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Optimizing the Therapeutic Window of Targeted Drugs in Oncology: Potency-Guided First-in-Human Studies
Matthew J Goldstein1, Malte Peters2, Barbara L Weber1
1Tango Therapeutics, Cambridge, Massachusetts, USA.
Abstract:
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 (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 Css was remarkably similar to the IC50 . The median Css /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 Css /IC50 value > 25. Seven other therapies targeting the same 3 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.
Insights
Precision medicine offers a wider therapeutic window for targeted cancer therapies. New trial designs are needed to optimize dosing, potentially using lower, more tolerable doses based on drug potency and exposure levels.
Area of Science:
- Pharmacology and Clinical Trial Design
- Precision Medicine
- Oncology Drug Development
Background:
- Many targeted therapies are administered near their maximum tolerated dose (MTD).
- Precision medicine aims to increase the therapeutic window for drugs.
- Current early clinical trial designs may not be optimal for dose optimization in precision medicine.
Purpose of the Study:
- To analyze the relationship between drug exposure and in vitro potency for targeted therapies.
- To provide insights for a new approach to dose selection in early clinical trials.
- To propose a revised first-in-human trial design optimizing the therapeutic window.
Main Methods:
- Analyzed publicly available data for 21 kinase inhibitors and 4 poly (ADP-ribose) polymerase inhibitors.
- Compared free average steady-state concentration (Css) at approved doses with in vitro cell potency (IC50).
- Extracted data from drug labels, regulatory reviews, and peer-reviewed literature.
Main Results:
- The median Css/IC50 ratio was 1.2, with 76% of values within 3-fold of unity, indicating similar exposure and potency.
- Three drugs (encorafenib, erlotinib, ribociclib) showed significantly higher Css/IC50 values (>25).
- Other kinase inhibitors targeting the same kinases had lower Css/IC50 values (0.5-4), suggesting an unexploited therapeutic window.
Conclusions:
- Kinase inhibitors may possess a larger therapeutic window than currently utilized, allowing for lower, potentially more tolerable doses.
- A revised first-in-human trial design, incorporating a potency-guided approach, is proposed.
- This approach aims to maximize the therapeutic window and improve patient outcomes by initiating dose expansion below MTD when clinical activity and exposure thresholds are met.
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