The results of this study have just been published:
https://www.ncbi.nlm.nih.gov/pubmed/29722661
http://sci-hub.tw/https://linkinghub.elsevier.com/retrieve/pii/S0360301618300014
(Thanks to Stephen for the tip!)
"To assess the safety and efficacy of upfront treatment using bortezomib combined with standard radiation therapy (RT) and temozolomide (TMZ), followed by adjuvant bortezomib and TMZ for ≤24 cycles, in patients with newly diagnosed glioblastoma multiforme (GBM).
Bortezomib was initially given via intravenous (IV) infusion, but the protocol was later modified to subcutaneous (SC) injection at ~10 months after the first patient had begun treatment (e.g., August 2012), due to the reported similar efficacy with improved safety profile...
Our cohort included 13 male and 11 female patients with a median age of 57 years old (range 27-75), and a
median KPS score at the time of enrollment of 90 (range 60-100). Thirteen patients had gross total resection and 11 patients had subtotal resection. Molecular biomarkers were tested in 24 patients for IDH1 and 21 for IDH2 mutation status: 3 (13%) were found positive for IDH1 mutation and 0 (0%) were positive for IDH2 mutation (Table 1). MGMT methylation was tested in 23 patients: 10 (43%) were methylated and 13 (57%) were unmethylated.
No unexpected adverse events occurred from the addition of bortezomib. The efficacy analysis showed a median progression-free survival (PFS) of 6.2 months (95% confidence interval [CI] 3.7-8.8), with promising PFS rates at ≥18 months compared with historical norms (25.0% at 18 and 24 months; 16.7% at 30 months). In terms of overall survival (OS), the median OS was 19.1 months (95% CI 6.7-31.4), with improved OS rates at ≥12 months (87.5% at 12, 50.0% at 24, 34.1% at 36-60 months) compared with the historical norms. The median PFS was 24.7 months (95% CI 8.5-41.0) in 10 MGMT methylated and 5.1 months (95% CI 3.9-6.2) in 13 unmethylated patients. The estimated median OS was 61 months (95% CI upper bound not reached) in the methylated and 16.4 months (95% CI 11.8-21.0) in the unmethylated patients.
The estimated value of median OS was 61 months for the 10 MGMT methylated patients; however, the upper bound of 95% confidence interval could not be calculated because 7 of 10 (70%) methylated patients are still alive at the time when data was analyzed.
The addition of bortezomib to current standard radiochemotherapy in newly diagnosed GBM patients was tolerable. The PFS and OS rates appeared promising, with more benefit to MGMT methylated patients. Further clinical investigation is warranted in a larger cohort of patients."
____________________________
Also I found other interesting articles about bortezomib:
Phase I trial of dose-escalating metronomic temozolomide plus bevacizumab and bortezomib for patients with recurrent glioblastoma.
https://www.ncbi.nlm.nih.gov/pubmed/27502784
"Three groups of three patients were scheduled to receive daily doses of temozolomide at 25, 50, and 75 mg/m2. Fixed doses of bortezomib and bevacizumab were given at standard intervals.
Progression-free survival was 3.27 months for all patients and mean overall survival was 20.75 months. The MTD of temozolomide was 75 mg/m2 in combination with bevacizumab and bortezomib for recurrent glioblastoma."
A phase II trial of tamoxifen and bortezomib in patients with recurrent malignant gliomas.
https://www.ncbi.nlm.nih.gov/pubmed/26285768
"The study was closed due to poor accrual and therapeutic futility. Combination tamoxifen and bortezomib has no activity in recurrent malignant gliomas. Poor penetration across blood brain barrier of bortezomib likely limited efficacy."
Bortezomib is an FDA approved proteasome inhibitor indicated for multiple myeloma and mantle cell lymphoma, and has been investigated in various solid tumors as single agent or in combination.
Bortezomib is available, inexpensive and can easily be added to the cocktail. His side effects are not so serious. Your thoughts about adding bortezomib to cocktails and about the fantastic results for MGMT-methylated patients (median OS was 61 months)?
Why did one study with bortezomib fail, and another showed such fantastic results?
The sci-hub link didn't work for me and I was unable to download this article from sci-hub, as is often the case with very new studies. I did get a copy through a university account and will post to the Brain Tumor Library (I'll make a Bortezomib subfolder in the Therapies - Human Studies folder.
ReplyDeleteI am very skeptical that bortezomib has any value for brain tumors given negative results in previous trials, and the poor pharmacokinetic profile (poor blood-brain barrier crossing), but the long survival of these MGMT-methylated patients can't be ignored, and I'll be looking more closely to see if that can be explained in any other way.
The long median survival (at least 4 years, not yet reached) in the 10 MGMT methylated patients seems exceptional. Additional contributing factors in this trial included the fact that all patients had resection (biopsy only patients excluded) and the trial allowed for up to 24 monthly cycles of TMZ, rather than the more common 12 cycle limit. Unfortunately the MGMT-methylated group was small (n = 10) and a larger number of patients would have given an increased statisticial power.
DeleteIt would have also been helpful to present the statistics excluding the three patients with IDH1 mutation. If we assume for the sake of hypothesis that all three IDH1 mutant patients were MGMT methylated, that would bring the total number of MGMT methylated, IDH wild-type patients down to 7, with a probably lower median PFS and OS.