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July 17, 2017

On July 17, 2017, the U.S. Food and Drug Administration 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 the ExteNET trial (NCT00878709), a multicenter, randomized, double-blind, placebo-controlled trial of neratinib following adjuvant trastuzumab treatment. Women (n=2,840) with early-stage HER2-positive breast cancer and within two years of completing adjuvant trastuzumab were randomized to receive either neratinib (n=1420) or placebo (n=1420) for one year.

The major efficacy outcome measure was invasive disease-free survival (iDFS) defined as the time between the randomization date to the first occurrence of invasive recurrence (local/regional, ipsilateral or contralateral breast cancer), distant recurrence, or death from any cause, within two years and 28 days of follow-up. After two years, iDFS was 94.2% in patients treated with neratinib compared with 91.9% in those receiving placebo (HR 0.66; 95% CI: 0.49, 0.90, p=0.008).

The most common adverse reactions (>5%) were diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, AST or ALT increase, nail disorder, dry skin, abdominal distention, weight loss, and urinary tract infection. The most common adverse reaction leading to discontinuation was diarrhea, observed in 16.8% of neratinib-treated patients. Hepatotoxicity or increases in liver transaminases led to drug discontinuation in 1.7% of neratinib-treated patients.

The recommended dose is 240 mg (6 tablets) given orally once daily with food, continuously for one year. Antidiarrheal prophylaxis should be initiated with the first neratinib dose and continued during the first 2 cycles (56 days) of treatment and as needed thereafter.

Details are available in the full prescribing information:

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).


Pharmacist’s Applications to Practice

Neratinib for Extended Adjuvant Treatment of HER2 Overexpressed/Amplified Breast Cancer Following Adjuvant Trastuzumab-Based Therapy

Author: Sarah Francis, PharmD BCOP
Clinical Hospital Pharmacist, Hematology/Oncology
Jackson Memorial Hospital
Miami, FL

What is the potential role for neratinib in the extended adjuvant treatment of human epidermal growth factor receptor 2 (HER2)–positive breast cancer following adjuvant trastuzumab-based therapy?1,2

  • For patients with HER2 overexpressed/amplified breast cancer, adjuvant HER2 targeted monoclonal antibodies have significantly changed the outcome of early-stage disease. Despite these improvements, more than 10% of patients develop distant disease recurrence.
  • Neratinib is an irreversible kinase inhibitor of the epidermal growth factor receptor (EGFR), HER2, and HER4, reducing autophosphorylation and downstream signaling in EGFR- and/or HER- expressing cell lines.
  • The ExteNET trial investigated the benefit of 1 year of neratinib therapy after trastuzumab-based therapy in 2,840 women with early-stage breast cancer. The primary end point was 2-year invasive disease-free survival (iDFS). Secondary end points included disease-free survival, time to distant recurrence, distant disease-free survival, incidence of central nervous system recurrence, overall survival, and safety. The iDFS at 2 years was 94.2% in the neratinib group, compared with 91.9% in placebo (hazard ratio [HR] = .66, 95% confidence interval [CI]: .49–.90). Overall survival data were not mature at the time of study publication.
  • In a prespecified subgroup analysis, the 2-year iDFS of adjuvant neratinib was significantly greater in patients with hormone receptor–positive disease (95.6% neratinib vs. 91.5% placebo; HR = .49, 95% CI: .31–.75; p =.0013). No significant difference was seen in patients with hormone receptor–negative disease (92.2% neratinib vs. 92.4% placebo; HR = .93, 95% CI: .60–1.43). Although more data are needed, this finding raises the possibility that neratinib may be involved in the reversal of endocrine resistance. It should also be noted that the U.S. Food and Drug Administration (FDA) required Puma Biotechnology to revise its statistical analysis for iDFS rates from what was published in the ExteNET trial on the basis of the FDA guidance documents, which explains why percentages in the product labeling differ slightly from what had been previously published.
  • Neratinib was approved for the extended adjuvant treatment of HER2-positive patients following adjuvant trastuzumab-based therapy; however, it is important to note that several trial amendments were made that limit the generalizability of study findings. Most notably, a global amendment limited recruitment to higher-risk patients, defined as those with node-positive disease who had completed trastuzumab therapy up to 1 year previously.
  • Neratinib is the first agent in its class to receive FDA approval for the extended adjuvant treatment of HER2-positive breast cancer following adjuvant trastuzumab-based therapy. Its role in therapy will likely be determined on the basis of a better understanding of risk stratification. Given the global amendments, consideration for extended adjuvant treatment with neratinib should be limited to those with high-risk disease. Hormone receptor status may also prove to be an important factor in treatment selection.

What role can the pharmacist play in the management of patients on neratinib?1-3

  • The most common treatment-emergent adverse event associated with neratinib reported in ExteNET was diarrhea, which occurred in 95% of patients receiving the medication. Grade 2, 3, and 4 diarrhea was reported in 33%, 40%, and <1% of patients receiving neratinib, respectively, compared with 7%, 2%, and 0% in the placebo group. The majority of patients experienced diarrhea during the first month of treatment. Based on trial results, antidiarrheal prophylaxis with loperamide is recommended for the first two cycles of treatment.
    • Dosing recommendations for loperamide are as follows: 4 mg by mouth three times daily during weeks 1 and 2, and 4 mg by mouth twice daily during weeks 3–8. Following the completion of the first two cycles, patients should receive loperamide 4 mg by mouth as needed, not to exceed 16 mg/day. Loperamide should be titrated to 1–2 bowel movements per day.
    • For patients experiencing diarrhea, antidiarrheal treatment should be escalated. Early intervention with aggressive hydration, dietary modifications, and electrolyte repletion should be initiated as needed, along with dose interruptions for any persistent grade 2 or grade 3 diarrhea.
    • Antidiarrheal prophylaxis was not administered in the ExteNET trial; however, cross-trial comparison of studies using loperamide prophylaxis reported grade 3 diarrhea in only 0%–17% of patients.
  • Pharmacists can play an important role in educating patients and providers regarding administration instructions and important drug-drug interactions.
    • Neratinib should be administered once daily with food. Studies assessing the effect of food demonstrate that the maximum concentration and area under the curve are both increased with the administration of food.
    • Gastric reducing agents such as proton pump inhibitors and H2-receptor antagonists should be avoided because they also reduce drug exposure. If necessary, antacids can be administered if separated by 3 hours before the administration of neratinib.

Clinical Pearls2,4

  • The initial recommended dose of neratinib is 240 mg daily; however, neratinib is supplied as 40-mg tablets. Patients should be made aware of tablet quantity per dose to ensure optimal administration. Tablets should not be chewed, crushed, or split.
  • Findings from animal studies indicate that neratinib may cause fetal harm. Females of reproductive potential should use effective contraception during neratinib therapy and for at least a month following drug discontinuation.
  • Puma Biotechnology provides access and reimbursement support through its Puma Patient Lynx program. Program benefits include access to reimbursement counselors who conduct benefit investigations, identify sources for financial support, and provide co-pay assistance to patients who qualify, along with a free 3-week supply to eligible patients experiencing delays in access to treatment.



  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.
  2. Nerlynx (neratinib) [package insert]. Los Angeles, CA: Puma Biotechnology, Inc.; June 2017.
  3. Ustaris F, Saura C, Di Palma J, et al. Effective management and prevention of neratinib-induced diarrhea. Am J Hematol Oncol. 2015;11:13-22.
  4. Puma Patient Lynx Support Program. Nerlynx website. Accessed August 8, 2017.