Best Published Trial Outcomes for Newly Diagnosed Glioblastoma
by Stephen Western
MGMT promoter unmethylated
Nimotuzumab added to TMZ and radiation
As of 2014, only one phase III trial for newly diagnosed glioblastoma has reported an improved survival outcome with an experimental drug in addition to standard radiochemotherapy. This trial has been reported in abstract form, at the 2012 meeting of ASCO. Overall survival and progression-free survival was improved somewhat in the nimotuzumab arm. The advantage of adding nimotuzumab to standard radiochemotherapy was most notable in the patients with unmethylated MGMT promoter: 28 patients in the nimotuzumab arm (RT+TMZ+nimotuzumab) were compared with 28 patients in the control arm (RT+TMZ). Median survival in the nimotuzumab arm was 19.6 months compared with 15 months in the control arm. It is hoped that full details of this trial will be forthcoming.
Availability: Nimotuzumab, a monoclonal antibody which binds to the extracellular region of EGFR (epidermal growth factor receptor) was developed at the Center of Molecular Immunology (CIM), Havana, Cuba. Its use is approved in countries including Cuba, Argentina, Colombia, India and China. Though granted orphan drug status in the USA and Europe, it has not been approved for any indication in the USA, Canada, EU, or Japan (7).
ICT-107 dendritic cell vaccine following surgery and chemoradiation
The details of this trial are described below, in the MGMT promoter methylated section. In this randomized phase II trial, MGMT unmethylated, HLA-A2 positive patients vaccinated with ICT-107 had a median PFS of 10.5 months, and a median overall survival of 15.8 months, compared to 6 months PFS and 11.8 months OS in the placebo group. Though there is clearly a trend towards improved outcomes in this patient subgroup with vaccination, the differences have not reached statistical significance (PFS p=.442, OS p=.175).
These statistics are measured from the time of randomization, after completion of radiochemotherapy. Average interval in this trial between surgery and randomization was 83 days (2.7 months). If we add 2.7 months onto the reported statistics, we can approximate outcomes from the time of surgery/diagnosis. For the vaccinated (and MGMT unmethylated, HLA-A2 positive) group this works out to 13.2 months median PFS and 18.5 months median OS. This would perhaps be the best PFS outcome yet reported for unmethylated MGMT patients in a phase II or III trial for newly diagnosed GBM. A median OS of 18+ months in this subgroup is also one of the best outcomes reported for MGMT unmethylated GBM, surpassed somewhat by the outcome reported in the nimotuzumab trial (see above).
Not yet available outside of clinical trials.
MGMT promoter methylated
ICT-107 dendritic cell vaccine following surgery and chemoradiation
On June 1, 2014, ImmunoCellular Therapeutics published a press release in conjunction with their presentation at the 2014 annual meeting of ASCO. This press release included preliminary results of their randomized phase II trial of ICT-107 vaccine for newly diagnosed glioblastoma patients. All patients in the trial underwent surgery and standard radiochemotherapy with temozolomide, and were positive for human leukocyte antigen-A1 or -A2 (HLA-A1, HLA-A2) which are antigen-presenting proteins at the cell surface. 124 patients were randomized to receive either ICT-107 vaccine or placebo. 62% of these patients belonged to the HLA-A2 class.
For the MGMT methylated, HLA-A2 positive group, median survival has not yet been reached in either the treatment or placebo group. Progression-free survival in the vaccinated group is reported to be 24.1 months compared to 8.5 months in the placebo group. These statistics are measured from the time of randomization, after the completion of chemoradiation. The average interval between surgery and randomization in this trial was 83 days (2.7 months). In order to compare these results with other trials measured from the time of diagnosis or trial registration, we must then add approximately 2.7 months onto the reported statistics. A PFS of 24 to 27 months for MGMT methylated patients in the vaccinated group not only surpasses the PFS of the placebo group nearly 3-fold, it also far exceeds the PFS of MGMT methylated patients reported in any other phase II or III trial, to the best of my knowledge.
