Nerlynx (Neratinib) First Extended Adjuvant Therapy Approved for HER2-Positive Breast Cancer

March 2018, Vol 11, Ninth Annual Payers' Guide - Select Drug Profiles, Payers' Guide
Loretta Fala
Medical Writer

Breast cancer is the most common type of cancer in women, representing 15% of all new cancer cases in the United States.1 In 2017, 252,710 new cases of breast cancer were estimated to be diagnosed, and more than 40,600 women to die from the disease.1 Breast cancer can also, rarely, affect men, with approximately 2470 new cases diagnosed annually.2

Approximately 15% to 20% of breast cancer tumors are HER2-positive.3 Breast cancers with high levels of HER2 have an increased risk for metastasis, inadequate treatment response, and recurrence.3,4

The development and subsequent US Food and Drug Administration (FDA) approval of trastuzumab (Herceptin), a HER2 receptor antagonist, changed the treatment paradigm for patients with HER2-positive disease. When trastuzumab was added to chemotherapy, the overall survival rates for women with early-stage HER2-positive breast cancer improved by up to 37%.5 However, approximately 26% of patients have recurrent disease after treatment with trastuzumab.6

Other therapies that target HER2-positive breast cancer include pertuzumab (Perjeta), a monoclonal antibody; ado-trastuzumab emtansine (Kadcyla), a monoclonal antibody attached to a chemotherapy drug; and lapatinib (Tykerb), a kinase inhibitor.7

Nerlynx for Extended Adjuvant Treatment

On July 17, 2017, neratinib (Nerlynx; Puma Biotechnology), a kinase inhibitor, was approved by the FDA for the extended adjuvant treatment of adults with early-stage HER2-overexpressed or amplified breast cancer, after adjuvant trastuzumab-based therapy.8,9

“HER2-positive breast cancers are aggressive tumors and can spread to other parts of the body, making adjuvant therapy an important part of the treatment plan,” said Richard Pazdur, MD, Director of the FDA’s Oncology Center of Excellence. “Now, these patients have an option after initial treatment that may help keep the cancer from coming back.”8

Mechanism of Action

Neratinib is a kinase inhibitor that irreversibly binds to HER2, HER4, and epidermal growth factor receptors (EGFRs).9 Neratinib blocks several enzymes that promote cell growth; in preclinical studies, neratinib showed antitumor activity in EGFR and/or HER2-positive carcinoma cell lines.8,9

Dosing and Administration

The recommended dose of neratinib is 240 mg (6 tablets), taken orally once daily with food, and used continuously for 1 year. Neratinib is available as a 40-mg tablet.9

For antidiarrheal prophylaxis, loperamide should be used concomitantly with the first dose of neratinib and continued during the first 2 cycles (ie, 56 days) of treatment, and then as needed. Patients should be instructed to maintain 1 to 2 bowel movements daily, and should be instructed on how to use antidiarrheal treatment regimens.9

Specific dose interruption and/or dose reduction recommendations, based on the patient’s individual tolerability, are outlined in the prescribing information. For patients with severe hepatic impairment, the starting neratinib dose should be reduced to 80 mg.9

Pivotal Clinical Trial: ExteNET

The FDA approval of neratinib was based on the safety and efficacy data from the ExteNET clinical trial, a randomized, double-blind, placebo-controlled, phase 3 study that included 2840 patients with early-stage, HER2-positive breast cancer who had completed adjuvant treatment with a trastuzumab-based regimen within the previous 2 years.6,9

Patients were randomized to receive neratinib (N = 1420) or placebo (N = 1420). The majority (81%) of patients were enrolled in the study within 1 year of completing trastuzumab therapy.9 The median patient age was 52 years (range, 23-83 years); 10% of the patients had stage I disease, 41% had stage II disease, and 31% had stage III disease.9

After 2 years, 94.2% of patients who received neratinib did not have disease recurrence and did not die compared with 91.9% of patients who received placebo (Table).9


In an exploratory subgroup analysis of patients who were reconsented for extended follow-up beyond 24 months, the invasive disease-free survival rates at 5 years were consistent with those of the 2-year findings from the ExteNET study.9

Adverse Reactions

The most common (>5%) adverse reactions in patients who received neratinib were diarrhea (95%), nausea (43%), abdominal pain (36%), fatigue (27%), vomiting (26%), rash (18%), stomatitis (14%), decreased appetite (12%), muscle spasms (11%), dyspepsia (10%), alanine aminotransferase increase (9%), nail disorder (8%), aspartate aminotransferase increase (7%), dry skin (6%), abdominal distention (5%), weight decrease (5%), and urinary tract infection (5%).9 A total of 26.7% of patients discontinued neratinib treatment because of adverse reactions; diarrhea was the most common (16.8%) side effect leading to treatment discontinuation.9

Drug Interactions

Nursing women should not breastfeed while taking neratinib and for at least 1 month after the last dose.9

