Personalised dosing of oral targeted anticancer drugs: Finding the right drugs, the right exposure and the right evidence for therapeutic drug monitoring

Traditionally, most medical treatments were designed for the average patient, with a one-size-fits-all approach. In the last years, the focus of cancer treatments has shifted towards precision medicine. This focus toward precision medicine in oncology could progress even further by personalising drug doses. Therapeutic Drug Monitoring (TDM) is one approach for doing this. With TDM, drug doses are adjusted based on measured drug exposure and set pharmacokinetic targets. These pharmacokinetic targets are based on exposure-response and exposure-toxicity relationships.
There is a strong rationale for considering TDM of oral targeted anticancer drugs. These drugs are currently still prescribed in a fixed dose, although they often show high and unpredictable variability in exposure. With the narrow therapeutic window of these drugs, this variability makes patients at risk for suboptimal efficacy and unnecessary toxicity, and as a result, treatment with a one-size fits-all approach does not seem appropriate. Personalising drug doses by using TDM could be very beneficial for these drugs, and improve treatment outcomes.
The general aim of this thesis was to provide insight into the impact of personalised dosing of oral targeted anticancer drugs on clinical outcomes, with the goal of finding the right evidence needed for implementation of TDM. Additionally, this thesis also explored exposure-response and exposure-toxicity relationships of these drugs, with the goal to find the right drugs - that might benefit from routine TDM - and the right exposure targets that should be aimed for.

Conclusion

With the aim to advance TDM of oral targeted anticancer drugs, there is a need to find the right drugs, the right sampling methods, the right exposure targets, the right patients and the right evidence for TDM. This thesis aimed to find the right drugs and the right exposure targets, by providing evidence on exposure-response and exposure-toxicity relationships for a substantial number of oral targeted anticancer drugs. The clinical studies in this thesis aimed to provide the right, prospective, evidence necessary for implementation of routine TDM. This evidence was sufficient for abiraterone, and routine TDM should be used to enhance treatment outcomes. For ten other oral targeted anticancer drugs, routine TDM was not feasible; but TDM could still be used on indication, to ensure reasonable drug exposure in individual cases. For imatinib, sunitinib and pazopanib, a favourable effect of routine TDM on survival outcomes could not be demonstrated. The small number of patients who received a successful TDM-guided dose increase most likely affected the results in all these studies and might have limited the ability to detect a potential difference in survival. For imatinib, a final analysis will follow when data maturity is reached, as a difference in follow-up time might also have influenced the results. In future studies on the efficacy of TDM, it is crucial to use the right study design, to enhance the ability to detect a true effect. Additionally, there should at least be certainty regarding the used drug exposure target and recommendations to perform drug increases should be adequately followed, to ensure optimal statistical power.