[en] [en] BACKGROUND: Standard treatment for patients with newly diagnosed glioblastoma includes surgery, radiotherapy (RT), and temozolomide (TMZ) chemotherapy (TMZ/RT→TMZ). The proteasome has long been considered a promising therapeutic target because of its role as a central biological hub in tumor cells. Marizomib is a novel pan-proteasome inhibitor that crosses the blood-brain barrier.
METHODS: European Organisation for Research and Treatment of Cancer 1709/Canadian Cancer Trials Group CE.8 was a multicenter, randomized, controlled, open-label phase 3 superiority trial. Key eligibility criteria included newly diagnosed glioblastoma, age > 18 years and Karnofsky performance status > 70. Patients were randomized in a 1:1 ratio. The primary objective was to compare overall survival (OS) in patients receiving marizomib in addition to TMZ/RT→TMZ with patients receiving the only standard treatment in the whole population and in the subgroup of patients with MGMT promoter-unmethylated tumors.
RESULTS: The trial was opened at 82 institutions in Europe, Canada, and the U.S. A total of 749 patients (99.9% of the planned 750) were randomized. OS was not different between the standard and the marizomib arm (median 17 vs. 16.5 months; HR = 1.04; P = .64). PFS was not statistically different either (median 6.0 vs. 6.3 months; HR = 0.97; P = .67). In patients with MGMT promoter-unmethylated tumors, OS was also not different between standard therapy and marizomib (median 14.5 vs. 15.1 months, HR = 1.13; P = .27). More CTCAE grade 3/4 treatment-emergent adverse events were observed in the marizomib arm than in the standard arm.
CONCLUSIONS: Adding marizomib to standard temozolomide-based radiochemotherapy resulted in more toxicity, but did not improve OS or PFS in patients with newly diagnosed glioblastoma.
Disciplines :
Oncology
Author, co-author :
Roth, Patrick ; Department of Neurology and Brain Tumor Center, University Hospital Zurich, Zurich, Switzerland ; Department of Neurology, University of Zurich, Zurich, Switzerland
Gorlia, Thierry; European Organisation for Research and Treatment of Cancer (EORTC), Brussels, Belgium
Reijneveld, Jaap C; Department of Neurology & Brain Tumor Center, Amsterdam University Medical Centers, Amsterdam, The Netherlands
de Vos, Filip; Department of Medical Oncology, University Medical Center Utrecht, University Utrecht, Utrecht, The Netherlands
Idbaih, Ahmed ; Sorbonne Université, AP-HP, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, DMU Neurosciences, Service de Neurologie 2-Mazarin, Paris, France
Frenel, Jean-Sébastien; Department of Medical Oncology, Institut de Cancerologie de L'Ouest, Saint-Herblain, France
Le Rhun, Emilie ; CHU Lille, Service de neurochirurgie, Lille, France ; Univ. Lille, Inserm, CHU Lille, U1192, Laboratoire Protéomique, Réponse Inflammatoire et Spectrométrie de Masse (PRISM), Lille, France ; Department of Neurosurgery & Clinical Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland
Sepulveda, Juan Manuel; Neuro-Oncology Unit, Department of Medical Oncology, Instituto de Investigación Hospital 12 de Octubre, Madrid, Spain
Perry, James; Division of Neurology, Sunnybrook HSC, University of Toronto, Toronto, Ontario, Canada
Masucci, G Laura; Department of Radiation Oncology, Centre Hospitalier de l'Université de Montréal (CHUM), Montréal, Québec, Canada
Freres, Pierre ; Université de Liège - ULiège > Département des sciences cliniques
Hirte, Hal; Department of Oncology, McMaster University, Hamilton, Ontario, Canada
Seidel, Clemens; Department of Radiation Oncology, University Hospital Leipzig, Leipzig, Germany
Walenkamp, Annemiek; Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
Lukacova, Slavka; Department of Oncology, Aarhus University Hospital, Aarhus, Denmark
