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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).
Background: Neratinib (N) is an irreversible pan-HER tyrosine kinase inhibitor with clinical efficacy in trastuzumab (T) pre-treated HER2-positive (HER2+) metastatic breast cancer. In HER2+ early breast cancer (EBC), a significant proportion of patients (pts) recur with invasive disease despite T-containing adjuvant therapy.Methods: Women with stage 1–3c EBC with the last T dose ≤2y (later modified to stage 2–3c and ≤1y, respectively) and locally confirmed HER2+ were eligible. Pts were randomized to N 240mg PO once daily or placebo (P) for 12m, stratified by ER/PR, nodal status and T schedule. A global amendment reduced follow-up to 2y from study entry. A current amendment restores the original 5-y follow-up. Invasive DFS (IDFS) at 2y is the primary endpoint and other secondary endpoints include DFS + DCIS, distant DFS (DDFS), CNS incidence, and patient-reported outcomes. Overall survival (OS) is an event-driven secondary endpoint. Efficacy analyses were ITT using a stratified Cox model and log-rank test (1-sided α=0.025). Results: 2,821 pts were randomized between 07/2009 and 10/2011 (1,409 N; 1,412 P). Median time from last T was 4.4m N vs 4.7m P. Baseline characteristics were balanced between arms. Efficacy results are shown below. Pre-plannedsubset analyses showed a lower IDFS HR in ER/PR+ pts (n=1,616; HR=0.51 [0.33–0.77]) and in a centrally confirmed HER2+ cohort (HR=0.52 [0.34–0.79]). Diarrhea was the most common adverse event (AE) for N pts with 40% G3 (1pt G4). Other individual AEs ≥G3 occurred in < 4% N pts. Ejection fraction decrease ≥G2 was seen in 1.3% N vs 1.1% P pts. Mean relative dose intensity (RDI) was 88% in N vs 98% in P pts. Conclusions: ExteNET demonstrates that 12m of N following standard chemotherapy + T improves IDFS and DFS-DCIS at 2y in HER2+ EBC. Diarrhea, the most common AE, was manageable. Additional follow-up will allow assessment of 5-y IDFS and OS. ClinicalTrials.gov: NCT00878709. Clinical trial information: NCT00878709
|2-y rate, %||HR|
Abstracts by Arlene Chan:
ETNA (Evaluating Treatment with Neoadjuvant Abraxane) randomized phase III study comparing neoadjuvant nab-paclitaxel (nab-P) versus paclitaxel (P) both followed by anthracycline regimens in women with HER2-negative high-risk breast cancer: A MICHELANGO study.Meeting: 2016 ASCO Annual Meeting | Abstract No: 502Category: Breast Cancer—HER2/ER - ER+
Invasive disease-free survival benefit following neratinib as extended adjuvant therapy in centrally-confirmed HER2+ early-stage breast cancer: The ExteNET phase III randomized placebo-controlled trial.Meeting: 2015 Breast Cancer Symposium | Abstract No: 117Category: Systemic Therapy - HER2+