S Michiels, L Pugliano, S Marguet, D Grun, J Barinoff, D Cameron, M Cobleigh, A Di Leo, S Johnston, G Gasparini, B Kaufman, M Marty, V Nekljudova, S Paluch-Shimon, F Penault-Llorca, D Slamon, C Vogel, G von Minckwitz, M Buyse, M Piccart

The gold standard endpoint in randomized clinical trials in metastatic breast cancer is overall survival. Although therapeutics have been approved based on progression-free survival, its use as a primary endpoint is controversial. We aimed to assess to what extent progression-free survival may be used as a surrogate for overall survival in randomized trials of anti-HER2 agents in HER2+ metastatic breast cancer. Eligible trials accrued HER2+ metastatic breast cancer patients in 1992-2008. A correlation approach was used: at the individual level, to estimate the association between investigator-assessed progression-free and overall survival using a bivariate model and at the trial level, to estimate the association between treatment effects on progression-free and overall survival. Correlation values close to 1.0 would indicate strong surrogacy. We identified 2545 eligible patients in 13 randomized trials testing trastuzumab or lapatinib. We collected individual patient data from 1963 patients and retained 1839 patients from 9 trials for analysis (7 first-line trials). During follow-up, 1072 deaths and 1462 progression or deaths occurred. The median survival time was 22 months (95% CI 21-23 months) and the median progression-free survival was 5.7 months (95% CI 5.5-6.1 months). At the individual level, the Spearman correlation was equal to ρ=0.67 (95% CI 0.66 to 0.67) corresponding to a squared correlation value of 0.45. At the trial level, the squared correlation between treatment effects (log hazard ratios) on progression-free and overall survival was provided by R2=0.51 (95% CI 0.22 to 0.81). In trials of HER2-targeted agents in HER2+ metastatic breast cancer, progression-free survival moderately correlates with overall survival at the individual level and treatment effects on progression-free survival correlate moderately with those on overall mortality, providing only modest support for considering progression-free survival as a surrogate. Progression-free survival does not completely substitute for overall survival in this setting.