SABCS: Bevacizumab Improves PFS in HER2-Positive Breast Cancer in AVEREL Study

SAN ANTONIO – Bevacizumab (Avastin) improved progression-free survival (PFS) in women with HER2-positive locally recurrent or metastatic breast cancer by an average of 3 months when added to standard treatment as first-line therapy in the multinational, randomized, phase III AVEREL study (Avastin in Combination With Herceptin/Docetaxel in Patients With HER2-Positive Metastatic Breast Cancer). Findings were reported by Luca Gianni, MD, director of medical oncology at the San Raffaele Cancer Center, Milan, Italy (SABCS 2011 abstract S4-8).

Ironically, the report came less than a month after the US Food and Drug Administration withdrew approval of the humanized monoclonal antibody for treatment of metastatic breast cancer.

Investigators from 60 centers enrolled 424 patients, randomly assigned 208 patients to receive trastuzumab (6 mg/kg) plus docetaxel (100 mg/m²) and 216 patients to receive that combination plus bevacizumab (15 mg/kg). Treatment consisted of a minimum of 6 cycles, or until disease progression or unacceptable toxicity was noted.

At a median follow-up of 26 months, investigator assessment showed an 18% percent reduction in risk of progression or death with the addition of bevacizumab compared with that of patients who received only trastuzumab and docetaxel. Analysis by an independent review committee, however, determined a 28% reduction in risk for progression or death with the addition of bevacizumab. 

"The concept of this trial was a test for the benefit observed in early phase I and phase II," said Dr. Gianni. "In a way, we confirmed that adding an antiangiogenic to other treatment is a good idea. But now we have to search the subset of women who have the characteristics associated with benefit from addition of an antiangiogenic." The goal, he said, is to attain a longer-lasting effect than that achieved in AVEREL. 

The AVEREL investigators used vascular endothelial growth factor (VEGF), a signal protein, as a biomarker. Dr. Gianni said this approach may uncover a potentially predictive effect for bevacizumab in patients with high VEGF-A levels exhibiting greater benefits from the drug combination.

"VEGF-A is basically something that triggers angiogenesis and is secreted by tumor cells and the vasculature," he said. "Bevacizumab is a monoclonal antibody that targets exactly that ligand, that receptor for angiogenesis. So it blocks the very progress of angiogenic development in the tumor."

Commenting on the AVEREL findings, Lisa Carey, MD, associate professor of hematology/oncology at the University of North Carolina, Chapel Hill, noted that bevacizumab "about doubles" the response rate, "which for my symptomatic patients is a clear benefit." The drug has improved PFS "to a greater or lesser degree in every trial it has ever been studied in," she added.

"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 that I'm giving them, particularly when it’s relatively well tolerated, as it typically is." 

She conceded, however, that the drug has not been shown to effect survival. The FDA cited the lack of improvement in overall survival for metastatic breast cancer patients in its decision. 

"Survival is a very important end point, but it’s not the only end point in metastatic breast cancer," said Dr. Gianni.

Gabriel Hortobagyi, MD, from the University of Texas MD Anderson Cancer, Houston, said he disagrees with the decision of the FDA and will continue to treat patients with bevacizumab in his clinic, "although I understand the challenges they face in making these decisions."