Avastin Has Modest Impact on PFS in Metastatic Breast Cancer

Three-Month Increase in Progression-Free Survival With Bevacizumab

Ron Zimmerman

December 09, 2011

December 9, 2011 (San Antonio, Texas) — Mere weeks after the US Food and Drug Administration (FDA) rescinded approval of the use of bevacizumab (Avastin, Genentech) in metastatic breast cancer, a new study of the drug in metastatic HER2-positive disease shows an improvement in progression-free survival (PFS).

The AVEREL (Study of AVastin [Bevacizumab] in Combination With HERceptin [Trastuzumab]/DocetaxEL in Patients With HER2 Positive Metastatic Breast Cancer) phase 3 study findings were presented here at the 34th Annual San Antonio Breast Cancer Symposium (SABCS), where the study’s authors said they believe it is the first randomized trial of bevacizumab in HER2-positive patients, unlike previous single-arm phase 2 studies.

The AVEREL phase 3 trial was an evaluation of bevacizumab in combination with trastuzumab and docetaxel as first-line therapy for HER2-positive metastatic breast cancer.

According to lead author Luca Gianni, MD, director of medical oncology at Istituto Nazionale Tumori, Milano, Italy, the 3-drug combination extended PFS by an average of 3 months. "There are women who are deriving a much longer duration benefit, but it also means there are women who are not deriving any benefit," he commented.

Dr. Gianni explained that there were strong preclinical rationales for combining trastuzumab and bevacizumab, including positive results in animal studies.

"This is a time when options for treating women with HER2-positive breast cancer are available and very effective ones," he told Medscape Medical News. The emerging treatment options include pertuzumab, which provided a substantial improvement in PFS in a new phase 3 study presented here this week.

AVEREL involved 424 women with previously untreated HER2-positive metastatic breast cancer. Half the study group received trastuzumab (6 mg/kg) plus docetaxel (100 mg/m2). The other half of the group (with balanced baseline characteristics) received that combination as well as bevacizumab (15 mg/kg); all drugs were given every 3 weeks. Treatment consisted of a minimum of 6 cycles, or until disease progression or unacceptable toxicity was noted.

Results for the study showed greater PFS rates for the 3-drug combination: the median PFS was 16.8 months for the group that had received triple therapy vs 13.9 months for the 2-drug group. Side effects included congestive heart failure, febrile neutropenia, and hypertension.

Opinions From Clinicians

Physicians in the trenches who attended the AVEREL presentation described the study’s results in positive terms. "As a treating clinician, you can say one thing that is consistent across all of the bevacizumab trials," Lisa Carey, MD, from University of North Carolina at Chapel Hill, told Medscape Medical News. "Bevacizumab added to chemotherapy improves the response rate. It about doubles it, which for my symptomatic patients is a clear benefit. It improves the progression-free survival to a greater or lesser degree in every trial it has ever been studied in."

Dr. Carey believes the drug has a demonstrable clinical use. "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 its relatively tolerated, as it typically is."  

Another physician, Gabriel Hortobagyi, MD, from University of Texas MD Anderson Cancer Center in Houston, believes that patients benefit from having another effective treatment modality.

He told Medscape Medical News, "Bevacizumab in my book is alive and well, I continue to treat patients with bevacizumab in my clinic, and we continue to run clinical trials that include bevacizumab. I have gone public several times criticizing the decision of the FDA, although I understand the challenges they face in making these decisions."

Dr. Carey also suggested that subsequent research using bevacizumab in combination with other drugs would focus on extending not just progression-free survival but overall survival. "It would be nice to see something to the survival advantage, because when we see that, then we're sort of done, we don't have to have a lot more discussion," she said.

Focus on Biomarker

Dr. Gianni and his team used vascular endothelial growth factor (VEGF), a signal protein, as a biomarker, and he believes his study suggests that his approach may uncover a potentially predictive effect with bevacizumab, with patients with high VEGF-A levels exhibiting greater benefits from the drug combination.

"If confirmed, that would pinpoint that those are the patients where we can expect the highest benefit, the patients we should treat with bevacizumab," Dr. Gianni said.

VEGF’s normal function in the body is to create new blood vessels, both vasculogenesis and angiogenesis, but when it is overexpressed, diseases can flourish, Dr. Gianni noted. Solid cancers need adequate blood supplies, and cancers that can express VEGF are able to grow and metastasize.

"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. And in the case of AVEREL, it is the strongest candidate for a very good biomarker."

A global biomarker study, GO25632 (MERiDIAN), that will also use bevacizumab in conjunction with paclitaxel is planned, but it will use plasma VEGF-A levels as a guide. "That is why we are supporting the idea behind a large prospective validation of VEGF-A as a biomarker," Dr. Gianni said. "There are also other candidate biomarkers that are actively being investigated and some are very promising. But the one that is most advanced is VEGF-A. So during that trial there will be a major effort in investigating also the other ones," he concluded.

The AVEREL trial was sponsored by Roche. Dr. Hortogabyi is a member of the scientific board of Allergan and is a consultant for Novartis, Genentech, and sanofi-aventis and has received grant support from Novartis. Dr. Gianni is a consultant to Roche, Novartis, Genentech, GSK, Wyeth, Eisai, Pfizer, Millennium Takeda, Boehringer Ingelheim, Biogen Idec, AstraZeneca, Genomic Health, Celgene, and sanofi-aventis.

34th Annual San Antonio Breast Cancer Conference; Abstract #S4-8. Presented December 8, 2011.

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