Neratinib for Breast Cancer

Neratinib is a new tyrosine kinase inhibitor for the treatment of breast cancer. It is indicated as extended adjuvant treatment of early-stage human epidermal growth factor receptor (HER) 2 -positive disease. Initiation is recommended to occur within 12 months of completing trastuzumab therapy.

Tyrosine kinases are important proteins involved in cellular signalling and have a range of biological actions. Members of the HER family of tyrosine kinases promote tumour cell proliferation and survival. Neratinib is known as a pan-HER inhibitor as it has activity at HER1, HER2, and HER4 receptors. Inhibition of these receptors prevents activation of the signal transduction pathway, leading to apoptosis and reduced cellular proliferation. Unlike other tyrosine kinase inhibitors, such as lapatinib, neratinib binds to its target irreversibly.

Diarrhoea is a very common adverse effect, reported in 93.6% of patients. It is recommended that anti-diarrhoeal prophylaxis be initiated with the first dose and continue during the first two months of treatment. Neratinib dose adjustment may be required with permanent discontinuation recommended in severe cases.

Neratinib has a number of clinically important drug interactions. As it is primarily metabolised via cytochrome P450 3A4, exposure can be significantly affected by inducers or inhibitors of this hepatic enzyme. It is contraindicated with strong inducers (e.g. carbamazepine, phenytoin, St John’s wort, and rifampicin) and moderate inhibitors (e.g. fluconazole, diltiazem, verapamil, and erythromycin). Drugs that alter the pH of the upper gastrointestinal tract may also affect therapy as neratinib requires an acidic environment for absorption.