Summary of Research: Two-Stage Estimation of Overall Survival in the Phase 3 CheckMate 9ER Trial, Adjusting for the Impact of Subsequent Therapy

This is a summary of a post hoc analysis of the phase 3 CheckMate 9ER study. CheckMate 9ER demonstrated a significant overall survival (OS) benefit for first-line cabozantinib plus nivolumab (CaboNivo) versus sunitinib (SUN) in patients with advanced renal cell carcinoma (aRCC). However, receiving subsequent therapy can distort true OS benefits. This analysis used two-stage estimation (TSE) to model a hypothetical scenario to assess the OS benefit of CaboNivo versus SUN, removing the effect of subsequent treatment. In stage 1, multivariate modeling estimated the extent to which subsequent therapy extended OS in patients who discontinued their original study treatment. In stage 2, an adjusted hazard ratio (HR) for OS assessed the relative impact of CaboNivo versus SUN without the effects of subsequent treatment. TSE-adjusted counterfactual median OS [95% confidence interval (CI)] was 42.7 (38.4-49.1) months for CaboNivo and 21.3 (18.1-24.9) months for SUN [HR 0.53 (95% CI 0.43-0.65; p < 0.001)]; unadjusted estimates were 46.5 (40.6-53.7) months for CaboNivo and 35.5 (29.2-42.8) months for SUN [HR 0.79 (95% CI 0.65-0.96; p = 0.0196)]. Removing the effect of subsequent therapy increased the estimated OS benefit of CaboNivo versus SUN, reinforcing CaboNivo as a first-line standard of care for aRCC.Trial Registration NCT03141177.