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

Abstract

Antibody-drug conjugates (ADCs) are a promising class of targeted cancer therapies. However, they need careful dose optimization to maximize effectiveness and minimize side effects. Sometimes, safety issues may only become apparent after approval, so ongoing evaluation is important. This study aimed to assess the benefit-risk profiles of two approved trastuzumab-drug conjugates: trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd). A systematic search of MEDLINE on May 1, 2024, identified clinical trials reporting the pharmacokinetics, pharmacodynamics, safety, and efficacy of T-DM1 and T-DXd. Summary-level data from 103 trials was used along with model-based meta-analysis to develop population pharmacokinetic and exposure-response models for both ADCs. The study combined the objective response rate (ORR) and dose-limiting toxicity (DLT) into a composite score called the clinical utility index (CUI) to determine optimal drug exposures and doses that maximize the benefit-risk balance. Different ORR/DLT weights and CUI thresholds representing desired minimum effect size were tested in three scenarios ("only phase I trials," "phase I/II trials," and "all phases"). Using a CUI threshold of 10%, the approved T-DM1 dose of 3.6 mg/kg for breast cancer was found to align with an efficacy-safety (ORR-DLT) ratio of 81:19 with all phases. Applying these weights to the T-DXd analyses successfully predicted the approved T-DXd dose (5.4 mg/kg, breast cancer), showing a CUI improvement compared to the 3.2 mg/kg dose of 8.3%, 8.2%, and 2.4% in the three respective scenarios. Overall, this proof-of-concept assessment of ADCs can save time and costs for pharmaceutical companies and optimize dosing to maximize patient benefit.