U.S. Food and Drug Administration Approval: Neratinib for the Extended Adjuvant Treatment of Early-Stage HER2-Positive Breast Cancer

Clin Cancer Res. 2018 Aug 1;24(15):3486-3491. doi: 10.1158/1078-0432.CCR-17-3628. Epub 2018 Mar 9.


On July 17, 2017, the FDA approved neratinib (NERLYNX; Puma Biotechnology, Inc.) for the extended adjuvant treatment of adult patients with early-stage HER2-overexpressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy. Approval was based on data from ExteNET, a randomized, double-blind, placebo-controlled multicenter trial. Women with early-stage HER2-positive breast cancer and within 2 years of completing adjuvant trastuzumab were randomized to neratinib (n = 1,420) or placebo (n = 1,420) for 1 year. The primary endpoint was invasive disease-free survival (iDFS), defined as the time between randomization date to first occurrence of invasive recurrence (local/regional, ipsilateral, or contralateral breast cancer), distant recurrence, or death from any cause, with 2 years and 28 days of follow-up. The trial showed a statistically significant treatment effect favoring neratinib with a stratified HR of 0.66 [95% confidence interval (CI), 0.49-0.90, P = 0.008]. The estimated iDFS rate at 2 years was 94.2% (95% CI, 92.6%-95.4%) in patients treated with neratinib versus 91.9% (95% CI, 90.2%-93.2%) in those receiving placebo. Diarrhea was the most common adverse event (AE), with a 40% incidence of grade 3 or 4 diarrhea, and represents the most common AE leading to treatment discontinuation. Other frequent AEs (>10% incidence) were nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, and muscle spasms. Other than diarrhea, neratinib is associated with a low incidence of severe AEs; toxicities are generally reversible and manageable with dose interruptions, dose reductions, and/or standard medical care. This article summarizes FDA decision-making and data supporting the neratinib approval. Clin Cancer Res; 24(15); 3486-91. ©2018 AACRSee related commentary by Unni et al., p. 3483.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Disease-Free Survival
  • Double-Blind Method
  • Drug-Related Side Effects and Adverse Reactions / classification
  • Drug-Related Side Effects and Adverse Reactions / pathology
  • Female
  • Humans
  • Middle Aged
  • Neoplasm Recurrence, Local / drug therapy*
  • Neoplasm Recurrence, Local / genetics
  • Neoplasm Recurrence, Local / pathology
  • Neoplasm Staging
  • Quinolines / administration & dosage*
  • Quinolines / adverse effects
  • Receptor, ErbB-2 / genetics
  • Trastuzumab / administration & dosage


  • Quinolines
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • neratinib
  • Trastuzumab