Boosting Osimertinib Blood Brain Barrier Penetration

One of the preferred first line treatment for metastatic epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) is osimertinib, a tyrosine kinase inhibitor (TKI). Despite the good intracranial efficacy of osimertinib compared with older-generation EGFR-TKIs, 10-20% of patients develop new or progressing central nervous system (CNS) metastases, the reason for which is unknown. Although the CNS penetration of osimertinib should be sufficient to reach therapeutic concentrations, drug efflux pumps in the blood brain barrier (BBB) could play a role in preventing therapeutic concentrations, especially in patients without baseline CNS metastases. In these patients the BBB is not compromised in contrast to patients with baseline CNS metastases, in whom a leaky BBB allows better penetration of osimertinib. As a result, microscopic CNS metastases then have the opportunity to grow.

Osimertinib is a substrate of drug transporters P-glycoprotein (P-gp; gene: ABCB1) and Breast Cancer Resistance Protein (BCRP) (ABCG2; gene: ABCG2), present in the BBB. Germline variations in these transporters influence intracerebral osimertinib efficacy. Patients without CNS metastases and with the ABCG2 34G\>A single nucleotide polymorphism (SNP) have a 72% reduced risk of developing CNS metastases compared to other genotypes, potentially due to diminished osimertinib BBB-efflux, resulting in higher cerebrospinal fluid (CSF) penetration. This finding offers rationale to combine osimertinib with febuxostat, a strong selective ABCG2 transporter inhibitor, in order to enhance the intracerebral osimertinib concentration in patients without the ABCG2 34G\>A SNP (\~85% of patients).

The main trial endpoint is the change in the CSF to unbound plasma concentration ratio of osimertinib before and after co-administration with febuxostat.