American Clinical Society of Oncology (ASCO) 2015
ASCO 2015. Abstract 508. 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).
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
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
CARE Faculty Perspective:
- Since the introduction of adjuvant trastuzumab in combination with chemotherapy in HER2+ early stage breast cancer, this subtype has arguably gone from the worst prognosis to now being one with one of the better prognoses
- In particular, the prognosis in trastuzumab-treated node-negative HER2+ breast cancer across various trials and population-based studies approximates 95%
- 12 months of adjuvant trastuzumab is the standard of care, with 2 years not demonstrating any additional advantage (HERA trial) and 6 months not meeting a non-inferiority end-point (PHARE study)
- The ExteNET study is the first study to demonstrate an advantage of anti-HER 2 therapy beyond 1 year of trastuzumab. Though the hazard ratio (0.67) is relatively impressive, the absolute improvement in 2-year iDFS was only 2.3%
- The toxicity profile of neratinib, with a reported rate up to 40% of grade 3-4 diarrhea, is significant. Recent studies with aggressive loperamide prophylaxis have demonstrated a reduction in the rate of grade 3-4 diarrhea.
- We will need to wait for more mature data, and hopefully for an overall survival benefit prior to routine clinical consideration. Furthermore the intriguing data suggesting a differential benefit of neratinib primarily in the ER+ subset would suggest a cohort that may derive greater benefit and to whom to preferentially consider neratinib therapy.
- We also eagerly await the translational substudy in attempts to identify predictive biomarker(s) to further select and enrich the benefit of extended anti-HER 2 therapy with neratinib.
- CARE Oncology Faculty