Please could you give us a brief introduction to HER2-positive breast cancer?
Approximately 20% of all breast cancer patients have overexpression of HER2 (human epidermal growth factor receptor 2), resulting in a more aggressive phenotype, and a poor prognosis.
Current treatment of HER2 positive early breast cancer involves chemotherapy and trastuzumab (with trastuzumab being administered concurrently or after chemotherapy). Trastuzumab adjuvant treatment for early breast cancer usually consists of 3-weekly IV infusions during 1 year. In metastatic disease it is used until clear progression of disease or intolerable toxicity.
Neo-adjuvant treatment with chemotherapy and concurrent trastuzumab has shown very interesting results in terms of efficacy, with encouraging rates of pathological responses.
By what mechanism does Herceptin® (trastuzumab) treat HER2-positive breast cancer?
Trastuzumab is a monoclonal anti-HER2 antibody. It is 95% human and 5% murine and binds directly to an extracellular domain of the HER2 receptor. Its mechanism of actions can be described below:
- Activation of immune effector functions
(Trastuzumab mediates antibody dependent cellular cytotoxicity, ADCC)
- Inhibition of HER2 extra-cellular domain (ECD) shedding
- Reduction of HER2 phosphorylation and downstream signalling
- Reduced signalling entails secondary effects like inhibition of angiogenesis
What method is currently used to deliver Herceptin® (trastuzumab)?
Intravenous (IV) formulation is the current formulation to deliver trastuzumab.
What are the problems with this delivery method?
The essential concerns with IV delivery are:
- Requirement of a patent IV line;
- Infusion time.
Your recent research was on a new potential delivery method for Herceptin® (trastuzumab). Please could you tell us a little bit more about this?
The aim of this study is to show comparability of a SC formulation of trastuzumab with standard IV formulation.
This comparison involves a fixed dose in the SC formulation versus weight based dosing in IV beyond comparison of the administration route.
The fixed dose was determined by PK modelling and simulation based on Phase I data.
The study clearly shows the non-inferiority of SC formulation of trastuzumab, when compared with the IV formulation, considering both primary endpoints: PK analysis and efficacy (with the comparison of complete pathological response rates).
There was no new safety signal for SC trastuzumab and the safety profile was consistent with what we know from IV trastuzumab (with the exception of the quite manageable injection site reactions).
We have observed an imbalance in serious adverse events reports, with more grade 3 and grade 2 events being reported as serious in the SC arm. However we were not able to identify any clinical reason explaining this.
Finally, based on comparable PK, efficacy and safety, we came to the conclusion that the SC formulation and regimen provide an alternative treatment to IV.
What benefits would this delivery method have over the traditional delivery method?
Practically, SC regimen means a shorter infusion time. This may bring convenience and comfort to our patients and also may enhance medical resources. It is valid to mention that we have ongoing studies for SC trastuzumab (PrefHer and SafeHer) generating more safety data and investigating patients preferences and medical resource savings.
What potential problems could there be with this new method of delivery?
The study required a 5 minutes manual infusion. This was performed in Hospitals that participated in the trial, by the nurse team. We have ongoing trials that evaluate an automated device that could standardise the infusion procedure, offering more convenience and safety for patients and health professionals.
Javier Cortes, of the Vall d´Hebron Institute of Oncology in Spain, has been quoted as saying that this new delivery method could mean that Herceptin® (trastuzumab) could be administered at home. Would this be safe for patients?
Here, again, I believe that it is too early for this. We need to wait for the evaluation of the automated device that could perform the infusion with more safety and compliancy. Maybe we can have this home convenience in the future.
Cortes was also quoted as saying that home administration would reduce hospital dependence, “which is an important psychological aspect”. How much of a psychological problem is hospital dependence for breast cancer patients?
If we consider that trastuzumab treatment demands time, a short infusion (away from Hospital, in a better scenario) could bring more comfort, convenience and quality of life.
How soon will it be before this new delivery method for Herceptin® (trastuzumab) will be put into practice?
We hope this alternative could be available soon, offering more benefits to our HER2 positive breast cancer patients.
Are there any plans to use this method for other cancer treatments?
This is this first trial that evaluated a SC formulation of a monoclonal antibody. It is, remarkably, an opened door for other cancer treatments, especially for monoclonal antibodies.
How do you see the future of drug delivery of Herceptin® (trastuzumab) developing?
SC formulation is an alternative route of administration to the standard IV formulation. Patients and health professionals will have options to choose the better way to deliver this treatment. Efforts should be made to combine efficacy, safety, convenience, comfort and enhancement of health care resources in the treatment of such aggressive disease.
What plans do you have for further research into this area?
We have current trials evaluating the SC formulation in the adjuvant treatment (PrefHER and SafeHER). Moreover, automated infusion will be evaluated in these trials, which may also bring more data on efficacy (considering disease free survival and overall survival) and in the safety profile.
Would you like to make any further comments?
On behalf of our Investigators from HannaH trial, I would like to thank our patients and their families. Herein, we would also thank this opportunity to speak about our study, saying that we are fully available for further questions and discussions.
Where can readers find more information?
About Dr Gustavo Ismael
Dr Ismael graduated in Medicine (1994), at Botucatu School of Medicine (UNESP), at Botucatu, São Paulo State, Brazil.
He trained in Internal Medicine and Hematology at Hospital das Clínicas/Ribeirão Preto School of Medicine, São Paulo University, at Ribeirão Preto, São Paulo State, Brazil (1995-1997).
He trained in Clinical Oncology at Amaral Carvalho Hospital, at Jaú, São Paulo, Brazil (1998-2000).
Fellowship in Clinical Research on Oncology, at Jules Bordet Institute, Brussels, Belgium (2005-2006).
Medical Chief, Clinical Research Center, Amaral Carvalho Foundation, Jaú, São Paulo State, Brazil (since 2006).