R/R HER2+ Metastatic Breast Cancer: Neratinib AE Management

Adam M. Brufsky, MD, PhD:I think people are afraid of neratinib. I think that people fear the diarrhea. And it’s interesting to note in this trial, in the NALA trial, while the incidence of grade 3 diarrhea, which is more than 7 stools a day, was about 24%, it turns out that the mean time of grade 3 diarrhea was only 4 days. The reason it was so short is that everybody had prophylaxis. You had prophylaxis with loperamide, and there was a very specific schedule that they took.

With that intensive prophylaxis, the length of grade 3 was very short, and more importantly, only 2.6% of the patients on the NALA trial, in the neratinib arm, discontinued therapy because of diarrhea. So it’s very manageable. Given the fact that this irreversible binder of HER2 [human epidermal growth factor receptor 2] significantly improves progression-free survival, has a trend toward overall survival, reduces the incidence of intervention for symptomatic brain metastases, has a higher duration of response, and has manageable toxicity in a randomized phase 3 trial, this could be one of several standards of care that we now have for this disease.

The question is, does the management differ in the relapsed setting as it would say in the extended adjuvant setting, and the answer is no. The key is here to use intensive prophylaxis, to use loperamide, to use dose-reduction when needed, or to use dose escalation. I think that’s the newest strategy. We have a lot of strategies that we’re employing, potentially colestipol, potentially budesonide.

And it usually tachyphylaxes within a month. But again, I think you look at the data. The data are that, yes, people can get grade 3 diarrhea, but the mean time that it lasts is 4 days, then it’s done. And people don’t realize that. They think, oh, you’re going to have grade 3 diarrhea. They’re going to have grade 3 diarrhea forever; the whole time you’re on it you can be miserable. That’s the reputation that the drug has, and that’s simply not true.

The clinical trials data show that, again, with the combination of a variety of strategies, fairly intensive prophylaxis the first couple of weeks, people generally do well. And we have other drugs like this. Abemaciclib now is another drug that has a lot of diarrhea upfront. We manage it because now we have evidence that these drugs work, and it’s worth it to go through a couple of weeks of this to get them through it, and then it should be fine after that, generally. Obviously there are people who are going to have issues no matter what, but in my experience and the experience in the trials is that grade 3 episode is fairly limited and usually it’s within that first month, and it’s no more than 4 to 5 days and then they’re done.

It turns out that in the clinical trials, the original clinical trials with no prophylaxis, the incidence of grade 3 diarrhea is like 40%. When we started using intensive loperamide prophylaxis, basically TID [3 times a day], for a week or two and then BID [twice a day] for a week or two, and then QD [every day] for a week or two and then off, that went down to about 24% of grade 3. It turns out there’s even more intensive ways of doing this. Colestipol, a cholesterol drug, a bile acid sequestrant, lowers the instance of grade 3 diarrhea I think about, if I’m not mistaken, probably in the teens. Budesonide, which is an oral steroid used in Crohn disease, colitis, and inflammatory bowel disease, lowers it to the mid-teens as well.

The newest strategy that we’re employing in the CONTROL trial, which is a trial trying all these strategies, we’re using a dose escalation. So we’re starting at 160 mg. So 4 pills a day, 160 mg a day, and gradually escalating it with loperamide prophylaxis. And I think that’s going to actually probably be a very effective strategy as well. Because it turns out people who’ve been dose de-escalated in their clinical trials do just as well as those who started the 240 mg. So their clinical benefit, at least in extended adjuvant therapy, looks to be as good. What I’m doing is a combination of everything at some point, that’s where I’m going to when the trials lead us there. So it’s probably going to be dose escalation starting at 160 mg, gradually increasing, and including loperamide or budesonide with loperamide. Again, for the first month. I think once you get through the first month, you should be OK.

How do patients manage nausea? There are a lot of things people do that are less than using things like ondansetron and palonosetron and things like that, and Compazine. I think that ginger, sour things, or eating frequent small meals generally helps. In terms of the diarrhea, it’s like we say, the bland diet, the BRAT [bananas, rice, applesauce, and toast] diet. Bland things, bananas, eat that sort of thing for a while.

In terms of fatigue, I think the most important thing that’s come out is you’re trying to get yourself up and just move around. Exercising I think for fatigue is one of the biggest things you could do. And you don’t have to go crazy, just go for a walk around the block or something. Just do a little more than you have been doing and that can tend to help the fatigue.

When I use agents like this, the incidence of LFT [liver function test] abnormalities with these drugs was small. But I tend to monitor LFTs every other cycle probably. So if it’s a 3-week cycle, I probably would end up doing it probably every 6 weeks or so, 6 to 9 weeks, especially someone who has liver metastases. Someone who has liver metastases will probably get it almost every 3 weeks, at least for a while. And if their liver disease is stable and the liver abnormality has normalized, they will probably get it every 3 months or so.

Transcript edited for clarity.