Six versus 12 months' adjuvant trastuzumab in patients with HER2-positive early breast cancer: the PERSEPHONE non-inferiority RCT

Abstract

Background: The addition of adjuvant trastuzumab to chemotherapy has significantly improved outcomes for people with human epidermal growth factor receptor 2 (HER2)-positive, early, potentially curable breast cancer. Twelve months' trastuzumab, tested in registration trials, was adopted as standard adjuvant treatment in 2006. Subsequently, similar outcomes were demonstrated using 9 weeks of trastuzumab. Shorter durations were therefore tested for non-inferiority.

Objectives: To establish whether or not 6 months' adjuvant trastuzumab is non-inferior to 12 months' in the treatment of HER2-positive early breast cancer using a primary end point of 4-year disease-free survival.

Design: This was a Phase III randomised controlled non-inferiority trial.

Setting: The setting was 152 NHS hospitals.

Participants: A total of 4088 patients with HER2-positive early breast cancer who it was planned would receive both chemotherapy and trastuzumab took part.

Intervention: Randomisation (1 : 1) to 6 months' or 12 months' trastuzumab treatment.

Main outcomes: The primary end point was disease-free survival. The secondary end points were overall survival, cost-effectiveness and cardiac function during treatment with trastuzumab. Assuming a 4-year disease-free survival rate of 80% with 12 months' trastuzumab, 4000 patients were required to demonstrate non-inferiority of 6 months' trastuzumab (5% one-sided significance, 85% power), defining the non-inferiority limit as no worse than 3% below the standard arm. Costs and quality-adjusted life-years were estimated using a within-trial analysis and a lifetime decision-analytic model.

Results: Between 4 October 2007 and 31 July 2015, 2045 patients were randomised to 12 months' trastuzumab and 2043 were randomised to 6 months' trastuzumab. Sixty-nine per cent of patients had ER-positive disease; 90% received anthracyclines (49% with taxanes; 41% without taxanes); 10% received taxanes without anthracyclines; 54% received trastuzumab sequentially after chemotherapy; and 85% received adjuvant chemotherapy (58% were node negative). At 6.1 years' median follow-up, with 389 (10%) deaths and 566 (14%) disease-free survival events, the 4-year disease-free survival rates for the 4088 patients were 89.5% (95% confidence interval 88.1% to 90.8%) in the 6-month group and 90.3% (95% confidence interval 88.9% to 91.5%) in the 12-month group (hazard ratio 1.10, 90% confidence interval 0.96 to 1.26; non-inferiority p = 0.01), demonstrating non-inferiority of 6 months' trastuzumab. Congruent results were found for overall survival (non-inferiority p = 0.0003) and landmark analyses 6 months from starting trastuzumab [non-inferiority p = 0.03 (disease-free-survival) and p = 0.006 (overall survival)]. Six months' trastuzumab resulted in fewer patients reporting adverse events of severe grade [365/1929 (19%) vs. 460/1935 (24%) for 12-month patients; p = 0.0003] or stopping early because of cardiotoxicity [61/1977 (3%) vs. 146/1941 (8%) for 12-month patients; p < 0.0001]. Health economic analysis showed that 6 months' trastuzumab resulted in significantly lower lifetime costs than and similar lifetime quality-adjusted life-years to 12 months' trastuzumab, and thus there is a high probability that 6 months' trastuzumab is cost-effective compared with 12 months' trastuzumab. Patient-reported experiences in the trial highlighted fatigue and aches and pains most frequently.

Limitations: The type of chemotherapy and timing of trastuzumab changed during the recruitment phase of the study as standard practice altered.

Conclusions: PERSEPHONE demonstrated that, in the treatment of HER2-positive early breast cancer, 6 months' adjuvant trastuzumab is non-inferior to 12 months'. Six months' treatment resulted in significantly less cardiac toxicity and fewer severe adverse events.

Future work: Ongoing translational work investigates patient and tumour genetic determinants of toxicity, and trastuzumab efficacy. An individual patient data meta-analysis with PHARE and other trastuzumab duration trials is planned.

Trial registration: Current Controlled Trials ISRCTN52968807, EudraCT 2006-007018-39 and ClinicalTrials.gov NCT00712140.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 40. See the NIHR Journals Library website for further project information.

Keywords: ADJUVANT AND NEOADJUVANT THERAPY; DISEASE-FREE SURVIVAL; EARLY BREAST CANCER; HER2-POSITIVE; TRASTUZUMAB DURATION.

