Matthias Preusser1, Antonio Silvani2, Emilie Le Rhun3,4,5,6, 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 Clement19,20, Sarah Dumont21, Marc Sanson22, Charlotte Bronnimann23,24, Carmen Balaná25, Niklas Thon26, Joanne Lewis27, Maximilian J Mair1, Philipp Sievers28,29, Julia Furtner30, Josef Pichler31, Jordi Bruna32, Francois Ducray33,34, Jaap C Reijneveld35,36, Christian Mawrin37, Martin Bendszus38, Christine Marosi1, Vassilis Golfinopoulos39, Corneel Coens39, Thierry Gorlia39, Michael Weller40, Felix Sahm28,29, Wolfgang Wick41. 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.
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.
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.
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