The Emerging Role of Neratinib in HER2+ MBC

Transcript:Adam M. Brufsky, MD, PhD: This is perfect. It’s an absolutely perfect segue to talk about, a quasi-new kid on the block, neratinib. It’s been around, and I’ll tell you, to be honest with you, over the years I think it’s been a little under the radar for a lot of us, at least in my opinion, it really was kind of lapatinib with more diarrhea. But I think we really have a lot of very, very exciting data that are very head-turning. The NEfERTT trial, which was published in JAMA Oncology a few weeks ago, for me was really a turning point in my thoughts about this drug. Does anybody want to take on the NEfERTT trial? Joyce, you want to talk about it?

Joyce A. O’Shaughnessy, MD: It was a large randomized trial of first-line trastuzumab plus paclitaxel versus paclitaxel with neratinib. It had equivalent PFS and the incidence of progression in the brain—development of brain metastasis—was about 50% less with the neratinib. But it was striking because the same exact trial had been done with lapatinib/paclitaxel and it was substantially inferior.

Adam M. Brufsky, MD, PhD: Correct.

Joyce A. O’Shaughnessy, MD: It is as good as trastuzumab, so that’s not anything we’ve seen so far with an HER2 TKI. So that was very, very important, as is the penetration to the brain.

Kimberly L. Blackwell, MD: I think we’ve been a bit distracted by the diarrhea. That’s a weird statement, but I think neratinib from its very early days had better preclinical data.

Adam M. Brufsky, MD, PhD: Yes. It had better as a single agent; Hal’s study with it as a single agent, and I did a study in combination with trastuzumab. My clinical experience is that this was a very different drug long when it was owned by Wyeth, very early days. We saw patients who had received a lot of lapatinib, whether they had responded or not, we gave them this drug. So, I think it’s definitely different. I think where we’re trying to position it is, where do we get that benefit translated to the patient, in what setting do we use it in? Lots of things we give cause diarrhea. I think it’s a huge hassle for the patient. It’s a huge hassle for my nursing staff, my triage staff.

Joyce A. O’Shaughnessy, MD: Let me just say a word about the diarrhea because there’s an ongoing trial. I think it’s called the PUMA-NER-6201 trial, and there are already data emerging from it. And basically what it is for the first 56 days—although the diarrhea is way down after the first even week—it’s prophylactic loperamide Imodium, and it’s 4-mg t.i.d. for the first 2 weeks, and 4-mg b.i.d. thereafter. But, if you actually look, what it boils down to is in the 40% who will get any diarrhea—so that means 60% will not get diarrhea—13% to 15% will get grade 3 diarrhea, it lasts one day, and then it quickly becomes tachyphylaxis. It’s really interesting and it’s pretty much gone by 30 days, although the prophylaxis continues for 56 days. So, there’s a lot of information emerging, and those data will go in with the regulatory submission and be part of the label.

Kimberly L. Blackwell, MD: That’s going to be my statement. It’s a hassle but we now know how to deal with it.

Adam M. Brufsky, MD, PhD: Right. You say it’s predictable. If you tell a woman it’s predictable, controllable, and limited, I think if you can say that to people and mean it, and if it’s really true—which it sounds like it is—it’s something people can tolerate. People worry about if it’s going to be forever.

Carlos L. Arteaga, MD: I would add that the reason why we see more diarrhea with neratinib than with lapatinib, it’s because it is a better inhibitor or HER2. That’s why the data on the NEfERTT trial makes sense. And I agree with you, it’s totally manageable. It’s almost abatable with prophylaxis. And it’s interesting. I think this happens to other targeted therapies. It happens with EGF receptor inhibitors and rash. There’s some adaptation of stem cells in the gut, in the skin, and if cancer cells adapt, then why wouldn’t our own stem cells? So, patients learn how to manage it and the body may adapt to these side effects.

Kimberly L. Blackwell, MD: I think we all now appreciate it’s a different drug than lapatinib, even though it has a similar side effect profile. But I think where we need to turn our attention to is really the data that are emerging, especially in the early-stage setting from whether you look at I-SPY 2 or the ExteNET study because I think we’ve gotten a little distracted comparing it to other small molecule inhibitors, comparing the toxicity. And I do think we should let the data speak for itself.

Adam M. Brufsky, MD, PhD: Tell us about ExteNET since you brought it up.

Kimberly L. Blackwell, MD: The bottom line here was ExteNET was a study where patients had completed a year of trastuzumab. We know that for our patients and ourselves, that’s a hard moment, right? We’re going to stop the trastuzumab, especially if they had like a high PCR in the neoadjuvant setting, and we really don’t know who to continue on HER2-based therapy. For now, we’d stop it at a year. And we’ll learn later today that 15 years is better than 10 years. So, why would a highly effective therapy we randomly…I love it when George Sledge says we picked a year of trastuzumab because that’s the time it takes the earth to cycle the sun, something like that. The bottom line is we have data now that if you add a year of neratinib after a year of trastuzumab, it makes an impact on invasive disease—free survival. And the most impressive subset, and the number sticks in my head, is that we have an over 8% absolute difference in disease-free survival for women that got neratinib after a year of trastuzumab. So, yesterday during the plenary breast sessions, we were debating should we give an anthracycline for 2%, 2.5% absolute difference in disease recurrence. We’re not supposed to look at subgroups but that’s what we do, and we’re contemplating Xeloda, a drug that 1 out of 4 women will get grade 3 diarrhea in the adjuvant setting for somewhere between a 2% to 4% absolute reduction. We have a drug that when added after a year of trastuzumab, results in an 8% absolute reduction in invasive disease events in the ER-positive. And I think we have to start paying attention to it and just be fair, put it in the perspective of other things we do for patients in the curable setting.

Transcript Edited for Clarity