T-DM1: ASCO Showcases a Victory for Science, But Is It a Victory for Women?

By Laura Nikolaides, Director of Research and Quality Care Programs

Laura Nikolaides
Laura Nikolaides answers questions at the Project LEAD® Advanced Topics session during the NBCC 2012 Annual Advocate Summit.

I just got back from spending the weekend in Chicago at the annual meeting of the American Society of Clinical Oncology (ASCO).  As you all know, this meeting always generates a flurry of headlines and media stories about new findings in the treatment of cancer.  This year, it was T-DM1 for metastatic breast cancer that was given a top presentation spot at the meeting and created the biggest stir in the media.

But, as always, the facts or complexities of the results often get lost in the headlines and stories. The New York Daily News said the drug delivered “stunning results” in delaying progress of breast cancer.  Huffington Post headlines called T-DM1 a “wonder drug.”

The truth is that the results of the Phase III trial of T-DM1 (named EMILIA by drugmaker and sponsor Genentech) were modest, but encouraging, and more time is needed before we know definitively if, and for how long, the drug increases survival in women with HER2+ metastatic breast cancer.

The study compared T-DM1 to a combination regimen of Xeloda and Tykerb (XT) in 991 women with HER2+ metastatic breast cancer that had progressed, despite treatment with Herceptin and taxanes and/or anthracyclines . The women receiving T-DM1 had an average time until disease progression of 9.6 months, compared to 6.4 months for those receiving XT.  The final overall survival analysis is not yet complete, but an interim analysis fell short of the predetermined boundary for stopping the trial and allowing crossover, by just one patient. 

At 12 months, 84% of those on T-DM1 were still alive, compared to 77% on XT, and at two years that gap had widened to an 18% difference, 65% alive on T-DM1, compared to 47% on XT.  Statistically, it is still possible that the differences in survival could be due to chance and will need confirmation in the final analysis.  There were five adverse events leading to death in the XT arm, compared to one in the TDM1 arm, cardiotoxicity was minimal, at less than 2% in both arms.  The main T-​​DM1 tox­i­c­ities were low platelet counts and abnormal liver function, which the investigators reported were reversible, while those on XT experienced more nausea, hand-foot disease, diarrhea and hair loss.

“These results left me feeling cautiously optimistic that this new agent does indeed deliver meaningful benefit to women with HER2+ metastatic breast cancer, with less toxicity.”

These results left me feeling cautiously optimistic that this new agent does indeed deliver meaningful benefit to women with HER2+ metastatic breast cancer, with less toxicity.  And there is no doubt for me that the EMILIA results do represent a major victory for science, and may open the door to a long sought after goal for all cancer patients—being able to deliver toxic agents that kill malignant cells directly while avoiding damage to normal cells.  According to an article in the New York Times, approximately 24 other similar agents, called antibody-drug conjugates, are in development. These antibody-drug conjugates, or hybrids, consist of antibodies that are linked to the chemotherapy agents.  In the case of T-DM1, the monoclonal antibody Herceptin is attached to the chemotherapy emtansine, or DM1, a chemotherapy agent that is potent and intolerable if given directly to patients.

After decades of effort by scientists, the scientific victory for TDM1 was in the linking technology; the link used to combine the antibody and chemotherapy allows the drug to remain intact outside the cancer cell, but in an inactive state until it enters the cancer cell, thereby minimizing exposure of normal cells to the chemotherapy. After finding the cancer cells in the body by their over-expression of HER2 and attaching, T-DM1 is then absorbed into those cancer cells, and the potent DM1 is released to destroy the malignant cells.  

I look forward eagerly to the final results of this trial, and to results of additional trials of T-DM1, including MARIANNE, a 3-arm, multicentre, phase III study comparing T-DM1 combined with pertuzumab, TDM1 alone, and the combination of Herceptin plus a taxane in patients with HER2-positive progressive or previously untreated metastatic breast cancer. And I look forward to ultimately seeing a translation of this new technology to create other agents that can target a wider group of breast cancer patients, giving more women the opportunity for less toxic treatment.

Genentech plans to submit an application for drug approval for T-DM1 to both the FDA and the European counterpart sometime this year.  To avoid compromising the final results on overall survival, which could delay or prevent drug approval in the US or abroad, Genentech is not currently offering an early access program, but is actively recruiting metastatic HER2+ breast cancer into the TH3RESA trial at 210 sites, including 90 within the US.  Women entering into this trial will be randomized at a 2 to 1 ratio to receive T-DM1 or physician’s choice for treatment.

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9 Responses to T-DM1: ASCO Showcases a Victory for Science, But Is It a Victory for Women?

  1. Musa Mayer says:

    Excellent analysis, and balanced in a way that none of the overblown media stories have been. Like you I’m waiting for the MARIANNE trial results, for a direct comparison with Herceptin+Taxol. Given that lapatinib+capecitabine is arguably inferior to Herceptin+Taxol, not to mention worse in terms of QOL, that is the trial that will actually tell us if the much more potent chemo, delivered directly to the cancer cell, will be more than equivalent.

  2. Ilene Winkler says:

    Hi Laura, thanks for the report. What’s the explanation for liver and platelet side effects from a drug that is supposed to be inactive until it is inside the cancer cells?

  3. Jody Schoger says:

    Thanks for such a good write-up, Laura, the acknowledgement of the scientific progress that was made and as important, what we can look for in upcoming trials.

    Jody

  4. Excellent post. Unlike so many about this subject, this one was balanced, fair and accurate. And very clear. Well done.

    I did my own analysis of this “breakthrough” on my own blog yesterday and also tried to take an approach that went beyond the hype and high expectations. Feel free to check it out at http://www.michaelwosnick.com/new-breast-cancer-breakthrough-not-so-fast/

  5. judi bartek says:

    Hi Laura, Thanks for this truly balanced review of the TDM1 trial. It is so helpful to know that we can always count on the NBCC and your objective reviews to tell the true facts behind the story. Wish that the news reporters, PR groups and oncology world would do the same.

  6. Maurine Turcotte says:

    I participated in the Phase II trial of MARIANNE. At the time I was HER2+/ER/PR +, no staging criteria to stage me but metastatic with mets to regional and cervical nodes. No distant mets and no organ mets. I was originally diagnosed with lymphs only, no tumor in breast in 2007. Received standard of care and was NED for 9 months before relapse to supraclavicular nodes. Before I was to begin Xeloda/Tykirb, I had a shot at the trial and took it. I had 15 months without progression. I participated in my 3rd SGK 3 day and kept a normal schedule. I had some mild elevation of liver, mild hair loss, and some gastro issues, but all in all, a FABULOUS drug combination. I found it to be quite tolerable. I followed that with the Phase I BEZ 235 – not a good experience. I am now testing HER2-/ER/PR- and no one can quite figure that out except to propose that the HERs was killed off by treatment. Yet no one can figure out how it is that I have converted to ER/PR-. I am still on Herceptin and Xeloda after 5 months.

  7. Pingback: T-DM1: What We Know | Young Survival Coalition Blog

  8. Laura, This is such a clear and understandable analysis of a complicated scientific process — exactly the kind of reporting we need on the outcomes of clinical trials. Thank you! – Gayle Sulik

  9. As a breast cancer survivor which has been in remission for 19 years, I am thrilled to know that every day we are a step closer to new forms of treatments. Still today after so many years after chemotherapy I have my white blood cells count low. It is important that they can find new treatments that can target the malignant cells.
    Thank you for the great report.