A MCP-Mod approach to designing and analyzing survival trials with potential non-proportional hazards

Non-proportional hazards have been observed in many studies especially in immuno-oncology clinical trials. Traditional analysis using the combined approach with log-rank test as the significance test and Cox model for treatment effect estimation becomes questionable as this approach relies heavily on the proportional hazards assumption. Inspired by the MCP-Mod (multiple comparisons and modeling approach) that has been widely used in dose-finding studies, we propose a similar approach to handle non-proportional hazards. Using this approach, efficacy signal is first established by a max-combo test, after which hazard ratios across time will be estimated using a logically nested splines model. Simulations studies and real-data examples are used to illustrate the use of this approach.