Neratinib for Early Stage Breast Cancer


Neratinib (Nerlynx) is an extended adjuvant treatment for patients with early stage HER2 positive breast cancer who are receiving trastuzumab therapy.

Neratinib (Nerlynx, Puma Biotechnology) was approved by the FDA in July 2017 for use as extended adjuvant treatment in patients with early stage human epidermal growth factor receptor 2 (HER2) positive breast cancer who are receiving trastuzumab therapy. Neratinib irreversibly binds to epidermal growth factor receptor (EGFR), HER2, and HER4 receptors, resulting in reduced phosphorylation and reduced activity of downstream signaling pathways.


The ExteNET trial demonstrated neratanib’s efficacy in women with HER2-positive breast cancer. It was a multicenter randomized double-blind placebo-controlled trial of 2,480 participants who completed trastuzumab treatment within 2 years of inclusion in the trial.1 Participants received either neratinib 240 mg or placebo once daily for 1 year.

Efficacy was assessed using the invasive-disease-free survival interval (time from entrance into the trial to time of first invasive or distant recurrence of disease or death from any cause within the follow-up).  At 2 years, the invasive-disease-free survival rate among participants administered neratinib and placebo was 93.9% (95% CI, 92.4 – 95.2) and 91.6% (95% CI, 90.0 – 93.0), respectively. Neratinib adjuvant therapy for HER2-positive patients resulted in reduced tumor growth.


The most common adverse events in the ExteNET study were diarrhea, nausea, abdominal pain, vomiting, stomatitis, dyspepsia, a reduction in appetite, weight loss, abdominal distension, fatigue, rash, nail changes, muscle spasms, increases in AST or ALT, and urinary tract infection.  Diarrhea occurred in 95% of participants receiving neratinib;  onset typically occurs within the first month of therapy. Adverse reactions leading to a dose reduction occurred in 31.2% of participants administered neratinib and 2.6% of patients receiving placebo.

Diarrhea is the most common reason given for discontinuation of therapy. Of the patients administered neratinib, 27.6% permanently discontinued therapy due to adverse reactions, of which 16.8% discontinued therapy due to diarrhea. The manufacturer recommends prophylactic and aggressive management of diarrhea, as it may lead to adverse events such as dehydration, hypotension, and renal failure. Liver function tests should be conducted at baseline and every 3 months with neratinib. Reduce the dose or discontinue neratinib therapy if significant liver abnormalities occur.


Neratinib is approved for up to 1 year of daily 240 mg dose administration.2 The medication is available as 40 mg tablets and 6 tablets should be taken with food as a single dose. Due to the incidence of diarrhea associated neratanib, the manufacturer recommends starting loperamide with the first dose of neratinib and for the first 56 days of therapy.2 Loperamide may be adjusted to allow for one to two bowel movements daily. However, therapy interruptions or dose reductions may be necessary to manage adverse reactions despite additional therapies. Neratinib 80 mg daily is the starting dose for patients with severe hepatic dysfunction. Neratinib should not be taken concomitantly with proton pump inhibitors, H2 receptor antagonists, or strong or moderate inhibitors or inducers of CYP3A4, as these may alter blood concentration of neratinib.  


1. Chan A, Delaloge S, Holmes FA, et al. Neratinib after trastuzumab-based adjuvant therapy in patients with HER 2-positive breast cancer (ExteNET): A multicenter, randomized, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2016 Mar;17(3):367-377.
2. Nerlynx [package insert]. Los Angeles, CA: Puma Biotechnology, Inc. July 2017.

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