The news this afternoon that an FDA advisory panel recommended removing approval for bevacizumab (Avastin®) as a treatment for advanced breast cancer is certainly going to be difficult for patients, their families, supporters and doctors alike.
The unfortunate reality is that despite earlier reports that this targeted therapy (which has been successful in treating a number of other cancers and works by inhibiting the growth of new blood vessels that feed cancer tumors) was successful in treating advanced breast cancer didn't hold up when studied in further clinical trials.
Bevacizumab in the treatment of breast cancer has followed a long, somewhat tortuous course beginning as early as 2005 with an announcement by the National Cancer Institute that the drug was successful in a clinical trial where women with advanced breast cancer were treated with the drug.
Following that announcement, it took an additional almost 3 years until the FDA approved bevacizumab as a treatment for breast cancer. However, that approval was not a "slam dunk", after another FDA advisory panel had recommended against approval on a close vote. The FDA overrode the panel's recommendation, and gave the drug a conditional approval while further clinical trials were underway.
It was the results of those clinical trials that were presented to the FDA's cancer drug advisory panel today, resulting in an overwhelming (12-1) vote to remove approval of bevacizumab as an effective treatment for advanced breast cancer.
The trials in question used standard chemotherapy with or without bevacizumab, and looked to see how long the treatment(s) delayed the progression of breast cancer (what we call "progression free survival", or PFS) as well as how long the women lived after they received their treatment ("overall survival" or OS).
The reports from a couple of years ago showed the addition of bevacizumab almost doubled progression free survival from 5.8 months to 11.3 months. However, the data at that time did not show that bevacizumab increased survival, which up to this point in time has been the "gold standard" for approving almost all cancer treatment drugs. That is one of the reasons the FDA asked for more information.
For some of us, the core question at that time was whether or not women had a better quality of life during that period of extended progression free survival, even if the drug did not increase the length of their days. The thinking was that even if total survival wasn't improved, at least if they had better function and less pain, it would still be worthy to consider the drug effective. Unfortunately, the studies were not designed to give an answer to that question.
Now come the two new studies, and the news wasn't particularly impressive that bevacizumab made a real difference in the treatment of the women in the trials.
According to an FDA report, although the drug was effective in increasing the progression free survival, the duration of that effect was around 0.82 to 0.88 months in one study and 1.2 months in the other. When looking at survival, there was no real difference in women who received bevacizumab compared to those who did not. In fact, if anything, the data suggested (but did not prove) that women who did not get bevacizumab lived longer than those who did.
The safety review of the drug also showed many more severe adverse side effects when bevacizumab was added to the treatment regimens.
So where does this leave us?
Although there were suggestions that bevacizumab had some effect in increasing response rates in breast cancer treatment, that did not translate into particularly long increases in how long it took breast cancer to progress. It clearly did not increase the survival for these women. In fact, the overall survival appeared to be shorter in women who took the drug. The reasons for that are not clear, and the possibility remains that some known or unknown side effect of the drug could have contributed to this outcome.
The panel was overwhelming in its decision, but that does not mean the FDA will withdraw the drug for this particular treatment indication. The panel voted previously in December of 2007 not to approve the drug, but the vote then was much closer (5-4) and the FDA eventually overrode that recommendation and provided the conditional approval. So one should not draw conclusions based on today's reports alone as to what the FDA will do in this particular situation.
There are clearly women out there who have had significant responses to bevacizumab when used either alone (during clinical trials) or with other chemotherapy. And for them and their families today's reports are going to be difficult to accept. But the information is what it is, and given the FDA's published concerns about the earlier clinical trials, it may be that today's evidence is a bit more solid than that presented previously.
There are several real issues that patients and their physicians will have to address immediately, such as what do you do if you are currently receiving bevacizumab as part of a treatment program? And, especially, what if you are a woman with advanced breast cancer and have had a response to your chemotherapy regimen which contains bevacizumab?
For women currently on the drug, it is vital that you have an open and honest conversation with your oncologist who knows you best. The FDA has not withdrawn approval of the drug, and no one should take any drastic action (such as insurance companies stopping payment for this treatment) based on today's committee vote.
For women with advanced breast and their doctors who may be contemplating treatment options, situation has become a bit more complex, and there is no easy answer. I suspect there will be a lot of experts who will be offering their thoughts in various media and other reports from respected medical organizations which might give some guidance to oncologists as to what their next steps should be.
And-and this is a very important "and"-this recommendation does not apply to other cancers such as colon cancer and lung cancer where bevacizumab has shown to be effective. Nothing about today's recommendation has anything to do with the approved use of bevacizumab in the treatment of other cancers.
Ultimately, this committee vote reflects some of the difficulties we have in determining which drugs are truly effective in treatment which cancers. With all of the new targeted therapies on the horizon, the situation is becoming even more complicated. Think back to Iressa®-another targeted therapy that was conditionally approved for lung cancer and then withdrawn-and the recent events surrounding the approval of Provenge® for advanced prostate cancer, and you have a sense of what I mean.
In the meantime, it is critical that we make our best efforts to design clinical trials in such a way that interpretation of the results leaves little to chance. We can't go through too many of these events before we begin to question why we got into this situation in the first place. When it comes to bevacizumab and breast cancer, we have had reports of success, followed by tempering of those reports, followed by a limited success resulting in a conditional approval, to today's decision to recommend withdrawing approval for treatment in advanced breast cancer be removed.
During the swing and sway of all of these decisions and recommendations over the past 5 years there have been patients, families and their doctors looking for some hope that a new drug was effective in treating a deadly disease. Too much back and forth that never should have happened. Too many lives have been caught in the crossfire of indecision that has enveloped this drug in the treatment of this disease.
I suspect the FDA won't take a long time to make its final decision, but no one knows for sure. In the meantime too many women and their families are left hanging, wondering whether the cost in human and financial terms is worth it for a drug that may or may not work.
We need to do better.