Postmarketing Assessment of Antibody–Drug Conjugates: Proof-of-Concept Using Model-Based Meta-Analysis and a Clinical Utility Index Approach

This study explores a model-based meta-analysis (MBMA) and a clinical utility index (CUI) approach to assess the benefit–risk profiles of antibody–drug conjugates (ADCs). The focus is on two approved trastuzumab-drug conjugates: trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd). Using data from 103 clinical trials, the study develops population pharmacokinetic and exposure–response models to evaluate efficacy and safety.

The CUI method integrates objective response rate (ORR) and dose-limiting toxicity (DLT) into a composite score to determine optimal drug exposures and doses. Three scenarios were tested: Phase I trials, Phase I/II trials, and all trial phases. The study confirmed that the approved doses for T-DM1 (3.6 mg/kg) and T-DXd (5.4 mg/kg) provide a favorable benefit–risk balance.

This proof-of-concept approach can streamline drug development, optimize dosing, and reduce costs. While demonstrated with ADCs, it is broadly applicable to other drug modalities, supporting continuous benefit–risk assessments throughout a drug’s lifecycle.