Neratinib should not be used concomitantly with proton pump inhibitors and H2-receptor antagonists. The administration of neratinib should be separated by 3 hours after antacids are administered.9

Concomitant use of neratinib with a strong cytochrome (CY) P3A4 inhibitor (eg, ketoconazole) may increase neratinib concentrations and should be avoided.9

Concomitant use of neratinib with strong or moderate CYP3A4 inducers (eg, rifampin) may decrease neratinib concentrations and should be avoided.9

Use in Specific Populations

In a clinical trial of neratinib that included 172 patients aged ≥65 years (25 patients were aged ≥75 years), the frequency of adverse reaction–related treatment discontinuations was higher in patients aged ≥65 years than in younger patients.9

No dose modifications are needed in patients with mild-to-moderate hepatic impairment; the neratinib dose should be reduced in patients with severe impairment.9

Warnings and Precautions

Diarrhea that occurs with neratinib despite recommended prophylaxis should be aggressively managed with additional antidiarrheals, fluids, and electrolytes as clinically indicated. Neratinib should be withheld for patients who have severe and/or persistent diarrhea. Neratinib should be permanently discontinued in patients who have grade 4 diarrhea or grade ≥2 diarrhea that persists after maximal dose reduction.9

Liver function tests should be monitored monthly for the first 3 months of treatment, then every 3 months during treatment and as clinically indicated. Neratinib should be withheld for patients with grade 3 liver abnormalities, and discontinued for patients with grade 4 liver abnormalities.9

Neratinib can cause fetal harm. Women using neratinib should be advised of the potential risk to the fetus and should use effective contraception during treatment with neratinib and for at least 1 month after the last dose.9


The FDA approval of neratinib, an oral kinase inhibitor, marked the availability of the first extended ad­juvant treatment option for appropriate patients with early-stage, HER2-positive breast cancer. Patients with HER2-positive breast cancer who received neratinib for 1 year achieved a significantly improved 2-year invasive disease-free survival compared with patients who received placebo, after chemotherapy and trastuzumab-based adjuvant therapy.

1. National Cancer Institute. SEER cancer stat facts: female breast cancer. Accessed September 22, 2017.
2. National Cancer Institute. Male breast cancer treatment (PDQ)–health professional version. Updated May 25, 2017. Accessed September 22, 2017.
3. National Cancer Institute. Targeted agents active against HER2-positive breast cancer: questions and answers. Updated June 1, 2014. Accessed September 22, 2017.
4. National Cancer Institute. A story of discovery: HER2’s genetic link to breast cancer spurs development of new treatments. Accessed September 22, 2017.
5. Perez EA, Romond EH, Suman VJ, et al. Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol. 2014;32:3744-3752.
6. Chan A, Delaloge S, Holmes FA, et al; for the ExteNET Study Group. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2­positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo­controlled, phase 3 trial. Lancet Oncol. 2016;17:367-377.
7. American Cancer Society. Targeted therapy for breast cancer. Revised September 27, 2017.­therapy-for-breast-cancer.html. Accessed October 4, 2017.
8. US Food and Drug Administration. FDA approves new treatment to reduce the risk of breast cancer returning. Press release. July 17, 2017. Accessed September 21, 2017.
9. Nerlynx (neratinib) tablets [prescribing information]. Los Angeles, CA: Puma Biotechnology; July 2017.

Related Items
Balversa (Erdafitinib), First-in-Class FGFR Kinase Inhibitor, Approved for Patients with Metastatic Urothelial Carcinoma and FGFR Mutations
Loretta Fala
2019 Payers' Guide Mid-Year Addendum published on August 13, 2019 in Select Drug Profiles
Cablivi (Caplacizumab-yhdp): First Targeted, Nanobody-Based Therapy Approved for Adults with Acquired Thrombotic Thrombocytopenic Purpura
Loretta Fala
2019 Payers' Guide Mid-Year Addendum published on August 13, 2019 in Select Drug Profiles
Doptelet (Avatrombopag) Receives FDA Approval for the Treatment of Patients with Chronic Immune Thrombocytopenia
Loretta Fala
2019 Payers' Guide Mid-Year Addendum published on August 13, 2019 in Select Drug Profiles
Eylea (Aflibercept), a VEGF Receptor Inhibitor, Receives New Indication for All Stages of Diabetic Retinopathy
Lilly Ostrovsky
2019 Payers' Guide Mid-Year Addendum published on August 13, 2019 in Select Drug Profiles
Imbruvica (Ibrutinib) plus Gazyva (Obinutuzumab) First Chemotherapy-Free Combination Approved as First-Line Treatment for Patients with CLL or SLL
Lilly Ostrovsky
2019 Payers' Guide Mid-Year Addendum published on August 13, 2019 in Select Drug Profiles
Last modified: May 9, 2018
Copyright © Engage Healthcare Communications, LLC. All rights reserved.