Comparing the efficacy of cancer therapies between subgroups in basket trials

Abstract

SUMMARYAn increase in the number of targeted anti-cancer drugs and growing genomic stratification of patients has led to the development of basket clinical trials in which a single drug is tested simultaneously in multiple tumor subtypes under a master protocol. Basket trials typically involve few patients per type, making it difficult to rigorously compare responses across types. We describe the use of permutation testing to analyze tumor volume changes and Progression Free Survival across subtypes in basket trials for neratinib, larotrectinib, pembrolizumab, and imatinib. Permutation testing is a complement to the standard Simon’s two-stage binomial approach and can test for differences among subgroups using empirical null distributions while controlling for multiple hypothesis testing. This approach uncovers examples of therapeutic benefit missed by a binomial test; in the case of the SUMMIT trial, our analysis identifies an overlooked opportunity for use of neratinib in lung cancers carrying ERBB2 Exon 20 mutations.