Adding bevacizumab to initial treatment for glioblastoma did not improve overall patient survival or progression-free survival, according to results of a randomized phase III trial, RTOG 0825. The trial results were presented by the Radiation Therapy Oncology Group (RTOG) at the 2013 annual meeting of the American Society of Clinical Oncology, which was held in early June in Chicago, Illinois.
Glioblastoma is the most common primary malignant brain tumor in adults. Despite treatment advances in recent years, the average survival of patients enrolled in clinical trials is less than 16 months. Few patients live beyond 5 years. Glioblastoma is characterized by angiogenesis, which is the formation of new blood vessels that support tumor growth and are stimulated by vascular endothelial growth factor A (VEGF-A). Bevacizumab is a monoclonal antibody that targets VEGF-A production to block the growth of tumor-derived blood vessels.
“Clinical trials evaluating the addition of bevacizumab to standard treatment for recurrent glioblastoma demonstrated clinical benefit and led to the drug’s FDA approval for this indication,” said RTOG 0825 principal investigator Mark Gilbert, MD, of The University of Texas MD Anderson Cancer Center, Houston, Texas.
“Additionally, compelling preclinical data suggest that antiangiogenic targeted therapies may normalize the tumor’s rapidly forming and underdeveloped blood vessels, resulting in improved oxygen and chemotherapy delivery to the tumor and potentially enhancing radiotherapy and chemotherapy treatment,” explained Gilbert. The RTOG 0825 study tested this hypothesis.
The multicenter trial enrolled 637 patients into one of two study arms, with treating physicians blinded to treatment assignment. All the patients received standard radiotherapy (60 Gy) and daily temozolomide. Bevacizumab (experimental arm) or a placebo (standard treatment arm) was administered starting at week 4 of radiotherapy and continued every 2 weeks until disease progression, severe treatment-related toxicity, or completion of adjuvant therapy. At the time of disease progression, the treatment was unblinded to allow follow-on treatment with or without bevacizumab.
Data taken at 18 months after the completion of patient enrollment in May 2011 revealed no statistical difference in overall survival between the two study arms (median 16.1 months for the standard-treatment arm vs. 15.7 months for the bevacizumab arm). Though progression-free survival differed (7.3 months for the placebo arm vs. 10.7 months for the bevacizumab arm), the established level of benefit for progression-free survival was not reached.
“The relevant result is that the upfront use of bevacizumab is not indicated,” said Gilbert. “It’s important to emphasize that the question we sought to answer was whether administering bevacizumab as first line treatment improved survival; the cross-over component allowed comparison of risk and benefit of early versus late treatment We now know by giving it late you delay the risk of toxicity, and that may be relevant.”
Study participants were stratified equally across study arms by prognostic molecular markers of methylation status and a tumor-based 9-gene assay. Investigators, however, did not find a subgroup of patients based on the molecular marker analysis who survived longer from first-line bevacizumab administration.