Time to deterioration of patient-reported outcomes as a surrogate of overall survival: a meta-analysis

Background Overall survival is the optimal marker of treatment efficacy in randomized clinical trials (RCTs) but can take considerable time to mature. Progression-free survival (PFS) has served as an early surrogate of overall survival but is imperfect. Time to deterioration in quality of life (QOL) measures could be a surrogate for overall survival.Methods Phase 3 RCTs in solid malignancies that reported overall survival, PFS, and time to deterioration in QOL or physical function published between January 1, 2010, and June 30, 2022, were evaluated. Weighted regression analysis was used to assess the relationship between PFS, time to deterioration in QOL, and time to deterioration in physical function with overall survival. The coefficient of determination (R2) was used to quantify surrogacy.Results In total, 138 phase 3 RCTs were included. Of these, 47 trials evaluated immune checkpoint inhibitors and 91 investigated non-immune checkpoint inhibitor agents. Time to deterioration in QOL (137 RCTs) and time to deterioration in physical function (75 RCTs) performed similarly to PFS as surrogates for overall survival (R2 = 0.18 vs R2 = 0.19 and R2 = 0.10 vs R2 = 0.09, respectively). For immune checkpoint inhibitor studies, time to deterioration in physical function had a higher association with overall survival than with PFS (R2 = 0.38 vs R2 = 0.19), and PFS and time to deterioration in physical function did not correlate with each other (R2 = 0). When time to deterioration in physical function and PFS are used together, the coefficient of determination increased (R2 = 0.57).Conclusions Time to deterioration in physical function appears to be an overall survival surrogate measure of particular importance for immune checkpoint inhibitor treatment efficacy. The combination of time to deterioration in physical function with PFS may enable better prediction of overall survival treatment benefit in RCTs of immune checkpoint inhibitors than either PFS or time to deterioration in physical function alone.