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.