Treatment effects measured by restricted mean survival time in trials of immune checkpoint inhibitors for cancer

Background: The hazard ratio (HR) is used routinely to quantify the treatment effect for time-to-event end points in oncology trials, but its use requires that there be proportional hazards in the treatment arms. Non-proportional hazards are observed frequently in cancer immunotherapy trials due to the long-term survival and delayed clinical effect. Although values of HR are quoted in such trials, they are not valid measures of outcome. Methods: Reports of parallel group randomized controlled trials (RCTs) evaluating immune checkpoint inhibitors with overall survival data were eligible. For each trial, the ratio of restricted mean survival time (RMST) between the arms was based on reconstructed individual patient data for overall survival. Results: Twenty-five RCTs totaling 12 870 patients were included in this study. Overall survival was used as primary or coprimary end point in 18 trials (72%). In all trials, there was agreement between the ratio of RMST or RMTL and the reported HR about the direction of treatment effect. Estimates of HR provided larger estimates of treatment effect than the ratio of RMST or RMTL in all these trials. The estimated HR and RMST-based measures were in agreement regarding the statistical significance of the effect in all but two trials. Conclusions: Ratio of RMST is a complementary technique that provides alternative method of summarizing treatment effects. Proportional hazards of the treatment effect should not be assumed in RCTs evaluating immune checkpoint inhibitors, and RMST analysis should be reported in such trials.