General Information

Nerlynx (neratinib) is a kinase inhibitor that irreversibly binds to Epidermal Growth Factor Receptor (EGFR), Human Epidermal Growth Factor Receptor 2 (HER2), and HER4.

Nerlynx is specifically indicated for the extended adjuvant treatment of adult patients with early stage HER2-overexpressed/amplified breast cancer, to follow adjuvant trastuzumab based therapy. The FDA has also approved Nerlynx in combination with capecitabine for the treatment of adult patients with advanced or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting.

Nerlynx is supplied as a tablet for oral administration. The recommended dose of Nerlynx is 240 mg (six tablets) given orally once daily with food, continuously for one year. Nerlynx should be administered at approximately the same time every day. Nerlynx tablets should be swallowed whole (tablets should not be chewed, crushed, or split prior to swallowing).  If a patient misses a dose, do not replace missed dose, and instruct the patient to resume Nerlynx with the next scheduled daily dose. Please see drug label for dose modifications based on adverse reactions.

Antidiarrheal prophylaxis with loperamide is recommended during the first 2 cycles (56 days) of treatment and should be initiated with the first dose of Nerlynx. Additional antidiarrheal agents may be required to manage diarrhea in patients with loperamide refractory diarrhea.

Mechanism of Action

Nerlynx (neratinib) is a kinase inhibitor that irreversibly binds to Epidermal Growth Factor Receptor (EGFR), Human Epidermal Growth Factor Receptor 2 (HER2), and HER4. In vitro, neratinib reduces EGFR and HER2 autophosphorylation, downstream MAPK and AKT signaling pathways, and showed antitumor activity in EGFR and/or HER2 expressing carcinoma cell lines. Neratinib human metabolites M3, M6, M7 and M11 inhibited the activity of EGFR, HER2 and HER4 in vitro. In vivo, oral administration of neratinib inhibited tumor growth in mouse xenograft models with tumor cell lines expressing HER2 and EGFR. 

Side Effects

Adverse effects associated with the use of Nerlynx may include, but are not limited to, the following:

• diarrhea
• nausea
• abdominal pain
• fatigue
• vomiting
• rash
• stomatitis
• decreased appetite
• muscle spasms
• dyspepsia
• AST or ALT increase
• nail disorder
• dry skin
• abdominal distention
• weight decreased
• urinary tract infection

Clinical Trial Results

The FDA approval of Nerlynx was based on the Phase III ExteNET trial, a multicenter, randomized, double-blind, placebo-controlled trial of neratinib following adjuvant trastuzumab treatment. The trial enrolled 2,840 women with early-stage HER2-positive breast cancer and within two years of completing adjuvant trastuzumab. The subjects were randomized to receive either neratinib (n=1420) or placebo (n=1420) for one year. The results of the ExteNET trial demonstrated that after two years of follow-up, invasive disease-free survival (iDFS) was 94.2% in subjects treated with neratinib compared with 91.9% in those receiving placebo.

Nerlynx was also evaluated in the Phase III NALA trial, a randomized controlled trial of neratinib plus capecitabine in patients with HER2-positive metastatic breast cancer who have received two or more prior anti-HER2-based regimens. The trial enrolled 621 patients who were randomized (1:1) to receive neratinib 240 mg orally once daily on days 1-21 in combination with capecitabine 750 mg/m2 given orally twice daily on days 1-14 for each 21-day cycle (n=307) or lapatinib 1250 mg orally once daily on days 1-21 in combination with capecitabine 1000 mg/m2 given orally twice daily on days 1-14 for each 21-day cycle (n=314). Patients were treated until disease progression or unacceptable toxicity. Treatment with neratinib in combination with capecitabine resulted in a statistically significant improvement in progression-free survival (PFS) compared to treatment with lapatinib plus capecitabine. The PFS rate at 12 months was 29% for patients who received neratinib plus capecitabine vs 15% for patients who received lapatinib plus capecitabine; the PFS rate at 24 months was 12% vs 3%, respectively. Median OS was 21 months for patients who received neratinib in combination with capecitabine compared to 18.7 months for patients who received lapatinib in combination plus capecitabine.