Neratinib is an irreversible pan-human epidermal growth factor receptor (HER) inhibitor. It targets the tyrosine-kinase activity of the epidermal growth factor receptors EGFR/ HER1, HER2 and HER4. Through the inhibition of tyrosine-kinase activity, downstream signalling pathways get activated and phosphorylation is reduced. Currently, neratinib is neither approved in the US nor in Europe for any indication.

The safety and efficacy of neratinib after trastuzumab-based adjuvant treatment in patients with early stage HER2-positive breast cancer were assessed in the ExteNET trial, a randomised, multicentre, double-blind, placebo-controlled phase III study. 2,840 women were enrolled and randomly assigned in a 1:1 ratio to receive either neratinib (n=1,420; 240 mg daily) or matching placebo (n=1,420). The stratification of randomisation (permuted block randomisation) was based on the hormone receptor status, nodal status, and the type of previously received trastuzumab-based adjuvant regimen. The median follow-up of the study was 24 months (IQR 20–25) in the neratinib group and 24 months (IQR 22–25) in the placebo group. The primary outcome of the study was invasive disease-free survival (DFS). After a 24-month follow-up, significantly fewer invasive DFS events had occurred in the neratinib group compared to the placebo group (70 vs. 109 events). The two-year invasive DFS rate was 93.9% (95% CI 92.4–95.2) and 91.6% (95% CI 90.0–93.0) in the neratinib and placebo groups, respectively. At the time of primary analysis the secondary outcome, overall survival (OS), was immature, since the target number of OS events had not been reached. The most common treatment-emergent adverse event (AE) in the neratinib group was diarrhoea: Over 90% of the patients had diarrhoea of any grade (40% had grade 3 diarrhoea). Serious AEs occurred in 103 patients (7%) of the neratinib group and in 85 patients (6%) of the placebo group.

Currently, no cost estimates are available for neratinib neither in the US nor in Europe. However, additional costs for possible prospective biomarkers as well as increased costs due to the treatment and monitoring of possible gastrointestinal and cardiac toxicities are likely to incur. Although neratinib offers an improvement in invasive DFS, the gastrointestinal toxicities in combination with possible cardiac toxicities suggest an unfavourable benefit-risk ratio. Further studies are needed to determine the appropriate patient population, to verify the long-term benefit, and to exclude toxic effects of the cardiovascular system.