May 11 2022
Glioblastoma (GBM) is the most common primary malignant brain tumor, and it is estimated that around 12,000 Americans are diagnosed with this disease each year. Unfortunately, the outlook for patients diagnosed with GBM is currently quite grim: the median length of survival after diagnosis is 15-18 months, while the disease’s five-year survival rate is around 10%. In the United States, GBM causes more than 10,000 deaths a year. 1, 2
The current standard treatment regimen for GBM was established in 2005, when it was shown that the inclusion of alkylating temozolomide (TMZ) chemotherapy to postoperative radiotherapy (RT) improves median overall survival (OS) from 12.1 months to 14.6 months.4 Shortly thereafter, it was revealed that the patients who most benefitted from the addition of TMZ had MGMT promoter methylation, suggesting that MGMT methylation—found in 30% of glioblastoma patients—is a strong predictor of benefit from alkylating chemotherapy drugs.3
Since 2005, progress in GBM has been elusive, and numerous attempts at improving outcomes have failed to show benefit. A single trial has shown a modest improvement in OS by introducing tumor-treating fields (TTFields) to the upfront management of GBM 5, but the median OS in the experimental arm remains a sobering 20.5 months, while in the methylated MGMT promoter subgroup, the median OS was 31.6 months for TTFields and TMZ and 21.2 months for TMZ alone. Clearly, there is a great need for better treatment options in this patient population.
Given the low toxicity of TMZ and the realization that MGMT promoter methylation is predictive of benefit from alkylating chemotherapies, several studies—the largest of which was the German CeTeG/NOA-09 trial—explored whether the combination of TMZ and lomustine (Gleostine), a second alkylating chemotherapy already approved by the FDA for use in brain tumors, could improve OS in patients with MGMT methylated tumors. However, these studies were not adequately powered and therefore produced results that, though provocative, were inconclusive.
NRG Oncology’s BN011 seeks to meet the need for an adequately powered Phase III study that will confirm the potential benefit of this drug combination and establish dual alkylating therapy as a new standard of care for the treatment of GBM patients with MGMT promoter methylated glioblastomas.
The trial will randomly assign 306 patients newly diagnosed with methylated MGMT glioblastomas to one of two treatment arms: either the current standard treatment of radiation therapy with concomitant and adjuvant temozolomide, or the proposed new regimen of radiation therapy with concomitant and adjuvant temozolomide and lomustine (Gleostine).
In addition to the primary aim of determining if the new regimen will prolong overall survival (OS), the study also seeks to determine if it will prolong progression-free survival (PFS) and if it is associated with inferior short-term change in patient reported outcomes (PROs). A final secondary aim is to assess toxicity in both the new and standard regimens. Exploratory aims include assessing the association between both absolute and CD4+ lymphocyte counts and outcomes and comparing the two regimens in terms of long-term PROs at years 1 and 2.
“Given both the considerable percentage of glioblastoma patients with the MGMT promoter methylation biomarker and the clinically meaningful survival benefit suggested by the underpowered German CeTeG/NOA-09 study, confirmation of benefit in an adequately powered study is of great importance,” commented the trial’s Principal Investigator, Fabio Iwamoto, MD, of Colombia University Irving Medical Center.
For more information about the NRG-BN011 study, click here:NCT05095376
1 The University of Texas MD Anderson Cancer Center. (2022). Glioblastoma. Retrieved from https://www.mdanderson.org/cancer-types/glioblastoma.html#:~:text=Glioblastoma%20is%20the%20most%20common,the%20United%20States%20each%20year
2 National Brain Tumor Society. (2022). About Glioblastoma. Retrieved from https://braintumor.org/take-action/about-gbm/
3 Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in
glioblastoma. N Engl J Med 2005;352:997-1003.