The decision yesterday by the FDA’s Oncology Drug Advisory Committee to recommend that Avastin (bevacizumab) not be approved for the treatment of metastatic breast cancer is one more step in a discussion that has significant implications not only for the use of Avastin in breast cancer, but also how this type of decision-making is going to influence cancer treatment in the future.

Avastin is a type of drug that we call “targeted therapy.”  These newer drugs generally target a specific process in a cancer cell that can then influence the function of the cell and lead to its death.  In the case of Avastin, the targets are the blood vessels that cancers need to grow.  Avastin interferes with that process, and has been demonstrated to be effective in a number of cancers, including colon and lung cancers.

In April, 2005, the National Cancer Institute announced that a clinical trial of Avastin with chemotherapy used in the treatment of women with recurrent breast cancer (compared to a “control” group that received only the chemotherapy) resulted in such positive results that the oversight committee monitoring the study ordered it to be stopped and the results released immediately.

This study showed that women who received the combination therapy extended the time for the cancer to progress by an average of four months, according to one news report.  The design of the study had anticipated about two months of improvement.

Although this increase sounds modest, the reality is that when applied to large numbers of women receiving treatment for recurrent breast cancer, the impact for some women can be far greater.

The results were so positive that the then director of the National Cancer Institute, Dr. Andrew von Eschenbach, called a news conference to be help disseminate the information as widely as possible.

The trial results were presented soon thereafter at the annual meeting of the American Society of Clinical Oncology, and expectations were high that Avastin would quickly be approved by the FDA.

But that was not to be.

In September 2006, the Food and Drug Administration asked for more information from the drug’s developer, Genentech, before the drug could be approved.

Then, yesterday, the FDA committee decided to recommend to the FDA that the drug not be approved for treating recurrent breast cancer.  The vote was close at 5-4.

Why the turnabout for a drug that held such promise for the treatment of an unfortunately common situation faced by breast cancer patients and their doctors?

The data presented to the committee apparently showed that for these patients, in this more current analysis, the drug delayed progression of their breast cancer by 5.5 months.  The women who took Avastin in addition to the chemotherapy went 11.3 months before their disease progressed compared to 5.8 months for women who took only the chemotherapy.

But the Avastin group also had more side effects, including 6 deaths attributed to Avastin treatment, or 1.7% of the women who participated in the study.

The key determining factor, according to press reports, was that the women who received Avastin did not live significantly longer than women who did not receive it.  And, this is considered an important statistic.

No prolonged survival, no approval.

Or will that be the eventual outcome?

The same Dr. von Eschenbach who held the news conference announcing the results of the trial in 2005 is the same doctor who now heads the FDA making the decision regarding approval.

To me, the more important question is whether a delay in progression-free-survival really has no value, even in the face of a small but definite risk of significant side effects?

Progression-free-survival is a very sterile, clinical way of saying that the patients’ breast cancers either regressed or at least stabilized.  And, the increase in this survival may have meant for many women that they remained more functional, and less symptomatic—with potentially less pain.

Personally, I am not so certain that an almost doubling in progression-free-survival with less pain should be ignored.   But the problem in this situation is that the researchers apparently didn’t measure this factor during the course of the study.  So, for all anyone knows, the patients may have lived longer, but their quality of life may or may not have been improved.  We have no evidence either way.

There is clearly a bias among doctors that if a cancer drug increases the time until the cancer recurs, that it is almost certainly associated with an improved quality of life.  And, I suspect, if that had been clearly been demonstrated, the drug would have been approved by the panel—the serious side effects notwithstanding.

But it wasn’t measured, and the vote was negative. 

The FDA has until late February to make a decision and I suspect that in this situation there is going to be a great deal of discussion within the agency as to whether or not they should follow the panel’s recommendation.

I think it is fair to say that doctors have been using Avastin to treat women with metastatic breast cancer since the first announcement in 2005.  This is what we call an “off label indication,” which means that there have been reports in the scientific literature that a drug is effective in a particular situation but hasn’t been approved by the FDA for that indication.

If the FDA doesn’t approve the drug, will off-label usage continue? 

I feel comfortable in predicting that insurers may well balk at paying for the drug under this scenario if the FDA looks at the evidence and decides not to approve Avastin for treatment of metastatic breast cancer.

In no small part, this decision will be driven by the high cost of the drug (tens of thousands of dollars) and the frequency with which it could be used.

And that has the potential to set off a cascade of events, likely even litigation, pitting patients and their doctors against the insurers and the government.  The heart of the argument will be whether a patient should be able to receive a drug that may improve the quality of their lives, even if there is no evidence that it may prolong their survival.

So, the end of the story has not been written and probably won’t be for some time.

In the meanwhile, there is likely to be intense discussion about how we got into the mess we are in, and what we need to do in the future to avoid repeating this scenario with other drugs and other clinical trials.