Evaluating relapse-free survival as an endpoint for overall survival in adjuvant immunotherapy trials

BACKGROUND: Relapse-free survival (RFS) has been considered a primary endpoint to assess the effects of immunotherapy in the adjuvant setting among patients with early-stage disease. However, it is not clear whether RFS is a valid surrogate endpoint for overall survival (OS) in this clinical context. METHODS: Phase II or III clinical trials of adjuvant immunotherapy that reported hazard ratios on OS and RFS were identified. We used a weighted regression analysis at the arm and trial levels to assess the efficacy of RFS as a surrogate for OS, quantified by the weighted coefficient of determination (R(2)). Strong correlations (R(2) ≥ 0.7) at the arm and trial levels indicated valid surrogacy. The surrogate threshold effect was also evaluated. RESULTS: Fifteen high-quality randomized clinical trials involving 13 715 patients were included. At the arm level, moderate and strong associations were observed between RFS(2-year) and OS(3-year) (R(2) = 0.58, 95% confidence interval [CI] = 0.25 to 0.92) and RFS(3-year) and OS(5-year) (R(2) = 0.72, 95% CI = 0.38 to 1.00), respectively. At the trial level, a moderate association was observed between effect of treatment on RFS and OS (R(2) = 0.63, 95% CI = 0.33 to 0.94). The surrogate threshold effect for RFS was 0.86. Consistent results were confirmed in several sensitivity analyses based on different trial phases, experimental arms, cancer types, and treatment strategies. CONCLUSIONS: Our meta-analysis failed to find a clinically strong association between RFS and OS in randomized clinical trials of adjuvant immunotherapy. Our findings challenge the use of RFS as the primary efficacy endpoint and suggest the use of OS in this clinical context.