SAN FRANCISCO—The role bevacizumab will play in metastatic breast cancer care is a matter of great debate, with the US Food and Drug Administration set to rule on the issue next month. With a lopsided vote in July, the agency's Oncologic Drugs Advisory Committee recommended against its approval in that setting. However, in a discussion here at the Oncology Congress in October, it was clear that some oncologists who treat the disease think the drug should remain available for some patients.
“I hope they will keep some approval of it, because I do think it helps some patients,” said Ruth O'Regan, MD, Associate Professor of Hematology & Medical Oncology and Director of the Translational Breast Cancer Research Program at Emory University Winship Cancer Institute, who chaired the breast cancer session.
And Scott Christensen, MD, Professor of Hematology and Oncology and Director of the Clinical Trials Support Unit at the University of California Davis Cancer Center, during his talk on antiangiogenic agents, reviewed the clinical trial data that support bevacizumab's use in first- and second-line metastatic breast cancer, noting that the first Phase III trial showed no improvement in progression-free survival with the addition of bevacizumab to capecitabine in women with pretreated metastatic breast cancer. But the addition of the drug came with added toxicity, including hypertension, bleeding, and proteinuria.
That trial nearly killed the drug, according to Dr. Christensen, but a positive trial in gastrointestinal cancer revived researchers' interest and confidence, and they launched the Eastern Cooperative Group trial 2100 (E2100).
In that study, researchers saw a near doubling of progression-free survival (PFS) in women with previously untreated locally recurrent or metastatic breast cancer who received paclitaxel plus bevacizumab compared with paclitaxel only (11.4 vs 6.1 months).
“At the time these results were announced, this was considered groundbreaking and, literally, the standard of care changed overnight in these United States,” Dr. Christensen said.
The final results of E2100, though, showed no overall survival benefit with the addition of bevacizumab.
Moreover, three subsequent trials in metastatic breast cancer—AVADO, RIBBON1, and RIBBON2—showed smaller gains in progression-free survival than E2100 and, like E2100, no improvement in overall survival.
AVADO, which tested bevacizumab in combination with docetaxel, was the first trial to report and showed a 1.9-month difference in median progression-free survival, which was statistically significant.
“What is interesting about this trial,” Dr. Christensen said, “is that while you can say there was a benefit with the addition of bevacizumab to the chemotherapy backbone, notice the magnitude of the difference. We are no longer at six months, we are at one month, or maybe a little over. That struck many of us as somewhat concerning.”
In RIBBON1, physicians could choose the chemotherapy, including capecitabine, which was the agent used in the first Phase III trial that was negative. However, in this trial, the median PFS improved by 3.6 months when bevacizumab was added to capecitabine and by 2.4 months when it was combined with anthracyclines or taxanes.
“So this is a second trial in which we are not seeing, in my opinion, really a confirmation of the ECOG 2100 results,” Dr. Christensen said. (And the results should, he thinks, raise interesting biological questions regarding why the capecitabine combination would work in first-line therapy but not later.)
The results of RIBBON2, which tested bevacizumab plus chemotherapy in previously treated metastatic breast cancer patient, followed what was appearing to be a pattern, with a 2.1-month improvement in median PFS, which was statistically significant.
“That is the major clinical experience that we have with bevacizumab,” Dr. Christensen said. “As you well know the advisory committee to the FDA voted 12-to-1 not to approve this agent in the metastatic setting, basically due to the lack of robustness of the data.”
Awaiting a Decision
The decision by the FDA was due in September, but the agency delayed it until December, which has left the community in limbo, and in some cases altering practice patterns.
“I haven't really given it with capecitabine since all of this started,” Dr. O'Regan said. “I only give it with paclitaxel now, because I am afraid I won't be able to continue it with capecitabine after the decision.”
When asked by an audience member what he expects the agency will do, Dr. Christensen said, “I think they are not going to allow it.” And, he speculated that the delay in the decision was done to give the agency the time to “make sure they have every i dotted and every t crossed” before they release it, because the issue is so charged.
“The ideal situation would be that they approve it for a very narrow indication, so that we will still be able to utilize this agent,” he continued. “They could also remand this back to the manufacturer and say you need to do more studies, or they could do what is typically done, which is say a blanket ‘no,’ which in my opinion would be a mistake.”
For her part, Dr. O'Regan said she thinks it's difficult to know what the agency will do at this point, but that the lack of overall survival benefit is an issue.
One theory why that might be the case is that withdrawal of the drug at the completion of therapy may allow the tumor blood vessels to regrow rapidly, causing a rebound effect.
On the other hand, any survival benefit may be diluted out by the numerous regimens most breast cancer patients undergo over the course of their disease.
“Those are the two possible explanations,” she said. “The concerning thing would be—and for which there is some preclinical data—is that when you stop bevacizumab, something happens within the tumor that it starts behaving more aggressively. It has never been totally proven, but I think that is the FDA's concern essentially.”
In fact, the optimal duration of bevacizumab therapy has never been settled. A third RIBBON trial was designed to address the question, but was never launched. And, therefore, the question remains unanswered, though it may be at the heart of the current debate.
Cost & Politics
Interestingly, both Dr. Christensen and Dr. O'Regan said they think cost and politics will infl uence the FDA's decision. “I do think, with all due respect, that the decision the FDA is going to make will not be based entirely on science,” Dr. Christensen said.
(Bolstering the view that science will not be the only thing influencing the agency, the National Comprehensive Cancer Network published updated breast cancer guidelines in mid-October “to affi rm its recommendation regarding the use of bevacizumab...in the treatment of metastatic breast cancer.”)
In an interview following the session, Dr. O'Regan said “Cost is a huge issue. The FDA isn't allowed to put that in, but I am sure that is a major part [of their discussion]. It is outrageously expensive, particularly if you consider giving it indefi - nitely, which it is looking like.
“If we were in a country like the United Kingdom, where you had a restricted formulary, there would be no way this drug would be available because the benefi ts are just not worth the extra cost.”
(In fact, the companies that make bevacizumab did not pursue regulatory approval in the UK after the National Health Service regulatory agency requested cost-effectiveness data for the drug, according to agency documents.)
Dr. O'Regan said she would like to see the drug remain available at least for some patients. “Leaving it as is for use in combination with paclitaxel would be totally reasonable. I would like to have it available for patients with very resistant cancers, like triple negative that have relapsed from adjuvant taxanes. I think they are the group we need to focus on.”