Two months ago, the Oncology Drugs Advisory Committee (ODAC) ruled 5-4 that the Food and Drug Administration (FDA) should not approve the drug Avastin (bevacizumab) as a treatment for advanced breast cancer. (Currently, Avastin is only approved for use in patients with colorectal cancer.) The committee's reason for recommending against approval for use in breast cancer was that Avastin had not been proven to convey significant patient advantage in terms of either improved overall survival or quality of life.

To read our December, 2007 newsletter on the ODAC decision, please click here or go to:
http://www.cancerdecisions.com/121607.html

As a result of our December newsletter on this decision, many of our readers wrote to urge FDA officials to uphold the advisory board's decision.

Since December, executives of the California-based biotech firm Genentech (which manufactures Avastin), and its major stockholder, Roche, have been working and lobbying hard to overcome this FDA hurdle. This week they finally revealed their strategy and, unless there is an upsurge of objections from medical consumers, they may well get approval of the drug by FDA's February 23rd decision-making deadline.

On Tuesday, February 12, Genentech issued a statement on the so-called AVADO study, which is being conducted by Roche. The study was designed to compare outcomes in 736 patients with advanced breast cancer, all of whom received the standard chemotherapy drug docetaxel (Taxotere®), but half of whom also received Avastin.

"Genentech believes that the results of the AVADO study provide confirmation of Avastin's efficacy and safety in this patient population," the company said in its statement.

On what basis did Genentech make this confident assertion? What were the actual results of the study? Apparently nobody except a handful of company insiders and a few individuals at FDA know, since all the company was prepared to release publicly was a very general statement claiming that Avastin had "met its primary endpoint of prolonging progression-free survival (PFS) in patients who had not received prior chemotherapy for their locally recurrent or metastatic HER2-negative breast cancer. No new safety signals related to Avastin were observed. These data will be submitted for presentation at an upcoming medical meeting."

Attentive readers know that progression-free survival (PFS) and overall survival are not the same thing. Progression-free survival refers to the length of time a patient survives after treatment with no sign that the disease is advancing. By contrast, overall survival (OS) refers to the percentage of people in a study or treatment group who are alive for a given period of time after diagnosis or treatment.

The difference between these two measures is not trivial. PFS is by no means always synonymous with increased survival. Neither is progression free survival easy to measure objectively. As both FDA staff and ODAC members pointed out at the December meeting, it is difficult to gauge precisely when a cancer starts to progress, or worsen. Although achieving a period of stabilization or remission sounds like a worthwhile objective, if the patient does not live any longer as a result of this interlude its benefit is, to say the least, questionable.

In other words, a drug may change the shape of the patients' survival curve, but not alter the ultimate outcome. Treated patients may die on average at the same time as those who were not treated; sometimes they may even die sooner. So what has one actually accomplished with the intervention? Advocates of chemotherapy are apt to say that at least chemotherapy may improve patients' quality of life by increasing the period of time in which they are in remission. Remission is, they say, a psychological benefit. But that assumption is debatable, since patients who believe their disease is being controlled can feel an even greater sense of loss and disappointment when the disease again progresses than do those without any illusions about being cured of the disease. Disease-free survival in any case does not seem like sufficient reason to approve a new indication for a drug.

Genentech and Roche indicated that they would release the actual AVADO data at a future scientific meeting. They did not say whether the data would demonstrate an improvement in overall survival. Overall survival was considered one of the "secondary endpoints" in the AVADO study. But it is unclear if FDA has been provided with such data. Neither they, nor the company, have made such data available to outside scientists or to the concerned public.

Barbara Brenner, executive director of Breast Cancer Action, has demanded the full data from the company. "We are quite disturbed that this uninformative press release seems timed to coincide with the imminent decision by the FDA on the currently pending sBLA [supplemental Biologics License Application, ed.] for Avastin in the metastatic breast cancer setting," she wrote both Richard Pazdur, MD, of the FDA and David Shenkein, MD, of Genentech on Feb. 12, 2008.

Brenner also demanded release of so-called Phase IV data on Avastin's actual performance in clinical trials with colorectal cancer patients. (Phase IV studies are post-marketing reports on the actual safety and effectiveness of drugs as they are used in the real clinical setting. Such studies are often requested by FDA as a condition of drug approval, but are rarely carried out or published by drug companies.)

"We understand that Genentech is engaged in a thorough Phase IV trial of Avastin in the colorectal cancer setting," Brenner wrote. "If Avastin is approved for breast cancer based on information other than overall survival or improved quality of life, the FDA should require prompt and thorough Phase IV review as a condition of approval."