When the FDA issued an accelerated approval for the use of bevacizumab (Avastin) for metastatic breast cancer, the approval was contingent on additional clinical trials demonstrating efficacy for that indication. Now, nearly 2½ years later, the results of those trials have prompted FDA's Oncologic Drugs Advisory Committee (ODAC) to recommend that the FDA withdraw its approval of bevacizumab for metastatic breast cancer. The recommendation was widely reported by national news organizations, including the business press, which speculated on the potential economic impact if bevacizumab loses its FDA-approved indication for metastatic breast cancer, and the medical media, which looked at what it might mean to patients and physicians if the FDA decides to accept ODAC's recommendations.

Patients Want Answers

"I'm getting questions from patients who are on bevacizumab about what this will mean for them," said Nicholas Robert, MD. "Will they be able to continue to stay on the drug? That, of course, may depend on what FDA says, but it is hard if you have someone that has metastatic breast cancer and is doing well on a bevacizumab regimen to stop that regimen." Dr. Robert is Associate Chair of the Breast Committee of US Oncology, a physician practice management group with about 1,200 oncologists, Chair of the Cancer Committee at INOVA Fairfax Hospital in Virginia, and an ASCO University faculty member. He also served as principal investigator of RIBBON-1, one of the two new studies ODAC analyzed before making its recommendations.

"For patients who are tolerating treatment and responding, it would probably be prudent for the FDA to permit them to stay on treatment until they experience disease progression or develop a complication," Dr. Robert said. "It would be pretty tough from a patient perspective to stop a regimen if you are doing well on it." In the US Oncology practice, that would primarily involve patients using first-line paclitaxel and bevacizumab, the combination used in the E2100 study that led to FDA's accelerated approval in 2008 of bevacizumab for advanced breast cancer.

"I was the principal investigator for the RIBBON-1 study and serve as a consultant and lecturer for Roche, so I am familiar with both research and clinical considerations. From a clinical perspective, I do think weekly paclitaxel with bevacizumab should still be available, and I think that opinion is shared by a lot of people in the breast cancer community," Dr. Robert said. He added that the combination of capecitabine (Xeloda) and bevacizumab, which was used in one arm of the RIBBON-1 study, should also be an option for women with metastatic breast cancer.

Is Progression-free Survival a Meaningful Endpoint?

Dr. Robert attended the ODAC meeting as an observer. "It was an interesting process," he remarked, "because there seemed to be a few things going on that are frankly unresolved. One is the debate about progression-free survival vs overall survival. A number of us in the breast cancer community who do research feel that progression-free survival is potentially a clinically meaningful endpoint." Dr. Robert noted that progression-free survival was the primary endpoint for the three trials the FDA used in making its decision on bevacizumab for advanced breast cancer-the E2100 trial that prompted the accelerated approval and the follow-up RIBBON-1 and AVADO trials.

In all three trials, the drug combinations used were active and "succeeded achieving the endpoint of each trial, which was progression-free survival statistically, and that was never a debate," Dr. Robert said. "No one argued that the progression-free survival data were not robust. The issue was the trade-off with side effects, and the problem I had was that all of the trials were put into one category." He argued that "another approach" would have been to look at the data for the different drug regimens and approve the combination regimens that produced clinically meaningful results, which he considers to be paclitaxel with bevacizumab, as used in the E2100 trial, and capecitabine plus bevacizumab, as used in one arm of the RIBBON-1 trial.

What about Toxicity?

"The other big issue" discussed by ODAC, Dr. Robert noted, "was the concern about toxicity, which is real." Hypertension is not uncommon as a side effect of bevacizumab, he said, "but we are all internists-oncologists in this country are specialists in internal medicine first. We can manage hypertension. We can manage neutropenia and febrile neutropenia. Those are complications of treatment, and it's our job to manage the complications. I've not had a patient for whom I've had to hold bevacizumab for hypertension, because we monitor patients for that and we treat it," he said. "All of the drugs we use for chemotherapy have risks for toxicity, and it is really an art in terms of how to use them carefully so you don't produce harm. It is the art of managing patients with metastatic breast cancer, the art of oncology."

Dr. Robert argued that the toxicity "is acceptable given the gains" of an additional 5.5 months of progression-free survival in the E2100 study, and an additional 2.9 months of progression-free survival in the capecitabine arm of the RIBBON-1 study. "For me that would have passed muster as a risk-benefit ratio that was acceptable, worthy of use, and worthy of being available in clinical practice," he said.

What Is the Chronic Disease Model?

"The more drugs we have available, the more treatments we have available for the patient, the better chance we have of keeping the patient's disease under control for a longer period of time," Dr. Robert said. "The rationale is that we think of metastatic breast cancer as a chronic disease, and we give sequential treatment, moving from one drug to another drug." According to this rationale, "if a drug produces a few more months of controlled cancer," it could be useful as part of the sequential strategy. Registry data show that "women are living longer with stage IV breast cancer today than 20 years ago, and that is partly due to having multiple treatments available so you can use that strategy," he added.

All of the women in the cited studies were HER2-negative and therefore not candidates for hormonal therapy. "So you only have chemotherapy," Dr. Robert pointed out. Paclitaxel and capecitabine without bevacizumab also "are very reasonable regimens," he said. "If bevacizumab is not available, we will continue to use the arsenal of agents we have available and continue to use single agents. We have other drugs." ■