6 versus 12 months of adjuvant trastuzumab in patients with HER2 positive breast cancer (PERSEPHONE): definitive 4-year disease-free survival results of an open label randomised phase 3 non-inferiority trial.

Abstract

Summary Background: Adjuvant trastuzumab significantly improves outcomes in human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (EBC). The standard duration is 12 months but shorter treatment could provide similar efficacy whilst reducing toxicities and cost. Methods: We randomly assigned patients with HER2 positive EBC to receive either 6-months or 12-months trastuzumab, in a phase 3 non-inferiority trial. Assuming a 4-year disease-free-survival (DFS) rate of 80% for the 12-month arm, 4000 patients were required to assess the non-inferiority of 6-months (5% 1-sided significance, 85% power), defining non-inferiority as no worse than 3% below the standard arm. A pre-planned, event-driven DFS analysis required 500 events. This trial is registered with EudraCT (2006-007018-39), ISRCTN (52968807), and ClinicalTrials.gov (NCT00712140). Findings: Between 4th October 2007 and 31st July 2015, 2045 patients were randomised to 12-months trastuzumab and 2043 to 6-months. 69% had ER-positive disease; all patients received chemotherapy (85% as adjuvant treatment); 90% received anthracyclines (48% with taxanes) and 10% taxane-only combinations; 53% had trastuzumab sequentially after chemotherapy. At 5·4 years median follow-up with 335 (8%) deaths, and 512 (13%) DFS events, 4-year DFS rates were 89·4% (95%CI, 87·9-90·7) in the 6-month group and 89·8% (95%CI 88·3-91·1) in the 12-month group (Hazard Ratio 1·07; 90%CI 0·93–1·24, non-inferiority p=0·01), demonstrating non-inferiority of 6-months trastuzumab. Congruent results were found for overall survival (OS) (non-inferiority p=0·001), and landmark analyses 6 months from starting trastuzumab (non-inferiority p=0·02 (DFS) and p=0·02 (OS)). 6-months trastuzumab resulted in fewer patients reporting severe adverse events (373/1939 (19%) versus 459/1894 (24%) 12-month patients, p=0·0002) or stopping early because of cardiotoxicity (61/1939 (3%) versus 146/1894 (8%) 12-month patients, p<0·0001). Interpretation: We have demonstrated 6-months trastuzumab is non-inferior to 12-months in HER2-positive EBC, with less cardiotoxicity and fewer severe adverse events. Funding: National Institute for Health Research, Health Technology Assessment Programme (grant number 06/303/98).