ASCO 2015

Extended adjuvant therapy for HER2-positive early breast cancer

Prof Arlene Chan - The Mount Hospital, Perth, Australia

You’ve been looking at something called extended adjuvant therapy for early breast cancer. Could you explain what is the basic approach that you wanted to investigate here?

We know that with the use of adjuvant trastuzumab and chemotherapy to women with early breast cancer and HER2 positive disease that their survival is already significantly improved. However, over the last ten years since the introduction of adjuvant trastuzumab, up to 26% of these women, having been treated with adjuvant trastuzumab, may still experience a breast cancer relapse. So we wanted to evaluate the role of a new anti-HER2 agent in the extended adjuvant setting to see whether we could improve disease free survival.

And that agent is a tyrosine kinase called neratinib. What exactly was it hoped it would do?

The intention was that, being an oral tyrosine kinase inhibitor having a different mechanism of action to the monoclonal antibody trastuzumab, that it would have the ability to reduce the relapse rate by eradicating micrometastatic disease in these women who would remain at risk of relapse after adjuvant trastuzumab and chemotherapy.

Now, you’ve got nearly 3,000 patients in your study, what did you do with them and when did you give them the trastuzumab and when did you add the neratinib?

The trial commenced in April of 2009 and these women all had received adjuvant trastuzumab and chemotherapy prior to that date. At the onset of the study commencement in 2009 we permitted women with stage 1 to 3 breast cancer who had received trastuzumab anything up to 24 months earlier into the trial. We then randomised these women in a one to one basis to receive neratinib 240mg orally per day or a matched placebo.

What happened?

The results were evaluated at the two year mark which was the primary analysis time-point. We demonstrated a statistically significant improvement in invasive disease free survival in those women who received neratinib with a hazard ratio of 0.67, therefore a 33% reduction in the risk of these women developing an invasive disease recurrent event. This was statistically significant at 0.009.

That sounds pretty significant to me. You chose your words very carefully, you said invasive disease free survival not just disease free survival. Why was that fact important?

Invasive disease recurrences are clearly the event that leads to death. We felt that we needed to make this a very pertinent clinical endpoint. However, bearing in mind that other studies have also used the inclusion criteria of including ductal carcinoma in situ as an event, that was one of our secondary analyses. So in the secondary analyses when we looked at our patients, looking for all events, whether they were in situ events or invasive events, again there was a statistically significant benefit with the administration of neratinib with the even more significant hazard ratio of 0.63.

Now, in the invasive disease you had a hazard ratio of two-thirds, now that sounds really exciting. What are the clinical lessons coming out of this?

So to be very clear, the absolute benefit with this degree of hazard ratio benefit is in the order of 2.3% absolute difference between the treated arm and the placebo arm. I was questioned about the clinical relevance of that and I made two points. Firstly, we are evaluating this combination of treatment in a group of women who have already received the most effective breast cancer therapy that we have discovered in the last ten years. So to try and achieve that degree of magnitude again in the extended setting would be very unlikely to be feasible. Therefore 2.3% is a real, statistically relevant endpoint. The second point I would make is that we have an analogous situation in an endocrine trial, really the first trial that was conceived by Professor Paul Goss, the MA.17 trial, which evaluated the same concept. So in that trial women had already received five years of tamoxifen and they were randomised to receive letrozole, an aromatase inhibitor, or a placebo. In that particular trial, which has now registered and is currently regarded as standard of care, at the two year interval letrozole provided an absolute benefit of 1.9%. So I believe in the setting of our study design and the robustness of our results that this is a clinically relevant finding.

Of course it is a surrogate endpoint because you haven’t got the overall survival yet and you’re adding two anti-HER2 agents, they could have combined toxicities which could land you in trouble in the long term. What are your thoughts?

These are two different mechanisms of action and remember this is being given sequentially so women have already recovered from whatever trastuzumab toxicities they have. I presented the toxicity data of our trial and we don’t make any excuses for it but there were a significant incidence of diarrhoea, which is the primary toxicity one sees with oral tyrosine kinase inhibitors. In our trial 39.9% of women experienced at least one episode of grade 3 diarrhoea. Recognising that as a finding now, we have already pursued studies that demonstrate that if we actually co-administer loperamide, which is an effective anti-diarrhoeal agent, at the time of initiating neratinib we can very successfully reduce the toxicity rates.

So what’s your brief take home message for cancer doctors as of this point?

At the time that neratinib becomes available I would certainly discuss this as a treatment option to those women who have received adjuvant chemotherapy and trastuzumab. I would clearly state the degree of benefit to be balanced against the potential adverse effect which is largely gastrointestinal. At this point I think this is a valid treatment option for our patients.