Introduction. Osimertinib is a third generation, CNS active, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) used for treatment of patients with locally advanced and metastatic T790M mutation positive non-small cell lung cancer (NSCLC). Osimertinib has shown efficacy superior to that of EGFR-TKIs (erlotinib and gefitinib) in the first-line treatment of EGFR mutation-positive advanced NSCLC and with reduced risk of CNS progression (Soria et al 2017). Furthermore, rapid osimertinib response on brain metastases has been reported (Koba et al 2017). Preliminary examination in non-human primates using 11C-labeled osimertinib indicates penetration of the intact blood brain barrier (BBB) and a high brain exposure compared to other EGFR-TKI agents, which may potentially contribute to improved efficacy in patients with brain metastases compared to other TKIs (Ballard et al 2016).

Aim. The aim of this positron emission tomography (PET) study was to measure the brain exposure of [11C]osimertinib administered intravenously in healthy volunteers with an intact BBB.

Methods. Eight male healthy volunteers (age 52±8 years) were examined for ~90 minutes with PET after single intravenous microdose of [11C]osimertinib. Concentration of [11C]osimertinib was also measured in arterial and venous blood and plasma. Brain MRI was acquired and used for co-registration of the PET data and automatic delineation of regions of interest in the brain. PK parameters Cmax (brain), Tmax (brain) and AUC0-90 minbrain/blood ratio were calculated.

Results. In all healthy volunteers, [11C]osimertinib distributed to the brain rapidly, with mean Tmax=13 min (range 5-30 min), Cmax= 1.4±0.3 SUV (range 1-1.8) corresponding to 2.2±0.2% of injected radioactivity and AUC0-90 min brain/blood ratio=3.8±0.3 (range 3.3-4.1). [11C]Osimertinib was distributed in all regions of the brain with uptake being highest in putamen followed by thalamus, frontal cortex, temporal cortex, caudate, cerebellum and white matter.

Conclusions. This study indicates that [11C]osimertinib has a good brain exposure in human subjects with intact BBB and may potentially contribute to the efficacy of treatment with osimertinib. In NSCLC, patients with brain metastasis may benefit from treatment with osimertinib due to favorable brain exposure of the drug. Future studies in patients with NSCLC are required to examine uptake and kinetic properties of [11C]osimertinib in brain metastases. References: Ballard P, Yates JW, Yang Z, Kim DW, Yang JC et al. Preclinical Comparison of Osimertinib with Other EGFR-TKIs in EGFR-Mutant NSCLC Brain Metastases Models, and Early Evidence of Clinical Brain Metastases Activity. Clin Cancer Res. 2016 Oct 15;22(20):5130-5140. Koba T, Kijima T, Takimoto T, Hirata H, Naito Y et al. Rapid intracranial response to osimertinib, without radiotherapy, in nonsmall cell lung cancer patients harboring the EGFR T790M mutation: Two Case Reports. Medicine (Baltimore). 2017 Feb;96(6):e6087. Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B et al.; FLAURA Investigators. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med. 2017 Nov 18

Citation Format: Karthick Vishwanathan, Andrea Varrone, Katarina Varnas, Aurelija Jucaite, Zsolt Cselenyi, Peter Johnstrom, Magnus Schou, Ana Vasquez-Romero, Mohammed Mahdi Moein, Christer Halldin, Andrew P. Brown, Lars Farde. Osimertinib displays high brain exposure in healthy subjects with intact blood-brain barrier: a microdose positron emission tomography (PET) study with 11C-labelled osimertinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT013.