Embracing Project Optimus: Can we Leverage Evolutionary Theory to Optimize Dosing in Oncology?
- Focus on tumor evolution, which leads to therapeutic failure and disease relapse.
- Emphasis on the effect of tumor evolution on the exposure-response (E-R) relationships of oncology drugs.
- Advocacy for prioritizing tumor evolution during clinical development to select optimal doses for targeted therapies and immunotherapies.
- Evidence supports alternative dosing strategies for targeted therapies, but robust characterization of E-R relationships is often overlooked.
- Combining evolutionary theory with conventional PK/PD modeling can help elucidate E-R relationships and support dose selection for long-term clinical benefit.
- Importance of discovering and validating biomarkers of tumor evolution.
Demonstration of superior clinical efficacy is a major barrier to the approval of investigational oncology drugs. For indications with limited treatment options, sponsors frequently conduct efficacy trials under expedited timelines in hopes of making their therapy available to patients in need as quickly as possible. These factors lead sponsors to use high drug doses in hopes of maximizing drug exposure, eliciting strong signals of efficacy, and supporting expeditious regulatory approval.
This “more is better” dogma is rooted in the use of cytotoxic chemotherapies at their maximum tolerated dose (MTD) to treat hematological malignancies. Physicians may prefer to use the MTD despite increased toxicity out of fear that lower doses, while more tolerable, could lead to subtherapeutic drug exposure and therapeutic failure...
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