European Breast Cancer Conference, Vienna, March 2012
Anti-HER2 treatment in metastatic breast cancer: trastuzumab and beyond
Dr Evandro De Azambuja – Institut Jules Bordet, Brussels, Belgium
This has been a very exciting area because since the last five to ten years we’ve had many new drugs for the treatment of those patients. So the survival of those patients is very prolonged nowadays, it’s not because they relapse it means they’re going to die shortly, no, we have many options now. We started off with trastuzumab many years ago, which was approved in 1998 more or less. It was approved for the treatment of metastatic breast cancer and this was translated into the adjuvant treatment of breast cancer later on, in 2005. So with the progress that we made in the metastatic sense we could cure more patients in the adjuvant setting. So we prolonged disease free survival and overall survival in those patients using one year of trastuzumab. So that was the first excitement.
After that many new drugs and combinations of drugs have been tested and have showed very good efficacy in HER2 positive metastatic breast cancer. Most recently we have seen that the combination of two anti-HER2 drugs works better than one alone. So I’ll give you the results from the CLEOPATRA trial which is a double-blind multi-centre randomised trial in first line metastatic breast cancer. This trial randomised approximately 800 patients and patients were treated with the combination of docetaxel, which is a chemotherapy, trastuzumab, which is a monoclonal antibody, and pertuzumab, or the second arm was docetaxel, trastuzumab plus placebo. So with this treatment we could see a six month improvement in progression free survival from those patients. So this is something that you don’t see very often in the metastatic setting and it is a hope for our patients. Also we saw a trend towards an improvement in overall survival for these patients and, in terms of safety, it seems very well tolerated, both treatments. One of our concerns was if you combine two anti-HER2 drugs, two monoclonal antibodies, would this increase the rate of congestive heart failure or cardiac dysfunction, that was our main concern. But no, it did not increase, it shows to be safe.
This combination of these two drugs, pertuzumab, trastuzumab and chemotherapy, docetaxel, was also tested in the neoadjuvant setting which means that patients that were recently diagnosed with breast cancer, they were treated with this treatment before surgery and in this trial, which was a four arm trial, they looked into the combination of pertuzumab-trastuzumab-docetaxel or trastuzumab-docetaxel, which was considered a standard of care, or pertuzumab-docetaxel or the two anti-HER2 drugs, trastuzumab and pertuzumab with no chemotherapy. We could see that the patients that were treated with trastuzumab, pertuzumab and docetaxel, the three drugs, when you look into surgery almost 50% of those patients, they had no residual tumour, all evidence of cancer has disappeared with the treatment. This is a very promising thing for patients because you know that the disappearance of tumour at the moment of surgery is correlated with longer follow-up, better outcome in the follow-up.
What was also interesting from this trial was that the arm that did not use chemotherapy, the arm with trastuzumab and pertuzumab, two monoclonal antibodies alone, we could see disappearance of tumour in almost 17% of patients. And if you break down those patients between hormonal receptor positive and hormonal receptor negative, those patients who were hormonal receptor negative, almost 30% of them achieved a pathological complete response which means no tumour at the moment of surgery. So this is a very active treatment prior to surgery.
Because of those two trials now we just launched a very important trial which is the AFFINITY trial. It’s a trial that we started last November and we randomised patients between standard chemotherapy plus trastuzumab for one year, which is a standard of care today, plus pertuzumab for one year or chemotherapy - trastuzumab plus placebo. The importance is that the combination of both drugs, trastuzumab, pertuzumab, in the adjuvant setting, you improve the invasive disease free survival meaning that the patient will have less relapses. This trial started last November and is accruing very fast and you accrue approximately 3,800 patients. So it’s a global trial and is led by the Breast International Group and sponsored by a pharmaceutical company.
What have you found in the preventative setting?
In the preventative setting we are doing mostly endocrine therapy. It was not the focus of my talk today but there are some studies in patients diagnosed with non-invasive breast cancer, meaning DCIS, or in patients with a high risk of developing breast cancer, there are some trials that show that the use of different types of endocrine therapy may reduce the incidence of breast cancer. There are some trials, the last trial that was published was last year and it was exemestane, aromatase inhibitor, versus placebo in post-menopausal patients who had high risk for developing breast cancer. This trial leads to about a 70% reduction in the risk of having breast cancer in the future with this treatment.
Are there any other treatments developing in this area?
The dual combination of two other drugs which is lapatinib and trastuzumab, one is the monoclonal antibody trastuzumab and the other is a tyrosine kinase inhibitor lapatinib. One blocks the extracellular domain and the other blocks the intracellular domain. This combination of drugs also was tested in the metastatic setting and was superior to one anti-HER2 drug alone and it was also tested in the neoadjuvant setting and was published at the beginning of this year. The combination of lapatinib, trastuzumab and chemotherapy, paclitaxel in this case, showed that 50% of patients did not have any tumour at the moment of surgery. So it’s also a good combination. This combination was tested and is being tested in the adjuvant setting, the large phase III trial, ALT trial which is a trial that accrued 8,300 patients, the accrual has stopped and they are awaiting results. In this trial we were looking for single agent trastuzumab, single agent lapatinib, the sequence of both drugs or the combination of both drugs and also we expected the combination would be better based on the results of the metastatic setting and the neoadjuvant setting.
There are other options, there is a very promising agent which is trastuzumab DM1, that is a combination of a monoclonal antibody and a very potent chemotherapy. You combine those two and this goes inside the tumour cell and when it’s inside the tumour cell releases the chemotherapy and destroys the cancer cell which is very attractive. This has been tested in randomised trials showing that, in terms of progression free survival, it has a better progression free survival compared to docetaxel-trastuzumab but also in terms of side effects, you have much less side effects because you are delivering the drug inside the cancer cells. So we have approximately half of the adverse events you have with the combination of chemotherapy and trastuzumab.
This is a very promising drug and the new combination that’s coming is the combination of trastuzumab and everolimus. Everolimus has shown important activity in patients with HER2 negative disease, hormonal receptor positive, who are post-menopausal and the combination of exemestane and RAD-001, everolimus, showed important benefit. This was tested with trastuzumab and also showed a significant benefit on those patients so it’s also a combination that will be developed in the future. There are some new drugs in the pipeline that are being tested – PI3 kinase inhibitors, this is also another drug that will be tested in HER2 positive disease. So there are several new drugs being tested and for our patients it is very important, it represents hope in their disease in case their disease relapses.