Multicentre, open-label, proof-of-concept study consisting of pharmacokinetic analyses of osimertinib steady-state trough concentrations in blood and CSF when given alone and in combination with the ABCG2 inhibitor febuxostat

Combination of osimertinib with ABCG2 inhibitor febuxostat, during 21 to 24 days of combined use

To determine the effect of combining osimertinib with the ABCG2 inhibitor febuxostat on cerebrospinal fluid to unbound plasma (CSF:plasma) osimertinib concentration ratio in patients with EGFR mutated NSCLC without CNS metastases on brain MRI and without the ABCG2 34G>A SNP

1. Pathologically confirmed metastatic EGFR-mutated nonsquamous NSCLC treated with osimertinib as part of regular care with CT-confirmed stable disease or better. Patients with (signs of) disease progression, are also eligible if their treating physician deems the treatment to be appropriate beyond progression and the expected osimertinib treatment duration is at least 1 month.
   o All patients with an EGFR ex19del or ex21 L858R mutation are eligible for inclusion.
2. ECOG-PS of 0-1.
3. Male or female, 18 years of age or older.
4. Able and willing to sign informed consent prior to any tests or procedures, which includeds compliance with the requirements and restrictions listed in the informed consent form (ICF) and protocol
5. Able and willing to undergo additional blood sampling for e.g. therapeutic drug monitoring.
6. Able and willing to undergo two lumbar punctions to obtain CSF.
7. Patients must meet the criteria stated in the approved regulatory indication(s) for osimertinib where the clinical study will be performed and agree to the restrictions, monitoring, and dose-adjustment criteria stipulated in the associated product label.
8. Absence of ABCG2 34G>A SNP.
9. Absence of CNS metastases.

1. Acute gout attack, and medical history of gout or xanthinuria
2. Use of urate-lowering agents, azathioprine, 6-mercaptopurine, tioguanine
3. Use of potent inducers of UDP-glucuronosyltransferase (UGT) enzymes, such as rifampicin and carbamazepine
4. Use of prohibited co-medication
5. Prior intrathecal chemotherapy
6. Moderate or severe hepatic dysfunction (Child Pugh B or C)
7. Significantly increased rate of uric acid production (such as in Lesch-Nyhan syndrome)
8. Pregnancy or breast-feeding
9. Severe cardiovascular conditions (including history of myocardial infarction, stroke or instable angina pectoris, or congestive heart failure)
10. Creatinine >1.5 times ULN concurrent with creatinine clearance <50 ml/min (measured or calculated by Cockcroft and Gault equation)
11. Known galactose-intolerance, Lapp lactasedeficiency or glucose-galactose malabsorption