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Novel Drug Shows Promise in Her2+ Form of Breast Cancer

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This weekend, researchers at the annual meeting of the American Society of Clinical Oncology presented new findings on a novel agent that targets some forms of breast cancer. The new drug, called T-DM1, is designed to deliver a toxic chemotherapy directly to tumor cells.

In a Phase III trial called EMILIA, the drug delayed tumor growth by several months, relative to other treatment in women with Her2+, metastatic breast cancer. What's more, the new medication appears to be relatively safe and well-tolerated, as compared to the other, FDA-approved drugs used in the randomized study of nearly 1,000 women.

The new drug is a hybrid and interesting compound, designed by linking a traditional kind of chemotherapy, DM1 to the Herceptin antibody (trastuzumab). Herceptin is old news in breast cancer: this antibody binds a signaling molecule, Her2, that's expressed at high levels in approximately 1 in 5 breast tumors. The FDA approved Herceptin for use in patients with metastatic, Her2+ breast cancer in 1998 and, for some women with localized, lymph node positive disease, in 2006.

The chemo part of the new agent, DM1, is related to maytansine, an old compound derived from an Ethiopian plant, Maytenus serrata. DM1 is a microtubule inhibitor; this chemotherapy binds to tubulin, a protein that's critical for dividing cells. The antibody works, in principle and apparent effect, by delivering the toxic chemo directly to the malignant cells and destroying those.

Genentech, the drug's manufacturer, sponsored the EMILIA trial. The latest data involve 978 women with confirmed Her2+, metastatic breast cancer. All had disease that had progressed through prior therapy including Herceptin. The randomized trial assigned participants to receive either the experimental agent, T-DM1, every 3 weeks by intravenous infusion or "XL" - a combination of FDA-approved pills, Xeloda (capecitabine) and Tykerb (lapatinib). Median follow-up was just over one year -- not bad for a study of metastatic breast cancer, but not great, either.

Among women who received T-DM1, the time until their disease progressed was a median of 9.6 months; for those who got the non-experimental pills, it was 6.4 months. This difference of just over three months, was statistically significant. Although that doesn't sound like a lot of time -- and I have to admit, it's not -- it is meaningful in the context of comparing drug regimens for people with advanced malignancies. Both regimens delayed progression of the disease for over half a year. The T-DM1 agent did so alone.

Many cancer medications, like drugs for HIV, are most effective in combination; T-DM1 is, clearly, a powerful single agent. We don't yet know what will be the overall survival for those treated with this new compound, and how it might be buttressed by the addition of newer, future therapies.

The main side effects attributed to T-DM1 were low platelets and abnormal liver function. These problems were reversible, according to the investigators. The XL pill regimen caused more toxicity, overall -- including diarrhea, hand-foot syndrome and nausea. Evidently, hair loss isn't an issue for women who get T-DM1. While this detail may seem trivial to some observers, as it might have to me when I was practicing years ago, for women living with metastatic breast cancer it's the kind of quality-of-life issues that can render a drug preferable and tolerable, besides that it may be life-extending.

Speaking of survival -- there is encouraging, but less definitive news: Among the women on study for two years, 65 percent were alive after receiving T-DM1; only 47 percent were alive on the XL pill regimen. The statistical details for this comparison are not available; evidently it was of weak significance. Nonetheless, an overall survival rate of 65 percent at two years is impressive (although, of course, not good enough) for women with progressive disease after other treatments.

One concern I have is that the study, though randomized, is not "blinded," and can't be: It's impossible for the women and their doctors to not know whether they're getting an intravenous drug or a combination of pills. Still, the initial, observed difference in overall survival is striking, especially as the drug appears to have fewer side effects.

I wonder how this new agent, if approved, will fit in with other options available and in the pipeline for patients with Her2+ disease. The key question, as considered in a 2010 Journal of Clinical Oncology paper, is how T-DM1 -- if effective and less toxic -- will fit in to the growing options for women with Her2+ breast cancers. The drug is sure to be expensive (price not yet known); it's a proprietary monoclonal antibody-conjugate that's necessarily given by infusion, which is necessarily inconvenient for patients, besides more costly to administer. Testing this drug against all the other current and up-and-coming alternatives, in varying combinations and doses, will be tricky. The trials alone will cost more money than some -- even big pharmaceutical companies -- might want to spend, besides the costs of potential toxicity and women's lives, which won't necessarily be improved.

In sum, the EMILIA study results are promising. T-DM1 appears to be relatively effective and safe for women with metastatic, Her2+ breast cancer, in itself and as compared to the standard XL regimen. Hopefully we'll soon see similar kinds of good news and treatment options for women with other forms of this disease, including triple negative breast cancer.

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