Abstract / Summary
The objective of this systematic review and meta-analysis was to evaluate the validity of progression-free survival (PFS) and the objective response rate (ORR) as surrogate end points for overall survival (OS) in randomized controlled trials (RCTs) of metastatic renal cell carcinoma. The MEDLINE, Embase, and Cochrane CENTRAL databases were searched from inception to June 10, 2025. Associations between treatment effects on OS, PFS, and ORR were assessed using Pearson correlation coefficients (r). Surrogate threshold effect (STE) analyses determined the minimum PFS hazard ratio (HR) or ORR odds ratio (OR) required to predict OS benefit. Subgroup analyses were conducted by treatment class, line of therapy, and histology. Sixty-two randomized controlled trials comprising 24,518 patients were included. PFS-OS demonstrated a moderate correlation (r = 0.52; 95% confidence interval [CI], 0.38-0.66), with an STE (HR, 0.92; 95% CI, 0.79-1.09). ORR-OS demonstrated a moderate correlation (r = -0.59; 95% CI, -0.72, -0.45), with an STE (OR, 1.40; 95% CI, 0.99-1.89). Subgroup estimates varied across treatment settings and were frequently imprecise, particularly for ORR and in smaller treatment-class subgroups; limited representation of non-clear cell renal cell carcinoma precluded reliable histology-specific conclusions. Overall, PFS and ORR had moderate trial-level associations with OS in metastatic renal cell carcinoma, but the overall analyses did not demonstrate sufficiently consistent surrogacy to reliably predict OS benefit. These findings should be interpreted cautiously given the substantial heterogeneity of the included trials. Surrogate validity appears to be context-dependent, supporting continued reliance on OS and the need for more robust surrogate end points.