Bayesian and frequentist approaches to sequential monitoring for futility in oncology basket trials: A comparison of Simon’s two-stage design and Bayesian predictive probability monitoring with information sharing across baskets

Abstract

This article discusses and compares statistical designs of basket trial, from both frequentist and Bayesian perspectives. Baskets trials are used in oncology to study interventions that are developed to target a specific feature (often genetic alteration or immune phenotype) that is observed across multiple tissue types and/or tumor histologies. Patient heterogeneity has become pivotal to the development of non-cytotoxic treatment strategies. Treatment targets are often rare and exist among several histologies, making prospective clinical inquiry challenging for individual tumor types. More generally, basket trials are a type of master protocol often used for label expansion. Master protocol is used to refer to designs that accommodates multiple targets, multiple treatments, or both within one overarching protocol. For the purpose of making sequential decisions about treatment futility, Simon’s two-stage design is often embedded within master protocols. In basket trials, this frequentist design is often applied to independent evaluations of tumor histologies and/or indications. In the tumor agnostic setting, rarer indications may fail to reach the sample size needed for even the first evaluation for futility. With recent innovations in Bayesian methods, it is possible to evaluate for futility with smaller sample sizes, even for rarer indications. Novel Bayesian methodology for a sequential basket trial design based on predictive probability is introduced. The Bayesian predictive probability designs allow interim analyses with any desired frequency, including continual assessments after each patient observed. The sequential design is compared with and without Bayesian methods for sharing information among a collection of discrete, and potentially non-exchangeable tumor types. Bayesian designs are compared with Simon’s two-stage minimax design.