FDA Advisory Committee Votes Against Approving Avastin

I was greatly heartened this week to hear that the FDA's influential Oncology Drugs Advisory Committee (ODAC) has voted 5-4 against approving the drug Avastin for use alongside chemotherapy in advanced breast cancer.

The five ODAC panel members who voted against recommending Avastin did so primarily on grounds that the drug has not been shown to prolong life in breast cancer patients.

As readers of this newsletter will know, I have long been an outspoken critic of FDA's apparent willingness to approve expensive new cancer drugs that have never been shown to prolong life. The FDA now has until the end of February, 2008, to decide whether or not to follow its advisory panel's recommendation. If industry lobbyists prevail - and they intend to try - FDA may yet override ODAC and grant approval for the use of Avastin in advanced breast cancer despite its less than encouraging performance in clinical trials.

I will be writing more about this subject in the very near future, and will be telling readers how they, too, can effectively make their voices and opinions heard. Meanwhile I congratulate patient advocacy groups such as Breast Cancer Action which have worked tirelessly to ensure that the best interests of patients are not drowned out by relentless industry pressure at the highest levels within FDA.

Ixempra - A New Drug For Advanced Breast Cancer

In October 2007, the FDA approved Ixempra (ixabepilone) for the treatment of advanced breast cancer. Specifically, the drug was approved for the treatment of patients whose metastatic or locally advanced breast cancer has become resistant to standard drugs such as anthracyclines, taxanes, and capecitabine (Xeloda). Ixempra is classified as a "microtubule inhibitor." It is thus similar to the taxanes but is said by the manufacturer, Bristol-Myers, to be somewhat less toxic.

"Previously, patients with aggressive metastatic or locally advanced breast cancer no longer responding to currently available chemotherapies had limited treatment options," said Linda Vahdat, M.D., of New York-Presbyterian Hospital/Weill Cornell Medical Center, in a statement released by the company. "The approval of Ixempra means that we now have an important new option for patients with metastatic breast cancer who have rapidly progressed through currently approved chemotherapies."

Let's therefore examine just how "important" this new option is likely to be to patients with metastatic breast cancer.

First of Two Trials

FDA's approval of Ixempra was based on two clinical trials that included a total of 878 patients. The first of these studies was a phase II (non-randomized) trial of Ixempra as a stand-alone treatment. That study enrolled 126 patients with either metastatic or locally advanced breast cancer that had proven resistant to three prior therapies. There was an "objective partial response" in 12.4 percent of 113 evaluable patients. In other words, fewer than one out of eight patients who got the drug saw their tumors shrink. (And, by the way, whatever happened to the other 13 "unevaluable" patients in the study? Under the commonly observed intent-to-treat rule of medical statistics, they should have been included in this analysis.)

A partial response is generally defined as an incomplete shrinkage of the tumor by more than 50 percent for one month or more. As long-time readers of this newsletter will know, a partial response generally does not correlate with increased survival.

Side effects of Ixempra in this trial included the following:

• Peripheral sensory neuropathy in 62 percent of patients, with serious to severe effects (Grades 3 and 4) in 14 percent;
• Fatigue/asthenia 56 percent (Grade 3/4: 13 percent);
• Myalgia/arthralgia 49 percent (Grade 3/4: 8 percent);
• Alopecia 48 percent (Grade 3/4: 0 percent);
• Nausea 42 percent (Grade 3/4: 2 percent);
• Stomatitis/mucositis 29 percent (Grade 3/4: 6 percent);
• Vomiting 29 percent (Grade 3/4: 1 percent);
• Diarrhea 22 percent (Grade 3/4: 1 percent);
• Musculoskeletal pain 20 percent (Grade 3/4: 3 percent).

Major hematologic (blood-related) adverse events included neutropenia (Grade 3-4 in 54 percent) and leukopenia (Grade 3-4 in 49 percent).

Combination Trial

FDA also took into consideration a larger phase III randomized trial which evaluated the efficacy and safety of Ixempra combined with Xeloda (capecitabine) in comparison to Xeloda used as a stand alone treatment. This trial included 752 patients who were previously treated with anthracyclines (such as Adriamycin) and taxanes (such as Taxol), and whose tumors had already shown resistance to these therapies. In this trial, Ixempra in combination with Xeloda resulted in a slight improvement in progression-free survival (PFS) compared to Xeloda given alone.

The median survival with the combination of Ixempra and Xeloda was 5.7 months vs. 4.1 months for Xeloda alone - a gain of 1.6 months. But the side effects included peripheral sensory neuropathy in 65 percent, hand-foot syndrome in 64 percent, nausea in 53 percent, diarrhea in 44 percent, etc.

Again, readers will note that the above statistics do not yield any information on overall survival, i.e., how long on average Ixempra patients can be expected to live compared to those who got either Xeloda alone or no further treatment. The increase of 1.6 months (which you can be sure will be widely bandied about as indicative of the "value" of Ixempra) refers solely to an improvement in progression-free survival. But progression-free survival is not at all the same thing as improved overall survival. Progression-free survival is the time during which the disease appears stable before once again beginning to advance. It is entirely possible that two groups of patients could have a significant difference in this parameter, but the disease could still claim their lives at roughly the same time.

A Bristol-Myers spokesperson has been quoted as saying that the cost of a full course of Ixempra would be between $18,440 to $23,050.

There was a time when FDA required proof of increased survival before it would approve a new drug. Now Bristol-Myers has gotten Ixempra onto the market, having only shown a slight increase in a surrogate marker of doubtful benefit.

--Ralph W. Moss, Ph.D.

References:

Ixempra company web site:
http://www.ixempra.com/

Cost of Ixempra:
http://www.topnews.in/bristol-myers-breast-cancer-drug-won-us-fda-approval-23921

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