PDF: MIRAGE
(2024)Objective
Marizomib added to standard temozolomide-based radiochemotherapy (TMZ/RT→TMZ) vs standard alone — to test whether the blood-brain barrier-penetrant pan-proteasome inhibitor marizomib improves overall survival in newly diagnosed glioblastoma.
Study Summary
• No benefit even in MGMT-unmethylated tumors (15.1 vs 14.5 mo; HR 1.13; p=0.27), the prespecified high-need subgroup.
• Progression-free survival was also equivalent (6.3 vs 6.0 mo; HR 0.97; p=0.67).
• Grade 3/4 nervous system AEs 33% vs 20% and psychiatric AEs 14% vs 3% with marizomib.
• 8 treatment-related deaths in the marizomib arm (soft tissue necrosis, cerebral hemorrhage, leukoencephalopathy).
• First phase 3 trial of a proteasome inhibitor in GBM — pan-proteasome inhibition in combination with TMZ/RT is not the path forward.
Intervention
Marizomib 0.8 mg/m² IV on days 1, 8, 15, 29, 36 during radiotherapy and on days 1, 8, 15 of each 28-day cycle during maintenance TMZ, with up to 12 additional cycles after TMZ completion (maximum 18 cycles), added to standard TMZ 75 mg/m² daily with RT 60 Gy + maintenance TMZ 150-200 mg/m² days 1-5 of 28-day cycle.
Inclusion Criteria
Newly diagnosed histologically confirmed glioblastoma (WHO grade 4), age ≥18, KPS ≥70, no prior GBM treatment other than surgery, stable or decreasing corticosteroid dose, post-op MRI within 14 days. IDH-mutant tumors excluded.
Study Design
Arms: TMZ/RT→TMZ alone (standard) vs TMZ/RT→TMZ + Marizomib
Patients per Arm: Standard 374; Marizomib 375
Outcome
• OS in MGMT-unmethylated (coprimary): Marizomib 15.1 mo vs standard 14.5 mo; HR 1.13 (95% CI 0.88-1.44); p=0.27
• PFS (ITT): 6.3 vs 6.0 mo; HR 0.97 (95% CI 0.82-1.13); p=0.67
• Grade 3/4 AE any cause: 67% marizomib vs 48% standard; nervous system 33% vs 20%; psychiatric 14% vs 3%
• Treatment-related deaths: 8 (marizomib) vs 1 (standard); 36% marizomib arm had dose withdrawal
Clinical Question
In adults with newly diagnosed glioblastoma, does adding the blood-brain barrier-penetrant pan-proteasome inhibitor marizomib to standard TMZ/RT→TMZ improve overall survival compared with standard therapy alone — particularly in MGMT-unmethylated tumors?
Bottom Line
In 749 adults with newly diagnosed glioblastoma randomized 1:1 to marizomib plus standard TMZ/RT→TMZ vs standard alone (EORTC 1709/CCTG CE.8), median overall survival was 16.5 vs 17.0 months (HR 1.04; p=0.64) with no benefit in the MGMT-unmethylated subgroup (15.1 vs 14.5 months; HR 1.13; p=0.27). Marizomib added significant neurological and psychiatric toxicity (grade 3/4 nervous system AE 33% vs 20%; psychiatric 14% vs 3%) without survival benefit.
Major Points
- Multicenter (82 institutions, Europe/Canada/US) open-label phase 3 superiority RCT with futility rule (Roth 2024)
- N=749 patients (99.9% of planned 750); 1:1 randomization to standard or standard + marizomib
- Stratified by institution, age (≤55 vs >55), KPS (70/80 vs 90/100), extent of surgery (partial/biopsy vs gross total)
- Primary endpoint: OS in ITT and in MGMT-unmethylated subgroup (coprimary)
- OS ITT: 16.5 vs 17.0 months; stratified HR 1.04 (95% CI 0.87-1.22); p=0.64 — futile
- OS MGMT-unmethylated: 15.1 vs 14.5 months; HR 1.13 (95% CI 0.88-1.44); p=0.27 — also no benefit
- PFS ITT: 6.3 vs 6.0 months; HR 0.97 (95% CI 0.82-1.13); p=0.67
- No subgroup (age, sex, KPS, MMSE, steroids, surgery extent, MGMT status) showed treatment-by-subgroup interaction (all p>0.15)
- Toxicity: Grade 3/4 AEs 67% vs 48%; nervous system AEs 33% vs 20%; psychiatric AEs 14% vs 3% with marizomib
- 8 treatment-related deaths in marizomib arm (soft tissue necrosis, intestinal perforation, seizure, cerebral hemorrhage, leukoencephalopathy, meningitis, head injury) vs 1 in standard
- 32% of marizomib patients discontinued the drug for AEs; 36% required dose withdrawal
- Conclusion: pan-proteasome inhibition with marizomib adds toxicity without benefit — proteasome pathway as monotherapy not viable in GBM
Study Design
- Study Type
- Multicenter open-label phase 3 superiority RCT with futility stopping rule (EORTC 1709 / CCTG CE.8, NCT03345095)
- Randomization
- Yes
- Blinding
- Open-label (no blinding)
- Sample Size
- 749
- Follow-up
- Median 29.1 mo (marizomib) / 27.5 mo (standard)
Primary Outcome
Definition: Overall survival (ITT); coprimary in MGMT-unmethylated subgroup
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| Median OS 17.0 mo (95% CI 15.9-18.6); 12-mo KM 71.9% | Median OS 16.5 mo (95% CI 15.4-17.6); 12-mo KM 71.1% | - (0.87-1.22) | p=0.64 (log-rank) |
Limitations & Criticisms
- Open-label design may have influenced subjective AE reporting and crossover to second-line therapy decisions
- Per-protocol exclusion of 52% of marizomib patients (largely for missing ECG evaluations after a protocol amendment) complicated sensitivity analysis
- CNS AEs indicate brain penetration, but quantitative tissue concentration of marizomib was not measured — cannot exclude insufficient intratumoral drug
- Trial predated the 2021 WHO CNS classification reclassifying some GBM histologies; IDH testing was recommended but not mandatory
- 8 treatment-related deaths in marizomib arm raise serious risk-benefit concerns even independent of efficacy
- No exploration of alternative proteasome inhibitors, lower doses, or combination with immunotherapy/TTF — proteasome pathway closure is based on this one trial