Model-supported patient stratification using multi-objective synergy optimization in combination therapy

The challenge of stratifying patients for combination therapy is both technically demanding and clinically crucial. In previous work, we introduced a multi-objective optimization framework for identifying optimally synergistic combination protocols that are robust to varying definitions of additivity. This manuscript extends this methodology to quantify how inter-individual heterogeneity in drug sensitivity influences the combination doses that optimally balance the competing objectives of synergy of efficacy and synergy of potency (a proxy measure of toxicity). For this methodology, we introduce a voxel-based stratification approach to characterize individuals (model parameterizations) into subgroups based on sensitivity to each drug as a monotherapy and in combination. As a case study, we apply the method to a preclinical dataset of murine response to the combination of an immune checkpoint inhibitor and an antiangiogenic agent. We demonstrate that the algorithm not only quantifies how robustly optimal therapies vary across treatment response subgroups, but also identifies specific subpopulations for which no meaningfully efficacious combination exists. As applying the methodology requires knowledge of specific parameter values for which measurable biomarkers may be unavailable, we also propose an initiation protocol that permits identification of the parameters necessary to place an individual in a subgroup. This methodology is a step in the direction of determining the right combination therapy for a subgroup and finding the right subgroup for an existing therapy.