Final Efficacy Results of Neratinib in HER2-positive Hormone Receptor-positive Early-stage Breast Cancer From the Phase III ExteNET Trial

Abstract

Background: The ExteNET trial demonstrated improved invasive disease-free survival (iDFS) with neratinib, an irreversible pan-HER tyrosine kinase inhibitor, versus placebo in patients with human epidermal growth factor receptor 2-positive (HER2⁺)/hormone receptor-positive (HR⁺) early-stage breast cancer (eBC).

Patients and methods: ExteNET was a multicenter, randomized, double-blind, phase III trial of 2840 patients with HER2⁺ eBC after neoadjuvant/adjuvant trastuzumab-based therapy. Patients were stratified by HR status and randomly assigned 1-year oral neratinib 240 mg/day or placebo. The primary endpoint was iDFS. Descriptive analyses were performed in patients with HR⁺ eBC who initiated treatment ≤ 1 year (HR⁺/≤ 1-year) and > 1 year (HR⁺/> 1-year) post-trastuzumab.

Results: HR⁺/≤ 1-year and HR⁺/> 1-year populations comprised 1334 (neratinib, n = 670; placebo, n = 664) and 297 (neratinib, n = 146; placebo, n = 151) patients, respectively. Absolute iDFS benefits at 5 years were 5.1% in HR⁺/≤ 1-year (hazard ratio, 0.58; 95% confidence interval [CI], 0.41-0.82) and 1.3% in HR⁺/>1-year (hazard ratio, 0.74; 95% CI, 0.29-1.84). In HR⁺/≤ 1-year, neratinib was associated with a numerical improvement in overall survival (OS) at 8 years (absolute benefit, 2.1%; hazard ratio, 0.79; 95% CI, 0.55-1.13). Of 354 patients in the HR⁺/≤ 1-year group who received neoadjuvant therapy, 295 had residual disease, and results showed absolute benefits of 7.4% at 5-year iDFS (hazard ratio, 0.60; 95% CI, 0.33-1.07) and 9.1% at 8-year OS (hazard ratio, 0.47; 95% CI, 0.23-0.92). There were fewer central nervous system events with neratinib. Adverse events were similar to those previously reported.

Conclusion: Neratinib significantly improved iDFS in the HER2⁺/HR⁺/≤ 1-year population, and a similar trend was observed in patients with residual disease following neoadjuvant treatment. Numerical improvements in central nervous system events and OS were consistent with iDFS benefits and suggest long-term benefit for neratinib in this population.

Keywords: Adjuvant therapy; Disease-free survival; Distant disease-free survival; Neoadjuvant therapy; Overall survival.