To complement last month’s podcast (‘We can work it out!’), we reached out to Amy Rieborn, a PhD student working with Teun Van Gelder and Dirk Jan Moes on various projects involving anticancer drugs. It was really a pleasure to hear about this innovative body of work. Amy started out as a medical doctor and became interested in the TDM of anticancer drugs after wondering why it is so little used in this context compared to the antimicrobials we often see monitored. I’m impressed with the breadth of her work that covers a variety of anticancer drug classes, including hormonal agents, kinase inhibitors and monoclonal antibodies. It was also great to hear about the clinical use of microsampling for home-based monitoring of immunosuppressants. Another great interview from a bright Young Scientist who will no doubt achieve big things.
After graduating as a medical doctor and working at the department of internal medicine at a local hospital, I started my PhD in 2021 at the Leiden University Medical Center. Teun van Gelder is my promotor and Dirk Jan Moes my co-promotor. The subject of my work is individualized regimens in Oncology, especially in uro-oncology. Therapeutic drug monitoring is huge part of my daily research. The common goal of my projects is to improve treatments in oncology for patients.
Due to the wide variety of my projects, my working days vary every day, which I quite enjoy! A big part of my day is monitoring and steering our clinical trials. We are currently exploring the PK/PD and exposure-toxicity in patients with a new antibody drug conjugate. Furthermore, we are exploring if changes in immunotherapy clearance might be an early biomarker for response in several tumor types, and if we can use this information to optimize treatment regimens. We have validated the oncology mAbXmise kit in our laboratory.
We are currently conducting a clinical trial to determine the impact on cabozantinib AUC when taken with a light breakfast instead of in a fasted state. Administration with a light breakfast might be more patient friendly and may help increase bioavailability, which has the potential to result in using lower doses, or a longer dosing interval, and thus reduce the cost of this expensive drug.
At the moment, the ANZadapt trial is being conducted by the Leiden University Medical Center, together with ANZUP in Australia with the funding of the Anticancer Fund in Belgium. In this trial, we investigate if progression free survival can be prolonged in patients with metastatic castration-resistant prostate cancer who are treated with enzalutamide or abiraterone. For patients in the experimental arm, treatment will be interrupted if PSA drops by 50%. Pilot trial data from Zhang and colleagues suggests this tailored approach prevents treatment resistance. Although this is not classical therapeutic drug monitoring, it might provide novel insights in individual adjusted therapy regimens using biomarkers.
At our hospital, transplant patients treated with tacrolimus and mycophenolate are monitored at home using microsampling. This enables patients to take the multiple samples required to determine AUC at home, and spares them from spending a full day at the hospital. This is not only done for research purposes, but has been fully implemented in daily care of patients, also in the long-term follow-up after kidney transplantation. In oncology, most TDM is performed using trough concentrations. Our vision is that at home monitoring for oncology is also the future. It offers the opportunity to perform TDM at home more frequently in the Netherlands, where accessibility to health care and TDM is good. In other countries where accessibility to health care is suboptimal and TDM is not possible due to long travelling distances, home based microsampling might also be beneficial.
In recent years, use of LC/MS-MS has opened up many opportunities for the therapeutic drug monitoring of oncology drugs like tyrosine kinase inhibitors and more recently monoclonal antibodies. As the analytical techniques improve, it is possible to get results with lower blood volumes faster and therefore more feasible to use in daily practice for oncologists. The possibility to measure concentrations of monocloncal antibodies might bring an extra perspective to the floor. We believe it is possible to personalize treatment regimens, and therefore improve the toxicity profile and cost-effectiveness.
While I was working as a clinical doctor after graduating, TDM for some antibiotics was already very common, for example for vancomycin. It left me wondering why it wasn’t common in oncology, especially with the unfavorable toxicity profile of many drugs. For example, midostaurin was a new drug in treatment of FLT3-mutated Acute Myeloid Leukemia, and we were aware of the interaction with one of the prophylactic drugs we always used (voriconazole). Instead of checking the drug concentration of one or both of these drugs, toxicity is monitored with the QTc time of the ECG every now and then. I was convinced we have a lot to gain to improve TDM in oncology, to which I hope to contribute a small part.
I think it is very interesting to explore the possibility of TDM of immunotherapy in oncology patients. Therefore, I was very interested when I read the article about the validation of the LC/MS-MS method of Promise Proteomics together with our French colleagues. We have now validated the method in our laboratory as well, and are planning to explore possibilities for TDM in patients treated with immunotherapy.
I think many of the projects we are conducting now have that possibility. We hope to gradually update you in the upcoming years about these projects. We are currently wrapping up a project about intra-patient variability (IPV) in patients using pazopanib. In transplant medicine, high IPV of tacrolimus has associated with poor outcomes. We wanted to explore if there is a relation between pazopanib IPV and progression-free survival. Our analysis might show pazopanib IPV predicts therapy failure as well. There is a lot to gain regarding cost-effectiveness and toxicity in the field of immunotherapy. In our country, cost of treatment is a rising urgent issue. Are we giving effective treatment for the right costs to the right patient? With the help of TDM, we can work it out!
In the Netherlands, cost-effectiveness of new expensive cancer therapies is becoming an urgent issue. There is an increasing part of our population above 65 years of age, and this causes a rise in cancer diagnoses over the years. With the increased incidence in cancer diagnoses among many other factors, health care costs are rising and become unmanageable for governments. We believe that with TDM guided dosing, de-escalation of expensive immunotherapy is possible and improves cost-effectiveness and toxicity profiles. I am excited to see if we can work it out.
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