Neratinib extends adjuvant treatment of patients with HER2-positive breast cancer

Abstract

THE JOURNAL OF COMMUNITY AND SUPPORTIVE ONCOLOGY e185 Volume 16/Number 4 The small-molecule tyrosine kinase inhibitor neratinib is now approved for the extended adjuvant treatment of patients with early-stage HER2 [human epidermal growth factor receptor]-positive breast cancer following postoperative trastuzumab. Trastuzumab is a HER2-targeted monoclonal antibody that has become standard of care in combination with chemotherapy for the treatment of this patient population in which it signicantly improves survival. However, disease recurrence will occur in about a quarter of trastuzumab-treated patients owing to the development of resistance. Neratinib may help overcome trastuzumab resistance thanks to its potent inhibition of the downstream phosphorylation of HER2 and other members of the HER family. Its approval was based on the phase 3 ExteNET trial, in which extended adjuvant treatment with neratinib was compared with placebo among 2,840 patients who remained disease free after 1 year of adjuvant trastuzumab.1 ‡e ExteNET trial was performed at 495 centers in Europe, Asia, Australia, New Zealand, and South America. Patients aged 18 years or older (≥20 years in Japan), with stage 1-3 HER2-positive breast cancer, who completed neoadjuvant and adjuvant trastuzumab therapy up to 1 year before randomization were eligible. Patients also had an Eastern Cooperative Oncology Group Performance Status of 0 or 1 (range, 0-5; 0, fully active, and 5, dead), normal organ function, and a left ventricular ejection fraction within normal institutional range. Patients with clinically signicant cardiac, gastrointesintal or psychiatric comorbidities and those who were not able to swallow oral medication were excluded from the study. Patients randomly received oral neratinib 240 mg per day or matching placebo, and randomization was stratied according to HR status (positive or negative), nodal status (0, 1-3, or ≥4) and trastuzumab-adjuvant regimen (sequentially or concurrently with chemotherapy). ‡e primary outcome was invasive disease-free survival (iDFS). ‡e 2-year iDFS rate was 93.9% for neratinib, compared with 91.6% for placebo (hazard ratio [HR], 0.66; P < .008). Recently, a 5-year analysis of the ExteNET trial showed that after a median follow-up of 5.2 years, the iDFS rates were 90.2% vs 87.7% (HR, 0.73; P = .0083).2 Adverse events ‡e most common adverse event (AE) was diarrhea, in 95% of patients, 40% of whom had grade 3 diarrhea, leading to dose reduction in 26% of patients and discontinuation in 16.8% of patients. Serious AEs occurred in 7% of patients in the neratinib and 6% of those in the placebo arms. In the 5-year analysis, there was no evidence of increased risk of long-term toxicity or adverse consequences of neratinibassociated diarrhea. Furthermore, the ongoing, open-label phase 2 CONTROL trial suggests that the occurrence and severity of neratinib-associated diarrhea can be e£ectively controlled with antidiarrheal prophylaxis, with drugs such as loperamide.3 At the January 2017 cut-o£, 137 patients treated with Neratinib extends adjuvant treatment of patients with HER2-positive breast cancer