The importance of targeting angiogenesis in glioblastoma has been the focus of a recent review by Dr. Mark Gilbert, MD, University of Texas MD Anderson Cancer Center, published in The Lancet Oncology journal, where a clinical study developed by a team of researchers from the Erasmus MC Cancer Institute, Rotterdam, Netherlands was analyzed.
In this randomized, three-arm, multi-center, open-label phase 2 clinical trial, 140 patients who experienced a first recurrence of glioblastoma after chemotherapy with temozolomide received a combination of lomustine plus bevacizumab, resulting in higher overall survival (OS) rates than either agent alone.
Glioblastoma is the most common aggressive malignant primary brain tumor, accounting for 52% of all functional tissue brain tumor cases and 20% of all intracranial tumors. Patients who have recurrent glioblastoma have few treatment options, with second-line chemotherapy showing reduced efficacy.
Lomustine (Ceenu, Bristol-Myers Squibb) is a highly lipid soluble alkylating nitrosourea compound used in chemotherapy that has the capacity to cross the blood-brain barrier, making it ideal for treating brain tumors. On the other hand, bevacizumab (Avastin, Genentech) is a recombinant humanized monoclonal antibody that prevents angiogenesis through inhibition of VEGF-A, and is commonly used in patients suffering from glioblastoma. However, so far there have been no well-controlled clinical trials, making it unclear if high response rates reported after bevacizumab treatment truly correlate with extended OS.
In this study, patients were randomly assigned to 110 mg/m2 oral lomustine alone once every 6 weeks, 10 mg/kg bevacizumab IV alone once every 2 weeks, or combination treatment with both agents, with the primary outcome measure set for OS at 9 months. Safety analysis included the first eight patients who completed two cycles of 6 weeks in the combination arm. Bevacizumab dose intensity was reduced after three patients experienced grade 3 thrombocytopenia and two patients experienced grade 4 thrombocytopenia. Additionally, researchers also reduced lomustine dosage to 90 mg/m2 in the combination arm only.
The observed side effects in the combination arm could be a result from longer treatment duration when compared with single-agent groups, since after the lomustine dose reduction, hematologic toxicities in the combination arm were similar to those observed with single-agent lomustine.
The final analysis surveyed 50 patients assigned bevacizumab alone, 46 assigned lomustine alone, 8 patients assigned to the original combination of bevacizumab plus 110 mg/m2 lomustine, and 44 assigned bevacizumab plus 90 mg/m2 lomustine. At 9 months, researchers reported OS rates of 87% among patients assigned bevacizumab plus 110 mg/m2 lomustine, 59% among patients assigned combination therapy with bevacizumab plus 90 mg/m2 lomustine, 43% among patients assigned lomustine alone, and 38% among patients assigned bevacizumab alone.
Most patients (87%) developed progressive disease, leading to the interruption of treatment, and at the time of the final analysis, 97% of patients had died and 2% remained on treatment.
“The combination of bevacizumab and lomustine met prespecified criteria for assessment of this treatment in further phase 3 studies, however, the results in the bevacizumab alone group do not justify further studies of this treatment,” wrote Dr. Gilbert.
He further raised questions about the pharmacological and drug delivery benefits of using bevacizumab–lomustine combination therapy, writing “Lomustine has been shown to have single-agent activity in recurrent glioblastoma, and nitrosoureas are well known to readily penetrate the blood–brain barrier, therefore, the failure of other agents, such as irinotecan, to show benefit in combination with bevacizumab might well be related to the decrease in blood–brain barrier permeability that is a known consequence of anti-angiogenic treatment. Future studies assessing treatment combinations with bevacizumab or other anti-angiogenic agents should either have strong preclinical in vivo data indicating adequate drug delivery or data from comparable studies using imaging-based measures of drug delivery.”
Dr. Gilbert concludes that even though the results seem encouraging, a future randomized phase 3 study is essential to definitively understand if the combination of bevacizumab and lomustine provides a survival benefit, making it the standard of care treatment for recurrent glioblastoma.