The validity of progression‐free survival 2 as a surrogate trial end point for overall survival.

Background: Overall survival (OS) is the gold‐standard end point for oncology trials. However, the availability of multiple therapeutic options after progression and crossover to receive investigational agents confound and delay OS data maturation. Progression‐free survival 2 (PFS‐2), defined as the time from randomization to progression on first subsequent therapy, has been proposed as a surrogate for OS. Using a meta‐analytic approach, the authors aimed to assess the association between OS and PFS‐2 and compare this with progression‐free survival 1 (PFS‐1) and the objective response rate (ORR). Methods: An electronic literature search was performed to identify randomized trials of systemic therapies in advanced solid tumors that reported PFS‐2 as a prespecified end point. Correlations between OS and PFS‐2, OS and PFS‐1, and OS and ORR as hazard ratios (HRs) or odds ratios (ORs) were assessed via linear regression weighted by trial size. Results: Thirty‐eight trials were included, and they comprised 19,031 patients across 8 tumor types. PFS‐2 displayed a moderate correlation with OS (r = 0.67; 95% confidence interval [CI], 0.08‐0.69). Conversely, correlations of ORR (r = 0.12; 95% CI, 0.00‐0.13) and PFS‐1 (r = 0.21; 95% CI, 0.00‐0.33) were poor. The findings for PFS‐2 were consistent for subgroup analyses by treatment type (immunotherapy vs nonimmunotherapy: r = 0.67 vs 0.67), survival post progression (<12 vs ≥12 months: r = 0.86 vs 0.79), and percentage not receiving subsequent treatment (<50% vs ≥50%: r = 0.70 vs 0.63). Conclusions: Across diverse tumors and therapies, the treatment effect on PFS‐2 correlated moderately with the treatment effect on OS. PFS‐2 performed consistently better than PFS‐1 and ORR, regardless of postprogression treatment and postprogression survival. PFS‐2 should be included as a key trial end point in future randomized trials of solid tumors. The treatment effect on progression‐free survival 2 correlates moderately to strongly with the treatment effect on overall survival. Progression‐free survival 2 performs consistently better than progression‐free survival 1 and the objective response rate across key subgroups. [ABSTRACT FROM AUTHOR]