Abstract
BACKGROUND: Event-free survival (EFS) has been listed on the FDA Table of Surrogate Endpoints as a surrogate measure that can be considered for accelerated or traditional approval in breast cancer. However, no studies have evaluated the correlation between the treatment effects on EFS and treatment effects on overall survival (OS). METHODS: We performed a systematic search of the literature until May 2020 according to the PRISMA guideline for all published randomized controlled trials (RCTs) in early breast cancer in the neoadjuvant setting. Data on EFS and OS, including the hazard ratio (HR) and 95% confidence intervals (CI), were extracted from each study and the association between the trial-level EFS HR and the trial-level OS HR was estimated using a linear mixed-effects model on the log scale. FINDINGS: Of the 7 RCTs (N = 2211) included in the analysis, 5 included patients with HER2 positive tumor type. The estimated linear association between log HR EFS and log HR OS indicated a positive slope ( β = 0.58 [95% CI: -0.32-1.48]) and the coefficient of determination confirmed a moderate trial-level association between log HRs for OS and EFS (R² 0.76 [95% CI 0.34-1.00], but with wide confidence intervals. INTERPRETATION: Treatment effects in EFS are moderately correlated with treatment effects in OS in early breast cancer in the neoadjuvant setting, but the association was not significant. Thus, there is currently insufficient evidence to support EFS for use as a surrogate endpoint for traditional approval, although it may be considered for accelerated approval. FUNDING: Arnold Ventures.