Bevacizumab Plus Trastuzumab and Docetaxel Improves Progression-Free Survival

Luca Gianni, MD

A study of bevacizumab (Avastin) in women with HER2-positive metastatic breast cancer demonstrated that combining the drug with standard therapy improves progression-free survival (PFS), adding further data to the debate over the controversial agent.

The AVEREL trial supports the concept that inhibiting angiogenesis, the process of blood vessel growth, is a valid strategy in breast cancer although the identification of biomarkers remains vital, according to lead investigator Luca Gianni, MD, director of Medical Oncology at the San Raffaele Cancer Center in Milano, Italy.

Gianni discussed findings from the phase III trial during the 2011 CTRC-AACR San Antonio Breast Cancer Symposium in Texas.

The trial explored the impact of adding bevacizumab to trastuzumab (Herceptin) and docetaxel as first-line therapy for women with HER2-positive, locally recurrent metastatic breast cancer.

It was the first randomized trial of bevacizumab in HER2-positive patients; the drug gained accelerated FDA approval in 2008 for use in combination with paclitaxel for patients with HER2-negative metastatic breast cancer not yet treated with chemotherapy.

FDA Commissioner Margaret A. Hamburg, MD, revoked that indication in November, saying that women with metastatic breast cancer who take the drug risk “potentially life-threatening side effects without proof that the use of Avastin will provide a benefit.” (The drug retains its approval for use in 4 other cancers.)

The dispute over adverse events was not rekindled during a discussion of the AVEREL results at a press briefing Thursday, but there were hints of other elements of the bevacizumab debate.

Gianni said analyses from the independent review committee (IRC) and the independent investigator assessment differ on the question of whether or not the improvement in PFS in the AVEREL trial is statistically significant.

The trial, conducted in 60 centers from September 2006 through February 2010, involved 424 patients randomized to receive either bevacizumab plus trastuzumab and docetaxel versus the 2 standard therapies alone.

At median follow-up of 26 months, the IRC analysis found that patients treated with the bevacizumab combination experienced a median PFS of 16.8 months versus 13.9 months for those treated with trastuzumab and docetaxel alone, for a 28% reduction in the risk of disease progression (hazard ratio [HR], 0.72; P = 0.0162). The IRC analysis found the benefit was statistically significant.

By comparison, the independent investigator analysis determined that patients in the bevacizumab group had a median PFS of 16.5 months versus 13.7 months in the standard therapy arm, for an 18% reduction in the risk of progression, which was not statistically significant (HR, 0.82; P = 0.0775).

Gianni said the IRC method is the one used by the FDA in evaluating clinical trials, while the investigator assessment was not censored for nonprotocol therapy.

“The most relevant element emerging from our trial is that bevacizumab is doing something in this group of women, as in the HER2-negative subset of cases,” said Gianni.

“The improvement is there,” Gianni said while adding that there is a need to determine the subset of patients with HER2-positive disease that would benefit the most from bevacizumab.

Investigators are exploring whether or not levels of plasma vascular endothelial growth factor (VEGF) correlate with response to the drug. Bevacizumab is a humanized monoclonal antibody that inhibits VEGF and preliminary indications indicate that greater benefit may correlate with high VEGF-A levels.

Lisa A. Carey, MD

Lisa A. Carey, MD, a professor in breast cancer research at the Lineberger Comprehensive Cancer Center at the University of North Carolina at Chapel Hill who served as moderator at the press conference, said the AVEREL trial fit the pattern of other bevacizumab research.

“You can say one thing that is consistent across all of the bevacizumab trials, and I suspect that in the end this will be the same: Bevacizumab added to chemotherapy improves the response rate—it about doubles it, which for my symptomatic patients is a clear benefit,” said Carey. “It improves the progression-free survival, to a greater or lesser degree, in every trial it has ever been studied in, and it doesn’t do anything to overall survival.”

She suggested the number of therapies that patients with metastatic disease have undergone before they try bevacizumab may cloud trial results. She said, however, that “it would be nice to see some hint of a survival advantage.”

“I would love to have the availability of the drug routinely for symptomatic patients in whom I would like to have more than one agent, particularly one that’s relatively well-tolerated as [bevacizumab] typically is,” Carey said.

Gabriel N. Hortobagyi, MD, chair of the Department of Breast Medical Oncology and director of the Multidisciplinary Breast Cancer Research Program at the University of Texas MD Anderson Cancer Center in Houston, said the AVEREL study shows the continued interest in antiangiogenic strategies to attack cancers and in bevacizumab in particular.

“Bevacizumab in my book is alive and well,” said Hortobagyi, who attended the briefing to discuss his own research. “I continue to treat patients with bevacizumab in my clinic, and we continue to run clinical trials that include bevacizumab.”

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