Full enrollment results from the phase 1/2, multicenter, open-label study of marizomib (MRZ) +/- bevacizumab (BEV) in recurrent WHO grade IV malignant glioma
Daniela Bota of UC Irvine presented these results. The trial was divided into three parts: Part 1 was a dose escalation and dose expansion trial of the brain penetrant proteasome inhibitor marizomib added to bevacizumab and consisted of 36 patients. Part 2 was a trial of single-agent marizomib consisting of 30 patients. Part 3 was an intra-patient dose escalation of marizomib combined with bevacizumab consisting of 35 patients.
In Part 1, 27 out of 36 patients (75%) were treated with 0.8 mg/m2, while 9 patients (25%) were treated at lower doses in the dose escalation phase. Patients in Part 1 also received standard dose bevacizumab. The overall response rate for the 36 patients receiving marizomib and bevacizumab was 16/36 or 44.4%. 11/36 or 31% had stable disease. Response plus stable disease rate is 27/36 or 75%. Median progression-free survival was 3.9 months and median overall survival was 9.4 months.
In Part 2, 30 patients were treated with marizomib alone. In this cohort there was only 1 partial response (1/30 or 3%) and 6 with stable disease (6/30 or 20%), for a response plus stable disease rate of 23%.
Patients in Part 1 experiencing central nervous system related adverse events (including ataxia, balance disorder, dizziness, fall, gait disturbance, hallucination) had increased PFS and OS compared to those who did not suffer from these side-effects, and this observation provided a justification for Part 3 of the study, an intra-patient dose escalation of marizomib combined with bevacizumab. In Part 3, 10 out of 35 patients were escalated to 1 mg/m2 of marizomib, but only 1 patient was able to tolerate this dose. No patient reached 1.2 mg/m2. The intra-patient dose escalation can therefore be said to have not succeeded, as the next higher dose of 1 mg/m2 was largely not tolerated.
It appears that single agent marizomib has some activity, but only for a minority of patients, while adding bevacizumab to marizomib leads to much higher response rates and increased survival at 12 months, but still leads to an average median overall survival statistic for recurrent glioblastoma.
I heard this approach was more effective in MGMT unmethylated patients. I am wondering if that subgroup had improved OS.
ReplyDeleteIn Part 1 (Marizomib dose escalation and expansion + BEV), median, 9-month and 12 month survival were all better in the MGMT-methylated group, but it's possible that salvage chemotherapy with alkylating agents could have contributed to this outcome.
DeleteIn terms of progression-free survival, the MGMT methylated group took the early lead with superior median PFS, but at later time points (6 and 9 months), the unmethylated group had slightly higher PFS rates.