Neratinib in the Adjuvant Setting The Paradigm Shift for HER2+ Breast Cancer Neratinib Toxicity Management

Adam Brufsky, MD, PhD: I’m being asked to discuss the upcoming approval of neratinib. And I don’t have any inside track with the FDA. I don’t know when it’s going to be approved. I assume it will be relatively soon. Again, I’m not quite sure what indication they’ve gone for; I haven’t kept up with that. However, my understanding, at least looking at the literature and looking at the clinical trials, like the ExteNET trial, I’m assuming it will be indicated for extended adjuvant therapy in certain women with HER2-positive early stage breast cancer on completion of their 1-year of adjuvant trastuzumab. That’s where I assume it’s going to be approved.

Subtleties in that are clear: will it be approved just for estrogen receptor-positive breast cancer? Will it be approved for estrogen receptor-positive, HER2-positive breast cancer? Will it be approved for all HER2-positive breast cancer? Will it be approved after 1 year of trastuzumab? How much longer after 1 year of trastuzumab? These are things that I’d be very interested in. I just am not privy; I don’t know exactly what went into their packet and their labeling with the FDA right now. And even if I knew, I couldn’t tell you because it’s proprietary. But nonetheless, I believe it’ll be something like that, something like women with HER2-positive early stage breast cancer that have had at least 1 year of trastuzumab as adjuvant therapy.

I think that clearly the treatment of early stage HER2-positive breast cancer has undergone a complete paradigm shift, when we now have trastuzumab and now even possibly pertuzumab coming to really help this disease. I think that most of us really expect a broad majority, or at least a preponderance, of women with early stage HER2-positive metastatic breast cancer to have at least a 4- to 5-year progression or disease-free survival of at least 85% to 90%. And I think that that’s great.

We potentially could even make that higher. And the way to make that higher is by giving something else as extended adjuvant therapy. There have been a number of HER2 tyrosine kinase inhibitors that have been proposed to do this. There have been a number of trials with lapatinib in an earlier phase; an earlier developed HER2 tyrosine kinase inhibitor. That trial, called the TEACH trial, did not achieve statistical significance.

So, really we didn’t know what to expect from neratinib. But clearly, in the neratinib trials, there is a small but significant improvement in disease-free survival, specifically in women who have triple-positive early stage breast cancer, and those are patients who have estrogen receptor-positive, HER2-positive breast cancer. I believe there’s about a 3% to 5% improvement in progression-free survival at 3 years and, I think, 4 years. So, this is something that is modest. It’s 3% or 4%, but still, it’s significant. I think there will be women who I think are at high enough risk, where we will clinically consider extended adjuvant therapy.

Those are the pluses of using neratinib in this extended adjuvant setting. The problem with neratinib, and we’ve seen this from the beginning, is that it does cause fairly substantial diarrhea if you don’t use prophylactic drugs for it. And I think that the diarrhea can be fairly substantial—30% to 40% of the patients may have at least 6 and potentially more than 8 stools a day. So, again, it’s not a watery explosive diarrhea that we see with other drugs. It’s just going to the bathroom more; the inconvenience having to go to the bathroom 6, 8, or 10 times a day. And it turns out that this can be managed quite adequately with an intensive tapered dose of loperamide.

There was an abstract that was presented at San Antonio a few months ago where an intensive dosage regimen was attempted. It did seem to reduce the incidence of this grade 3 diarrhea, which is more than 8 stools a day, substantially. And so, therefore, I think that, again, if we have a patient at high enough risk to really require additional therapy—and thankfully, in this day and age, those patients are not as frequent as they used to be—we give extended adjuvant therapy. We just need to understand up front and let the patient know that there may be severe diarrhea or severe frequency of bowel movements for the first month or so, but we control that with a dose of around-the-clock loperamide that we taper over a period of a couple of weeks. And then, usually after that first month, the diarrhea is not as severe as it used to be or as it initially is. And so, I think that that’s how we are going to get around what I think is probably the biggest barrier to using this drug. Because, clearly, the data just show a small but significant benefit. And so, the real issue is, how do we balance that small but significant benefit in people who really need it against just having to manage that diarrhea for the first 1 to 2 months?