To our knowledge, neratinib taken for 12 months is the first therapeutic intervention to significantly improve invasive disease–free survival beyond trastuzumab-based adjuvant therapy in women with HER2-positive early-stage breast cancer.— Arlene Chan, MD, and colleagues
In the phase III ExteNET trial reported in The Lancet Oncology, Arlene Chan, MD, of the Breast Cancer Research Centre-Western Australia, Perth, and colleagues found that 1 year of treatment with the HER1, HER2, and HER4 tyrosine kinase inhibitor neratinib improved invasive disease–free survival vs placebo after trastuzumab (Herceptin)-based adjuvant therapy in patients with early-stage HER2-positive breast cancer.1
In this double-blind trial, 2,840 women from 495 sites in Europe, Asia, Australia, New Zealand, and the Americas were randomized between July 2009 and October 2011 to receive oral neratinib at 240 mg/d (n = 1,420) or placebo (n = 1,420) for 12 months. Initially, the trial enrolled patients with stage I to III HER2-positive disease who had completed neoadjuvant and adjuvant trastuzumab up to 2 years previously. Inclusion criteria were amended in February 2010, to include patients with stage II to III HER2-positive disease who had completed trastuzumab therapy up to 1 year previously. Randomization was stratified by hormone receptor status, nodal status, and sequential vs concurrent adjuvant trastuzumab. The primary outcome measure was invasive disease–free survival at 2 years after randomization in the intent-to-treat analysis.
For the neratinib and placebo groups: median age was 52 years in both; race/ethnicity was white in 82% and 80% and Asian in 13% and 14%; 53% in both were postmenopausal; 24% in both were node-negative, 47% in both had one to three positive nodes, and 30% in both had at least four positive nodes; 57% in both were hormone receptor–positive; the previous trastuzumab regimen was concurrent in 62% and sequential in 38% in both; T stage was T1 in 31% and 32% and T2 in 41% and 39%; previous surgery was mastectomy in 67% and 64% and lumpectomy in 33% and 36%; previous neo/adjuvant therapy was an anthracycline plus taxane in 68%, an anthracycline only in 10%, and a taxane only in 22% in both; the median time from the last dose of trastuzumab was 4.4 and 4.6 months; and 93% and 94% received concomitant endocrine therapy for hormone receptor–positive disease.
Invasive Disease–Free Survival
Median follow-up was 24 months (interquartile range = 20–25 months) in the neratinib group and 24 months (interquartile range = 22–25 months) in the placebo group. At 2 years, 70 invasive disease–free survival events had occurred in the neratinib group vs 109 events in the placebo group (stratified hazard ratio [HR] = 0.67, P = .0091; unstratified HR = 0.68, P = .010). Invasive disease–free survival at 2 years was 93.9% (95% confidence interval [CI] = 92.4%–95.2%) vs 91.6% (95% CI = 90.0%–93.0%). Subgroup analysis indicated that the benefit of neratinib was greater in patients with hormone receptor–positive disease (HR = 0.51, P = .0013) than in those with hormone receptor–negative disease (HR = 0.93, P = .74; P = .054 for interaction).
Disease-free survival including ductal carcinoma in situ at 2 years was 93.9% vs 91.0% (HR = 0.63, P = .0017). Distant disease–free survival at 2 years was 95.1% vs 93.7% (HR = 0.75, P = .089). The cumulative incidence of central nervous system recurrence at 2 years was 0.91% vs 1.25% (P = .44).
The most common grade 3 or 4 adverse events in the neratinib group were diarrhea (grade 3 in 40% and grade 4 in < 1% vs grade 3 in 2% in the placebo group), vomiting (grade 3 in 3% vs grade 3 in < 1%), and nausea (grade 3 in 2% vs grade 3 in < 1%). Diarrhea led to dose reduction in 26% vs 1% of patients and discontinuation of treatment in 17% vs < 1%. QT prolongation occurred in 3% vs 7% of patients, and decreases in left ventricular ejection fraction of grade ≥ 2 occurred in 1% vs 1%. Serious adverse events occurred in 7% vs 6%. Death unrelated to disease progression occurred in four patients in the neratinib group and three patients in the placebo group, with none of the deaths considered to be related to study treatment.
The investigators concluded: “Neratinib for 12 months significantly improved 2-year invasive disease-free survival when given after chemotherapy and trastuzumab-based adjuvant therapy to women with HER2-positive breast cancer. Longer follow-up is needed to ensure that the improvement in breast cancer outcome is maintained…. To our knowledge, neratinib taken for 12 months is the first therapeutic intervention to significantly improve invasive disease-free survival beyond trastuzumab-based adjuvant therapy in women with HER2-positive early-stage breast cancer.” ■
Disclosure: Wyeth, Pfizer, and Puma Biotechnology funded this study. For full disclosures of the study authors, visit www.thelancet.com.
1. Chan A, Delaloge S, Holmes FA, et al: Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): A multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 17:367-377, 2016.
Neratinib is an oral anti-HER2 tyrosine kinase inhibitor that has shown promising activity in the treatment of HER2-positive metastatic breast cancer.1 It differs from monoclonal antibodies such as trastuzumab (Herceptin) because, as a small molecule, neratinib blocks the ATP binding site on the...