Marizomib Does Not Improve Survival in Patients With Newly Diagnosed Glioblastoma

The addition of marizomib to temozolomide-based radiochemotherapy for the treatment of newly diagnosed glioblastoma did not improve survival outcomes, but did increase toxicity, according to study results published in Neuro-Oncology.

Researchers conducted a multicenter, randomized, controlled, open-label, phase 3 superiority trial (MIRAGE; Clinicaltrials.gov Identifier: NCT03345095) to compare survival outcomes in patients with newly diagnosed glioblastoma who were treated with radiotherapy and temozolomide alone vs marizomib in combination with temozolomide-based radiotherapy and maintenance temozolomide therapy. Adult patients with newly diagnosed glioblastoma who had a Karnofsky performance score greater than 70 and no prior history of glioblastoma treatment were included. Patients were randomly assigned 1:1 to either the:

• Standard arm: radiotherapy (60 Gy in 30 fractions over 6 weeks) plus concomitant temozolomide (75 mg/m² daily for up to 6 weeks followed by a 4-week break) followed by maintenance treatment with temozolomide (150-200 mg/m² on days 1-5 of a 28-day cycle for up to 6 cycles); or
• Experimental arm: the same treatment regimen plus marizomib (10-minute intravenous infusions of 0.8 mg/m² on days 1, 8, 15, 29, and 36 during radiotherapy; days 1, 8, and 15 of each 28-day cycle during maintenance; and days 1, 8, and 15 of each 28-day cycle for another 12 cycles).

The primary outcome of interest was overall survival. The hazard ratio (HR) of the experimental arm over the standard arm were calculated using Cox proportional hazards models.

A total of 749 patients (median age, 58.0; men, 65.2%; gross total resection, 50.9%; no corticosteroids at baseline, 58.7%) were randomly assigned to either the experimental arm (n=375) or the standard arm (n=374).

In the intention to treat population, the median overall survival for the experimental arm was 16.5 (95% CI, 15.4-17.6) months vs 17.0 (95% CI, 15.9-18.6) months in the standard arm (HR, 1.04; 95% CI, 0.86-1.27; P =.64). At 12 months, overall survival was 71.1% (95% CI, 66.1-75.5) in the experimental arm vs 71.9% (95% CI, 66.9-76.2) in the standard arm.

Progression-free survival (PFS) was not statistically different between the experimental and standard arms (median PFS, 6.3 months; 95% CI, 5.9-7.7 vs 6.0 months; 95% CI, 5.2-6.4, respectively), indicating that the addition of marizomib to standard therapy did not improve PFS (HR, 0.97; 95% CI, 0.82-1.13; P =.67).

In patients with MGMT promoter-unmethylated tumors, median overall survival was not statistically different between the experimental and standard arms (15.1 months; 95% CI, 13.4-15.7 vs 14.5 months; 95% CI, 13.5-15.7, respectively; HR, 1.13; 95% CI, 0.88-1.44; P =.27).

Compared with patients receiving standard therapy, those receiving marizomib in addition to standard therapy experienced more grade 3 or 4 adverse events (AEs; 48% vs 67%).

In the experimental arm, 8 patients died from AEs (soft tissue necrosis, 2; intestinal perforation, 1; seizure, 1; cerebral hemorrhage, 1; leukoencephalopathy, 1; bacterial meningitis, 1; and head injury, 1) vs 1 patient in the standard arm who died from febrile neutropenia.

One study limitation included the use of the 2016 version of the World Health Organization classification of central nervous system tumors, which had been updated during the course of the study.

“Within an ongoing translational research program, we aim at understanding the underlying mechanism for the failure of marizomib to confer a clinical benefit despite its strong anti-proteasome activity and ability to cross the blood-brain barrier,” the researchers concluded.

Disclosures: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.