Neratinib Improves Invasive Disease–Free Survival After Trastuzumab-Based Therapy in HER2-Positive Breast Cancer


Key Points

  • Neratinib significantly improved invasive disease–free survival after trastuzumab-based adjuvant therapy in patients with early-stage HER2-positive breast cancer.
  • Benefit appeared to be greater in patients with hormone receptor–positive disease.

Chan et al found that 1 year of treatment with the HER1, 2, and 4 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, in the phase III ExteNET study reported in The Lancet Oncology.

Study Details

In this double-blind trial, 2,840 women from 495 sites in Europe, Asia, Australia, New Zealand, and the Americas were randomly assigned between July 2009 and October 2011 to receive oral neratinib at 240 mg/d (n = 2,840) 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 (25% in both ≥ 60 years); region was North America for 37% and 34%; Western Europe, Australia, New Zealand, and South Africa in 34% and 37%; and Asia-Pacific, eastern Europe, and South America in 29% 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; 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 anthracycline plus taxane in 68%, anthracycline only in 10%, and taxane only in 22% in both; 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 CNS recurrence at 2 years was 0.91% vs 1.25% (P = .44).

Adverse Events

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 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.”

The study was funded by Wyeth, Pfizer, and Puma Biotechnology.

Arlene Chan, MD, of the Breast Cancer Research Centre-Western Australia, Perth, is the corresponding author for The Lancet Oncology article.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.