Companion diagnostics and HER2-targeted antibody-drug conjugates

HER2-targeted antibody-drug conjugates (ADCs) have shown promising outcomes in the treatment of patients with various HER2-expressing solid tumors. The efficacy of ADCs is influenced by several factors, such as the antibody properties, linker design, payload type and potency, drug-to-antibody ratio, and target antigen expression.

This review specifically examines target antigen expression and the companion diagnostic (CDx) assays used to select patients for treatment with HER2-targeted ADCs. Pivotal clinical trials involving the two FDA-approved HER2-targeted ADCs, trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd), were identified and assessed to determine whether they included data on efficacy outcomes associated with varying levels of HER2 expression. In addition, the clinical utility of the current FDA-approved HER2 CDx assays for selecting patients eligible for treatment with HER2-targeted ADCs is also discussed.

High HER2 expression (IHC 3+) markedly affects the efficacy of T-DM1 and T-DXd in various solid tumors. Current data suggest that IHC should be used as the primary CDx assay to select patients for treatment with HER2-targeted ADCs. This recommendation aligns with the mechanism of action of ADCs, wherein increased receptor density facilitates receptor-mediated endocytosis of the drug molecules.