PFS/TTP As a Potential Surrogate for OS in HR+, HER2– MBC

Background: Several, recent randomized controlled trials (RCTs) in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) metastatic breast cancer (MBC) have demonstrated a significant improvement in progression-free survival (PFS); however, few have reported an improvement in overall survival (OS). OS may be an imperfect endpoint due to the impact of factors such as baseline characteristics and subsequent therapies. Investigation of the use of PFS or time to progression (TTP) as a surrogate for OS in HR+, HER2– MBC has been limited. This study assesses the correlation of PFS/TTP and OS in HR+, HER2– MBC across all lines of therapy. Methods: A systematic literature review of RCTs in HR+, HER2– MBC was conducted to identify studies that reported both median PFS/TTP and OS. The correlation between PFS/TTP and OS was evaluated using Pearson’s product-moment correlation and Spearman’s rank correlation. Subgroup analyses were performed to explore possible reasons for heterogeneity. Errors-in-variables weighted least squares regression (LSR) was used to model incremental OS months as a function of incremental PFS/TTP months. An exploratory analysis investigated the impact of 3 covariates (chemotherapy vs other, PFS vs TTP, and 1L vs > 1L) on the use of PFS/TTP in OS prediction. The lower 95% prediction band was used to determine the minimum incremental PFS/TTP months below which there would be no predicted OS benefit (the surrogate threshold effect [STE]). Results: A total of 39 studies were identified. There was a statistically significant correlation between median PFS/TTP and OS (Pearson=0.741, p < 0.000; Spearman=0.650, p < 0.000). Results were unchanged for chemotherapy and hormonal or targeted therapy, and for line of therapy. Initial LSR analysis yielded an R2 of 0.354; 1 PFS/TTP month corresponded to 1.13 OS months. The addition of 3 covariates improved R2 to 0.569; 1 PFS/TTP month corresponded to 0.78 OS months. The STE for OS benefit was 5–6 months of incremental PFS/TTP. Conclusions: Results of this study indicate a significant association between PFS/TTP and OS, which may justify the use of PFS/TTP as surrogate for OS benefit during regulatory approval and subsequent reimbursement of new therapies in HR+, HER2– MBC. Legal entity responsible for the study: Novartis Pharmaceuticals Corporation Funding: Novartis Pharmaceuticals Corporation Disclosure: A. Forsythe: Consultant for Novartis. D. Chandiwana, M. Thabane, J. Baeck: Novartis employee and Novartis stocks/shares. J. Barth: Novartis employee. All other authors have declared no conflicts of interest.