R. Separovic (Zagreb, Croatia)
University Hospital for Tumors, Sestre milosrdnice University Hospital CenterAuthor Of 1 Presentation
- A. Chan (Nedlands, Australia)
- B. Moy (Boston, MA, United States of America)
- J. Mansi (London, United Kingdom)
- M. Gnant (Vienna, Austria)
- C. Barrios (Porto Alegre, Brazil)
- R. Separovic (Zagreb, Croatia)
- A. Guerrero-Zotano (Valencia, Spain)
- I. Gore (Birmingham, AL, United States of America)
- J. Smith (Portland, OR, United States of America)
- R. Bryce (Los Angeles, CA, United States of America)
- F. Xu (Los Angeles, CA, United States of America)
- A. Wong (Los Angeles, CA, United States of America)
- M. Martin (Madrid, Spain)
- F. Holmes (Houston, TX, United States of America)
45P - Long-term Efficacy of Neratinib in HER2-Positive Early-Stage Breast Cancer: Overall Survival and Central Nervous System Outcomes from the Phase 3 ExteNET Trial
Abstract
Background
Neratinib (Nerlynx®) is an irreversible pan-HER inhibitor that significantly improves invasive disease-free survival (iDFS) vs placebo as extended adjuvant therapy in HER2-positive (HER2+) early-stage breast cancer (eBC) after trastuzumab-based therapy. The phase III ExteNET trial (NCT00878709) showed an absolute iDFS benefit of 2.5% and distant disease-free survival benefit of 1.7% with neratinib after 5 years’ follow-up. The brain is a common first site of metastasis after HER2-directed adjuvant therapy for eBC. To date, no HER2-directed therapies have prevented central nervous system (CNS) metastases in this setting.
Methods
Women with HER2+ eBC who had completed adjuvant therapy (± neoadjuvant therapy) with trastuzumab + chemotherapy were randomized to oral neratinib 240 mg/d or placebo for 1y. OS was analyzed after 248 events (powered for the ITT population). CNS outcomes: cumulative incidence of CNS recurrences (time from randomization to CNS recurrence as first distant recurrence); CNS disease-free survival (CNS-DFS, time from randomization to any CNS recurrence or death from any cause). Cut-off dates: 5y (Mar 2017); OS (Jul 2019).
Results
2840 patients were randomized (1420 per group). After a median follow-up of 8.1y, 8y OS rates were 90.1% (95% CI 88.3‒91.6) for neratinib and 90.2% (95% CI 88.4‒91.7) for placebo (absolute difference –0.1%; stratified HR=0.95; 95% CI 0.75‒1.21; p=0.6914). At 5y, cumulative incidence of CNS recurrences was 1.3% (95% CI 0.8–2.1) with neratinib and 1.8% (95% CI 1.2–2.7) with placebo, and CNS-DFS rates were 97.5% (95% CI 96.4–98.3) and 96.4% (95% CI 95.2–97.4), respectively (HR=0.73; 95% CI 0.45–1.17). No new safety signals were reported.
Conclusions
There were fewer deaths with neratinib than placebo in ExteNET, but the results did not reach statistical significance. Long-term CNS outcomes at 5y were also improved with neratinib. Neratinib is the first HER2-directed agent to show a trend towards improved CNS outcomes in HER2+ eBC, providing further support for current NCCN guidelines that recommend neratinib-based therapy for brain metastases from HER2-positive breast cancer.
Clinical trial identification
NCT00878709.
Editorial acknowledgement
Lee Miller, Miller Medical Communications Ltd.
Legal entity responsible for the study
Puma Biotechnology Inc.
Funding
Puma Biotechnology Inc.
Disclosure
B. Moy, I. Gore: Research grant/Funding (institution): Puma Biotechnology Inc. R.P. Bryce, F. Xu, A. Wong: Shareholder/Stockholder/Stock options, Full/Part-time employment: Puma Biotechnology Inc. F.A. Holmes: Travel/Accommodation/Expenses: Puma Biotechnology Inc. All other authors have declared no conflicts of interest.