Bevacizumab Results Offer Support for Upfront Therapy

Ben Leach
Published: Tuesday, Feb 05, 2013
Dr Timothy Cloughesy
Timothy Cloughesy, MD
Director Department of Neurology,
Neurological Services, and
Neuro-Oncology Program,
Jonsson Comprehensive Cancer Center, University of California-Los Angeles, Los Angeles, CA
Several recent clinical trials have yielded positive data that may open up new treatment options for patients with glioblastoma, the most commonly diagnosed primary brain cancer in adults, and a tumor type where the prognosis remains poor.

In 2009, the FDA approved bevacizumab (Avastin) as a single agent for use in patients with glioblastoma whose disease progresses after prior therapy. Those results were based on data that showed objective responses in 19.6% to 25.9% of patients treated in two single-arm trials, according to the National Cancer Institute. Now, new research suggests that bevacizumab could be used as a front-line therapy when given in combination with another agent.

According to the results of the phase III AVAglio trial, patients with newly diagnosed glioblastoma who received bevacizumab in combination with radiotherapy and temozolomide experienced a median improvement in progression-free survival (PFS) of 4.4 months compared with patients who received only radiotherapy, temozolomide, and a placebo.

The results were presented at the 17th Annual Scientific Meeting & Education Day of the Society for Neuro-Oncology, held in November 2012 in Washington, DC.

“So far, we’ve really only known about the benefits as a single agent in the second line,” said Timothy Cloughesy, MD, one of the authors of the study. “We’ve always been hopeful that we could bring bevacizumab upfront in treatment, and this study gives us some evidence that we might be able to do just that.”

The link between glioblastoma and the vascular endothelial growth factor (VEGF) pathway has been known for many years, Cloughesy said. However, he explained that many drugs have difficulty penetrating the blood–brain barrier, so while they may be effective in theory, they are unable to halt or slow down the progression of disease unless they can enter the brain and have an effect on the tumor.

The AVAglio study was designed to determine whether a VEGF inhibitor, specifically bevacizumab, would have an isolated effect on survival. In all, 921 patients were randomized to either the bevacizumab combination (n = 458) or the control group (n = 463). “This study was designed to really try to answer the question of whether there’s a clear benefit upfront,” Cloughesy said.

In patients who received bevacizumab plus radiotherapy and temozolomide, the median PFS was 10.6 months compared with 6.2 months in the group that received only radiotherapy and temozolomide (HR = 0.64; 95% CI, 0.55–0.74; P < .0001), according to the analysis performed by the investigators. The interim results for overall survival (OS) did not reach statistical significance (stratified HR = 0.89; 95% CI, 0.75–1.07; P = .2135). Final OS data are expected to be available in 2013, according to Genentech, the manufacturer of bevacizumab.

Cloughesy said that the key to determining the true clinical benefit of that 4.4-month improvement is whether it had any effect on the quality of life of the patients involved. In an encouraging finding, the researchers reported that patients who received the bevacizumab combination therapy maintained a median Karnofsky performance score (KPS) ≥70 for a median of nine months compared with six months in the control arm. The median duration of improved or stable status with regard to physical functioning, motor functioning, and social functioning were all longer in the combination arm than in the control arm.

Selected Patient Characteristics in the AVAglio Trial

Characteristic RT/TMZ/Pib
(n = 463)
(n = 458)
Median age, yr (range) 56.0 (18-79) 57.0 (20-84)
Gender, male 64 62
0 52 50
1-2 48 50
RPA class
III 16 17
IV 60 57
V 23 26
Surgical status
Biopsy 10 13
Partial resection 48 46
Complete resection 42 41
50-80 30 33
90-100 70 67

BEV indicates bevacizumab; KPS, Karnofsky performance score; Pib, placebo; PS, performance status; RPA, recursive partitioning analysis; RT, radiotherapy; TMZ, temozolomide; WHO, World Health Organization.

Mixed Results for Other Agents

In addition to the positive initial results from the AVAglio trial, other drugs designed to target and treat glioblastoma have met with varying levels of success. In December, the Geron Corporation halted development of their drug GRN1005, an experimental peptide drug conjugate that was being studied in patients who developed brain metastases from breast cancer. At the 2012 San Antonio Breast Cancer Symposium in December, an independent review of a phase II study showed that there were no intracranial responses among the first 30 evaluable patients in the trial.

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