Neratinib Improved 5-Year DFS in HER2-Positive Breast Cancer

A 5-year follow-up analysis showed that 1 year of extended adjuvant therapy with neratinib, given after chemotherapy and trastuzumab, can significantly improve rates of clinically relevant relapses in women with HER2-positive breast cancer.

“Despite the proven benefits of trastuzumab in the adjuvant setting, data from long-term follow-up show that 15% to 24% of patients’ breast cancers recur after a median of 8–11 years,” wrote study authors led by Miguel Martin, MD, PhD, of Universidad Complutense in Madrid. The ExteNET trial previously found that neratinib, a pan-HER tyrosine kinase inhibitor, can improve invasive disease-free survival (DFS) at a 2-year follow-up; results that led to US Food and Drug Administration approval of neratinib as extended adjuvant treatment in early-stage HER2-positive breast cancer following adjuvant trastuzumab-based therapy. The new analysis extends that follow-up period to 5 years.

The randomized, double-blind, phase III trial included 2,840 women with early HER2-positive breast cancer, divided evenly between a neratinib group and a placebo group. The study was conducted in 40 countries, and the median follow-up for the new analysis was 5.2 years; results were published online ahead of print in Lancet Oncology.

There were 116 invasive disease-free survival events in the neratinib group, compared with 163 such events in the placebo group, for a hazard ratio of 0.73 (95% CI, 0.57–0.92; P = .0083). The 5-year invasive DFS rate was 90.2% with the study drug and 87.7% without it.

There were also reductions in distant recurrence and local or regional recurrences with neratinib. There were 91 distant recurrences with neratinib (6.4%) compared with 111 with placebo (7.8%), and 12 local or regional recurrences with the study drug (0.8%) compared with 35 with placebo (2.5%). Overall survival data was not yet mature, with a total of 121 deaths in the study due to disease progression (102 patients) or other reasons (19 patients).

The primary safety analysis was reported at the 2-year follow-up; the most common adverse events with neratinib included diarrhea, vomiting, and nausea. The authors noted that the extended analysis yielded no suggestion of increased long-term toxicity, in particular with regard to cardiac toxicity or secondary malignancies.

“The 5-year analysis showed that the superior efficacy of neratinib, compared with placebo, was maintained every year after randomization, with a significant reduction in the risk of an invasive DFS event after 5 years of follow-up,” the authors concluded, adding that subgroup analyses suggest a greater benefit in patients with hormone receptor–positive disease. The overall survival analysis will be conducted after 248 deaths have occurred.