Expert Says Neratinib-Associated Diarrhea Manageable in HER2+ Breast Cancer

Priority Report, Management of Diarrhea in Breast Cancer, Volume 1, Issue 1

Michel Velez, MD, addresses how loperamide and other methods of prophylaxis are significantly reducing the risk of neratinib-associated diarrhea in patients with HER2-positive breast cancer.

Michel Velez, MD

Aggressive prophylactic intervention right at the initiation of neratinib (Nerlynx) therapy has eased the concern of diarrhea associated with the pan-HER TKI in patients with early-stage HER2-positive breast cancer, according to Michel Velez, MD.

In July 2017, the FDA approved neratinib for the extended adjuvant treatment of patients with early-stage HER2-positive breast cancer following 1 year of trastuzumab (Herceptin). The approval was based on findings from the ExteNET study, which showed a 5-year invasive disease-free survival rate of 90.2% with neratinib.1 However, the benefit appeared to come with a safety concern: in the 5-year analysis, 95.4% of patients treated with neratinib experienced diarrhea and 40% experienced it as a grade 3 event.

Nevertheless, the ongoing phase II CONTROL trial has indicated that 1 to 2 cycles of a loperamide prophylactic regimen reduces the incidence and severity of neratinib-associated diarrhea. Adding budesonide or colestipol to loperamide appeared to further subside this adverse event. In the loperamide arm, rates of grade 3 diarrhea were reduced from nearly 40% in the ExteNET trial to 30.7%, according to data presented at the 2017 San Antonio Breast Cancer Symposium.2 Budesonide with loperamide further diminished the rates to 25%, and colestipol with loperamide drove down the rates to 7.7%.

Velez, a medical oncologist at Holy Cross Hospital, explained that early, aggressive use of loperamide alone has been sufficient for his patients; however, the addition of budesonide or colestipol can be introduced, if necessary.

In an interview with OncLive®, Velez addressed how loperamide and other methods of prophylaxis are significantly reducing the risk of neratinib-associated diarrhea in patients with HER2-positive breast cancer.

OncLive: Where does neratinib fit into the HER2-positive breast cancer paradigm?

Velez: Neratinib is currently the only FDA-approved therapy for early-stage HER2-positive breast cancer after 1 year of adjuvant trastuzumab. That's where it fits in, but it depends on several factors—more so the data suggest that the benefit is greatest in patients with hormone receptor (HR)—positive, HER2-positive disease. The general consensus is that there is still an unmet need in the adjuvant management of HER2-positive breast cancer. There is still a significant proportion of patients who will relapse; based on the older adjuvant trials with trastuzumab, about 25% of patients are at risk of relapse.

In my practice, I discuss this information with patients, especially those with node-positive or HR-positive disease. There is still a benefit with neratinib in the HR-negative patients, so I discuss that with all of them. There's a signal even in the HR-negative patients; if we treat them early, they may benefit [from neratinib]. There is about a 3% benefit if they start in the first 6 months from the completion of adjuvant trastuzumab.

How much of a concern is the diarrhea associated with neratinib?

To me, it's not that big of a concern. The one good thing with regards to the diarrhea is that it's predictable. More than 90% of patients will have diarrhea only present within the first month, and it usually lasts just a few days. On average, it lasts about 5 days. Therefore, it's something that you know will happen, and based on the ExteNET data, we know there is about a 40% risk of grade 3 diarrhea.

You can be aggressive from the onset of therapy by predicting when the diarrhea is going to happen and how long it's going to last. If you're aggressive enough, I don't think you'll have any real issues with regard to secondary complications like kidney injury and dehydration. Therefore, the positive thing about the diarrhea is that we are able to predict it, and it's manageable if you are aggressive with antidiarrheal medications.

Could you further expand on the prophylactic management of diarrhea?

Based on the CONTROL data, which was a study basically done to help patients and clinicians deal with the side effect of diarrhea, we know all patients should receive prophylaxis. It's as easy as starting a patient on loperamide with the first dose of neratinib. Therefore, the patient should start loperamide with the initiation of neratinib therapy and take it on a prophylactic schedule, as per CONTROL.

For the first 2 weeks, patients should take 4 mg [of loperamide] 3 times daily and then they continue taking it twice daily for the remaining 6 weeks up until 2 months. Doing this has significantly decreased the onset of grade 3 diarrhea, especially in the first month, which we know is the crucial time to prevent that. You can always escalate from that prophylaxis, so if that dose is not enough to control the diarrhea, my take has always been to be aggressive with loperamide. We've learned from the past when treating patients with other drugs, such as irinotecan, that we needed to be really aggressive with loperamide.

I give my patients 4 mg [of loperamide] every 4 hours around the clock until they have no bowel movement for about 24 hours. That has worked for me. We just have to be cognizant about being aggressive, and loperamide has worked for me in most instances. The question is just, “How aggressive are you being with it.?”

That's my take, but there have been other strategies that have proven to be efficacious. Based on the CONTROL trial, one of them was the addition of the steroid budesonide and colestipol [to loperamide]. Again, there was a significant reduction [in diarrhea incidence and severity] within the first 4 weeks down to even 6% [severe diarrhea rates] in the colestipol arm. As clinicians, the simpler it is, the easier it is for us to make decisions in the clinic. Therefore, I would probably just start with being really aggressive with loperamide, and I wouldn't be shy with treating patients with 4 mg every 4 hours until they have no bowel movements for 24 hours. That has worked very well for me.

What would be your take-home message about the use of neratinib and its associated diarrhea?

Neratinib is a highly potent and effective pan-HER TKI that has demonstrated activity beyond 1 year of trastuzumab. Other drugs have failed to show activity in this setting. Neratinib has no long-term toxicities, so there is no concern for cardiac toxicity or secondary malignancies. There is a big proportion of patients who will benefit from this drug, including HR-positive and node-positive patients at a high risk of recurrence. Diarrhea is something that can be easily managed if we are aggressive. A lot of times, loperamide is all I've needed to manage the diarrhea, so I don't think diarrhea should be a deterring factor from being able to offer neratinib. Again, the diarrhea is predictable and manageable.


  1. Martin M, Holmes FA, Ejlertsen B, et al. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): 5-year analysis of a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;18(12):1688-1700. doi: 10.1016/S1470-2045(17)30717-9.
  2. Hurvitz SA, Chan A, Iannotti NO, et al. Effects of adding budesonide or colestipol to loperamide prophylaxis on neratinib-associated diarrhea in patients with HER2+ early-stage breast cancer: the CONTROL trial. Presented at: 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, TX. Abstract P3-14-01.