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

Patrick Roth, Thierry Gorlia, Jaap C Reijneveld, Filip de Vos, Ahmed Idbaih, Jean-Sébastien Frenel, Emilie Le Rhun, Juan Manuel Sepulveda, James Perry, G Laura Masucci, Pierre Freres, Hal Hirte, Clemens Seidel, Annemiek Walenkamp, Slavka Lukacova, Paul Meijnders, Andre Blais, Francois Ducray, Vincent Verschaeve, Garth Nicholas, Carmen Balana, Daniela A Bota, Matthias Preusser, Sarah Nuyens, Fréderic Dhermain, Martin van den Bent, Chris J O’Callaghan, Maureen Vanlancker, Warren Mason, Michael Weller,

Neuro Oncol

https://doi.org/10.1093/neuonc/noae053

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.