Ongoing Needs in HER2+ Breast Cancer

Transcript:Adam M. Brufsky, MD, PhD: Michael, are they now using neratinib in the GEPAR series? Are you doing any trials with neratinib?

Michael Untch, MD: Let me just add one more comment and then I will answer your question. I have reviewed, for ESMO 2016, the long-term follow-up of all adjuvant studies: NSABP, NCCDG, HERA study, and BCRG. And for the HERA study, 10-year follow-up just has been accepted for publication—David Cameron was the first author—this week. What we can tell is even in the optimal-treated patients with anthracycline/taxane and trastuzumab, the metastasis is not stopping in year 5. It continues to process, and especially in patients with hormone receptor-positive disease, that’s number 1. Number 2, we see recurrence and metastasis rate as high as 30% to 40%, even in the trastuzumab-treated patients if they have a higher lymph node burden more than 4 or 10 lymph nodes. So, there still is a medical need to be solved.

With ExteNET, I was positively surprised to see that, especially in those patients with a prolonged risk of recurrence after years 3 to 5, like the hormone receptor-positive patients, we have a long-lasting—and it’s lasting for the next years, more than probably 10 years—effect of the addition, the sequence of neratinib. So, to answer your last question, we don’t have to do GEPAR studies with neratinib because I’m so happy to be part of the extended-access program now in Germany. And we have some centers that we are going to have in this program, and hopefully, we will have an approval.

Patients are coming after their adjuvant treatment, when they have finished the trastuzumab, and asking us, “Professor, what can we do now? Am I cured?” And if they have more than 4 lymph nodes and they’re hormone receptor-positive, I know they have a prolonged risk of recurrence. I tell them, or will tell them, “Well, we have a new possibility, and I think we can cope with the side effects.” It really changed from a small height to an increasing height over the years, which is exactly the opposite to what we see in the oncology scenery at the moment or in the last years. So, yes, I’m excited. We will be part of the EAP, and I will offer it to my patients.

Adam M. Brufsky, MD, PhD: Ahmad, will you offer it to your patients?

Ahmad Awada, MD, PhD: I think it really is a topic well covered by Hope and Michael, but I will add something in relation to diarrhea: as I am following the program of neratinib, let’s say, at the clinical results level, I’m happy to see that all efforts are made to reduce this diarrhea problem. And it seems, from a clinical trial, by giving this prophylactic loperamide from the beginning and so on, we reduce significantly this problem. So, that’s really important information for clinical practice.

Adam M. Brufsky, MD, PhD: We’ll move on. Before we go on, one last comment about brain metastases. It seems to be that a lot of women now relapse in the brain with HER2+ disease, and it’s very interesting. It turns out their survival still is determined by their extracranial disease from the studies, at least the registry studies that we have, but, nonetheless, it is an important thing. Do you think there are things out, there like ONT-380 or something else, even neratinib, that may help us with the woman who already has existing brain mets right now?

Ahmad Awada, MD, PhD: I think, as I mentioned earlier, whenever the drug is to be studied in a brain metastasis, I think it’s really important to be clever in the developing these drugs because there are risks, let’s say, dropping an interesting drug, but one not well studied in a clinical result. I think we should look to design studies, which tell us if any new drugs could prevent or delay. Honestly, I am following all the new drugs studied in a brain metastasis, the progress of everything, and systemic and local therapy. And we have 1 or 2 responses or 2 stable diseases, and it doesn’t mean anything. But, to my comment, we should be clever there in designing trials.

Adam M. Brufsky, MD, PhD: Thinking about prevention as opposed to treating. Hope, do you agree with that?

Ahmad Awada, MD, PhD: No, sometimes you cannot prevent completely. Delaying as long as possible, this is a problem. Because it’s, in our clinical practice, really, really important.

Hope S. Rugo, MD: There are actually some published data that suggest that we may be able to predict who has a higher risk of getting brain metastases or not. Obviously, that’s a bigger issue in non—HER+ disease. I think we start with treatment trials, even though that’s not as appealing. ONT-380 does certainly show some activity with capecitabine, and there are going to be patients who have brain metastases on the neratinib/capecitabine trial. There are other oral tyrosine kinase inhibitors that are being used, poziotinib, some other drugs. I think once we start seeing effects, then what we do is move them into prevention, and certainly neratinib has had that course, too. With lapatinib, there are a little less exciting data overall, but still showing a delay or reduction in number of brain metastases. And so, now we’ll see ONT-380, which clearly seems to be able to cross the blood–brain barrier and is very potent. Because once you show activity in established brain metastases, then you can move it into the prevention setting.

Ahmad Awada, MD, PhD: We know that in the first-line setting, the incidence of brain metastasis is very low, let’s say, but increases with time. So, for clinical results reports, I think it’s important to take the first CNS event and from this event, try to avoid subsequent events.

Adam M. Brufsky, MD, PhD: That’s a very good strategy, avoid the growth of new micro-metastases. So, it’s the sentinel event as a brain metastasis, yes.

Ahmad Awada, MD, PhD: In other words, enriching the population to look at the efficacy of any drugs.

Hope S. Rugo, MD: So, rather than treat the ones that are growing and untreatable, you treat somebody after they already had a brain metastasis because you know they’re going to get more.

Adam M. Brufsky, MD, PhD: And then, you delay the time to progression of a new one, yes.

Transcript Edited for Clarity