Optimizing the Therapeutic Window of Targeted Drugs in Oncology: Potency-guided First-in-Human Studies.

Many targeted therapies are administered at or near the maximum tolerated dose (MTD). With the advent of precision medicine, a larger therapeutic window is expected. Therefore, dose optimization will require a new approach to early clinical trial design. We analyzed publicly available data for 21 therapies targeting six kinases, and four poly (ADP-ribose) polymerase inhibitors, focusing on potency and exposure to gain insight into dose selection. The free average steady-state concentration (Css ) at the approved dose was compared to the in vitro cell potency (IC50 ). Average steady-state area under the plasma concentration-time curve, the fraction unbound drug in plasma and the cell potency were taken from the US drug labels, US and European regulatory reviews and peer-reviewed journal articles. Css was remarkably similar to the IC50. The median Css /IC50 value was 1.2 and 80% of the values were within 3-fold of unity. However, three drugs (encorafenib, erlotinib and ribociclib) had a Css /IC50 value >25. Seven other therapies targeting the same three kinases had much lower Css /IC50 values ranging from 0.5 to 4. These data suggest that these kinase inhibitors have a large therapeutic window that is not fully exploited; lower doses may be similarly efficacious with improved tolerability. We propose a revised first-in-human trial design in which dose cohort expansion is initiated at doses less than the MTD when there is evidence of clinical activity and Css exceeds a potency threshold. This potency guided approach is expected to maximize the therapeutic window thereby improving patient outcomes.