Generalized Pairwise Comparisons in Dose Optimization Oncology Trials: Beyond Safety to Multi-outcome Dose Selection

The primary objective of dose-finding oncology trials (DFOT) is to determine the recommended phase II dose. Although dose selection has traditionally relied on clinician-reported safety outcomes, the goal of DFOTs increasingly focuses on the integration of safety, activity, and tolerability within decision-making, in line with modern dose optimization strategies. Seamless phase I/II designs often use decision frameworks to quantify trade-offs between outcomes to guide dose selection. However, assigning numerical values to reflect such trade-offs can be difficult as clinical judgments and interpretations often vary between investigators.

With stakeholders, including clinical teams and patients, potentially considering their own prioritization of outcomes, generalized pairwise comparisons, including the win ratio (WR), provide a statistical framework mirroring this clinical decision-making by evaluating treatment benefit against prioritized outcomes. Using the WR, doses are compared across prespecified prioritized outcomes sequentially, with the optimal dose yielding the largest proportion of favorable (winning) patient-pair comparisons. This article presents WIN-DOSE, a hierarchical, multi-outcome WR-based approach for dose optimization. We demonstrate the performance of WIN-DOSE in a two-arm randomized dose optimization trial incorporating dose-limiting toxicities for safety, preliminary response for activity, and both dose intensity and patient-reported outcomes for tolerability.

When one dose is clearly favorable, WIN-DOSE consistently identifies the optimal dose. We also demonstrate how the WR can accommodate different trade-offs between safety, activity, and tolerability, supporting transparent and clinically relevant dose selection.

The WR can support transparent and clinically relevant patient-centric dose selection decision-making, aligning with the broader goals of early-phase DFOTs.