MIDAS-2: an enhanced Bayesian platform design for immunotherapy combinations with subgroup efficacy exploration.

ABSTRACT

Although immunotherapy combinations have revolutionised cancer treatment, the rapid screening of effective and optimal therapies from large numbers of candidate combinations, as well as exploring subgroup efficacy, remains challenging. This necessitates innovative, integrated, and efficient trial designs. In this study, we extend the MIDAS design to include subgroup exploration and propose an enhanced Bayesian information borrowing platform design called MIDAS-2. MIDAS-2 enables quick and continuous screening of promising combination strategies and exploration of their subgroup effects within a unified platform design framework. We use a regression model to characterize the efficacy pattern in subgroups. Information borrowing is applied through Bayesian hierarchical modelling to improve trial efficiency considering the limited sample size in subgroups. Time trend calibration is also employed to avoid potential baseline drifts. Simulation results demonstrate that MIDAS-2 yields high probabilities for identifying the effective drug combinations as well as promising subgroups, facilitating appropriate selection of the best treatments for each subgroup. The proposed design is robust against small time trend drifts, and the type I error is successfully controlled after calibration when a large drift is expected. Overall, MIDAS-2 provides an adaptive drug screening and subgroup exploring framework to accelerate immunotherapy development in an efficient, accurate, and integrated fashion.