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Adding Bevacizumab to Radiotherapy and Temozolomide Does Not Improve Overall Survival in Newly Diagnosed Glioblastoma

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Key Points

  • Adding bevacizumab did not improve overall survival, and an improvement in progression-free survival did not reach the prespecified improvement threshold.
  • The bevacizumab group exhibited increased symptom burden, worse quality of life, and greater decline in neurocognitive function.

In a double-blind phase III trial reported in The New England Journal of Medicine, Gilbert et al assessed adding bevacizumab (Avastin), which is currently approved in recurrent glioblastoma, to radiotherapy and temozolomide in patients with newly diagnosed glioblastoma. The addition of bevacizumab did not improve overall survival, and although it improved progression-free survival, the improvement did not meet the prespecified improvement threshold. (A similar trial conducted by Chinot et al, published in the same issue of NEJM, reported slightly different conclusions.)

Study Details

In the trial, 637 adult patients received radiotherapy (60 Gy) plus daily temozolomide (75 mg/m2) and were randomly assigned to receive bevacizumab at 10 mg/kg (n = 320) or placebo (n = 317) every 2 weeks starting during week 4 of radiotherapy. At disease progression, the assigned treatment was revealed, and bevacizumab therapy could be initiated or continued. The trial was designed to detect a 25% reduction in risk of death and a 30% reduction in risk of progression or death with bevacizumab (coprimary endpoints). The two groups were well balanced for baseline characteristics.

At the time of the current analysis, treatment assignment had been revealed for 155 patients (48%) in the bevacizumab group and 178 patients (56%) in the placebo group. Salvage treatment was planned for 87 and 128 patients, respectively; among these, bevacizumab was continued in 25% of bevacizumab patients and started in 48% of placebo patients.

Overall and Progression-Free Survival

After a median follow-up of 20.5 months, median overall survival was 15.7 months in the bevacizumab group vs 16.1 months in the placebo group (hazard ratio [HR] = 1.13, P = .21). Median progression-free survival was 10.7 vs 7.3 months (HR = 0.79, P = .007 by log-rank test), a 21% reduction in risk of progression or death.

MGMT (O-6-methylguanine-DNA methyltransferase) status and recursive partitioning analysis class were prognostic regardless of study treatment, and a nine-gene molecular profile assay was not prognostic in either group.

Net Clinical Benefit

In a net clinical benefit substudy, greater deterioration over time was observed in the bevacizumab group in composite scores on a neurocognitive-function test battery, Controlled Oral Word Association Test scores, and the Trail Making Test–Part A (all P < .05). Greater deterioration in the bevacizumab group was also observed in MD Anderson Symptom Inventory-Brain Tumor Module composite symptom score, composite symptom-interference score, and scores for activity-related symptom interference, mood-related symptom interference, affective factors, cognitive factors, treatment factors, and generalized or disease factors (all P < .05), as well as on European Organisation for Research and Treatment of Cancer quality-of-life questionnaire/brain-cancer module scores for cognitive functioning, motor dysfunction, and communication deficit (all P < .05).

Toxicity

During chemoradiotherapy, serious lymphopenia occurred in approximately 10% of patients in both the bevacizumab and placebo groups, with no clinically significant opportunistic infection observed. Serious neutropenia (7.3% vs 3.7%) and serious thrombocytopenia (10.2% vs 7.7%) were more common in the bevacizumab group.

During maintenance therapy, serious adverse events were more common in the bevacizumab group, including fatigue (13.1% vs 9.0%), neutropenia (10.0% 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%); the frequency of serious thrombocytopenia was similar in the two groups (11.1% vs 11.7%).

The investigators concluded, “First-line use of bevacizumab did not improve overall survival in patients with newly diagnosed glioblastoma. Progression-free survival was prolonged but did not reach the prespecified improvement target.”

Mark R. Gilbert, MD, of The University of Texas MD Anderson Cancer Center, is the corresponding author for The New England Journal of Medicine article.

The study was funded by the National Cancer Institute and an unrestricted educational grant from Genentech. For full disclosures of the study authors, visit www.nejm.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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