Antidiarrheal Prophylaxis Optimizes Neratinib Use in HER2+ Breast Cancer

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

Martin Dietrich, MD, PhD, discusses ways of offsetting neratinib-associated diarrhea for patients with early-stage HER2-positive breast cancer at high risk of recurrence in need of extended adjuvant therapy.

Martin Dietrich, MD, PhD

Early prophylactic interventions have offset initial concerns regarding the incidence and severity of neratinib (Nerlynx)-associated diarrhea seen in the ExteNET trial, explained Martin Dietrich, MD, PhD, giving patients with HER2-positive breast cancer at high risk of recurrence a better chance of completing the full 1 year of extended adjuvant therapy and reducing their risk of developing invasive disease.

In the phase III ExteNET trial, neratinib induced an invasive disease-free survival (iDFS) rate of 94.2% versus 91.9% with placebo at 2 years among patients with early-stage HER2-positive breast cancer (stratified HR, 0.66; 95% CI, 0.49-0.90; stratified log-rank P-value [two-sided] = .008).1 Though this benefit was further compounded by hormone receptor (HR) positivity, 16.8% of patients discontinued treatment due to diarrhea.

However, findings from the ongoing phase II CONTROL trial showed that adding budesonide or colestipol to loperamide prophylaxis reduce the incidence of the toxicity, and may lead to stronger adherence rates and overall outcomes.2

“Early initiation of this prophylactic regimen is sparing patients the side effects of debilitating diarrhea, which is very helpful in optimizing outcomes for patients with HER2-positive breast cancer,” said Dietrich, a medical oncologist and member at Advent Health Cancer Institute in Orlando.

In an interview with OncLive, Dietrich discussed ways of offsetting neratinib-associated diarrhea for patients with early-stage HER2-positive breast cancer at high risk of recurrence in need of extended adjuvant therapy.

OncLive: Could you provide background on the ExteNET trial?

Dietrich: The phase III ExteNET trial was a randomized controlled trial of adjuvant therapy following trastuzumab-based therapy in HER2-positive breast cancer. The trial was done to assess the efficacy of extended HER2 blockade with neratinib. Interestingly, there was a 5.1% improvement in iDFS in patients with hormone receptor (HR)-positive breast cancer. In HR+ patients who initiated neratinib within a year of adjuvant trastuzumab based therapy, patients [who had not achieved a pathologic complete response], iDFS was 7.4% at 5 years.

However, diarrhea was one of the main adverse events (AEs) of neratinib. In the trial, 40% of patients experienced grade 3 diarrhea, and that was a major challenge. This was something we learned how to manage on the go, similarly to immunotherapy. We know the diarrhea is early onset and occurs in virtually all patients to a certain degree. Therefore, it is predictable, and with the right intervention, manageable.

Could you explain the design of the CONTROL trial and subsequent findings?

The CONTROL trial is an ongoing 3-arm study that looked at different management approaches for neratinib-associated diarrhea. Neratinib is an irreversible TKI across the HER family. The phase II trial is essentially an international, open-label study that is looking at the effects of loperamide prophylaxis alone or in combination with budesonide as an anti-inflammatory or colestipol as a bile sequestrant on neratinib-associated diarrhea. The CONTROL trial aimed to assess the impact of these regimens on incidence, severity and duration of diarrhea, as well as different quality-of-life measures with these interventions.

Results showed that loperamide intervention reduced the rate of grade 3/4 AEs from 30% with loperamide alone to 26% in the budesonide cohort down to 10.8% in the colestipol cohort. In my practice, these findings have resulted in early initiation of colestipol as the standard add on for loperamide for managing higher-grade diarrhea. As we have learned, this is a temporal relationship that is early in onset and that then equalizes in the gastrointestinal tract with a typical reduction in incidence. The exact mechanism of development of diarrhea has remained elusive and contains likely secretory and inflammatory components.

Based on the trial data and my clinical experience, diarrhea has become manageable. Patients are able to complete treatment to derive maximum clinical benefit from the addition of neratinib following trastuzumab-based therapy. In rare cases of persistent grade 3/4 diarrhea, I've used a switch add-on approach from loperamide and colestipol to loperamide and budesonide and have seen some differential effects. That poses the question about the nature of the diarrhea, and whether it is partly inflammatory that can be controlled with budesonide.

How are patients tolerating neratinib now?

In my practice, patient experience has significantly improved with this proactive approach. We learned a lot from the ExteNET trial. Now, we have a standard approach for preemptive treatment of diarrhea. Even though the [CONTROL] trial has not been finalized, it has given us definitive treatment guidance on diarrhea management. This allows patients to complete that 12-month course of neratinib in the adjuvant setting and reduce their risk of developing invasive disease.

Are there other toxicities to be aware of?

Diarrhea is an on-target effect of neratinib. Therefore, [the diarrhea] is within the range of physiological targets of the drug. Our initial concerns of tolerability were overcome by initiating this combination treatment early. The addition of the bile sequestrants were an insightful approach that led to a significantly improved toxicity profile and overall outcome for patients. We know that 3 months of therapy is a critical marker; if patients can make it through the first 3 months of therapy, they'll be able to finish the full course of treatment. Of note, no other long term or cumulative toxicities were seen in this trial.

Where do these data leave neratinib in the paradigm?

Neratinib has now been made a very tolerable regimen with the utilization of different antidiarrheal regimens. For patients who have undergone adjuvant trastuzumab therapy and are at high risk for relapse, especially those with HR-positive disease who have not achieved a pCR, the discussion should be had about extending adjuvant therapy. We have had some changes in the adjuvant setting with the addition of pertuzumab (Perjeta) and most recently ado-trastuzumab emtansine (T-DM1; Kadcyla), so it has to be a discussion between the provider and the patient.

Do real-world data reflect what was seen in these trials?

The difference between trial data and real-world experience is supportive of using neratinib in clinical practice. We've learned how to manage the toxicity of the drug, and therefore make it a very potent and utilizable tool. It's important for patients to understand that this is not a side effect like with chemotherapy. [The severity of diarrhea that we’ve seen] occurs because the affinity of the drug to its target is so high and so specific. However, with these management techniques, it’s use is certainly a standard approach in high-risk HER2-positive disease and one that has become significantly more manageable in the real world.


  1. Chan A, Delaloge S, Holmes FA, et al. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2016;17(3):367-377. doi: 10.1016/S1470-2045(15)00551-3.
  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.