T-DM1: Why So Much Interest?

Emerging Data in Metastatic Disease

Gunter von Minckwitz, MD, PhD: Hello. I am Gunter von Minckwitz, Chairman of the German Breast Group and Professor of Gynecology at the University of Frankfurt in Germany. Welcome to this edition of Medscape Oncology Insights on breast cancer. Today we will highlight some of the findings presented at the 2011 European Multidisciplinary Cancer Congress of the European Cancer Organisation (ECCO) and European Society of Medical Oncology (ESMO) being held here in Stockholm with a new record of 16,000 participants from all over the world.

Joining me is Fabrice André, Associate Professor at the Institut Gustave Roussy and co-chair of this year's advanced breast cancer track here at the ECCO/ESMO Congress. Welcome, Fabrice. What do you find are the most interesting data emerging from this conference?

Fabrice André, MD, PhD: We heard 3 very different sets of emerging data. I will just focus on metastatic breast cancer. The first set of data is in the field of HER2-overexpressing breast cancer, where we have a phase 2 randomized study^[1]showing that the trastuzumab-DM1 (T-DM1) immunoconjugate does better than a combination of docetaxel and trastuzumab.

The second set of data is the report of several phase 2 randomized studies showing that adding a mammalian target of rapamycin (mTOR) inhibitor could reverse the resistance to endocrine therapy.^[2,3] Then, we have some presentations related to basic science, preclinical studies. We had a very interesting presentation on microRNA to predict the occurrence of bone metastasis.^[4]

T-DM1: Why So Much Interest?

Dr. von Minckwitz: Let's start with the first topic, the T-DM1. Why is this compound of such high interest?

Dr. André: There are 3 reasons for this interest. The first is conceptual -- this is the first time that an immunoconjugate (a combination of a monoclonal antibody and a cytotoxic agent) has shown efficacy in cancer. It's a new concept, and we have the proof of concept today. The second reason is the finding that immunoconjugate is safer compared with conventional chemotherapy. We had the presentation today, during which we heard that the frequency of grade 3 adverse events was lower in patients treated with T-DM1. The third reason it is so important is that these drugs can be delivered for a long time. Because of this prolongation of the treatment, we had a better progression-free survival, specifically in HER2-positive breast cancer.

I would like to mention that this presentation done by Dr. Hurvitz was preceded by another presentation^[5] in which it was clearly shown that even if trastuzumab is a very effective drug, 90% of the patients do not have a complete response of duration more than 3 years. HER2-overexpressing breast cancer with metastatic disease is still a medical need, and now we have a new drug that addresses this medical need.

Dr. von Minckwitz: Was it expected that this one compound would be even more effective than the conventional combination of a taxane and trastuzumab?

Dr. André: We had 3 waves of data with T-DM1. The first set of data was a phase 2 study showing that T-DM1 could reverse resistance to trastuzumab. We had something like a 25% response rate in patients who were resistant to trastuzumab. That was very encouraging. Then, we had a second set of data, reported last year during ESMO, which was a phase 2 randomized trial comparing T-DM1 vs chemotherapy plus trastuzumab.^[6]This phase 2 randomized trial showed that the percentage of response was almost the same. This year the same trial is showing an improvement in progression-free survival.^[1] The reason for my point of view is the fact that T-DM1, because it's not toxic, can be administered for a long time period. Then we can get long-term progression-free survival. For me, it was unexpected, because last year we had this report that in terms of response rate, T-DM1 was not dramatically better than a combination of chemotherapy and trastuzumab.

Dr. von Minckwitz: If we look on the Kaplan-Meier curve, they look a little bit unusual because they have a very early crossover. At the beginning, the conventional chemotherapy was even better. Is there an explanation for that?

Dr. André: We are entering in a new era with this trial. At the very beginning, to obtain a response the drug is not better; because of that, we have the same curve during the first 6 months. Once we have a response and once the drug is working, we can administer the drug for a longer time period and know that the patient is not going to present with progressive disease, but at the opposite end -- in patients treated with trastuzumab and docetaxel -- we have to stop both the chemotherapy agents. Then the patient is going to have a progressive disease. In terms of induction of the response, there is not any major difference, but then the duration of the response is very long. We are going through a scenario where we have induction with T-DM1, and once the patient has a response, then the response can be long lasting. The patients who do not have a response (60% of patients) still have a medical need.

Dr. von Minckwitz: The mechanism of T-DM1 requires a real HER2-overexpressing cell, so could you imagine that maybe the detection of the right population might be a reason for that? To my knowledge, there was not a complete central confirmation of the HER2 status in the study, and especially not from the metastasis.

Dr. André: I think that 85% of the patients had HER2-overexpressing breast cancer. From my point of view, there are some previous data suggesting that we need to have HER2 overexpression to have optimal efficacy of T-DM1. What is emerging, actually, is that this is a model. We have trastuzumab, the binder, and the cytotoxic agent, but I can imagine that companies are now creating new immunoconjugates where we can have epidermal growth factor receptor antibody plus the cytotoxic agent, or insulin-like growth factor 1 receptor antibody plus a cytotoxic agent. This is the first drug that shows this concept, but in the next 5-10 years we will have a lot of these immunoconjugates, and it's going to be very interesting.