Meijnders, Paul; Department of Radiation Oncology, Iridium Network Antwerpen, University of Antwerp, Antwerp, Belgium
Blais, Andre; Service d'hématologie et d'oncologie, Centre intégré de cancérologie du CHU de Québec - Université Laval, Québec City, Québec, Canada
Ducray, Francois; Department of Neuro-Oncology, Hospices Civils de Lyon and Université Claude Bernard Lyon 1, Lyon, France ; Lyon Cancer Research Center (CRCL) UMR INSERM 1052 CNRS 5286, Lyon, France
Verschaeve, Vincent; Department of Medical Oncology, GHDC Grand Hopital de Charleroi, Charleroi, Belgium
Nicholas, Garth ; University of Ottawa, Division of Medical Oncology, Ottawa, Ontario, Canada
Balana, Carmen ; Badalona Applied Research Group in Oncology (B-ARGO Group), Institut Investigació Germans Trias i Pujol (IGTP), Badalona, Spain
Bota, Daniela A; Chao Family Comprehensive Cancer Center and Department of Neurology, University of California, Irvine, California, USA
Preusser, Matthias ; Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria
Nuyens, Sarah; European Organisation for Research and Treatment of Cancer (EORTC), Brussels, Belgium
Dhermain, Fréderic; Department of Radiation Oncology, University Hospital Gustave Roussy, Villejuif, France
van den Bent, Martin; Brain Tumor Center at ErasmusMC Cancer Institute, Rotterdam, The Netherlands
O'Callaghan, Chris J; Canadian Cancer Trials Group, Queen's University, Kingston, Ontario, Canada
Vanlancker, Maureen; European Organisation for Research and Treatment of Cancer (EORTC), Brussels, Belgium ; Princess Margaret Cancer Centre, Toronto, Ontario, Canada
Mason, Warren; Department of Medicine, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada
Weller, Michael ; Department of Neurology and Brain Tumor Center, University Hospital Zurich, Zurich, Switzerland ; Department of Neurology, University of Zurich, Zurich, Switzerland
Weller M, van den Bent M, Preusser M, et al. EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood. Nat Rev Clin Oncol. 2021;18(3):170–186.
Wen PY, Weller M, Lee EQ, et al. Glioblastoma in adults: a Society for Neuro-Oncology (SNO) and European Society of Neuro-Oncology (EANO) consensus review on current management and future directions. Neuro Oncol. 2020;22(8):1073–1113.
Stupp R, Taillibert S, Kanner A, et al. Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: a randomized clinical trial. JAMA. 2017;318(23):2306–2316.
Chinot OL, Wick W, Mason W, et al. Bevacizumab plus radiotherapy–temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014;370(8):709–722.
Gilbert MR, Dignam JJ, Armstrong TS, et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014;370(8):699–708.
Stupp R, Hegi ME, Gorlia T, et al; European Organisation for Research and Treatment of Cancer (EORTC). Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15(10):1100–1108.
Lassman AB, Pugh SL, Wang TJC, et al. Depatuxizumab mafodotin in EGFR-amplified newly diagnosed glioblastoma: a phase III randomized clinical trial. Neuro Oncol. 2023;25(2):339–350.
Weller M, Butowski N, Tran DD, et al; ACT IV trial investigators. Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial. Lancet Oncol. 2017;18(10):1373–1385.
Omuro A, Brandes AA, Carpentier AF, et al. Radiotherapy combined with nivolumab or temozolomide for newly diagnosed glioblastoma with unmethylated MGMT promoter: an international randomized phase III trial. Neuro Oncol. 2023;25(1):123–134.
Lim M, Weller M, Idbaih A, et al. Phase III trial of chemoradiotherapy with temozolomide plus nivolumab or placebo for newly diagnosed glioblastoma with methylated MGMT promoter. Neuro Oncol. 2022;24(11):1935–1949.
Reardon DA, Brandes AA, Omuro A, et al. Effect of Nivolumab vs Bevacizumab in patients with recurrent glioblastoma: the CheckMate 143 Phase 3 randomized clinical trial. JAMA Oncol. 2020;6(7):1003–1010.
