Influence of the drug transporters ABCB1 and ABCG2 and enzyme CYP3A4 on survival outcome and pharmacokinetics in patients with non-small cell lung cancer treated with osimertinib

Rationale
Brain metastases are frequently present in patients with lung cancer. Of all EGFR TKI’s, drug
penetration across the blood-brain barrier is highest for osimertinib. Possibly therefor, the
incidence of central nervous system (CNS) disease progression was lower for osimertinib compared
to other EGFR TKI’s. This could suggest treatment efficacy to be correlated with CNS drug
concentrations. Drug efflux transporters ABCB1 (P-glycoprotein; P-gP) and ABCG2 (breast cancer
resistance protein; BCRP) are highly frequent present on the blood-brain barrier and synergize the
efflux effect of various anti-cancer drugs, resulting in drug resistance. Osimertinib is a substrate of
P-glycoprotein and BCRP and is an inhibitor of BCRP, but does not inhibit P-glycoprotein. Multiple
single nucleotide polymorphisms (SNPs) are described which impair the function of both drug
transporters. Most frequent described are the C3435T SNP in ABCB1 and the C421A and G34A SNP
in ABCG2. The influence of P-gP and BCRP on intracerebral osimertinib concentrations is
unknown. Moreover, the effects of SNPs in these efflux transporters on treatment outcome
(response and occurrence of CNS metastases) are not yet studied. Also effects of P-gP and BCRP on
systemic osimertinib concentrations are unknown.
Osimertinib is mainly metabolized by CYP3A4. The SNP CYP3A4*22 is associated with low hepatic
CYP3A4 expression and CYP3A4 activity, thus potentially increasing the systemic concentrations of
osimertinib.
Population
Patients who are or have been treated with osimertinib for non-small cell lung cancer (NSCLC) and of
whom blood has been withdrawn for study or diagnostic purposes are eligible for usage in this study.
Treatment
No intervention is planned for this study nor will patients be informed of the outcomes of this study.
Methods
Blood samples of patients treated with osimertinib will be analyzed for the SNPs C3435T (ABCB1),
C421A and G34A (ABCG2) and CYP3A4*22. Analysis do not generate genetic information which will
be leading to a specific patient nor will any outcome involve predicting changes for (future) diseases
for the patient or his/her family.
Pharmacokinetics will be determined by quantifying the osimertinib concentration at steady state
with time between last intake and blood withdrawal of > 6 hours.
End points
Osimertinib treated patients will be divided in two groups, depending on the presence of CNS
metastases at start of treatment.
In the group with CNS metastases at baseline, primary outcome is the correlation of the SNPs C3435T
(ABCB1), C421A and G34A (ABCG2) and CYP3A4*22 with treatment response of CNS metastases. PFS
will be measured as time to cerebral progressive disease or death from any cause. In the group
without CNS metastases at baseline, primary endpoint is correlation between the four SNPs and de
novo occurrence of CNS metastases (defined as time to brain metastasis). Secondary endpoints are the
correlations between presence of SNPs and OS, PFS independent of site (CNS or extracranial), toxicity,
and pharmacokinetic parameters (AUC, Cmax, C/L) in the total cohort.

SNPs could increase systemic and CNS exposure, causing longer CNS PFS and less occurence of CNS metastasis

Full analysis of primary and secondary endpoints after last inclusion. Plasma drug concentrations are measured with LC/MS-MS.