Lomustine (CCNU) and Temozolomide combination therapy
Mature results of a phase II trial of lomustine and temozolomide combination therapy for newly diagnosed glioblastoma patients was published in 2009 (1). This trial resulted in outstanding survival results for this patient population compared to historical controls. Lomustine (CCNU) is an oral nitrosourea drug, most commonly administered in the context of PCV combination chemotherapy for gliomas. (PCV was a common chemotherapy regime for gliomas before the advent of temozolomide in the early 2000s.) Patients in this trial underwent standard radiotherapy during the first two chemotherapy cycles. Two dosing regimes were used in this trial. The standard dosing regimen consisted of 100 mg per square meter body surface area of lomustine on day 1, followed by 100 mg per square meter of temozolomide for the next five days of the six week cycle. The intensive dosing regimen upped the dose of lomustine to 110 mg per square meter on day 1, and the dose of temozolomide increased to 150 mg per square meter for the following five days. 31 patients (median age 51) received the standard dosing and 8 additional patients (median age 59) received the intensive dosing. A maximum of 6 cycles of chemotherapy were administered.
The 12 patients with an unmethylated MGMT (gene) promoter did not benefit from the addition of lomustine to the modified temozolomide protocol. For these patients, median overall survival was 12.5 months. This compares closely with a median survival of 12.7 months for 60 patients with unmethylated MGMT promoter receiving radiotherapy and temozolomide chemotherapy, reported in the landmark phase III trial, which published results in 2005 (2) and led to the current protocol for newly diagnosed glioblastoma.
In contrast, patients with a methylated MGMT promoter, which leads to inactivation of the MGMT DNA repair gene, benefitted impressively from this modification of the standard protocol. 11 patients with methylated MGMT promoter had a median survival of 34.5 months. This is a significant improvement over the 21.7 month median survival for the 46 patients with methylated MGMT promoter treated with standard radiotherapy and temozolomide in the phase III trial published in 2005 (2).
If we look at the eight patients who underwent the intensive dosing regimen, the results are even more impressive. Median progression-free survival for these eight was 26 months, which is longer than the overall survival achieved in most other trials. Median overall survival for these patients was not yet reached, with a median follow-up time of 41.5 months. Four of the eight (50%) were still alive at four years, which is outstanding considering that in the five-year follow up of the 2005 study, only 12% of patients receiving radiotherapy and temozolomide were still alive at four years.
A follow-up phase III trial of this regimen is currently enrolling patients in Germany.
In vitro cell culture studies have shown also that p53 mutant cell lines (which is the case for many grade II and III gliomas) have increased vulnerability to chloroethylating nitrosoureas such as lomustine (3). It is likely that lower grade gliomas would also benefit from the addition of oral lomustine to temozolomide chemotherapy. However, the intensive dose used in the trial described above led to an increased rate of grade IV myelotoxicity (57% compared to 16%).
Trials requiring surgical tumour resection
ACT III: phase II trial of rindopepimut (CDX-110) vaccine for EGFRvIII positive glioblastoma
Celldex Therapeutics is currently conducting a phase III trial of its rindopepimut vaccine for newly diagnosed, and a phase II trial of bevacizumab (Avastin) with or without rindopepimut vaccine for recurrent glioblastoma patients with a mutation in the EGFR gene, called EGFRvIII, which causes permanent activation of the epidermal growth factor receptor (EGFR). Rindopepimut (also called CDX-110) is a peptide vaccine which arouses an immune response against the EGFR variant III protein.
Three prior phase II trials have tested the vaccine in newly diagnosed glioblastoma patients, in conjunction with standard radiochemotherapy. The largest and most recent of these was called ACT III. In November 2012, Celldex released 3-year survival data for this trial. Only patients with the EGFRvIII mutation were included, and all patients had surgical tumour removal and had no disease progression upon completing radiochemotherapy. 65 patients were included (median age 56, 38% had methylated MGMT promoter). The median progression-free survival was 12.3 months, and the median overall survival was 24.6 months. The 3-year survival rate was 26%. The median progression-free survival statistic is the best I've seen for a phase II trial for newly diagnosed glioblastoma patients of unspecified MGMT status. View all Celldex press releases for rindopepimut here.
