Badalona, Barcelona, Spain.
²⁶ Department of Neurosurgery, Faculty of Medicine and University Hospital, University of Munich (LMU), Munich, Germany.
²⁷ Freeman Hospital, Newcastle, UK.
²⁸ Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
²⁹ Clinical Cooperation Unit Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
³⁰ Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria.
³¹ Department of Internal Medicine and Neurooncology, Neuromed Campus, Kepler University Hospital, Johannes Kepler University of Linz, Linz, Austria.
³² Unit of Neuro-Oncology, Hospital Universitari de Bellvitge-Institut Català D'Oncologia L'Hospitalet, Barcelona, Spain.
³³ Unit of Neuro-Oncology, Hospices Civils de Lyon, Lyon, France.
³⁴ Department of Cancer Cell Plasticity, Cancer Research Center of Lyon, Claude Bernard University, Lyon, France.
³⁵ Brain Tumor Center, Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands.
³⁶ Stichting Epilepsie Instellingen Nederland, Heemstede, the Netherlands.
³⁷ Department of Neuropathology, Otto-von-Guericke-University, Magdeburg, Germany.
³⁸ Department of Neuroradiology, University of Heidelberg, Heidelberg, Germany.
³⁹ European Organisation for Research and Treatment of Cancer (EORTC) Headquarters, Brussels, Belgium.
⁴⁰ Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland.
⁴¹ Neurology Clinic, Heidelberg University Medical Center, Clinical Cooperation Unit, Neurooncology, German Cancer Research Center, Heidelberg, Germany.

PMID: 34672349
PMCID: PMC9071312
DOI: 10.1093/neuonc/noab243

Clinical Trial

Trabectedin for recurrent WHO grade 2 or 3 meningioma: A randomized phase II study of the EORTC Brain Tumor Group (EORTC-1320-BTG)

Matthias Preusser et al. Neuro Oncol. 2022.

. 2022 May 4;24(5):755-767.

doi: 10.1093/neuonc/noab243.

Authors

Affiliations

¹ Department of Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria.
² Department of Neuro-Oncology, IRCCS Fondazione Istituto Neurologico Carlo Besta, Milan, Italy.
³ University of Lille, U-1192, Lille, France.
⁴ Inserm, U-1192, Lille, France.
⁵ General and Stereotaxic Neurosurgery Service, CHU Lille, Lille, France.
⁶ Medical Oncology Department, Oscar Lambret Center, Lille, France.
⁷ Department of Neuro-Oncology, University and City of Health and Science Hospital, Turin, Italy.
⁸ Department of Oncology 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
⁹ Neurooncology Unit, Hospital Universitario 12 de Octubre, Madrid, Spain.
¹⁰ Department of Oncology, Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway.
¹¹ St Thomas' Hospital, London, UK.
¹² Centre Leon Berard, Lyon, France.
¹³ Department of Medical Oncology, Centre Georges François Leclerc, Dijon, France.
¹⁴ Department of Medical Oncology, Centre Eugene Marquis, Rennes, France.
¹⁵ Department of Neuro-Oncology, Erasmus MC University Medical Center Cancer Center, Rotterdam, the Netherlands.
¹⁶ Edinburgh Cancer Centre, Western General Hospital, Edinburgh, UK.
¹⁷ Bristol Cancer Institute, University Hospitals Bristol, Bristol, UK.
¹⁸ Department of Neurosurgery, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.
¹⁹ Department of Oncology, KU Leuven, Leuven, Belgium.
²⁰ Department of General Medical Oncology, Leuven Cancer Institute, UZ Leuven, Leuven, Belgium.
²¹ Medical Oncology Department, Institut Gustave-Roussy, Université Paris-Saclay, Villejuif, France.
²² Sorbonne Université, Inserm, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Service de Neurologie 2-Mazarin, Paris, France.
²³ Department of Medical Oncology, Bordeaux University Hospital-CHU, Bordeaux, France.
²⁴ University of Bordeaux, Bordeaux, France.
²⁵ Department of Medical Oncology, Catalan Institute of Oncology, Badalona, Barcelona, Spain.
²⁶ Department of Neurosurgery, Faculty of Medicine and University Hospital, University of Munich (LMU), Munich, Germany.
²⁷ Freeman Hospital, Newcastle, UK.
²⁸ Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
²⁹ Clinical Cooperation Unit Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
³⁰ Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria.
³¹ Department of Internal Medicine and Neurooncology, Neuromed Campus, Kepler University Hospital, Johannes Kepler University of Linz, Linz, Austria.
³² Unit of Neuro-Oncology, Hospital Universitari de Bellvitge-Institut Català D'Oncologia L'Hospitalet, Barcelona, Spain.
³³ Unit of Neuro-Oncology, Hospices Civils de Lyon, Lyon, France.
³⁴ Department of Cancer Cell Plasticity, Cancer Research Center of Lyon, Claude Bernard University, Lyon, France.
³⁵ Brain Tumor Center, Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands.
³⁶ Stichting Epilepsie Instellingen Nederland, Heemstede, the Netherlands.
³⁷ Department of Neuropathology, Otto-von-Guericke-University, Magdeburg, Germany.
³⁸ Department of Neuroradiology, University of Heidelberg, Heidelberg, Germany.
³⁹ European Organisation for Research and Treatment of Cancer (EORTC) Headquarters, Brussels, Belgium.
⁴⁰ Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland.
⁴¹ Neurology Clinic, Heidelberg University Medical Center, Clinical Cooperation Unit, Neurooncology, German Cancer Research Center, Heidelberg, Germany.

