Adjuvant immunotherapy in patients with high-risk muscle-invasive urothelial carcinoma: The potential impact of informative censoring

Background The results of 2 studies exploring adjuvant immune checkpoint inhibition (aCPI) in high-risk muscle-invasive urothelial cancer have yielded conflicting results. A trial employing placebo as the control arm demonstrated a significant prolongation in disease-free survival (DFS) whereas a trial employing observation as the control arm (IMvigor010) demonstrated no prolongation in DFS with CPI. Here, the authors aimed to estimate the aCPI benefit and to model the potential impact of informative censoring on trial results. Methods Survival data from 1518 patients was reconstructed from Kaplan-Meier curves. A network meta-analysis approach was used to estimate aCPI benefit through the restricted mean disease-free survival time (RMDFST). To estimate the potential impact of informative censoring on IMvigor010, a simulation was performed. The minimum proportion of informative censoring on the observation arm that could account for the lack of observed improvement in DFS was estimated. Random variability from the time of censoring to progression was modeled using the exponential distribution. Results Patients receiving aCPI had better DFS: Delta RMDFST at 36 months of 2.2 (95% CI, 0.6-3.7, P = .006) months relative to observation/placebo. In IMvigor010, in the observation arm, 20.5% of patients were censored due to consent withdrawal, protocol violation and/or noncompliance, or lost to follow-up versus 8.2% in the treatment arm. On simulation, it was found that the lack of observed improvement in DFS could have resulted from as few as 14% of the censored patients on observation arm not being censored at random (simulated DFS with 14% informative censoring hazard ratio, 0.83; 95% CI, 0.69-0.99; P = .049). Conclusions Phase 3 trials comparing adjuvant therapies to observation are at risk for informative censoring that could potentially impact interpretation of study results.

Automated summary

This study integrated the results of two studies exploring the effect of adjuvant immune checkpoint inhibition (aCPI) in high-risk muscle-invasive urothelial cancer through a network meta-analysis approach. The results showed that patients receiving aCPI had better disease-free survival. Additionally, simulation results found that informative censoring could potentially impact the results in the observation arm, with fewer patients being censored at random potentially leading to unobserved improvements in disease-free survival.