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First-line bevacizumab failed to improve OS in newly diagnosed glioblastoma
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First-line bevacizumab did not improve OS and demonstrated only slight improvements in PFS compared with placebo among patients with newly diagnosed glioblastoma, according to study results.
Mark Gilbert, MD, professor of neuro-oncology at The University of Texas MD Anderson Cancer Center, and colleagues sought to evaluate the efficacy of bevacizumab (Avastin, Genentech) in the first-line glioblastoma setting. Bevacizumab is approved for use in recurrent glioblastoma.
Mark Gilbert
“Compelling preclinical data suggest that anti-angiogenic 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 enhanced radiotherapy and chemotherapy treatment,” Gilbert said in a press release.
The double blind analysis included 637 patients with newly diagnosed glioblastoma. All patients received 60 Gy radiation therapy plus temozolomide (Temodar, Schering). After 4 weeks of radiation therapy, researchers assigned 320 patients to bevacizumab every 2 weeks and 317 patients to placebo. Treatment continued for up to 12 cycles.
Treatment assignment could be revealed at the time of disease progression, allowing patients assigned to placebo to cross over into the bevacizumab arm.
At median follow-up of 20.5 months, 82.4% of patients had died or experienced tumor progression.
Overall, median OS was comparable between arms (15.7 months for bevacizumab vs. 16.1 months for placebo). Researchers calculated a 1.13 HR (95% CI, 0.93-1.37) for death in the bevacizumab arm.
Median PFS among patients assigned bevacizumab was 10.7 months, which demonstrated a trend toward improvement compared with the 7.3-month PFS achieved in the placebo arm (HR=0.79 for progression or death; 95% CI, 0.66-0.94).
Biomarker analyses indicated O6-methylguanine-DNA methyltransferase methylation status, molecular profile and recursive partitioning analysis class were not predictors of bevacizumab benefit.
“We postulated that patients with worse prognosis, determined by their tumor markers, would do better if they received bevacizumab as first-line treatment because they may not survive to take advantage of, or do well enough to be considered for, second-line treatment, but we didn’t find that result,” Gilbert said.
More patients assigned bevacizumab experienced fatigue (13.1% vs. 9%), severe neutropenia (10% vs. 5.1%), thromboembolic disease (7.7% vs. 4.7%), hypertension (4.2% vs. 0.9%), wound dehiscence (1.5% vs. 0.9%), serious hemorrhage (1.5% vs. 0.9%) and visceral perforation (1.2% vs. 0.4%) during maintenance therapy. Thrombocytopenia was more common in the placebo arm (11.7% vs. 11.1%).
More patients assigned bevacizumab experienced an increased symptom burden, a worse quality of life and declines in neurocognitive function with time.
“The relevant result is that the upfront use of bevacizumab is not indicated,” Gilbert said. “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.”
Disclosure: See the study for a full list of the researchers’ relevant financial disclosures.
Perspective
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Robert Fenstermaker, MD
Effective chemotherapeutic agents for glioblastoma multiforme are quite limited, with temozolomide being one of the very few drugs that have been proven to provide survival benefit in large studies. Against this backdrop, bevacizumab received accelerated approval for the treatment of recurrent glioblastoma following studies that showed radiologic and clinical responses in that setting. Consequently, there has been great interest and high expectation for studies meant to explore its use in combination with temozolomide in patients with newly diagnosed glioblastoma multiforme.
Recently, two randomized, prospective, placebo-controlled phase 3 studies (RTOG 0825 and AVAGlio) both failed to show a significant improvement in OS with the addition of bevacizumab to standard therapy. These results are consistent with two previous smaller studies that used historical and contemporary control groups. In RTOG 0825, Gilbert and colleagues used a crossover design to compare upfront bevacizumab with salvage therapy and found no benefit to early treatment with the drug. Both major studies do point toward an improvement in PFS, although each used a different criterion for its determination.
Of note, patients in RTOG 0825 who received bevacizumab had significantly poorer cognitive function, although those who received bevacizumab in AVAGlio maintained their quality of life and performance status longer. As with MGMT methylation status — which can predict responsiveness to temozolomide — efforts to define a molecular profile that might predict a benefit from bevacizumab remain ongoing. Continued drug discovery efforts are greatly needed to find agents that are active against malignant gliomas, along with the means to predict who may respond.
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