PMID: 34672349
PMCID: PMC9071312
DOI: 10.1093/neuonc/noab243

Abstract

Background: No systemic treatment has been established for meningioma progressing after local therapies.

Methods: This randomized, multicenter, open-label, phase II study included adult patients with recurrent WHO grade 2 or 3 meningioma. Patients were 2:1 randomly assigned to intravenous trabectedin (1.5 mg/m2 every 3 weeks) or local standard of care (LOC). The primary endpoint was progression-free survival (PFS). Secondary endpoints comprised overall survival (OS), objective radiological response, safety, quality of life (QoL) assessment using the QLQ-C30 and QLQ-BN20 questionnaires, and we performed tissue-based exploratory molecular analyses.

Results: Ninety patients were randomized (n = 29 in LOC, n = 61 in trabectedin arm). With 71 events, median PFS was 4.17 months in the LOC and 2.43 months in the trabectedin arm (hazard ratio [HR] = 1.42; 80% CI, 1.00-2.03; P = .294) with a PFS-6 rate of 29.1% (95% CI, 11.9%-48.8%) and 21.1% (95% CI, 11.3%-32.9%), respectively. Median OS was 10.61 months in the LOC and 11.37 months in the trabectedin arm (HR = 0.98; 95% CI, 0.54-1.76; P = .94). Grade ≥3 adverse events occurred in 44.4% of patients in the LOC and 59% of patients in the trabectedin arm. Enrolled patients had impeded global QoL and overall functionality and high fatigue before initiation of systemic therapy. DNA methylation class, performance status, presence of a relevant co-morbidity, steroid use, and right hemisphere involvement at baseline were independently associated with OS.

Conclusions: Trabectedin did not improve PFS and OS and was associated with higher toxicity than LOC treatment in patients with non-benign meningioma. Tumor DNA methylation class is an independent prognostic factor for OS.

Keywords: DNA methylation class; clinical trial; meningioma; quality of life; trabectedin.

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Figures

**Fig. 1**
Progression-free survival (A) and overall survival (B) in the per-protocol population (primary analysis).

**Fig. 2**
Exploratory comparison of progression-free survival (A) and overall survival (B) with the most commonly applied LOC treatments and trabectedin in the intention-to-treat population. Abbreviation: LOC, local standard of care.

**Fig. 3**
(A) Molecular alterations, methylation classes, and WHO grades in patients enrolled in the EORTC-1320-BTG trial. (B) Frequency of mutations according to methylation classes.

See this image and copyright information in PMC

Comment in

Trabectedin for recurrent WHO grade 2 or 3 meningiomas-Paving the road for new opportunities.
Alvarez-Breckenridge CA, Cahill DP, Brastianos PK. Alvarez-Breckenridge CA, et al. Neuro Oncol. 2022 May 4;24(5):768-769. doi: 10.1093/neuonc/noac017. Neuro Oncol. 2022. PMID: 35100424 Free PMC article. No abstract available.

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Trabectedin for recurrent WHO grade 2 or 3 meningioma: A randomized phase II study of the EORTC Brain Tumor Group (EORTC-1320-BTG)

Affiliations

Trabectedin for recurrent WHO grade 2 or 3 meningioma: A randomized phase II study of the EORTC Brain Tumor Group (EORTC-1320-BTG)

Authors

Affiliations

Abstract

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Comment in

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Medical