Final efficacy results of neratinib in HER2-positive hormone receptor-positive early-stage breast cancer from the phase III ExteNET trial

Structured 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 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 HER2+ eBC patients after neoadjuvant/adjuvant trastuzumab-based therapy. Patients were stratified by HR status and randomly assigned 1-year oral neratinib 240 mg/day or placebo. 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 (HR=0.58, 95% CI 0.41‒0.82) and 1.3% in HR+/>1-year (HR=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%; HR=0.79, 95% CI 0.55‒1.13). Of 354 HR+/≤1-year patients who received neoadjuvant therapy, 295 had residual disease and results showed absolute benefits of 7.4% at 5-year iDFS (HR=0.60; 95% CI 0.33‒1.07) and 9.1% at 8-year OS (HR=0.47; 95% CI 0.23–0.92). There were fewer CNS events with neratinib. Adverse events were similar to 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 CNS events and OS were consistent with iDFS benefits and suggest long-term benefit for neratinib in this population.