In an analysis from the phase III ExteNET trial reported in Clinical Breast Cancer, Arlene Chan, MD, and colleagues found significant improvements in efficacy outcomes with the administration of neratinib vs placebo starting at 1 year or sooner after neoadjuvant/adjuvant trastuzumab-based therapy in patients with hormone receptor (HR)-positive, HER2-positive early breast cancer.

Arlene Chan, MD

Study Details

In the double-blind trial, 2,840 HER2-positive patients were randomly assigned to receive oral neratinib at 240 mg once daily (n = 1,420) or placebo (n = 1,420) for 1 year or until disease recurrence, new breast cancer, or intolerable toxicity. Random assignment was stratified by HR status. In total, 816 patients (57%) and 815 patients (57%) had HR-positive disease.

At the primary analysis at 2 years, neratinib was associated with significant improvement in invasive disease-free survival (primary endpoint) in HR-positive patients, with a hazard ratio (HR) of 0.66 (P = .008). The benefit of neratinib was confirmed at 5-year analysis (HR = 0.73, P = .008).

The current analysis assessed efficacy outcomes in HR-positive patients who initiated neratinib or placebo at ≤ 1 year (n = 670 for neratinib, n = 664 for placebo) and invasive disease–free survival outcomes in patients initiating treatment at > 1 year (n = 146 for neratinib, n = 151 for placebo) after trastuzumab therapy. In the HR-positive/≤ 1-year population, the median time from last dose of trastuzumab to random assignment was 3.1 months.

Invasive Disease–Free Survival

At 2 years, invasive disease–free survival rates were 95.3% with neratinib vs 90.8% with placebo in the HR-positive/≤ 1-year population (absolute benefit = 4.5%; HR = 0.49, 95% confidence interval [CI] = 0.30–0.78; P = .002). In the HR-positive/> 1-year population, 2-year rates were 97.4% vs 94.4% (absolute benefit = 3.0%; HR = 0.43, 95% CI = 0.09–1.47; P = .194).

At 5 years, invasive disease–free survival rates were 90.8% vs 85.7% in the HR-positive/≤ 1-year population (absolute benefit = 5.1%; HR = 0.58, 95% CI = 0.41–0.82; P = .002). In the HR-positive/> 1-year population, rates were 93.0% vs 91.7% (absolute benefit = 1.3%; HR = 0.74, 95% CI = 0.29–1.84; P = .523).

The reduction in invasive disease with neratinib was primarily due to reduction in distant disease. At 5 years, distant disease–free survival was 92.4% vs 87.7% in the HR-positive/≤ 1-year population (absolute benefit = 4.7%; HR = 0.57, 95% CI = 0.39–0.83; P = .003). These findings supported the results from the primary 2-year analysis (absolute difference = 3.2%; HR = 0.53, 95% CI = 0.31–0.88; P = .015).

In the HR-positive/≤ 1-year population, the cumulative incidence of first central nervous system (CNS) recurrence at 5 years was 0.7% in the neratinib group vs 2.1% in the placebo group. At 5 years, 98.4% vs 95.7% of patients were alive without a CNS recurrence (HR for CNS-disease-free survival = 0.41, 95% CI = 0.18–0.85).

Overall Survival

In an overall survival analysis after median follow-up of 8.0 years (range = 0–9.8 years), death had occurred in 53 (7.9%) of 670 patients in the neratinib group and 68 (10.2%) of 664 in the placebo group in the HR-positive/≤ 1-year population. Estimated 8-year rates were 91.5% vs 89.4% (absolute difference = 2.1%; HR = 0.79, 95% CI = 0.55–1.13; P = .203).

Outcomes in Patients Receiving Neoadjuvant Therapy

Of 354 patients (27%) in the HR-positive/≤ 1-year population who received neoadjuvant therapy, 295 (83%) did not have pathologic complete response, 38 (11%) achieved pathologic complete response, and 21 (6%) patients had no outcome reported.

In patients who did not achieve pathologic complete response, numerical benefits were observed with neratinib in 5-year invasive disease–free survival (absolute benefit = 7.4%; HR = 0.60, 95% CI = 0.33–1.07; P = .086) and 5-year distant disease–free survival (absolute benefit = 7.0%; HR = 0.61, 95% CI=  0.32–1.11; P = .112); a significant benefit was also observed in 8-year overall survival (absolute benefit = 9.1%; HR = 0.47, 95% CI = 0.23–0.92; P = .031).

Among the patients who achieved pathologic complete response, the absolute 5-year invasive disease–free survival benefit was 9.8% (HR = 0.44, 95% CI = 0.06–1.89) and the absolute 8-year overall survival benefit was 19.6% (HR = 0.40, 95% CI = 0.06–1.88).

The investigators concluded: “Neratinib significantly improved invasive disease-free survival in the HER2-positive/[HR-positive]/≤ 1-year population, and a similar trend was observed in patients with residual disease following neoadjuvant treatment. Numerical improvements in CNS events and overall survival were consistent with invasive disease–free survival benefits and suggest long-term benefit for neratinib in this population.”

Dr. Chan, of the Breast Cancer Research Centre-WA & Curtin University, Perth, Australia, is the corresponding author for the Clinical Breast Cancer article.

Disclosure: The study was supported by Puma Biotechnology Inc. For full disclosures of the study authors, visit clinical-breast-cancer.com.