Researchers Remain in Pursuit of Angiogenesis Inhibition

Beth Fand Incollingo
Published Online: Friday, October 19, 2012
Dr. Hope Rugo

Hope Rugo, MD

Although the FDA revoked the indication for bevacizumab (Avastin) in metastatic breast cancer late last year, many researchers and oncologists anticipate a role for antiangiogenic strategies in future treatment paradigms. Yet just what that role will be remains elusive, said Hope S. Rugo, MD, clinical professor and director of the Breast Oncology Clinical Trials Program at the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco.

“We had very high hopes and were very excited about the role of bevacizumab, as well as other antiangiogenic agents, and here we are today really in a gray area, where we’re not quite sure what the direction is (going) forward,” Rugo said during a presentation at the 11th International Congress on the Future of Breast Cancer. “We do know that antiangiogenic therapy does have activity in breast cancer, we just don’t know exactly how to use it, and where the activity is best seen or where the agents are best used.”

Rugo called for a change in approach when investigating antiangiogenic agents, which she defined as those specifically targeted to a pathway involved with the vascular endothelial growth factor (VEGF) receptor. She said researchers must focus on defining the subsets of patients most likely to benefit from angiogenesis inhibitors, adding that it will be worthwhile to try combining “new agents with angiogenesis agents, maybe looking at vascular disrupting or angiopoietin inhibitors in combination with antiangiogenesis agents like bevacizumab.”

“There are many different ways to activate PI3-kinase, and Raf, Ras, MEK, etc,” Rugo said. “If you block downstream, you can still get activation of VEGF, and if you block VEGF, you can get activation of the downstream pathways, so it’s very complicated, and it suggests that in the future we need combinations of agents to be most effective.”

Potential Bevacizumab Biomarkers Explored

Bevacizumab, a humanized monoclonal antibody that binds to and inhibits the activity of VEGF, has demonstrated in clinical trials an improvement in progression-free survival (PFS) but not overall survival (OS) in patients with metastatic breast cancer when combined with chemotherapy.

Last year, the FDA revoked bevacizumab’s approval for use in combination with paclitaxel in HER2-negative metastatic breast cancer on the basis that the drug did not offer enough benefit to outweigh its health risks, including high blood pressure, bleeding, and heart failure. (Avastin retains its label indications in four other tumor types.)

Rugo maintained that many of the bevacizumab trials could have provided more and better information if they had been designed differently. She said a pooled safety analysis of bevacizumab plus chemotherapy versus chemotherapy alone showed that the main increased risk in the experimental groups was hypertension, although the number of deaths did not increase with the addition of bevacizumab.

“We need to go back to the drawing board because we know patients benefit,” Rugo said. “All of these studies showed a PFS benefit, and there are a few patients out there who’ve continued to have disease control many years after starting bevacizumab—we just weren’t smart enough to figure out who was going to benefit.”

Investigators have, for some time, been seeking to identify biomarkers to help predict which patients would benefit from bevacizumab, Rugo said. She said there’s some evidence that a “VEGF signature” might exist and correlate with bevacizumab benefit, possibly in patients with triple-negative breast cancer (TNBC). The RIBBON 2 trial supported that idea, she said, by demonstrating a median PFS of six months in patients with TNBC who took bevacizumab, compared with a median PFS of 2.7 months for the study’s overall population (J Clin Oncol. Published online ahead of print October 11, 2011, doi: 10.1200/ JCO.2010.34.1255).

In two neoadjuvant trials whose results were published earlier this year, bevacizumab was added to standard chemotherapy in subgroups of breast cancer patients, with a primary endpoint of improved pathologic complete response (pCR). In the GeparQuinto study (Lancet Oncol. 2012;13(2):135-44), patients with TNBC demonstrated the most benefit, while the NSABP B-40 study (N Engl J Med. 2012; 366(4):310-320) showed a greater response in hormone receptor-positive patients, Rugo explained.

While both trials “showed an increase in pCR in tumors with high-grade histology,” there was vast disagreement in the study designs regarding what constituted TNBC and pCR, which makes it difficult to compare and apply their results, Rugo said.

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