Dose selection criteria to identify the optimal dose based on ranked efficacy-toxicity outcomes without reliance on clinical utilities

Abstract

Recently, targeted and immunotherapy cancer treatments have motivated dose-finding based on efficacy-toxicity trade-offs rather than toxicity alone. The EffTox and utility-based Bayesian optimal interval (U-BOIN) dose-finding designs were developed in response to this need, but may be sensitive to elicited subjective design parameters that reflect the trade-off between efficacy and toxicity. To ease elicitation and reduce subjectivity, we propose dose desirability criteria that only depend on a preferential ordering of the joint efficacy-toxicity outcomes. We propose two novel order-based criteria and compare them with utility-based and contour-based criteria when paired with the design framework and probability models of EffTox and U-BOIN. The proposed dose desirability criteria simplify implementation and improve robustness to the elicited subjective design parameters and perform similarly in simulation studies to the established EffTox and U-BOIN designs when the ordering of the joint outcomes is equivalent. We also propose an alternative dose admissibility criteria based on the joint efficacy and toxicity profile of a dose rather than its marginal toxicity and efficacy profile. We argue that this alternative joint criterion is more consistent with defining dose desirability in terms of efficacy-toxicity trade-offs than the standard marginal admissibility criteria. The proposed methods enhance the usability and robustness of dose-finding designs that account for efficacy-toxicity trade-offs to identify the optimal biological dose.