Dr. von Minckwitz: What do you see as the future development of this interesting compound?

Dr. André: We will need this compound in first-line treatment for HER2-overexpressing breast cancer and also because this treatment presents less toxicity compared with the usual treatment. The other potential indication is going to be in the adjuvant setting, because currently in the adjuvant setting we treat patients with adjuvant chemotherapy plus trastuzumab. Maybe there is an opportunity for this drug in the adjuvant setting to compare with the conventional treatment and show that with T-DM1 we can avoid the side effects of adjuvant chemotherapy -- both the midterm side effects and the long-term side effects. Here is a real opportunity to investigate safety in the adjuvant setting and develop a drug that avoids side effects.

mTOR Inhibitors: Reversing Resistance

Dr. von Minckwitz: Another group of compounds -- the mTOR inhibitors -- has been discussed, and as far as I know even more data will be presented tomorrow. Can you tell us what an mTOR inhibitor is and what it does?

Dr. André: The mTOR is serine/threonine kinase, and mTOR is activated by phosphatidylinositol 3-kinase and tyrosine kinases. Overall, it's a pathway that is activated in around 40%-50% of breast cancer. Once activated, this protein induces cell proliferation but also metabolism and resistance to endocrine therapy. It has been shown in preclinical studies that mTOR inhibitors can reverse the resistance to endocrine therapy. On this basis, several trials have been developed that evaluate whether adding mTOR inhibitor to conventional endocrine therapy can improve the outcome.

Today, we have 2 presentations that are phase 2 randomized trials. The first one is a trial named TAMRAD^[7] that was already presented at the San Antonio Breast Cancer Symposium. Here, the new data are on overall survival. There is still an improvement in overall survival for these patients. The second update, a small amount of data but potentially very interesting, is the preliminary report on biomarkers.^[8] They have observed -- on a very a small number of patients -- that if the mTOR pathway is activated, the mTOR inhibitor is very effective. In contrast, efficacy is reduced when the pathway is not activated. Maybe we are entering a new era where we can evaluate the activity of the kinases using antibody against phosphoproteins. This is potentially really interesting data.

The second trial was done by an Indian group^[3] that compared endocrine therapy with endocrine therapy plus sirolimus. This trial showed data consistent with the previous one. We had another trial in the neoadjuvant setting reported by José Baselga in Journal of Clinical Oncology, and tomorrow we will have the trial of endocrine therapy plus or minus everolimus.^[2] We now have a consistent set of data suggesting that mTOR inhibitors could reverse the resistance to endocrine therapy.

Predicting Bone Metastases

Dr. von Minckwitz: We come now to the last topic, to the more basic science. You told us about the microRNA. Can you tell us a little bit more about this presentation?

Dr. André: Yes, it was a very interesting presentation done by a group from Lyon.^[4]This was a research group that were experts in bone metastasis. They wanted to identify whether microRNA could mediate the bone metastatic process. In fact, the microRNA had noncoding RNA that decreased the gene expression. What they observed was very striking; in a model of bone metastasis in mice there is a family of microRNA (microRNA-30) that is highly associated with the occurrence of bone metastasis. They did all the preclinical studies to show that indeed microRNA-30 is really mediating bone metastasis.

For the clinician, at this time, there are no direct implications. For me, there are 2 very important messages. First, it's really important to predict, specifically, the occurrence of bone metastasis because we have some drugs that could potentially be used to avoid these metastases, so developing molecular predictors for bone metastasis is a really important field. The second reason that this presentation is important is the fact that the noncoding RNA are becoming more and more important in the field of molecular predictors. We now have some signature with microRNA that could predict the prognosis. This concept of noncoding RNA is now arriving in translational medicine and in the field of molecular predictors. I think this presentation is not conclusive. Tomorrow we will discuss microRNA 30, but the concept is here. That is microRNA could predict some clinical events.

Dr. von Minckwitz: Are there already attempts to use it also as a treatment target?

Dr. André: There are some drugs that could decrease the expression of microRNA, but as far as I know it's really still in the preclinical studies. It's not yet ready for our practice. The point that really interested me was the fact that they want to go in the prediction of bone metastasis using quantification of the expression of microRNA. That was really interesting.

Closing Remarks

Dr. von Minckwitz: So I believe this is a very good conference this year with some very new data. Of course, we are already aware that the HER2-positive field brings more and more options, but I especially liked to hear that for our patients with luminal cancers, there appears a new option. I am strongly convinced that we will hear much more about this. Several of these mTOR inhibitors are on the way. We will soon have them in the clinic, so this is a real step forward.

Fabrice, thank you very much. It was a pleasure. I would also like to thank our audience for joining us at this edition of Medscape Oncology Insights. This is Gunter von Minckwitz signing off from the 2011 European Multidisciplinary Cancer Congress in Stockholm.