Therapeutic Drug Monitoring of BRAF- and MEK-inhibitors in a *Real Life* Cohort of Melanoma Patients

In clinical practice interpatient (and intrapatient) variability in
pharmacokinetics may be a major determinant in BRAF inhibitor (BRAFi) therapy
outcome since this may lead to unpredictable efficacy and safety. In case of
vemurafenib large interpatient variability in plasma levels has been found in
phase I clinical trials. There is already emerging evidence for a relationship
between plasma levels and clinical efficacy/occurrence of side effects. In
addition the interaction with food is under investigation. Knowledge of this
PK-PD relationship can be used to optimize therapy in order to prevent failure
of BRAFi and MEKi by monitoring of drug resistance and reducing drug toxicity.
Most frequently reportedadverse events with vemurafenib (960 mg twice daily
(BID)) in the clinical trials are cutaneous events (rash, photosensitivity and
development of SCC), arthralgia and fatigue; photosensitivity skin reactions of
grade 2 or 3 were seen in 12% of the patients. Cutaneous squamous-cell
carcinoma (CSCC) developed in 18% of the patients. The dose was reduced when
intolerable grade 2 toxic effects or worse were seen. In total 38% of the
patients needed dose reductions because of toxic effects. These results
indicate that the currently used dosing schedule is far from optimal. A better
insight on the pharmacokinetics could improve the dosing schedule of
vemurafenib.
The current limitation of routine clinical use of full TDM is the lack of data
confirming PK/PD relations of BRAFi and MEKi and of data demonstrating improved
outcome of patients when TDM is routinely applied. Rational quantification of
these drug levels might provide a better understanding of decreased response,
primary and secondary resistance and adverse events in patients receiving BRAFi
and/or MEKi.
While vemurafenib was getting registered new BRAFi were in development
(dabrafenib, LGX 818). It is expected that BRAFi have large similarities in
mechanism of action and similar PK-PD relations are to be expected for all BRAF
inhibitors. This underlines the rationale for a structured prospective follow
up of patients using any BRAF inhibitor.

To describe the PK variability in exposure to vemurafenib, dabrafenib and
trametinib and relationship with treatment outcome (Radiological tumor
assessments as per RECIST Version 1.1) and toxicity (graded on basis of the
National Cancer Institute Common Toxicity grading Criteria for adverse events1
(CTC version 4.03)) in a *real life* cohort. In addition parameters will be
evaluated that might influence pharmacokinetics and -dynamics. To make
therapeutic drug monitoring less invasive a dried blood spot method will be
validated.

A longitudinal follow up cohort study of all patients of the Antoni van
Leeuwenhoek Hospital using vemurafenib, dabrafenib (both BRAF inhibitors)
and/or trametinib (MEK inhibitor) for treatment of cancer. Patients will be
treated with vemurafenib, dabrafenib and/or trametinib (as monotherapy or
combination therapy between them) on a dose according to the prescription of
the physician. No further intervention is needed. The patients will be sampled
during routine follow up. Patients that receive combination therapy with other
kinds of therapy may be included.

- Blood will be drawn for pharmacokinetic (fingerprik, 4 mL blood, monthly) and
pharmacogenetic research (once 4 mL).
- Patients might be asked to collect urine and faeces (once during this study).
- Patients will be asked to keep a diary and note daily whether or not the
drugs are taken on an empty stomach.