Transcript:Adam M. Brufsky, MD, PhD: We’ve just heard from ODAC—José was actually at the ODAC meeting—about neratinib. Can someone start by explaining to our audience what the extended adjuvant trial ExteNET was? Does someone want to take a stab at that first, before José gives us the blow-by-blow? Is anybody familiar with this trial?

Debu Tripathy, MD: This was a randomized trial taking patients who had completed standard chemotherapy plus trastuzumab for HER2-positive breast cancer and who, within a year of completing trastuzumab, were randomized to neratinib or placebo. It initially included all patients. They later narrowed it down to higher-risk patients. The trial was a little complicated because it went through different sponsors, although the same CRO was involved. Nevertheless, it did, when put together and followed over a long period of time, produce a clear difference in disease-free survival—a little greater in the hormone receptor-positive subgroup. But the trial as a whole was positive.

Adam M. Brufsky, MD, PhD: I agree. I think it was about 3% to 5% improvement.

Debu Tripathy, MD: The issue with diarrhea tended to happen early, but it happened in a great number of patients, so the grade 3 diarrhea rate was rather high. It did attenuate over time. It was mostly within the first month or so, the first couple of weeks, but that was one of the concerns, of course. But I think this tells us that there is the potential for residual disease. What I found fascinating about this trial is that we’ve known from hormonal therapy that you can make an impact on the natural history with very late interventions, 5 to 10 years. Now we’re learning that the same is true in other diseases.

Adam M. Brufsky, MD, PhD: It’s an interesting study. I think if you asked a panel like this—from what I gathered, having asked panels like this—the odds were 50/50 or 30/70 that it would not pass at ODAC, and it turned out it was a 12-to-4 vote. José, can you describe that a little bit?

José Baselga, MD, PhD: I think it was based on the data. So, the big part of the trial is what Debu had mentioned, that it had different sponsors. They also changed the primary endpoint a few times. That’s something, but the FDA came up with a very good statistical analysis looking at all the variable situations and what would have happened if a condition had not been changed and so on. The consensus was that the primary endpoint, as it was presented, was solid. This was a substantial increase in the comfort of these patients.

To me, what’s fascinating is the concept that you have 2 types of HER2-positive disease, the HER2-positive/ER-positive and the HER2-positive/ER-negative. And you have patients who are HER2-positive/ER-positive who continue to relapse even after many years of having stopped therapy. And that’s where these extended therapies may play a role. There is a lot of cross talk between ER and HER2 disease.

Carlos has published extensively in this area, and I think it makes a lot of sense—this concept of the persistent blockade of both HER2 and ER. And I think that’s what the ExteNET study is showing. So, it becomes an option for patients who are perceived to be at high risk, and I agree also with Debu that the diarrhea is short in duration and that we have learned a lot on how to manage that with loperamide and also by dose interruption, etc.

Debu Tripathy, MD: Steroids.

Adam M. Brufsky, MD, PhD: Will people at the Sarah Cannon Research Institute use neratinib? And for whom?

Denise A. Yardley, MD: I think so. Our early experience has really been difficult in trying to now look at those data and accept they’re positive, figuring out how to integrate those data with the APHINITY trial, and finding if we have different standards looking at our hormone receptor-negative and hormone receptor—positive patients. Are we starting to now change the way we look at our HER2-positive patients and have different algorithms? I do still think it’s going to depend on the expertise of the physician managing those patients and not having early discontinuations.

For a high-risk patient, absolutely, we’re all trying to continue to reduce the risk of relapse. But I think there’s going to be an art to getting that patient through diarrhea, because these are all patients who are cured. They’re back in their normal daily life, and diarrhea, different than the heme toxicities, is a bit of a showstopper for a patient. It really is something that disrupts their life, so I think we have to really challenge ourselves to help manage that in the first couple of months they’re on neratinib.

Adam M. Brufsky, MD, PhD: Kim?

Kimberly L. Blackwell, MD: Yes, if it receives regulatory approval, I will use it in the majority of my patients. I don’t think we have a really good way of predicting, even with the prophylaxis, who’s going to get diarrhea. So, just like we do across all of oncology, we say, “We think this drug might help you— you’ve finished your year of trastuzumab.” That’s always a trying moment. I’m very impressed with the ER-positive data, and I will say that I was one of those people who, had you asked me 2 or 3 years ago, “Does this trial make sense? Is it really resonating that this is a drug that will benefit your patients facing early stage HER2-positive disease?” would have been really hesitant about it.

But we now have 5 years’ longer follow-up. I think the trial has been raked over the coals with extensive analysis, and the data now with longer follow-up have stayed true, especially in the ER-positive setting. I will offer it to my patients with the caveat that there is a side effect, just like with everything else I do, and we’ll try it and try to minimize the side effects. At least I will feel obligated to offer it to the majority of my patients.

Adam M. Brufsky, MD, PhD: Does it make sense, scientifically, to do this?

Carlos L. Arteaga, MD: I think it does, yes. I never dismiss the data based on the fact that there was mechanistic plausibility throughout it. Neratinib also inhibits EGF receptors, which in some cases can mediate escape and cross the blood-brain barrier. We’ve used neratinib in the context of basket trials in HER2 mutations, and frankly, it hasn’t been much of a problem for us. We prophylax, and after 2 cycles there are some patients who don’t even need Imodium anymore.

Adam M. Brufsky, MD, PhD: Yes, that’s my experience.

Carlos L. Arteaga, MD: If cancer cells adapt, I’m sure that the stem cells in the gut are adapting, too. So now, in terms of would I use it—I will use it in a minority, not in many. I would like to see the patients in the APHINITY trial who are at a particularly high risk of recurrence. I wouldn’t be surprised if those who are with a high number of nodes have extensive disease post-neoadjuvant therapy.

Adam M. Brufsky, MD, PhD: Who are basically ER-positive, hormone-positive patients. Those are the patients who generally have residual disease.

Carlos L. Arteaga, MD: So, in those patients, I would use it. I would not use it with trastuzumab and pertuzumab, because the diarrhea would then be unmanageable. I would wait.

Kimberly L. Blackwell, MD: And as much as you said lapatinib was a poor HER2 inhibitor, I think this is a much better HER2 inhibitor. I was the PI on a trial with this drug in trastuzumab, and although Harold Burstein had a single-agent neratinib study in heavily pretreated metastatic HER2-positive patients, our diarrhea rate was actually a little bit lower than what he saw. I don’t think that means much, but what I think will be interesting is seeing how people will utilize this if it’s approved in the metastatic setting, assuming you can get some coverage for it. Because I actually think it’s a very potent HER2 inhibitor, and I would feel completely comfortable combining it with trastuzumab in the metastatic setting—very similar to the way we combine lapatinib right now.

Transcript Edited for Clarity