Speaker
Description
The challenge of stratifying patients for combination therapy is both technically demanding and clinically crucial. We build upon our previous framework for identifying Pareto optimal doses, reconciling competing definitions of synergy through multi-objective optimization to balance synergy of efficacy and potency (a measure of toxicity) such that no further improvement is possible in one without detriment to the other, and extend it to address interpatient heterogeneity. We apply the methodology to our previously developed model of a combination of an immune checkpoint inhibitor and an antiangiogenic agent and extend it to address interpatient heterogeneity. We demonstrate that depending on patient-specific drug sensitivities, different regimens may be Pareto optimal for different subgroups. We also highlight that there exist subpopulations for whom no meaningfully efficacious combination exist, suggesting that these individuals are not good candidates for this drug combination. In situations where measurable biomarkers are unavailable, we propose an initiation protocol with explicit, practical criteria that permit the estimation of patient-specific sensitivities to both monotherapies and to the combination therapy. Taken together, the proposed approach provides a potential way to find the right combination therapy for a patient, and to find the right patient for existing therapy.
