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).

Breast Cancer—HER2/ER
Session Type and Session Title: 
Oral Abstract Session, Breast Cancer—HER2/ER
Abstract Number: 


J Clin Oncol 33, 2015 (suppl; abstr 508)
Arlene Chan, Suzette Delaloge, Frankie Ann Holmes, Beverly Moy, Hiroji Iwata, Vernon J. Harvey, Nicholas J. Robert, Tajana Silovski, Erhan Gokmen, Gunter Von Minckwitz, Bent Ejlertsen, Stephen K. L. Chia, Janine Mansi, Carlos H. Barrios, Michael Gnant, Alvin Wong, Richard Bryce, Bin Yao, Miguel Martin; Breast Cancer Research Centre - WA & Curtin University, Perth, WA, Australia; Institut Gustave Roussy, Villejuif, France; Texas Oncology, P.A., Houston, TX; Massachusetts General Hospital, Boston, MA; Aichi Cancer Center, Chikusa-Ku Nagoya, Japan; Auckland Hospital, Auckland, New Zealand; Virginia Cancer Specialists, The US Oncology Network, Fairfax, VA; University Hospital For Tumors, UHC "Sestre milosrdnice", Zagreb, Croatia; Ege University Faculty of Medicine, Division of Medical Oncology, Izmir, Turkey; Luisenkrankenhaus, GBG Forschungs GmbH, Düsseldorf, Neu-Isenburg, Germany; Rigshospitalet, Copenhagen, Denmark; BC Cancer Agency, Vancouver, BC, Canada; Guy's Hospital, London, United Kingdom; PUCRS School of Medicine, Porto Alegre, Brazil; Medical University of Vienna, Vienna, Austria; Puma Biotechnology Inc, Los Angeles, CA; Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense de Madrid, Madrid, Spain

Abstract Disclosures


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, %
(95% CI)
P-value (1-sided)
log rank
IDFS93.991.60.67 (0.50–0.91)0.0046
DFS-DCIS93.991.00.63 (0.46–0.84)0.0009
DDFS95.193.70.75 (0.53–1.05)0.0447