European Multidisciplinary Cancer Congress (EMCC) 2011, 23-27 September, Stockholm

Trastuzumab emtansine, Phase II trial for HER2

Dr Sara Hurvitz – UCLA Santa Monica Hematology Oncology, USA

Good morning everyone, I’m incredibly pleased to present to you this morning the primary results of a phase II study evaluating a very exciting new molecule called TDM1 which is compared with standard chemotherapy, docetaxel plus trastuzumab, for the treatment of HER2 positive advanced breast cancer.

For the treatment of HER2 positive breast cancer, let me back up one moment. Many of you are aware if not all, but about 25% of breast cancer is characterised by over-expression of the HER2 protein on the breast cancer cells. This causes the cancer to behave in a very aggressive fashion. The current standard treatment for HER2 over-expressed in metastatic breast cancer is the monoclonal antibody that is HER2 targeted, trastuzumab, combined with chemotherapy such as docetaxel. While this is very effective, the docetaxel can be quite toxic and can lead to a low white count, neutropenia, increased rate of infection, hair loss, etc. So an idea was proposed to combine the Herceptin, the trastuzumab which is directed to the tumour cell, in one molecule with the chemotherapy so that the chemotherapy would not be released until the Herceptin had attached to the HER2 positive cancer cell and the entire molecule had gone inside the cell and released the chemotherapy, setting the bomb off.

That is what TDM1 is. TDM is trastuzumab, the HER2 directed monoclonal antibody, combined in one molecule with a very potent chemotherapy called DM1. The magic of this molecule is in the linker which is stable, as it is not releasing the chemotherapy until the TDM1 has been internalised in the cell. Furthermore, this molecule retains the anti-tumour cell activity of trastuzumab.

So this was a phase II study, it was a randomised trial, and it’s the first study comparing TDM1 to standard therapy. 137 patients with HER2 positive advanced breast cancer who had never been treated for their advanced breast cancer were randomly assigned to receive either TDM1 or trastuzumab plus docetaxel given separately. Patients were treated until progression of disease or until unacceptable toxicity developed. Patients in the control arm were allowed to cross over to TDM1 at the time of progression, however the data I’m showing you today is data from before anyone crossed over. The primary endpoint of this study is progression free survival and that is the length of time that patients live without their disease growing worse. I am going to show you that on the next slide.

Here is the Kaplan-Meier plot of TDM1 versus trastuzumab. The green line is TDM1 and, as you can see, patients treated with TDM1 lived five months longer than patients treated with standard chemotherapy plus Herceptin without their disease growing worse. This is statistically significant with a p-value of 0.0353. Another way to state this data is by looking at the hazard ratio of 0.594. One could state then that patients treated with TDM1 had a 40% reduction in the risk of progression relative to patients treated with the standard chemotherapy plus Herceptin.

Objective response rate is shown here on the top row, you can see that the percentage of patients who had either shrinkage of their tumour or disappearance of their tumour on scans, that’s objective response, was 58% in the control arm, 64% in TDM1. This was statistically similar. If you include patients who had stable disease for at least six months with the objective response that is clinical benefit. 81% of patients had clinical benefit in the control arm compared to 75% in TDM1, again statistically similar. What’s more interesting is the median duration of response, so if you look at the patients who achieved an objective response and looked at how long that response is maintained, patients who are treated with docetaxel trastuzumab had their response maintained a median of 9.5 months. The median duration of response has not even been reached yet for the targeted delivery of chemo with TDM1 meaning that it is probably very durable and is definitely longer than the patients treated with standard chemo plus trastuzumab. The bottom table shows you the median duration of treatment of each of the agents, remember that docetaxel and trastuzumab are given separately so you see two agents represented separately here.

Patients were able to be treated with TDM1 for an average of 10 months; compare that to patients who are treated with docetaxel was only about 5½ months. So the patients were unable to tolerate or continue therapy with the chemotherapy but it wasn’t linked to the Herceptin. One of the reasons for this difference in how long patients might be able to receive therapy probably has to do with toxicity, which I’ll show you on this slide now. This slide is a particularly important and very clinically meaningful slide. Patients had moderate to severe toxicity with trastuzumab and docetaxel 89% of the time, compared to half of that in TDM1. This is underscoring that targeted delivery of chemotherapy in this combined molecule leads to less toxic therapy. If you look at what the grade 3/4 or moderate to severe toxicities were in the trastuzumab docetaxel arm, 61% of patients had moderate to severe neutropenia, which is a low white blood cell count. As you know, the white blood cells are important in the immune system and this places patients at risk for infections and hospitalisations. Compare that to only 6% in TDM1.

Another very clinically meaningful side effect for patients is alopecia or hair loss. 67% of patients receiving chemotherapy plus Herceptin lost their hair, this is very difficult for patients, compared to only 4% in TDM1. The bottom four rows show you a few other differences in terms of toxicity – there’s more diarrhoea and swelling in the standard care arm and there is more thrombocytopenia, which is a low platelet count, and increased AST, which is liver enzyme, with the TDM1. It should be mentioned that the thrombocytopenia was primarily grade 1 or 2 which is mild.

So in summary, this is the first randomised study to evaluate the antibody drug conjugate TDM1. We showed that first line treatment of HER2 positive metastatic breast cancer with TDM1, compared to giving trastuzumab with docetaxel separately, was associated with much less toxicity, which is very important. Surprisingly and interestingly as well, we also showed a significant improvement in progression free survival of five months with TDM1 compared to standard first line treatment.

I’m very excited that the phase III randomised studies, one of them has recently closed with data expected in 2012 and so we’re very eager to see the results of these phase III studies. Thank you very much.