Successful implementation of a model-based Therapeutic Drug Monitoring framework within the ON-TARGET study: A first step towards precision dosing of oral anticancer drugs

Introduction: Targeted oral anticancer drugs (tOADs) allow a selective tumour therapy, yet optimal treatment is often impaired by drug toxicity or lack of efficacy. Dose individualisation could substantially improve treatment compared to the almost exclusively applied ‘one-dose-fits-all’ approach. However, Therapeutic Drug Monitoring (TDM) strategies are still not widely used in oncology in Germany [1]. Their successful implementation requires close interprofessional collaboration, infrastructure, and comprehensive TDM evaluation supporting clinical treatment decision-making. The ON-TARGET study aimed to set up and explore the feasibility of a model-based TDM process in clinical practice in Germany. Methods: The prospective, multi-centre, non-interventional ON-TARGET study evaluated TDM in patients with renal cell carcinoma treated with axitinib (AXI) or cabozantinib (CABO) [2]. Venous and capillary blood samples were collected during routine check-up visits and drug concentrations were analysed using validated bioanalytical LC-MS/MS methods [3-5]. Leveraging pharmacometric modelling, first, drug concentrations were compared with simulated expected individual pharmacokinetic (PK) profiles. Second, simulated individual PK metrics were compared with published toxicity thresholds. A comprehensive risk assessment was reported back to the physician to support treatment decisions. Physicians were asked to rate the usefulness of the TDM evaluation choosing between “very helpful”, “somewhat helpful”, “not really helpful” and “not helpful at all”. Results: As of December 2023, a total of 364 visits with the intention of carrying out TDM was reported. TDM samples were available from 358 of these, corresponding to 98% of all reported visits. Bioanalytical quantification of venous drug concentrations was carried out in 352 TDM samples, corresponding to 98% of all obtained TDM samples. With 344 model-based TDM evaluations reported back to physicians, 98% of the measured venous drug concentrations were evaluated. Overall, the TDM process was successfully completed for 95% of all reported visits, highlighting the successful implementation of an infrastructure for a model-based TDM process in this pilot study. The risk assessment for experiencing adverse drug reactions revealed an increased or inconclusive risk for 10% and 48% of the evaluated AXI and CABO samples, respectively. Furthermore, treating physicians perceived the TDM service positive: In 79% of the cases, the TDM was rated “very helpful” or “somewhat helpful”. Conclusion: The interim analysis of the ON-TARGET study highlighted the feasibility and potential for model-based TDM to improve treatment with tOADs in clinical practice: An infrastructure for a model-based TDM process was successfully implemented and the first analysis of evaluated TDM samples revealed a high need for TDM of tOADs and high acceptance among participating physicians. To inform the design of the extension study, a comprehensive analysis of the real-world data will next be carried out, thus setting the foundation for model-informed precision dosing of tOADs in clinical routine. Interested centres are encouraged to contact the study group (www.fu-berlin.de/on-target).