Review of dose justifications for antibody-drug conjugate approvals from clinical pharmacology perspective: A focus on exposure-response analyses

Highlights•Antibody-drug conjugates (ADCs) offer improved therapeutic window but are not free from unwanted side effects.•ADCs need optimization of the dosing regimen through integrated analysis of the data and risk-benefit profile like any other modalities.•In this review, exposure-response analyses that form critical components of dose justification for all currently FDA-approved ADC products are discussed.AbstractAntibody-drug conjugates (ADCs) are revolutionizing cancer treatment by specific targeting of the cancer cells thereby improving the therapeutic window of the drugs. Nevertheless, they are not free from unwanted toxicities mainly resulting from non-specific targeting and release of the payload. Therefore, the dosing regimen must be optimized through integrated analysis of the risk-benefit profile, to maximize the therapeutic potential. Exposure-response (E-R) analysis is one of the most widely used tools for risk-benefit assessment and it plays a pivotal role in dose optimization of ADCs. However, compared to conventional E-R analysis, ADCs pose unique challenges since they feature properties of both small molecules and antibodies. In this article, we review the E-R analyses that have formed the key basis of dose justification for each of the 12 ADCs approved in the USA. We discuss the multiple analytes and exposure metrics that can be utilized for such analysis and their relevance for safety and efficacy of the treatment. For the endpoints used for the E-R analysis, we were able to uncover commonalities across different ADCs for both safety and efficacy. Additionally, we discuss dose optimization strategies for ADCs which are now a critical component in clinical development of oncology drugs.