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

Joanne Mortimer, Jack Di Palma, Kendra Schmid, Yining Ye, Mohammad Jahanzeb

Research output: Contribution to journalArticle

Abstract

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: ClinicalTrials.gov NCT00878709. Registered 9 April 2009.

Original languageEnglish (US)
Article number32
JournalBreast Cancer Research
Volume21
Issue number1
DOIs
StatePublished - Feb 27 2019

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Diarrhea
Breast Neoplasms
Antidiarrheals
Placebos
Therapeutics
N-(4-(3-chloro-4-(2-pyridinylmethoxy)anilino)-3-cyano-7-ethoxy-6-quinolyl)-4-(dimethylamino)-2-butenamide
Safety
National Cancer Institute (U.S.)
Terminology
Hospitalization
Quality of Life

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Patterns of occurrence and implications of neratinib-associated diarrhea in patients with HER2-positive breast cancer : Analyses from the randomized phase III ExteNET trial. / Mortimer, Joanne; Di Palma, Jack; Schmid, Kendra; Ye, Yining; Jahanzeb, Mohammad.

In: Breast Cancer Research, Vol. 21, No. 1, 32, 27.02.2019.

Research output: Contribution to journalArticle

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abstract = "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: ClinicalTrials.gov NCT00878709. Registered 9 April 2009.",
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