Lassman AB, Polley MC, Iwamoto FM, et al. NRG Oncology Study BN007: randomized phase II/III trial of ipilimumab (IPI) plus nivolumab (nivo) vs. temozolomide (TMZ) in MGMT-unmethylated (UMGMT) newly diagnosed glioblastoma (NGBM). Neuro Oncol. 2023;25(Suppl ement_2):ii2.
Manasanch EE, Orlowski RZ. Proteasome inhibitors in cancer therapy. Nat Rev Clin Oncol. 2017;14(7):417–433.
Kong XT, Nguyen NT, Choi YJ, et al. Phase 2 study of bortezomib combined with temozolomide and regional radiation therapy for upfront treatment of patients with newly diagnosed glioblastoma multiforme: safety and efficacy assessment. Int J Radiat Oncol Biol Phys. 2018;100(5):1195–1203.
Di K, Lloyd GK, Abraham V, et al. Marizomib activity as a single agent in malignant gliomas: ability to cross the blood–brain barrier. Neuro Oncol. 2016;18(6):840–848.
Roth P, Mason WP, Richardson PG, Weller M. Proteasome inhibition for the treatment of glioblastoma. Expert Opin Investig Drugs. 2020;29(10):1133–1141.
Badros A, Singh Z, Dhakal B, et al. Marizomib for central nervous system-multiple myeloma. Br J Haematol. 2017;177(2):221–225.
Bota DA, Mason W, Kesari S, et al. Marizomib alone or in combination with bevacizumab in patients with recurrent glioblastoma: phase I/II clinical trial data. Neurooncol Adv. 2021;3(1):vdab142.
Mason WP, Kesari S, Stupp R, et al. Full enrollment results from an extended phase I, multicenter, open label study of marizomib (MRZ) with temozolomide (TMZ) and radiotherapy (RT) in newly diagnosed glioblastoma (GBM). J Clin Oncol. 2019;37(15_suppl):2021–2021.
Louis DN, Perry A, Reifenberger G, et al. The 2016 World Health Organization Classification of tumors of the Central Nervous System: a summary. Acta Neuropathol. 2016;131(6):803–820.
Bretz F, Maurer W, Brannath W, Posch M. A graphical approach to sequentially rejective multiple test procedures. Stat Med. 2009;28(4):586–604.
Roth P, Gorlia T, Reijneveld JC, et al. EORTC 1709/CCTG CE.8: a phase III trial of marizomib in combination with temozolomide-based radiochemotherapy versus temozolomide-based radiochemotherapy alone in patients with newly diagnosed glioblastoma. J Clin Oncol. 2021;39(15).
Boccellato C, Kolbe E, Peters N, et al. Marizomib sensitizes primary glioma cells to apoptosis induced by a latest-generation TRAIL receptor agonist. Cell Death Dis . 2021;12(7):647.
Lin GL, Wilson KM, Ceribelli M, et al. Therapeutic strategies for diffuse midline glioma from high-throughput combination drug screening. Sci Transl Med. 2019;11(519):eaaw0064.
Wick W, Gorlia T, Bady P, et al. Phase II study of radiotherapy and temsirolimus versus radiochemotherapy with temozolomide in patients with newly diagnosed glioblastoma without MGMT promoter hypermethylation (EORTC 26082). Clin Cancer Res. 2016;22(19):4797–4806.
Bota D, Kesari S, Piccioni DE, et al. A phase 1, multicenter, open-label study of marizomib (MRZ) with temozolomide (TMZ) and radiotherapy (RT) in newly diagnosed WHO grade IV malignant glioma (glioblastoma, ndGBM): dose-escalation results. J Clin Oncol. 2018;36:suppl.e14083.
Singh K, Hotchkiss KM, Parney IF, et al. Correcting the drug development paradigm for glioblastoma requires serial tissue sampling. Nat Med. 2023;29(10):2402–2405.
