Bayesian group sequential enrichment designs based on adaptive regression of response and survival time on baseline biomarkers.

Precision medicine relies on the idea that, for a particular targeted agent, only a subpopulation of patients are sensitive to it and thus may benefit from it therapeutically. In practice, it often is assumed based on pre-clinical data that a treatment-sensitive subpopulation is known, and moreover that the agent is substantively efficacious in that subpopulation. Due to important differences between pre-clinical settings and human biology, however, data from patients treated with a new targeted agent often show that one or both of these assumptions are false. This paper provides a Bayesian randomized group sequential enrichment design that compares an experimental treatment to a control based on survival time, and uses early response as an ancillary outcome to assist with adaptive variable selection and enrichment. Initially, the design enrolls patients under broad eligibility criteria. At each interim decision, submodels for regression of response and survival time on a baseline covariate vector and treatment are fit, variable selection is used to identify a covariate subvector that characterizes treatment-sensitive patients and determines a personalized benefit index, and comparative superiority and futility decisions are made. Enrollment of each cohort is restricted to the most recent adaptively identified treatment-sensitive patients. Group sequential decision cutoffs are calibrated to control overall type I error and account for the adaptive enrollment restriction. The design provides a basis for precision medicine by identifying a treatment-sensitive subpopulation, if it exists, and determining whether the experimental treatment is superior to the control in that subpopulation. A simulation study shows that the proposed design reliably identifies a sensitive subpopulation, yields much higher generalized power compared to several existing enrichment designs and a conventional all-comers group sequential design, and is robust. This article is protected by copyright. All rights reserved.