A phase III study of Avastin failed to increase overall survival or statistically significant progression-free survival for glioblastoma patients in the frontline setting. The international study was a collaboration among the cooperative groups RTOG, NCCTG, and ECOG.
The randomized, double-blind, placebo-controlled study enrolled 637 newly diagnosed glioblastoma patients. The study was designed with two primary endpoints: PFS and overall survival OS. The study was published in the New England Journal of Medicine, and was first presented at the plenary session of the American Society of Clinical Oncology 2013 Annual Meeting.
Participants underwent surgery to resect some or most of the tumor, received the standard of care of chemoradiation with temozolomide, and were randomized to receive either Avastin (bevacizumab) or placebo.
The authors reported data at a median follow-up time of 20.5 months, which 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 Avastin arm).
Although there was a difference in progression-free survival (7.3 months for the placebo arm vs. 10.7 months for the Avastin arm), the pre-established level of benefit for PFS was not reached.
Study participants were stratified equally across study arms by prognostic molecular markers of tumor O6-methylguanine-DNA methyltransferase methylation status and a tumor-based, nine-gene assay. Investigators did not find a subgroup of patients based on the molecular marker analysis who survived longer from first-line Avastin administration.
Because Avastin is known to confound magnetic resonance imaging examination results used to assess GBM tumor progression, investigators incorporated a “net clinical benefit” component in the trial design to determine if quality of life, symptom burden and neurocognitive function test results corroborate MRI-reported stable or improved disease status.
More than 80 percent of study participants agreed to take part in the net clinical benefits component, which demonstrated a greater decline of cognitive function for patients in the Avastin arm compared with those in the placebo arm. Avastin was also associated with a higher rate of toxicities, including hypertension, bleeding, deep vein thrombosis and pulmonary embolism, and gastrointestinal perforation.
Avastin is a monoclonal antibody against VEGF-A, which is produced by glioblastoma to stimulate blood vessel growth. The angiogenesis inhibitor first showed promise in glioblastoma as clinicians reported positive results treating the disease under approved compassionate use.
Several institutional studies then found similar results. In May 2009, the FDA granted an accelerated registration of Avastin in the second-line setting. Before this trial, no randomized, double-blind studies with the drug in glioblastoma had been conducted.
