Companion diagnostics and HER2-targeted antibody-drug conjugates

Area of Science:

• Oncology
• Pharmacology
• Diagnostics

Background:

• HER2-targeted antibody-drug conjugates (ADCs) demonstrate significant promise in treating HER2-expressing solid tumors.
• ADC efficacy hinges on factors including antibody characteristics, linker technology, payload potency, drug-to-antibody ratio, and target antigen expression levels.

Purpose of the Study:

• This review focuses on the role of target antigen expression and companion diagnostic (CDx) assays in patient selection for HER2-targeted ADCs.
• It assesses pivotal trials of FDA-approved HER2-targeted ADCs (trastuzumab emtansine and trastuzumab deruxtecan) for efficacy data related to HER2 expression levels.
• The clinical utility of current FDA-approved HER2 CDx assays for patient eligibility is also evaluated.

Main Methods:

• Literature review of pivotal clinical trials for trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd).
• Analysis of trial data to correlate HER2 expression levels with treatment efficacy outcomes.
• Evaluation of the performance and clinical utility of current FDA-approved HER2 companion diagnostic assays.

Main Results:

• High HER2 expression (IHC 3+) is strongly associated with enhanced efficacy for both T-DM1 and T-DXd across various solid tumors.
• Current evidence supports the use of immunohistochemistry (IHC) as the primary CDx assay for selecting patients for HER2-targeted ADC therapy.
• This aligns with the mechanism of action, where higher HER2 density enhances receptor-mediated endocytosis.

Conclusions:

• Immunohistochemistry (IHC) is the recommended primary companion diagnostic (CDx) assay for patient selection in HER2-targeted ADC therapy.
• High HER2 expression is a critical determinant of treatment success with ADCs like T-DM1 and T-DXd.
• Optimizing patient selection through accurate HER2 assessment is crucial for maximizing ADC efficacy in solid tumors.