Patterns of occurrence and implications of neratinib-associated diarrhea in patients with HER2-positive breast cancer: analyses from the randomized phase III ExteNET trial

Breast Cancer Res. 2019 Feb 27;21(1):32. doi: 10.1186/s13058-019-1112-5.


Background: We characterized patterns of occurrence and the impact of neratinib-associated diarrhea in the absence of protocol-directed antidiarrheal prophylaxis or a formal diarrhea management plan using data from Extended Adjuvant Treatment of Breast Cancer with Neratinib (ExteNET).

Methods: ExteNET is a multicenter, double-blind, placebo-controlled, randomized phase III trial involving community-based and academic institutions in 40 countries. Women with HER2-positive early-stage breast cancer with prior standard primary therapy and trastuzumab-based (neo)adjuvant therapy were randomized to neratinib 240 mg/day or placebo for 12 months. Safety, a secondary outcome, was assessed using the National Cancer Institute Common Terminology Criteria version 3.0. Health-related quality of life by diarrhea grade was assessed using Functional Assessment of Cancer Therapy-Breast (FACT-B).

Results: Two thousand eight hundred sixteen women (1408 per group) were safety-evaluable. Grade 3 and 4 diarrhea occurred in 561 (39.8%) and 1 (0.1%) patients with neratinib versus 23 (1.6%) and 0 patients with placebo, respectively. In the neratinib group, 28.6% of patients had grade 3 events during month 1 decreasing to ≤ 6% after month 3. The median cumulative duration of grade 3/4 diarrhea with neratinib was 5 days (interquartile range, 2-9). Serious diarrheal events (n = 22, 1.6%) and diarrheal events requiring hospitalization (n = 20, 1.4%) were rare with neratinib. Changes in FACT-B total score by diarrhea grade in the neratinib group did not meet the threshold for clinically important differences.

Conclusions: In the absence of antidiarrheal prophylaxis, neratinib-related diarrhea is short-lived and not associated with complications or long-term sequelae. This suggests that targeted preventive management with antidiarrheal prophylaxis early during neratinib treatment is appropriate.

Trial registration: NCT00878709. Registered 9 April 2009.

Keywords: Diarrhea; Early-stage breast cancer; HER2 positive; Health-related quality of life; Neratinib; Pan-HER inhibition; Patient-reported outcomes.

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Antidiarrheals / therapeutic use
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / adverse effects*
  • Breast / pathology
  • Breast / surgery
  • Breast Neoplasms / pathology
  • Breast Neoplasms / therapy*
  • Chemotherapy, Adjuvant / adverse effects
  • Chemotherapy, Adjuvant / methods
  • Diarrhea / chemically induced
  • Diarrhea / diagnosis
  • Diarrhea / epidemiology*
  • Diarrhea / prevention & control
  • Double-Blind Method
  • Female
  • Humans
  • Mastectomy
  • Quality of Life*
  • Quinolines / administration & dosage
  • Quinolines / adverse effects*
  • Receptor, ErbB-2 / antagonists & inhibitors
  • Receptor, ErbB-2 / metabolism
  • Severity of Illness Index
  • Young Adult


  • Antidiarrheals
  • Antineoplastic Agents
  • Quinolines
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • neratinib

Associated data