Conflict of interest statement

Helena Earl reports grants from Roche (Basel, Switzerland) and Sanofi-Aventis (Paris, France), personal fees and travel expenses from Daiichi Sankyo (Tokyo, Japan), AstraZeneca plc (Cambridge, UK) and Intas Pharmaceuticals (Ahmedabad, India), travel expenses from Pfizer Inc. (New York, NY, USA) and Amgen Inc. (Thousand Oaks, CA, USA) and personal fees from prIME Oncology (Atlanta, GA, USA), all outside the submitted work. Karen McAdam reports grants from Roche and personal fees from Roche, Novartis International AG (Basel, Switzerland), Pfizer and Eisai Co., Ltd (Tokyo, Japan), all outside the submitted work. Daniel Rea reports personal fees and grants from Roche during the conduct of the study, as well as personal fees from Novartis, Pfizer, Genomic Health (Redwood City, CA, USA) and Daiichi Sankyo, and grants from Celgene Corporation (Summit, NJ, USA), all outside the submitted work. Chris Plummer reports personal fees and non-financial support from Roche Products Limited, Novartis UK Limited, Pfizer UK Limited, Celgene and Incyte Corporation (Wilmington, DE, USA) for attending education meetings. He also reports personal fees and non-financial support from Amgen Limited for attending education meetings and advisory boards, all outside the submitted work. Jean Abraham reports fees to her institution, and accommodation and travel expenses from AstraZeneca for session boards and advisory chairs, as well as fees to her institution, and accommodation and travel expenses from Pfizer for a lecture, all outside the submitted work. Carlos Caldas reports grants from Genentech, Inc. (South San Francisco, CA, USA), Roche, Servier Laboratories (Suresnes, France) and AstraZeneca outside the submitted work, and that he is a member of the AstraZeneca iMED External Science Panel. Peter Hall reports grants from Roche, Pfizer, AstraZeneca, Novartis, Eisai and Daiichi Sankyo outside the submitted work. Christopher McCabe’s institution holds research contracts with Roche and reports grants from Roche, all outside the submitted work. David Miles reports personal fees from Roche/Genetech, outside the submitted work. Claire Hulme reports that she is a member of the National Institute for Health Research (NIHR) Health Technology Assessment Commissioning Board. Andrew M Wardley reports personal fees from Roche, Napp Pharmaceuticals Ltd (Cambridge, UK), Amgen, Merck Sharp & Dohme (Hoddesdon, UK), Novartis, Pfizer, AstraZeneca, Laboratoires Pierre Fabre (Paris, France), Accord (Barnstaple, UK), Athenex (Buffalo, NY, USA), Gerson Lehrman Group (New York, NY, USA), Coleman Research Expert Network Group (New York, NY, USA) and Guidepoint Global (New York, NY, USA). He also reports personal fees and other from Eli Lilly and Company (Indianapolis, IN, USA) and Daiichi Sankyo, all outside the submitted work. He is leading the National Cancer Research Institute Breast Group Initiative to develop the next de-escalation trial for HER2-positive breast cancer. David A Cameron reports funds to his institution from Novartis, Astrazeneca, Pfizer, Roche, Eli Lilly and Company, Puma Biotechnology (Los Angeles, CA, USA), Daiichi Sankyo, Synthon (Nijmegen, the Netherlands), SeaGen International GmbH (Zug, Switzerland), Zymeworks (Vancouver, BC, Canada), Elsevier (Amsterdam, the Netherlands), European Cancer Organisation (Brussels, Belgium), Celgene Corporation, Succinct Medical Communications (Wilmington, DE, USA), Immutep (Sydney, NSW, Australia), Oncolytics Biotech (U.S) Inc. (San Diego, CA, USA), Celldex Therapeutics Inc. (Hampton, NJ, USA), San Antonio Breast Cancer Consortium (TX, USA), Highfield Communication (Oxford, UK), Samsung Bioepis Co. Ltd (Incheon, South Korea), prIME Oncology, Merck Sharp & Dohme Ltd, Prima Biomed Ltd, RTI Health Solutions (Research Triangle, NC, USA) and Eisai, all outside the submitted work. Janet A Dunn reports that she is a member of the NIHR Efficacy and Mechanism Evaluation funding board and an NIHR senior investigator.