Background The data from immuno-oncology therapy trials often show delayed effects, cure rate, crossing hazards, or some mixture of these phenomena. Thus, the common assumption of proportional hazards is often violated such that the commonly used log-rank test can be very underpowered. In these trials, the conventional hazard ratio for describing the treatment effect may not be a good estimand due to the lack of an easily understandable interpretation. To overcome this challenge, restricted mean survival time (RMST) has been strongly recommended for survival analysis in clinical literature due to its independence of the proportional hazard assumption as well as a more clinically meaningful interpretation. The RMST also aligns well with the estimand associated with the analysis from the recommendation in ICH E-9 (R1), and the test/estimation coherency. Currently, the Kaplan Meier (KM) curve is commonly applied to RMST related analyses. Due to some drawbacks of the KM approach such as the limitation in extrapolating to time points beyond the follow-up time, and the large variance at time points with small numbers of events, the RMST may be hindered.
Methods To fully enhance the RMST method, the survival curve using a mixture model is proposed in this paper to construct dynamic RMST curves to evaluate and monitor survival analysis in clinical trials.
Results This new dynamic RMST curve overcomes the drawbacks from the KM approach. The good performance of this new proposal is illustrated through three real examples.
Conclusions RMST provides a clinically meaningful and easily interpretable measure for survival clinical trials. The proposed dynamic RMST approach provides a useful tool for assessing treatment effect over different time frames for survival clinical trials. This dynamic RMST curve can also be useful for checking whether the follow-up time for a study is long enough to demonstrate a treatment difference. The prediction feature of the dynamic RMST analysis may also be used for determining an appropriate time point for an interim analysis , and an evaluation tool for study recommendation from DMC .