Combination Prevents Diarrhea in HER2+ Breast Cancer

Preventative treatment with the combination of loperamide and budesonide reduced the rate of grade 3 diarrhea associated with neratinib in a recent early-stage HER2-positive breast cancer trial. The rate fell from 39.9 percent to 15 percent in the the ExteNET trial, explained Carlos H. Barcenas, M.D., M.Sc.

Can you five an overview of the study and the findings?

In an interview with CURE, Barcenas, assistant professor, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, discussed the detailed findings of the interim analysis from the multicenter, open-label phase 2 control trial, and the next steps following these findings.The importance of the study was because previously the ExteNET clinical trial had shown a benefit of the drug neratinib in patients with stage 1 through 3 HER2-positive breast cancer. Some of them are hormone receptor (HR)-positive and some of them are HR-negative.

What were the findings in each of the cohorts?

There is a benefit of neratinib given in the adjuvant setting, which is after one year of Herceptin (trastuzumab)—an additional year of neratinib. The problem with this drug is that it gives a lot of diarrhea, and so the incidence of diarrhea in ExteNET of grade 3 was almost 40 percent. The idea of this study was to characterize the diarrhea and try to control it with prophylactic treatment with loperamide. There’s different cohorts that have been established and so we’re looking at how these different cohorts have improved the diarrhea.The loperamide cohort basically consists of two cohorts itself. It’s very detailed regarding how much loperamide they receive. It’s consistent for the first one and two cycles. The reduction of grade 3 diarrhea was around 25 percent with that cohort. The next cohort was treated with loperamide with the addition of budesonide, which is an anti-inflammatory and a kind of steroid. That one reduced the grade 3 diarrhea to about 15 percent.

What are the next steps going to be following these findings?

Of course, everything comes with a cost. With this combination, there was actually an increase of constipation, nausea and fatigue. It’s like a balancing act between decreasing diarrhea, but also trying to not increase constipation.So 15 percent is what we have seen so far with the loperamide/budesonide combination. That’s actually a good number, but the idea is to try to decrease it even more. Of course, the mechanism of action of the diarrhea, although we think it’s inflammatory, there may be other factorials, so the idea is to use other agents.

The next agent we will be testing is Colestid (colestipol), which is an acid bile sequestrant. It seems like in some of the phase 1 clinical trials in the metastatic setting it had a great response to diarrhea, so we want to see if it works in the adjuvant setting also. There’s going to be a cohort with Colestid, and then eventually there may be other cohorts down the line.

Down the line, what would be the normal dosing or indication for any of these agents?

Anecdotally, can you discuss how patients have tolerated neratinib?

There are also potential ideas, for example, decreasing the dose of loperamide, or giving single-agent budesonide and using loperamide on an as-needed basis. These are all decisions that have not been made yet and these are decisions that will be made by Puma, [the manufacturer of neratinib].The whole idea of this study is to be able to keep the patient on neratinib for a whole year, and we know diarrhea is an issue. We also know that if diarrhea is an issue, it’s going to be in the first one or two months. If they are able to go beyond those two months, they should be doing OK. We’re trying to see what is the best strategy so they don’t have too much diarrhea during those first two months and hopefully they will continue for the next year. The whole idea is so that we have a strategy to control symptoms to keep the patients on neratinib, which we know is helpful for them.This is a multi-center trial. It is clear that patients want to get on the trial because they think neratinib is a good drug. If someone is predisposed to diarrhea, they may be more hesitant to be enrolled. There was one investigator stating that one patient was actually very baseline constipated and that patient actually did really well. She was happy with the drug because now she’s not so constipated. So it’s very individual. Of course, we have to look at things like constipation, fatigue, and nausea, which may be secondary to loperamide, and so obviously we would have to think about backing off a little bit, probably. This is more of a balancing act, but overall, they’re doing quite well.