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

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. Randomization was stratified by HR status. Both groups had comparable numbers of patients with HR-positive disease (57% in both groups). Adjuvant endocrine therapy for women with HR-positive disease was recommended according to local guidelines.

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 of 0.66 (P = .008). The benefit of neratinib was confirmed at 5-year analysis (hazard ratio [HR] = 0.73, P = .008).

The current analysis assessed post hoc efficacy outcomes in HR-positive patients who initiated neratinib or placebo at ≤ 1 year (HR+/≤ 1-year group; n = 670 for neratinib, n = 664 for placebo) and invasive disease–free survival outcomes in patients initiating treatment at > 1 year (HR+/> 1-year group; n = 146 for neratinib, n = 151 for placebo) after trastuzumab therapy. In the HR+/≤ 1-year population, the median time from last dose of trastuzumab to randomization was 3.1 months. In the HR+/≤ 1-year population, 93% of patients in the neratinib group and 95% in the placebo group were receiving endocrine therapy at baseline, the most common being an antiestrogen agent alone (52% and 47%) or an aromatase inhibitor alone (44% and 48%). Results reported for the HR-positive patients who initiated treatment within a year of trastuzumab completion are of a descriptive nature.

Invasive Disease–Free and Overall Survival

At 2 years, invasive disease–free survival rates were 95.3% with neratinib vs 90.8% with placebo in the HR+/≤ 1-year population (absolute benefit = 4.5%; HR = 0.49, 95% confidence interval [CI] = 0.30–0.78, P = .002). In the HR+/> 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+/≤ 1-year population (absolute benefit = 5.1%; HR = 0.58, 95% CI = 0.41–0.82, P = .002). In the HR+/> 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+/≤ 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+/≤ 1-year population, the cumulative incidence of first central nervous system (CNS) recurrences 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).

In an overall survival analysis after median follow-up of 8.0 years (range = 0–9.8 years), death had occurred in 53 of 670 patients (7.9%) in the neratinib group and 68 of 664 (10.2%) in the placebo group in the HR+/≤ 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+/≤ 1-year population who received neoadjuvant therapy, 295 (83%) did not have pathologic complete response (pCR), 38 (11%) achieved pCR, and 21 (6%) patients had no outcome reported.

In patients who did not achieve pCR, 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), and a significant benefit was 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 pCR, 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).

Among patients who did not achieve pCR, 2 vs 10 patients had CNS recurrences and 5-year CNS disease–free survival was 98.4% vs 92.0% (HR = 0.24, 95% CI = 0.04–0.92). Among patients who achieved pCR, zero vs three patients had CNS recurrences, and 5-year CNS disease–free survival was 100% vs 81.9% (HR = 0.00, 95% CI = not estimable to 1.08).

Additional Subgroup Analyses

Hazard ratios for neratinib vs placebo among 1,079 patients with node-positive disease were 0.60 (95% CI = 0.42–0.85) for 5-year invasive disease–free survival, 0.61 (95% CI = 0.41–0.89) for 5-year distant disease–free survival, and 0.79 (95% CI = 0.53–1.16) for overall survival. Among 225 patients with node-negative disease, respective hazard ratios were 0.37 (95% CI = 0.08–1.24), 0.16 (95% CI = 0.01–0.88), and 0.82 (95% CI = 0.29–2.20). Among 980 patients who received trastuzumab-based adjuvant therapy, the respective hazard ratios were 0.65 (95% CI = 0.41–1.01), 0.68 (95% CI = 0.41–1.11), and 1.10 (95% CI = 0.69–1.77). Among 354 who received neoadjuvant therapy, the respective hazard ratios were 0.54 (95% CI = 0.31–0.90), 0.49 (95% CI = 0.26–0.86), and 0.52 (95% CI = 0.28–0.92).

The investigators concluded: “Neratinib significantly improved [invasive disease–free survival] 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 [overall survival] were consistent with [invasive disease–free survival] benefits and suggest long-term benefit for neratinib in this population.” 

DISCLOSURE: The study was supported by Puma Biotechnology Inc. Dr. Chan has received honoraria from Amgen, Eisai, and Novartis; has served as a consultant or advisor to Lilly, Pfizer, and Special Therapeutics; and has received research funding from Eisai.

REFERENCE

1. Chan A, Moy B, Mansi J, et al: Final efficacy results of neratinib in HER2-positive hormone receptor-positive early-stage breast cancer from the phase III ExteNET trial. Clin Breast Cancer. October 6, 2020 (early release online).