Transcript:Hope Rugo, MD: In addition to the APHINITY trial, we have another study that took on the rather huge challenge of treating HER2-positive early-stage breast cancer. We know that there are continued recurrences over time, but we have had a big impact with trastuzumab. But it’s not as if we can’t improve on that. So, it really does justify these adjuvant trials with agents that we think will be useful. The ExteNET trial was one of those trials that has already been published now and reported. It actually looked at a novel oral tyrosine kinase inhibitor, a so-called pan-HER inhibitor—it blocks other parts of that HER family—called neratinib.

Neratinib has already been tested in the metastatic setting in a number of different trials, but it was mostly compared to trastuzumab or other chemotherapy combinations. Neratinib has actually been owned by a number of different companies, and that complicated the trials that were done both in the adjuvant setting—the ExteNET trial—and more importantly, in the metastatic setting. I think that the way we would study neratinib now is a little bit different than the way it was studied before. We understand it a little bit better. In fact, a metastatic trial is ongoing that may help with that.

But, ExteNET started a while ago, and the idea was that you do see continued recurrences in HER2-positive disease over time. So, maybe if you give a non-cross-resistant drug—what we knew about the metastatic setting, despite the messy randomized trials, was that neratinib was effective in patients whose cancer had progressed on any of the chemotherapy agents—and trastuzumab. A subset of patients responded to neratinib, so it must be non-cross-resistant. It made sense from preclinical models.

We also had a bit of data that we thought about afterwards, more than before the trial was designed, and that’s not uncommon. We knew that ER-positive breast cancer, that’s also HER2-positive, had relative resistance to hormone therapy. In fact, we had first-line metastatic trials that showed that the combination of lapatinib, a weaker oral pan-HER tyrosine kinase inhibitor, could improve the response and response duration to hormone therapy, as could trastuzumab. It’s just that the results with lapatinib looked a little better. We’ve shown subsequently in preclinical models that, actually, if you add neratinib, you can improve the response in ER-positive/HER2-positive breast cancer.

So, these are interesting data, but they weren’t the basis for the whole ExteNET trial. ExteNET said, “OK, people relapse late. Maybe if we give another drug that’s non-cross-resistant after a year of trastuzumab, we’ll improve outcome.” It’s a very simple question. So, the trial randomized patients who were at least a year out and had completed their trastuzumab to receive either neratinib or not for 1 year, and it was placebo controlled. We also knew something else about neratinib: it causes a lot of diarrhea. It causes more diarrhea than lapatinib. And when ExteNET was started, there was no specific approach to prevent the diarrhea.

Now, as ExteNET was ongoing, we were doing other trials. We actually incorporated neratinib into our I-SPY neoadjuvant study. We learned pretty quickly that people got diarrhea, they got it really early, in the first 2 or 3 days. And we learned a little bit from what the NSABP (National Surgical Adjuvant Breast and Bowel Project) was discussing, that starting with prevention upfront, prophylaxis, was better than reacting. If you get bad diarrhea in the first few days and then it quiets down, you should just get rid of that bad diarrhea in the first few days. So, we developed a prophylactic regimen with loperamide, and the idea was that people would take that up front, and really improve the tolerance in I-SPY 2 of using neratinib.

But that same approach wasn’t used in ExteNET. The results of ExteNET were complicated by the fact that it went through 3 different companies. It got reduced in size. People thought, “Oh, the metastatic trials are no good, so neratinib is no good, so we might as well cut our losses and stop the trial early.” So, they changed the follow-up time to just do a very early look to see what happened. If it wasn’t good, they would stop things then.

Well, Puma acquired the drug—thankfully, in many ways—and got that baggage, right? It was a smaller trial, although still quite respectable and with 2 years of follow-up. So, at 2 years, surprisingly enough, giving neratinib was found better than taking a placebo. And then when they looked at the subsets, it turned out that that benefit was almost all in the ER-positive group, which makes perfect sense based on what we understand about ER-positive disease. Now, the trial was designed to look at the whole group, the whole group benefited, and they benefited in a statistically significant way. But the difference in the ER-positive disease was much greater, and even more clinically important to us as practicing oncologists.

If you took patients who had ER-positive/HER2-positive breast cancer, you could make a big difference on their risk of recurrence by giving neratinib. So, we felt that those data were really very encouraging, and even more so when they were confirmed with 3 years of follow-up. Puma extended the duration of follow-up, of course, so that we can continue to see how these patients do over time and look for the gold key, which is survival benefit over time.

The one thing we had to deal with in that first 2-year presentation and publication was that everybody got diarrhea, and a lot of patients got serious diarrhea. Some of those patients stopped taking the drug fairly quickly. After time, of course, the diarrhea quiets down, people get used to it, and they do okay. But you have that loss of patients early on who don’t want to take the drug. They say, “Look, I already did my chemotherapy and trastuzumab, I don’t want diarrhea now. I’m better, I’m done.”

So, another trial was started called the CONTROL trial, which is giving everybody neratinib in that extended adjuvant setting for HER2-positive disease, by using upfront prophylaxis and shows, as had some smaller trials, that you could markedly reduce the rate of grade 3 diarrhea and probably discontinue it over time. Those data are still quite small. And then the idea was that with understanding the etiology of diarrhea, you could add in alternative preventive approaches along with loperamide—of course, not stopping it. Then you could see even better control of the diarrhea, unless forming constipation, which people don’t like.

The first cohort after loperamide was budesonide, an oral nonabsorbable steroid, and we did see a big improvement there, which is quite nice. And then the third cohort, which is still accruing, is colestipol, a really interesting lipid binding drug, a bile salt binding drug. This is a small cohort because it’s still accruing, but we’ve seen an even better control of diarrhea. So, we’re excited about those data that we’ll have a way of packaging neratinib with a prophylactic regimen, that will be quite effective and maintain the quality of life of our patients. This, of course, is really important in this setting, because you are not curing everybody, you’re helping people, so you want to make sure you can maintain quality of life at the same time.

Actually, neratinib went to our Oncology Drug Advisory Committee through the FDA, and had a positive result with 12 out of 16 people on the panel voting for approval. So, now it goes through the FDA and their evaluation, but the statistical evaluations by the FDA were also quite favorable. This is a very interesting approach: extended adjuvant therapy in HER2-positive disease. I expect when it is approved and goes into practice that it will be largely used in higher-risk, node-positive, ER-positive, HER2-positive breast cancer. But that remains to be seen.

Transcript Edited for Clarity