Terra Sigillata

As we discussed here yesterday, ixabepilone, a semi-synthetic anticancer drug derived from a soil bacterium was up for review by the US Food and Drug Administration (FDA). Just over a half hour ago the manufacturer, Bristol-Myers Squibb, announced that the drug has indeed been approved for the treatment of advanced breast cancer. The drug will be sold under the trade name, Ixempra.

“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., Associate Professor of Clinical Medicine and Associate Attending Physician, New York-Presbyterian Hospital/Weill Cornell Medical Center. “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.”

Ixabepilone is a chemically-modified form of a natural product called epothilone B. The epothilones have been studied widely, both in their natural form and with modifications intended to improve their duration of action in the body. Ixabepilone is an unusual drug at a time when companies are trumpeting “targeted therapies.” This approach, to find one drug that selectively targets one enzyme, has had limited success across cancers but can be very effective for patients with specific subsets of a given cancer. Ixabepilone is still a targeted therapy, primarily by preventing microtubule depolymerization in cancer cells, but it then triggers a series of events that lead to cell death. (In fact, I have yet to hear a convincing argument as to why some anticancer drugs are considered “targeted” while others are not.). Most importantly, ixabepilone continues to kill cancer cells that have grown resistant, or unresponsive, to other chemotherapeutic agents.

Of course, the drug is not without liabilities and can cause bone marrow suppression, peripheral neuropathy, and, in rare cases, cardiac impairment. The good news is that most of these side effects can be managed. But only time will tell how widely effective this drug will be across more diverse and less controlled patient populations than those enrolled in clinical trials.

Over the last decade, I have had the pleasure of knowing a great many chemists and pharmacologists at various academic institutes and pharmaceutical companies involved in the development of various epothilones, natural and synthetic. Seeing ixabepilone to market is a triumph for all in the field of natural products research and, most importantly, a new lifeline for patients with advanced breast cancer.

Comments

  1. #1 AnnR
    October 17, 2007

    Well I’m always happy to see new breast cancer drugs, but given the recent news that Taxol is only effective on her+ cancers I have to wonder whether this new element falls into that category also.

    As I understand it only 25% of breast cancers are her+. They’ve already got herceptin and another new drug Tyberb?

    So if you have the misfortune to have her+ disease, which is quite aggressive, the cabinet of tools is full with new weapons.

    But what about the 75% of women whose disease isn’t her+?

  2. #2 OncDoc
    October 17, 2007

    Ann R: This new analysis in NEJM only applies to women with node-positive disease treated with Taxol — in this case, AC (Adriamycin/cyclophosphamide) is as effective as AC plus Taxol in women with HER2 negative disease. In other words, women with HER2 negative disease need LESS chemotherapy as these tumors are less aggressive in general. It does not mean that Taxol is ineffective in these patients; it simply means that it provides no additional benefit over Adria/cyclophosphamide alone

    In contrast, docetaxel (Taxotere) appears to add benefit in the adjuvant setting whether a tumor is ER-positive or HER2-positive. These particular subgroups were evaluated in BCIRG001–TAC vs FAC. NEJM 2005;352:2302-2313.

    “Moreover, treatment with TAC, as compared with FAC, was associated with a 28 percent relative reduction in the risk of relapse. The reduction in the risk of relapse did not seem to be driven by nodal status or by hormone-receptor or HER2/neu status”

    In addition, a move towards individualized therapy using gene tests such as OncoTypeDx and newer assays that may predict a tumor’s sensitivity to specific chemotherapy will better answer the question of what chemo to use for a specific patient.

    In triple negative tumors a specific formulation of Taxol may be more effective.

    Finally, it appears to me that ixabepilone was tested primarily in HER2-negative disease, so it will likely be an excellent addition to regimens for those women with HER2-neg disease.

  3. #3 AnnR
    October 18, 2007

    That’s a helpful explanation. I don’t think the article in the paper made that distinction quite as clearly.
    Thanx –

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