The KATHERINE is a new generation of trials which we call a post-neoadjuvant treatment. What is it about? We know that patients with very high risk breast cancer, which is HER2 positive or triple negative breast cancer, have quite a high risk of recurrence and metastasis if, after neoadjuvant treatment, these patients still have breast and lymph node left tumours, so residual disease. In these patients we did a very new type of trial in the KATHERINE study which is post-neoadjuvant treatment. So that means that these patients received in the post-neoadjuvant treatment with residual disease in the breast after neoadjuvant therapy, they received either the standard treatment which is anti-HER2 treatment with trastuzumab or the TDM-1 which is an antibody-drug conjugate.

1,500 patients have been randomised and basically the study has shown a 50% reduction in the risk of recurrence and metastasis. The results, which have been published in The New England Journal of Medicine in December 2018, actually have changed worldwide the international guidelines for the treatment of breast cancer patients, meaning that breast cancer patients who have HER2 positive disease are now treated with neoadjuvant treatment with chemotherapy and anti-HER2 treatment with either trastuzumab or the doublet combination trastuzumab and pertuzumab and after the neoadjuvant treatment if they have residual disease in the breast or in the lymph nodes these patients are treated with TDM-1.

Now, the new results which we presented here at ESMO in Barcelona are aiming to three aspects, secondary endpoints. Number one, the incidence and resolution of peripheral neuropathy; number two, the incidence and resolution of thrombocytopenia and, number three, the incidence of CNS metastasis. For the first aspect, peripheral neuropathy, we know that the patients in the KATHERINE study most of them have been treated with a taxane which means they had either Taxotere or Taxol. These patients had already, in a certain percentage, peripheral neuropathy of grade 1. So the study was to see whether TDM-1 is adding more to this peripheral neuropathy. The answer is yes, TDM-1 was causing somewhat more peripheral neuropathy compared to trastuzumab but the good thing is after a certain amount of time, which is about 300 days, these patients had a complete resolution of the peripheral neuropathy. So there is none left over at a long time range follow-up in these patients. Obviously we also checked which of the taxanes was producing more peripheral neuropathy with the addition of TDM-1 afterwards. The answer is that it was not a big difference between the two taxanes, paclitaxel and docetaxel.

Second, the thrombocytopenia. A certain amount of patients have been treated in the KATHERINE study with platinum so we focussed especially in these patients. As expected, they had somewhat more development of thrombocytopenia, especially with TDM-1. The good thing about it, also, again after about 30 days the resolution rate was almost 100%. So the good news is again thrombocytopenia was somewhat higher with TDM-1 which is an antibody-drug conjugate compared to just the antibody trastuzumab but the resolution rate was very good.

The third aspect was the CNS metastasis. Now, CNS metastasis a big issue in patients who have very aggressive breast cancer which is either triple negative or HER2 positive breast cancer. We looked into this aspect in the KATHERINE study and the basic result is that the incidence of CNS metastasis in both arms was quite similar which was in the region of 5%. So negative news, we cannot avoid by TDM-1. We can avoid a big part of the peripheral metastasis but not the CNS metastasis, so occurrence was about 5%. Number two, as a first occurrence CNS metastasis in the TDM-1 arm was somewhat higher. Why? By statistical means we call this a concurrent risk meaning that with TDM-1 we can control the peripheral metastasis but not the CNS metastasis. So the first event as an invasive disease event was somewhat higher in the TDM-1 arm but at the end these patients had also a longer survival. So in both arms the incidence of peripheral metastasis was very, very different, 50% more in the standard arm as compared with TDM-1. So the bottom line of this finding is that we still aim to look how to avoid peripheral metastasis because even with TDM-1 we don’t have a solution. Again, this is just a small part of the patients which is 5%. The good news about the study is we have a very, very high control over the peripheral metastasis and this is why this is the new standard in the treatment of patients with residual disease after neoadjuvant treatment.