This weekend the American Society of Clinical Oncology (ASCO), to which I belong, is holding its annual meeting in Chicago. Some of the biggest buzz has to do with a new breast cancer drug called T-DM1. ASCO just lifted embargo of the relevant abstract.

The new agent is a hybrid of an old monoclonal antibody, Herceptin, that’s chemically attached to DM1, a traditional kind of chemotherapy. The chemo part, DM1 – also known as emtansine – is manufactured by ImmunoGen. It’s derived from maytansine, a compound that binds tubulin, a protein critical for microtubule formation in dividing cells. According to the NCI website, this chemical, which has antibiotic properties, was extracted from an Ethiopian plant, Maytenus serrata.

T-DM1 was designed by linking the DM1 compound to the trastuzumab (Herceptin) antibody. Trastuzumab is old news in breast cancer. It 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. In this new, hybrid drug, the antibody works like a tagged, toxic messenger. In effect, the antibody delivers and inserts the chemo into the malignant cell, where it causes cell death.

The new data, from the Genentech-sponsored EMILIA trial, were presented today:

The Phase III study evaluated 991 women with metastatic breast cancer. All participants had tumors with high levels of Her2 (confirmed in a central pathology lab, for the trial). All had disease that progressed despite treatment with Herceptin and, in most cases, other drugs too. After randomization, 978 women received either of two treatments: the experimental agent, T-DM1, every 3 weeks, by intravenous infusion, or a combination of two pills, “XL” – Xeloda (capecitabine) and Tykerb (lapatinib). Median follow-up was just over 1 year – not bad for a study of MBC, but not great, either.

The big news is this: Among the patients who got the experimental drug, T-DM1, the median time until disease progressed was 9.6 month; for those who took the XL pill combination, it was 6.4 months. This different was statistically significant. Although a difference of 3 months may not sound like much – and isn’t – each regimen in the study held the women’s disease in check for over half a year.

It’s striking that T-DM1 was used as a single agent. Most chemotherapy drugs, like those for HIV, work best in combination; it could be that we’ll see more powerful results in a few years, once we learn how to optimally combine drugs for women with Her2+ breast cancer.

As far as overall survival, the initial results seem quite favorable. Among women on the study for 2 years, 65 percent were alive who received T-DM1; among those taking the XL regimen, 47 percent were alive at 2 years. (The statistical details for this comparison are not available; evidently it was of weak significance.) The problem is – if only a few patients were analyzed “so far out” on the survival curves, the difference observed between the two study arms might be random. Still, and independently of the comparison, survival of 65 percent at 2 years in this patient group is (sadly) impressive, especially if it comes by a single agent with comparatively few side effects.

The main T-DM1 toxicities were low platelets and abnormal liver function, which were, reportedly, reversible. The XL combination caused more toxicity, overall, including diarrhea, hand-foot syndrome and nausea.  A much greater fraction of women on the XL arm (53 and 27 percent, respectively for Xeloda and lapatinib) needed dose reductions, as compared to the T-DM1 (16 percent had dose reductions due to toxicity). Evidently hair loss isn’t an issue for women who get T-DM1, which is nice.

My main, initial concerns are two:

First, the study, though randomized, is not “blinded,” and can’t be.  It’s impossible for women who are getting an intravenous drug, and their doctors, not to know that they’re not on the pill study arm. Although there were independent evaluators of progressive disease, which is a far more subjective measurement than overall survival, progression free survival can be influenced by the doctors’ and patients’ knowing they’re getting the T-DM1. That said, the initial, observed difference in overall survival – a clear, objective measurement – is impressive.

If these trial results, published in abstract form, pan out, and the quality of patients’ lives is maintained, that’d be helpful to as many as 1 in 5 women with MBC. It is plausible that an antibody like Herceptin that targets the tumor cells could, in fact, “deliver” the chemo effectively into the cancer cells with relatively low toxicity. And if the women are feeling better, which is hard to know from an abstract, great.

My second concern is how this drug will mesh with others now available and in the pipeline for patients with Her2+ disease. In a December, 2010 editorial in the JCO, two clinical investigators wrote: “the unique aspect of T-DM1 is clearly its high clinical activity by itself, without the need of concomitant additional systemic chemotherapy.” They’re right. The question – as considered by those authors – is how T-DMI will be used in the context of expanding treatment options for women with Her2+ breast cancer. This is an expensive (price not yet known) monoclonal antibody-conjugate that’s necessarily given by infusion. 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 big bucks, besides toxicity and women’s lives.

These EMILIA results are promising for some women with MBC and, possibly, patients with other cancer forms in which Her2 is expressed. Unfortunately, it’s unlikely to help those women with breast cancer whose tumors that lack Her2+.

I’ll write soon about this new class of oncology drugs – antibodies conjugated to chemotherapies, as a group.

All for now,

ES

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