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 (C_ss ) at the approved dose was compared to the in vitro cell potency (half-maximal inhibitory concentration (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. The C_ss was remarkably similar to the IC₅₀ . The median C_ss /IC₅₀ value was 1.2, and 76% of the values were within 3-fold of unity. However, three drugs (encorafenib, erlotinib, and ribociclib) had a C_ss /IC₅₀ value > 25. Seven other therapies targeting the same 3 kinases had much lower C_ss /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 C_ss exceeds a potency threshold. This potency-guided approach is expected to maximize the therapeutic window thereby improving patient outcomes.