Mechanisms that drive E-R confounding for large and small molecules: do we need to understand these to address E-R confounding in our analyses?

Confounded E-R and clearance-response (CL-R) relationships, as well as time-varying CL, are frequently observed for immunotherapies in cancer, where high baseline CL associates with poor outcomes, a greater decrease in CL over time associates with more favorable outcomes, and exposure does not associate with outcomes when evaluated across dose levels. While the growing consensus supports the driver for elevated mAb CL is hyper-catabolism in the context of advanced disease and cachexia, and not target-mediated CL via high baseline target expression, underlying mechanisms are poorly understood, and consequently robust baseline or longitudinal biomarkers are not available for predicting elevated baseline and time-varying CL. This talk will present an overview of the various potential mechanisms, current research probing these mechanisms and their integration into mechanistic models for guiding future biomarker exploration and development.