Joined PMX and QSP modeling to guide step-up dosing of a bispecific antibody for prostate cancer

Combined pharmacometrics (PMX) and quantitative systems pharmacology (QSP) approaches have been more commonly applied in the early clinical development of bispecific antibodies in oncology in order to shed light into the dose response relationship. In this presentation, we will highlight a joined PMX and QSP analysis of a bispecific antibody in the early clinical development for prostate cancer. The PMX analysis supported an early understanding of the dose and exposure relationship to the observed safety signals, increase in cytokine release syndrome (CRS) with increasing doses and exposures, and observed efficacy signals, decrease in time-to-progression (TTP) with increasing doses and exposures. The QSP model was developed to predict trimer formation in relationship to the efficacious dose levels as the observed decrease in TTP was hypothesized to be i) a result of overdosing the bispecific antibody leading to a favorable development of dimers over Target trimers or ii) factors unbalanced by dose group at higher dose levels. Both, the PMX and QSP model, were jointly used to predict the potential influence of patient factors influencing efficacy and safety signals. In addition, the joined PMX and QSP analysis was utilized to guide a step-up dosing regimen based on the triangulated information on trimer formation (QSP) and probability of CRS occurrence based on the PMX analysis.