What’s going on with neratinib/neratinib?

In patients with early-stage human epidermal growth factor receptor2 (HER2)-positive breast cancer, 1 year of adjuvant trastuzumab chemotherapy can significantly reduce the risk of disease recurrence and mortality. Although relapse rates are reduced and survival is prolonged after trastuzumab treatment, the clinical need to further improve treatment efficacy remains unmet due to persistent relapses. Long-term follow-up data indicate that despite the use of trastuzumab as adjuvant therapy, 23-30% of patients experience disease recurrence or death within 8-10 years. A recent trial investigating HER2-guided adjuvant therapy in a potentially low-risk population (node-negative disease, 38% of the study population versus 29-32% in trastuzumab trials) reported that 12% of patients had disease relapse or died at 8.4 years.

Extending the duration of HER2-guided adjuvant therapy with trastuzumab by one year did not improve disease-free survival. In contrast, in the phase 3 ExteNET trial, a significant disease-free survival benefit was observed in patients treated with adjuvant trastuzumab followed by the irreversible pan-HER tyrosine kinase inhibitor neratinib/neratinib for 1 year. After 2 years, invasive disease-free survival was 94.2% in the neratinib group and 91.9% in the placebo group (hazard ratio, 0.66; 95% confidence interval [CI], 0.49 -0.90; p=0.008) and 90.2% and 87.7% respectively after 5 years of follow-up (hazard ratio, 0.73; 95% confidence interval, 0.57-0.92; p=0.008). No further data on invasive disease-free survival were collected after 5 years. Based on the ExteNET study results, the U.S. Food and Drug Administration (FDA) approved neratinib as expanded adjuvant therapy in the intention-to-treat patient population, while the European Medicines Agency (EMA) approved neratinib for patients with HER2-positive, hormone receptor-positive early-stage breast cancer who initiate treatment within 1 year of completing trastuzumab-based therapy.

The safety profile of neratinib is that adverse events, mainly of a gastrointestinal nature, are usually transient, can be controlled by dose adjustment and/or conventional treatment, and do not lead to long-term morbidity. Improvements in diarrhea control with dose escalation of neratinib were described in a phase 2 controlled trial and added to the U.S. prescribing information. After a median follow-up of 8.1 years in ExteNET, 91% of patients in the neratinib arm were alive and there was no adverse effect on overall survival compared with placebo. This final analysis, in which no new safety signals were observed, further confirms the long-term safety of neratinib.

YesFinal analysis of the intention-to-treat population of the ExteNET trial showed that extended adjuvant neratinib treatment did not show an overall survival benefit compared with placebo after a median follow-up of 8 years in women with early-stage HER2-positive breast cancer. The long-term survival rates in both the neratinib and placebo groups were very high, with more than 90% of patients surviving 8 years.