A simulation-free group sequential design with max-combo tests in the presence of non-proportional hazards.

Abstract

Non-proportional hazards (NPH) have been observed in many immuno-oncology clinical trials. Weighted log-rank tests (WLRT) with suitable weights can be used to improve the power of detecting the difference between survival curves in the presence of NPH. However, it is not easy to choose a proper WLRT in practice. A versatile max-combo test was proposed to achieve the balance of robustness and efficiency, and has received increasing attention recently. Survival trials often warrant interim analyses due to their high cost and long durations. The integration and implementation of max-combo tests in interim analyses often require extensive simulation studies. In this report, we propose a simulation-free approach for group sequential designs with the max-combo test in survival trials. The simulation results support that the proposed method can successfully control the type I error rate and offer excellent accuracy and flexibility in estimating sample sizes, with light computation burden. Notably, our method displays strong robustness towards various model misspecifications and has been implemented in an R package.