Correlation of Milestone Restricted Mean Survival Time Ratio With Overall Survival Hazard Ratio in Randomized Clinical Trials of Immune Checkpoint Inhibitors

This systematic review and meta-analysis examines randomized clinical trials (RCTs) of immune checkpoint inhibitors to evaluate the use of milestone rate and milestone restricted mean survival time as intermediate end points in immune checkpoint inhibitor trials.
Key Points Question What intermediate end points could be useful in randomized clinical trials studying immune checkpoint inhibitors? Findings In this systematic review and meta-analysis of 26 trials studying immune checkpoint inhibitors in 12 892 participants, the ratio of milestone restricted mean survival time for overall survival was more strongly correlated with the overall survival hazard ratio than the ratio of overall survival milestone rates. Meaning Milestone restricted mean survival time could be studied as a potential intermediate end point for overall survival in future trials of immune checkpoint inhibitors.
Importance Immune checkpoint inhibitors (ICIs) have unique patterns of response and survival that differ from conventional chemotherapies. Novel intermediate end points are urgently required to detect the early signals of ICI activity. Objective To evaluate milestone rate (Kaplan-Meier estimates of survival probabilities at given time points) and milestone restricted mean survival time (RMST, the area under survival curves up to given time points) as potential intermediate end points for ICI trials. Data Sources Electronic databases (pre-MEDLINE, MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials) were searched for randomized clinical trials published between January 1, 2000, and December 31, 2017. Study Selection Phase 2 and phase 3 randomized clinical trials evaluating ICIs in advanced solid tumors. Data Extraction and Synthesis Two investigators extracted the data and reconstructed individual patient data to estimate the milestone rate or milestone RMST from the published Kaplan-Meier curves. Main Outcomes and Measures Trial-level milestone rates or milestone RMSTs were estimated for 6-month and 9-month progression-free survival (PFS) and 9-month and 12-month overall survival (OS). A weighted linear regression model evaluated the correlations of ratios of milestone rates or milestone RMSTs with OS hazard ratios (HRs). Results Twenty-six trials examining 8 different tumor types were identified, including 12 892 patients. Overall survival HR was correlated with the ratio of 9-month OS milestone rate (R2 = 0.45; 95% CI, 0.27-0.74), and with the ratio of 12-month OS milestone rate (R2 = 0.40; 95% CI, 0.22-0.70). The ratio of 9-month OS milestone RMST (R2 = 0.60; 95% CI, 0.28-0.74) and ratio of 12-month OS milestone RMST were correlated with OS HR (R2 = 0.64; 95% CI, 0.42-0.78). No correlations were observed between OS HR and the ratio of 6-month or 9-month PFS milestone rates or milestone RMSTs. Conclusions and Relevance Ratios of OS milestone RMSTs had a stronger correlation with OS HRs than ratios of OS milestone rates, whereas ratios of PFS milestone rates and ratios of PFS milestone RMSTs were not correlated with OS HRs. The OS milestone RMST could be further studied as an intermediate end point in future ICI trials.