Whole-cell lysate dendritic cells vaccine plus standard radiation and chemotherapy
Preliminary phase I trials with tumour lysate pulsed or peptide based dendritic cell vaccines for brain cancer have shown very good results, though phase I trials are designed to show safety and to establish dosages, rather than efficacy. There have been few published randomized phase II trials for these vaccines. One however, was carried out in China and published results in 2012 (4). In this small randomized phase II trial, 18 patients received standard radiochemotherapy along with up to 10 inoculations of tumour lysate pulsed dendritic cell vaccine over 6 months. 16 patients received standard radiochemotherapy without vaccine. While progression-free survival differed little between the groups (8.5 months versus 8 months), the vaccination group had a median overall survival of 31.9 months, while the control group had a median survival of 15 months. For the 18 vaccinated patients, median age was 58 years, 15/18 (83%) received radiation, 16/18 (89%) received TMZ chemotherapy, 78% had a total resection, 22% had a subtotal resection and 10/18 (56%) had methylated MGMT promoter. At recurrence 11/18 (61%) received gamma knife radiosurgery and 33% underwent re-operation. The benefit of gamma knife radiosurgery did not reach statistical significance in this study. While this was a small group with a high proportion of MGMT methylation and total surgical resection, a median survival of 31.9 months in newly diagnosed glioblastoma is certainly among the best for a randomized trial. Preliminary results for the phase III DCVax trial, using tumour lysate pulsed dendritic cells in newly diagnosed glioblastoma, should be forthcoming soon and will establish the efficacy of this method for newly diagnosed glioblastoma patients.
Another trial (phase I/II) of a tumour lysate-pulsed dendritic cell vaccine conducted at Cedar-Sinai Medical Center reported some results at the 2013 annual meeting of the Society for Neuro-Oncology (see abstract IT-029). 20 newly diagnosed glioblastoma patients, all with maximal surgical resection had a median progression-free survival of 8.6 months, and a median overall survival of 24.3 months.
ICT-107 peptide vaccine
ICT-107, developed by ImmunoCellular Therapeutics, is a vaccine composed of patient-derived dendritic cells pulsed with six tumour-associated antigens. 16 newly diagnosed glioblastoma patients were treated with this vaccine at Cedars-Sinai Medical Center after treatment with concurrent radiation therapy and temozolomide chemotherapy. All patients underwent surgery to remove the tumour, 75% having a complete resection, 25% having a subtotal resection. The median age was 54.5 years and the median KPS score was 90. The median progression-free survival was 16.9 months and median overall survival was 38.4 months. This is more than double the median survival for glioblastoma patients receiving standard therapy in recent phase III trials. In a recent update of this trial, presented at the 2013 meeting of the Society for Neuro-Oncology, seven of these 16 patients were still alive, at 56, 60, 60, 62, 66, 73, and 79 months post-treatment. The five year survival rate for the 16 patients is 50% and 5-year progression free survival was 37.5%. While these patients had all received maximal tumour resection, and were therefore selected for a more favorable outcome, the long-term survival seen in this trial is nonetheless impressive. Forthcoming results of an ongoing phase II trial for the ICT-107 vaccine will provide evidence for how well the vaccine works in a broader glioblastoma patient population.
Lysate-pulsed dendritic cell vaccine (DCVax)
Researchers at UCLA conducted a phase I trial for newly diagnosed or recurrent glioblastoma patients involving a tumour-lysate pulsed dendritic cell vaccine (5). 15 newly diagnosed patients underwent a surgical tumour resection and this tumour tissue was used to create the vaccine. Following concurrent radiochemotherapy, but before adjuvant chemotherapy, patients received three biweekly injections of the dendritic cell vaccine, followed by booster vaccinations with either imiquimod or Poly-ICLC (immune system stimulators) every 3 months.
