Hope S. Rugo, MD
Despite controversy over its breast cancer approval status, bevacizumab (Avastin) remains at center stage when it comes to antiangiogenic therapies for the disease.
In fact, nearly 70 clinical trials exploring bevacizumab in breast cancer are underway, according to Hope S. Rugo, MD, director of Breast Oncology and Clinical Trials Education at the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center.
Rugo said, however, that “there isn’t a clear path forward” when it comes to angiogenesis.
“We understand that there is an angiogenic switch, but we also understand that this is much more complex—like many of the things we’re trying to target— than just simply stopping one part of the pathway,” Rugo said in an interview.
“We’ve been enormously fortunate that blocking HER2 in a variety of ways has been so successful, but actually the angiogenic pathway may have even more redundancy, more mechanisms of resistance, just based on the fact that angiogenesis is so important for so many processes, both normal and abnormal angiogenesis,” she said.
Rugo said it is crucial for researchers to identify biomarkers that help clinicians evaluate which patients would benefit from bevacizumab.
“We really have a desperate need for markers,” she said during her presentation. “It is very unlikely that we are going to find a single marker like HER2 that’s going to tell us who benefits from antiangiogenic therapy. What we’re going to find most likely is a combination of markers.”
She also said the optimal chemotherapy drug and dosing schedule to partner with bevacizumab must be determined, as well as strategies to overcome resistance to antiangiogenic therapy.
Proposed Compromises to Drug Label
Rugo, who also is a professor of Medicine at UCSF, believes Avastin should remain available as an FDA-approved breast cancer drug.
In June, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted to uphold a prior recommendation to withdraw the label indication, citing concerns that the drug does not demonstrate an overall survival benefit and can result in serious toxicities. Pivotal trial data showed a benefit in progressionfree survival (PFS).
“I think it should be available because a subgroup of patients benefit. I think that trying the one-size-fits-all [approach] and trying to grab the biggest piece of the pie has really not worked here,” Rugo said.
“What we need to do is say okay, if you’re going to give a weekly taxane and bevacizumab, you can treat a patient until they progress or have toxicity and then you stop,” she said. “To me, the data support that approach, just as much as they support many of our new chemotherapy agents that only showed PFS benefit and had intense toxicity. So I don’t know that this agent should be held up to a different standard.”
Rugo said the issues surrounding the drug are “very much caught up in cost and the cost of treating metastatic cancer, where you’re treating essentially in a palliative setting.”
She said proving overall survival in a first-line setting would involve recruiting nearly 2400 participants for a randomized trial. “That is a very costly trial and really not what anyone thinks is feasible,” she said.
As it stands now, Avastin retains its approval for use in combination with paclitaxel for the treatment of patients who have not received chemotherapy for metastatic HER2-negative disease.
In August, the manufacturer, Genentech, put a plan the company described as a “middle-ground proposal” before the FDA.
The company proposed revising the label to restrict the drug’s breast cancer indication for use in combination with weekly paclitaxel in patients who have not received prior chemotherapy and whose tumors are characterized as aggressive hormone receptor (HR)-positive/HER2-negative or HR-negative/HER2-negative disease.
Genentech also proposed a Risk Evaluation and Mitigation Strategy, to monitor potential serious adverse events, which can include high blood pressure, hemorrhaging, and intestinal perforation.
At press time, FDA Commissioner Margaret A. Hamburg, MD, had not yet made a final decision on the ODAC recommendation.