You’re presenting here what looks like a very interesting study, the NSABP FB-7. Now, this is phase II and it’s a neoadjuvant therapy, in particular you’ve introduced neratinib. I want to ask you a little bit about that, first of all can you tell me, though, what was the underlying issue that you were taking on here? What were you concerned about?
The standard of care for HER2 positive patients has been the use of the monoclonal antibody trastuzumab with chemotherapy. The question is whether that’s sufficient, whether a TKI might be as good or the combination of trastuzumab and a TKI might actually be better.
And tell me, please, about your TKI neratinib?
Neratinib is an oral agent, it’s taken daily, it’s an irreversible pan-ErbB inhibitor.
What might be the attraction of using such an agent?
It’s a very potent drug and it’s given orally and if it can work either as well as or better than standard therapy that would be a nice advance.
Now, if trastuzumab is anti-HER2 anyway, why would neratinib be as well as or better than? Is it just an option?
There are different mechanisms of action and at least there’s a suggestion that combining anti-HER targeted therapies may be better than single agent.
So you have quite a simple elegant study and you’ve got three study groups, is that right?
Yes we do.
And they are?
So it was paclitaxel in combination with trastuzumab, paclitaxel with neratinib and then the paclitaxel with the combination of neratinib and trastuzumab. All of those for twelve weeks followed by standard AC followed by surgery with the primary endpoint being pathologic complete response in breast and nodes.
And the number of patients?
It was 126 patients, 42 patients in each arm.
And what did you find?
We found that by and large in the hormone receptor positive, HER2 positive patients that trastuzumab and neratinib were quite similar in their pCR rates. However, in patients that were hormone receptor negative the dual therapy of trastuzumab and neratinib with paclitaxel produced a higher complete response rate.
So in hormone receptor negative patients you were getting a better response with both drugs, why would that be?
That’s a very good question. One possibility is that there’s a difference in biomarkers in that, for example, the hormone receptor negative patients may be HER2 enriched. That’s a group of patients that may do better with dual therapy.
So there’s an interaction between ER and HER2?
There seems to be, yes, an interaction between the anti-HER agents and whether a patient is hormone receptor positive or negative.
What sort of clinical implications, I know this is phase II at the moment, small study, but what sort of clinical implications are you seeing beginning to emerge from this?
One issue is how one might improve the pathologic complete response rate in the hormone receptor positive patients. And further, whether just increasing that pathologic complete response rate really has an outcome benefit. Because those patients would ordinarily receive hormone therapy after their surgery so those are questions that are unclear at this point.
What’s the cautious way forward then?
The cautious way is to do the studies in which hormone is added to anti-HER therapy in the hormone responsive patients, in the ER positive patients, and see if the complete response is higher than it would be in the absence of hormone therapy.
Now, you’re getting some experience with neratinib here, what things should doctors take home from the study that you’ve published right now?
There’s a lot of concern about the toxicity of neratinib and the major toxicity is diarrhoea. What we’ve learned in our study and other studies is that if intensive anti-diarrhoeal prophylaxis is used that you can control that high grade diarrhoea. And that usually the diarrhoea occurs during the first cycle, beyond the first cycle it’s much more easily managed.
From this early data, these early data, how big a margin of improvement in those patients who do respond to the combination of trastuzumab plus neratinib is there? How big is that?
In our study the trastuzumab alone in the HER2 positive hormone receptor negative patients had a 57% complete response rate and in the combination it was 73.5%. But, again, this is a small study, it didn’t reach statistical significance. But our study, like several others in the literature, shows the same direction that dual anti-HER therapy in this group of patients is beneficial.
So what is the brief take home message for doctors right now?
The take home message is that, one, we’ve made improvement with dual therapy in the hormone receptor negative patients, that there’s still a ways to go and that we have to be innovative in thinking about other ways to increase that complete response rate. On the other hand, in the hormone receptor positive patients where the pCR rate is roughly 40%, there’s a lot of space to try to improve that with additional agents, hormonal regimens or other therapies.