Continuous monitoring of delayed outcomes in basket trials

TL;DR

This paper introduces a Bayesian continuous monitoring approach for basket trials with delayed outcomes, improving early decision-making and handling missing data efficiently in precision medicine studies.

Contribution

It extends existing Bayesian methods to address delayed outcomes using multiple imputation, enabling more practical and computationally efficient interim analyses in basket trials.

Findings

Multiple imputation effectively handles missing data at interim analyses.

Continuous monitoring can lead to sample size savings in basket trials.

Optimal data handling strategies depend on trial-specific factors.

Abstract

Precision medicine has led to a paradigm shift allowing the development of targeted drugs that are agnostic to the tumor location. In this context, basket trials aim to identify which tumor types - or baskets - would benefit from the targeted therapy among patients with the same molecular marker or mutation. We propose the implementation of continuous monitoring for basket trials to increase the likelihood of early identification of non-promising baskets. Although the current Bayesian trial designs available in the literature can incorporate more than one interim analysis, most of them have high computational cost, and none of them handle delayed outcomes that are expected for targeted treatments such as immunotherapies. We leverage the Bayesian empirical approach proposed by Fujiwara et al., which has low computational cost. We also extend ideas of Cai et al to address the practical challenge of performing interim analysis with delayed outcomes using multiple imputation. Operating characteristics of four different strategies to handle delayed outcomes in basket trials are compared in an extensive simulation study with the benchmark strategy where trial accrual is put on hold until complete data is observed to make a decision. The optimal handling of missing data at interim analyses is trial-dependent. With slow accrual, missingness is minimal even with continuous monitoring, favoring simpler approaches over computationally intensive methods. Although individual sample-size savings are small, multiple imputation becomes more appealing when sample size savings scale with the number of baskets and agents tested.