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Clinical Trial
. 2024 Sep 5;26(9):1670-1682.
doi: 10.1093/neuonc/noae053.

Marizomib for patients with newly diagnosed glioblastoma: A randomized phase 3 trial

Patrick Roth  1   2 , Thierry Gorlia  3 , Jaap C Reijneveld  4 , Filip de Vos  5 , Ahmed Idbaih  6 , Jean-Sébastien Frenel  7 , Emilie Le Rhun  8   9   10 , Juan Manuel Sepulveda  11 , James Perry  12 , G Laura Masucci  13 , Pierre Freres  14 , Hal Hirte  15 , Clemens Seidel  16 , Annemiek Walenkamp  17 , Slavka Lukacova  18 , Paul Meijnders  19 , Andre Blais  20 , Francois Ducray  21   22 , Vincent Verschaeve  23 , Garth Nicholas  24 , Carmen Balana  25 , Daniela A Bota  26 , Matthias Preusser  27 , Sarah Nuyens  3 , Fréderic Dhermain  28 , Martin van den Bent  29 , Chris J O'Callaghan  30 , Maureen Vanlancker  3   31 , Warren Mason  32 , Michael Weller  1   2
Affiliations
Clinical Trial

Marizomib for patients with newly diagnosed glioblastoma: A randomized phase 3 trial

Patrick Roth et al. Neuro Oncol. .

Abstract

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.

Keywords: EORTC 1709; MGMT; glioma; proteasome inhibitor; randomized study.

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Conflict of interest statement

P.R. has received honoraria for lectures or advisory board participation from Alexion, Bristol-Myers Squibb, Boehringer Ingelheim, Debiopharm, Merck Sharp and Dohme, Laminar, Midatech Pharma, Novocure, QED, Roche, Sanofi and research support from Merck Sharp and Dohme and Novocure. F.D.V. has received research grants from BMS, Novartis, Foundation Oncocode and Foundation STOPbraintumours.org. A.I. reports research grants from Carthera, Transgene, Sanofi, and Nutritheragene; travel funding from Enterome and Carthera; personal fees for the advisory board from Leo Pharma, Novocure, Novartis, and Boehringer Ingelheim outside the submitted work. J.S.F. reports personal fees from Roche Genentech, personal fees and nonfinancial support from SeattleGenetics, personal fees and nonfinancial support from Novartis, personal fees and nonfinancial support from Pfizer, personal fees and nonfinancial support from Lilly, personal fees and nonfinancial support from Novartis, personal fees and nonfinancial support from GlaxoSmithKline, personal fees, and nonfinancial support from Clovis Oncology, personal fees, and nonfinancial support from Astra Zeneca, personal fees and nonfinancial support from Daiichi Sankyo, personal fees and nonfinancial support from Gilead, personal fees and nonfinancial support from MSD, personal fees and nonfinancial support from Pierre Fabre, personal fees and nonfinancial support from Amgen, outside the submitted work. E.L.R. has received a research grant from BMS, and honoraria for advisory board participation from Astra Zeneca, Bayer, Janssen, Leo Pharma, Pfizer, Pierre Fabre, Seagen and Servier. J.M.S. has received research grants from Pfizer, CANTEX Pharmaceuticals and IDP Pharma, and honoraria for lectures or consulting from GSK, Novocure, MSD, and BMS. G.L.M. has received research grants from BMS. P.F. has received honoraria for advisory board participation from Merck-Pfizer and Astellas Pharma. H.H. has received honoraria for lectures or advisory board participation from AstraZeneca, Merck, and Novocure. C.S. has received honoraria for lectures or advisory board participation from AbbVie, Bristol-Myers Squibb, HRA Pharma, medac, Novocure, Roche, Seagen, and research support from Seagen and Amgen. A.B. has received honoraria for lectures or advisory board participation from Novartis, Merck, and Roche. F.D. has received honoraria for lectures and advisory board from Novocure. V.V. has received honoraria for lectures or advisory board participation from Astellas, Janssen, Merck Sharp and Dohm and Roche. C.B. has received honoraria for advisory board participation from Laminarpharma. D.B. has received honoraria for advisory boards and consulting from Epitopoietic Research Corporation and Telix Pharmaceuticals. M.P. has received honoraria for lectures, consultation or advisory board participation from the following for-profit companies: Bayer, Bristol-Myers Squibb, Novartis, Gerson Lehrman Group (GLG), CMC Contrast, GlaxoSmithKline, Mundipharma, Roche, BMJ Journals, MedMedia, Astra Zeneca, AbbVie, Lilly, Medahead, Daiichi Sankyo, Sanofi, Merck Sharp & Dome, Tocagen, Adastra, Gan & Lee Pharmaceuticals, Servier. M.v.d.B. has received honoraria from Agios, Servier, Astra Zeneca, Boehringer Ingelheim, Geneta, Incyte, Nerviano, Chimerix, Roche, Fore Biotherapeutics and Stemline Therapeutics. W.M. reports honoraria for advisory boards from Novocure, Merck; consultancy for Boehringer Ingelheim, Century Therapeutics; research funding from Hoffman La Roche, Servier Pharmaceuticals LLC, Orbus Therapeutics; serving on a data monitoring committee for Ono Therapeutics. M.W. has received research grants from Quercis and Versameb, and honoraria for lectures or advisory board participation or consulting from Bayer, Curevac, Medac, Novartis, Novocure, Orbus, Philogen, Pfizer, Roche, and Sandoz. The other authors declare no competing financial interests.

Figures

Figure 1.
Figure 1.
Consort chart. Abbreviations: AE, adverse event; ITT, intention-to-treat; PD, progressive disease; PP, per protocol; RT, radiotherapy; TMZ, temozolomide
Figure 2.
Figure 2.
Overall survival and progression-free survival in the ITT population. A. Kaplan–Meier curves, number of events and median overall survival are shown for patients treated with standard therapy alone (TMZ/RT) or standard therapy plus marizomib (TMZ/RT + marizomib). Hazard ratios and confidence intervals were estimated using a Cox proportional hazards model. B. Kaplan–Meier curves, number of events and median progression-free survival are shown for patients treated with standard therapy alone (TMZ/RT) or standard therapy plus marizomib (TMZ/RT + marizomib). Hazard ratios and confidence intervals were estimated using a Cox proportional hazards model.
Figure 3.
Figure 3.
Overall survival stratified for MGMT promoter methylation status. Kaplan–Meier curves, number of events and median overall survival are shown for patients treated with standard therapy alone (TMZ/RT) or standard therapy plus marizomib (TMZ/RT + marizomib). Hazard ratios and confidence intervals were estimated using a Cox proportional hazards model. A. Patients with MGMT promoter-unmethylated tumors. B. Patients with MGMT promoter-methylated tumors.
Figure 4.
Figure 4.
Overall survival in prespecified patient subgroups is defined by baseline clinical characteristics. Forest plot showing hazard ratios for death in the analysis of treatment effect in prespecified patient subgroups according to baseline characteristics.
See this image and copyright information in PMC

Comment in

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