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PERSEPHONE: 6 versus 12 months (m) of adjuvant trastuzumab in patients (pts) with HER2 positive (+) early breast cancer (EBC): Randomised phase 3 non-inferiority trial with definitive 4-year (yr) disease-free survival (DFS) results.

Abstract

506
Background: Adjuvant trastuzumab has significantly improved outcomes for HER2+ EBC pts, using the 12m duration empirically adopted from the pivotal registration trials. A shorter duration could reduce toxicities and cost whilst providing similar efficacy. No reduced-duration trial to date has demonstrated non-inferiority. Methods: PERSEPHONE is a randomised phase 3 non-inferiority trial comparing 6 to 12m trastuzumab, the largest reduced-duration non-inferiority trial internationally. Mapping onto standard UK practice, all HER2+ EBC pts were eligible. Stratification is by ER status, chemotherapy (CT) type, and CT and trastuzumab timing. The primary endpoint is DFS from diagnosis (first relapse or death from any cause). Randomising 4000 pts (1:1) enabled the trial to assess the non-inferiority of 6m (5% 1-sided significance, 85% power), defining non-inferiority as ‘no worse than 3%’ below the 12m arm’s assumed 80% 4-yr DFS. The pre-planned definitive DFS analysis required 500 events. Results: 4089 pts were randomised from 152 UK sites (Oct’07 – Jul’15). ER+ 69%; CT - 41% anthracycline (A)-based / 49% A and taxane (T)-based / 10% T-based; adjuvant CT 85%; sequential trastuzumab 54%. At 4.9 yrs median follow-up, there were 319 (8%) deaths and 500 (12%) DFS events. With a 4-yr DFS rate of 89% (95%CI 88 – 91) in both arms, the hazard ratio (HR) non-inferiority limit was set at 1.29. The calculated HR was 1.05 (95%CI 0.88 – 1.25, 95th percentile = 1.22) demonstrating non-inferiority (HR < 1.29) of 6m trastuzumab (1-sided p = 0.01). Congruent results were found for overall survival (OS) and for the pre-planned DFS and OS landmark analyses (after 6m of trastuzumab). Heterogeneity was observed in some stratification variables. Cardiac events were reduced in 6m pts (4% v 8% of 12m pts stopping treatment due to cardiotoxicity (p < 0.0001)). Conclusions: PERSEPHONE has demonstrated 6m of trastuzumab as non-inferior to 12m (3% non-inferiority margin). Given cardiac and other toxicities during months 7-12 of treatment, our results would support a reduction of standard trastuzumab duration to 6 months. Clinical trial information: 52968807.

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Journal of Clinical Oncology
Pages: 506

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Published in print: May 20, 2018
Published online: June 01, 2018

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Helena Margaret Earl
University of Cambridge, Department of Oncology & NIHR Cambridge Biomedical Research Centre & Cambridge University Hospitals NHS Foundation Trust, Cambridge Breast Cancer Research Unit, Cambridge, United Kingdom;
Louise Hiller
Warwick Clinical Trials Unit, University of Warwick, Coventry, United Kingdom;
Anne-Laure Vallier
Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom;
Shrushma Loi
Warwick Clinical Trials Unit, University of Warwick, Coventry, United Kingdom;
Donna Howe
Warwick Clinical Trials Unit, University of Warwick, Coventry, United Kingdom;
Helen B Higgins
Warwick Clinical Trials Unit, University of Warwick, Coventry, United Kingdom;
Karen McAdam
Cambridge University Hospitals NHS Foundation Trust, Department of Oncology, Cambridge, United Kingdom;
Luke Hughes-Davies
University of Cambridge, Department of Oncology, Cambridge, United Kingdom;
Adrian Nigel Harnett
Norfolk & Norwich University Hospital, Department of Oncology, Norfolk, United Kingdom;
Mei-Lin Ah-See
Mount Vernon Cancer Centre, Medical Oncology, London, United Kingdom;
Richard Simcock
Brighton and Sussex University Hospitals NHS Trust, Sussex Cancer Centre, Brighton, United Kingdom;
Daniel William Rea
University of Birmingham, Cancer Research UK Clinical Trials Unit (CRCTU), Birmingham, United Kingdom;
Janine Mansi
Guy's and St Thomas' NHS Foundation Trust and King’s College Medical School, London, United Kingdom;
Jean Abraham
University of Cambridge, Department of Oncology & NIHR Cambridge Biomedical Research Centre & Cambridge University Hospitals NHS Foundation Trust, Cambridge Breast Cancer Research Unit, Cambridge, United Kingdom;
Carlos Caldas
Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, United Kingdom;
Claire Hulme
University of Leeds, Academic Unit of Health Economics, Leeds, United Kingdom;
David Miles
Mount Vernon Cancer Center, Medical Oncology, London, United Kingdom;
Andrew M. Wardley
University of Manchester, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, Manchester, United Kingdom;
David A. Cameron
University of Edinburgh, Cancer Research UK Edinburgh Centre, Edinburgh, United Kingdom;
Janet Dunn
Warwick Clinical Trials Unit, Coventry, United Kingdom;
PERSEPHONE Trial Investigators
University of Cambridge, Department of Oncology & NIHR Cambridge Biomedical Research Centre & Cambridge University Hospitals NHS Foundation Trust, Cambridge Breast Cancer Research Unit, Cambridge, United Kingdom; Warwick Clinical Trials Unit, University of Warwick, Coventry, United Kingdom; Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom; Cambridge University Hospitals NHS Foundation Trust, Department of Oncology, Cambridge, United Kingdom; University of Cambridge, Department of Oncology, Cambridge, United Kingdom; Norfolk & Norwich University Hospital, Department of Oncology, Norfolk, United Kingdom; Mount Vernon Cancer Centre, Medical Oncology, London, United Kingdom; Brighton and Sussex University Hospitals NHS Trust, Sussex Cancer Centre, Brighton, United Kingdom; University of Birmingham, Cancer Research UK Clinical Trials Unit (CRCTU), Birmingham, United Kingdom; Guy's and St Thomas' NHS Foundation Trust and King’s College Medical School, London, United Kingdom; Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, United Kingdom; University of Leeds, Academic Unit of Health Economics, Leeds, United Kingdom; Mount Vernon Cancer Center, Medical Oncology, London, United Kingdom; University of Manchester, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, Manchester, United Kingdom; University of Edinburgh, Cancer Research UK Edinburgh Centre, Edinburgh, United Kingdom; Warwick Clinical Trials Unit, Coventry, United Kingdom

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Helena Margaret Earl, Louise Hiller, Anne-Laure Vallier, Shrushma Loi, Donna Howe, Helen B Higgins, Karen McAdam, Luke Hughes-Davies, Adrian Nigel Harnett, Mei-Lin Ah-See, Richard Simcock, Daniel William Rea, Janine Mansi, Jean Abraham, Carlos Caldas, Claire Hulme, David Miles, Andrew M. Wardley, David A. Cameron, Janet Dunn, PERSEPHONE Trial Investigators
Journal of Clinical Oncology 2018 36:15_suppl, 506-506

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