Median age of these 15 patients was 50 years (mean age was also 50 years). Median KPS score was 90 (mean 87). All patients underwent surgery prior to radiochemotherapy and vaccination. This group had a median survival of 35.9 months, which is more than double the median survival outcome of the standard treatment group in recent phase III trials (about 16 months). The mean follow-up was over 4 years. 1, 2, and 3 year survival rates were 93%, 77%, 58%. Similar to the ICT-107 phase I trial outcome described above, the survival outcomes seen in this phase I trial far exceeds outcomes with standard treatments alone. 100% of patients underwent surgical tumour removal in this trial, which likely contributed to the positive outcome.
Photodynamic therapy with talaporfin sodium
In a study published in 2013 in the Journal of Neurosurgery (6), Japanese investigators prospectively studied talaporfin sodium based photodynamic therapy of 27 malignant brain tumour patients at the time of surgery. 13 newly diagnosed glioblastoma patients were treated with surgery and photodynamic therapy. For these 13 patients:
- median age was 49, mean age 46
- tumours were predominantly (53.8%) located in the frontal lobe
- Median ECOG performance status (a rating of general functioning, 0= best) was 1
- 5/13 (38.5%) had a total resection, and 8/13 (61.5%) had a subtotal resection
The reported six-month progression free survival and 12 month overall survival rates for the newly diagnosed glioblastoma patients were 100% and 100%. Median overall survival was 24.8 months, median progression-free survival was 12 months and median local progression-free survival was 20 months. While this was a small group with younger median age than that usually seen in glioblastoma trials, such a high 12-month overall survival rate, and high median progression-free survival are rarely seen in glioblastoma trials.
Not yet published
Survival benefit of levetiracetam in glioblastoma treatment: a prospective, single center, and single arm study
This information comes from an abstract (NO-070) of a presentation at the 2013 annual meeting of the Society for Neuro-Oncology. The trial compares outcomes for newly diagnosed patients taking the anti-convulsant drug levetiracetam versus those taking valproic acid. 38 patients undergoing conventional radiochemotherapy while on levetiracetam had a median progression-free survival of 9.3 months and a median overall survival of 25.7 months. This outcome was superior to that for patients taking valproic acid instead, who had a median progression-free survival of 6.5 months and a median overall survival of 16.4 months.
Phase II study of valproic acid for patients with newly diagnosed glioblastoma
An abstract (AT-33) published as part of the 2014 Society for Neuro-Oncology annual meeting shows a very positive survival outcome for newly diagnosed glioblastoma patients who started valproic acid treatment one week prior to the first day of radiation therapy. 37 patients were started on valproic acid 10-15 mg/kg orally per day. This dose was tapered up to 25 mg/kg twice per day over the first week. Median PFS was 10.5 months and median OS was 29.6 months. Mean age of patients was 53 years. 27 of 34 (79%) patients evaluated for response had tumour stabilization, though no objective responses were seen. These results compare favorably with the results of the standard arm of the most recently published phase III trials for newly diagnosed glioblastoma. Median PFS in these three trials ranged from 6.2 to 7.5 months, and median OS ranged from 16.1 to 18.9 months. Upfront treatment with valproic acid during radiochemotherapy looks very promising and should progress to a phase III trial.
Long-term survival of patients with glioblastoma treated with radiotherapy and lomustine plus temozolomide. Glas et al. 2009.
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MGMT Gene silencing and benefit from temozolomide in glioblastoma. Hegi et al. 2005.
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Differential sensitivity of malignant glioma cells to methylating and chloroethylating anticancer drugs: p53 determines the switch by regulating xpc, ddb2, and DNA double-strand breaks. Batista et al. 2007.
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Adjuvant immunotherapy with whole-cell lysate dendritic cells vaccine for glioblastoma multiforme: a phase II clinical trial. Cho et al. 2012.
Gene expression profile correlates with T-cell infiltration and relative survival in glioblastoma patients vaccinated with dendritic cell immunotherapy. Prins et al. 2011.
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Phase II clinical study on intraoperative photodynamic therapy with talaporfin sodium and semiconductor laser in patients with malignant brain tumors. Muragaki et al. 2013.
Adverse Events with Biomedicines, "Nimotuzumab" chapter. Giuseppe Tridente. 2014.
This page was created on 04/14/2014 and last updated on 12/05/2014