IBIS: identify biomarker-based subgroups with a Bayesian enrichment design for targeted combination therapy

BACKGROUND: Combination therapies directed at multiple targets have potentially improved treatment effects for cancer patients. Compared to monotherapy, targeted combination therapy leads to an increasing number of subgroups and complicated biomarker-based efficacy profiles, making it more difficult for efficacy evaluation in clinical trials. Therefore, it is necessary to develop innovative clinical trial designs to explore the efficacy of targeted combination therapy in different subgroups and identify patients who are more likely to benefit from the investigational combination therapy. METHODS: We propose a statistical tool called ‘IBIS’ to Identify BIomarker-based Subgroups and apply it to the enrichment design framework. The IBIS contains three main elements: subgroup division, efficacy evaluation and subgroup identification. We first enumerate all possible subgroup divisions based on biomarker levels. Then, Jensen–Shannon divergence is used to distinguish high-efficacy and low-efficacy subgroups, and Bayesian hierarchical model (BHM) is employed to borrow information within these two subsets for efficacy evaluation. Regarding subgroup identification, a hypothesis testing framework based on Bayes factors is constructed. This framework also plays a key role in go/no-go decisions and enriching specific population. Simulation studies are conducted to evaluate the proposed method. RESULTS: The accuracy and precision of IBIS could reach a desired level in terms of estimation performance. In regard to subgroup identification and population enrichment, the proposed IBIS has superior and robust characteristics compared with traditional methods. An example of how to obtain design parameters for an adaptive enrichment design under the IBIS framework is also provided. CONCLUSIONS: IBIS has the potential to be a useful tool for biomarker-based subgroup identification and population enrichment in clinical trials of targeted combination therapy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12874-023-01877-w.