CHICAGO—Patients with HER2-positive early-stage breast cancer who received 12 months of neratinib following adjuvant chemotherapy and trastuzumab had improved invasive and ductal carcinoma in situ (DCIS) disease-free survival at 2 years, the phase 3 ExteNET trial concluded at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting.

“This is the first study intervention to demonstrate a significant improvement in invasive disease-free survival at 2 years,” said Arlene Chan, MB BS, MMed (Palliative Care), Breast Cancer Research Centre – WA & Curtin University in Perth, WA, Australia.

Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, has shown clinical efficacy in patients with HER2-positive metastatic breast cancer who were pretreated with trastuzumab.

Continue Reading

Among patients with HER2-positive early breast cancer, a significant proportion of patients recur with invasive disease, despite trastuzumab-containing adjuvant therapy.

Women eligible for the ExteNET trial were those with stage 1 to 3c early breast cancer who received their last dose of trastuzumab less than or equal to 2 years (later modified to stage 2–3c and less than or equal to 1 year) who had locally confirmed HER2-positive disease.

Patients were randomly assigned to oral neratinib 240 mg once daily or placebo for 12 months, stratified by estrogen receptor/progesterone receptor, nodal status, and trastuzumab schedule.

Dr. Chan said a global amendment to the study reduced follow-up to 2 years from study entry; however, a current amendment restored the original 5-year follow-up.

Invasive disease-free survival at 2 years was the primary end point. Secondary end points included DCIS and distant disease-free survival, CNS incidence, and patient-reported outcomes.

Between July 2009 and October 2011, the study investigators randomly assigned 2,821 patients to either neratinib (1,409 patients) or placebo (1,412 patients). Median time from last dose of trastuzumab was 4.4 months in the neratinib arm and 4.7 months in the placebo arm. Baseline characteristics were balanced between arms.

At 2 years, the invasive disease-free survival rate was 93.9% in the neratinib arm and 91.6% in the placebo arm (HR=0.67; 95% CI: 0.50, 0.91; P=0.0009).

The disease-free survival rate was 93.9% compared with 91.0%, respectively (HR=0.63; 95% CI: 0.46, 0.84; P=0.002), and the distant disease-free survival rate was 95.1% compared with 93.7%, respectively (HR=0.75; 95% CI: 0.53, 1.05; one-sided stratified log-rank P=0.0447).

Preplanned subset analyses showed a lower invasive disease-free survival hazard ratio (HR) in estrogen receptor/progesterone receptor-positive patients (1,631 patients; HR=0.51 [0.33–0.77]; P=0.001) and in a centrally confirmed HER2-positive cohort (HR=0.51 [0.33–0.77]; P=0.002).

RELATED: Palbociclib, Fulvestrant Improves Progression-Free Survival in HR+, HER2- Breast Cancer

The most common adverse event (AE) in the neratinib arm was diarrhea; 40% had grade 3 diarrhea and 1 patient had grade 4; however, it primarily occurred within the first 30 days of treatment and was manageable. Dr. Chan recommended intensive prophylaxis with loperamide to reduce the incidence of diarrhea.

Other individual AEs grade 3 or higher occurred in less than 4% of patients in the neratinib arm. Ejection fraction decrease grade 2 or higher was observed in 1.3% of patients in the neratinib arm and 1.1% in the placebo arm.

Mean relative dose intensity was 88% in neratinib-treated patients compared with 98% among those who received placebo.

Additional follow-up will allow assessment of 5-year invasive disease-free and overall survival.


  1. Chan A, Delaloge S, Holmes FA, et al. Neratinib after adjuvant chemotherapy and trastuzumab in HER2-positive early breast cancer: Primary analysis at 2 years of a phase 3, randomized, placebo-controlled trial (ExteNET). J Clin Oncol. 2015;33:(suppl; abstr 508).