Evaluating Relapse-Free Survival as an Endpoint for Overall Survival in Adjuvant Immunotherapy Trials
Menée à partir de l'analyse des données de 15 essais cliniques de phase 2 ou 3 évaluant des immunothérapies adjuvantes et incluant au total 13 715 patients atteints d'un cancer de stade précoce (durée médiane de suivi : 3,3 ans), cette méta-analyse examine la possibilité d'utiliser la survie sans récidive à la place de la survie globale comme critère principal d'évaluation dans les essais cliniques
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 OS in this clinical context.
Methods : Phase 2 or phase 3 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 (R2). Strong correlations (R2 ≥ 0.7) at both the arm and trial levels indicated valid surrogacy. The surrogate threshold effect (STE) was also evaluated.
Results : Fifteen high-quality RCTs involving 13,715 patients were included. At the arm level, moderate and strong associations were observed between RFS2-year and OS3-year (R2 = 0.58, 95% confidence interval [CI]: 0.25-0.92) and RFS3-year and OS5-year (R2 = 0.72, 95% CI: 0.38-1.00), respectively. At the trial level, a moderate association was observed between effect of treatment on RFS and OS (R2 = 0.63, 95% CI: 0.33-0.94). The STE 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 significantly strong association between RFS and OS in RCTs 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.
Journal of the National Cancer Institute , article en libre accès, 2022