A PET study in healthy subjects of brain exposure of ¹¹C-labelled osimertinib – A drug intended for treatment of brain metastases in non-small cell lung cancer

Abstract

Osimertinib is a tyrosine kinase inhibitor (TKI) of the mutated epidermal growth factor receptor (EGFRm) with observed efficacy in patients with brain metastases. Brain exposure and drug distribution in tumor regions are important criteria for evaluation and confirmation of CNS efficacy. The aim of this PET study was therefore to determine brain distribution and exposure of 11C-labelled osimertinib administered intravenously in subjects with an intact blood–brain barrier. Eight male healthy subjects (age 52 ± 8 years) underwent one PET measurement with 11C-osimertinib. The pharmacokinetic parameters Cmax (brain) (standardized uptake value), Tmax (brain) and AUC0–90 min brain/blood ratio were calculated. The outcome measure for 11C-osimertinib brain exposure was the total distribution volume ( VT). 11C-osimertinib distributed rapidly to the brain, with higher uptake in grey than in white matter. Mean Cmax, Tmax and AUC0–90 min brain/blood ratio were 1.5 (range 1–1.8), 13 min (range 5–30 min), and 3.8 (range 3.3–4.1). Whole brain and white matter VT were 14 mL×cm−3 (range 11–18) and 7 mL×cm−3 (range 5–12). This study in healthy volunteers shows that 11C-osimertinib penetrates the intact blood–brain barrier. The approach used further illustrates the role of molecular imaging in facilitating the development of novel drugs for the treatment of malignancies affecting the brain.

Efficacy of osimertinib against EGFRvIII+ glioblastoma

“…First, it penetrates the bloodbrain barrier very well ( Figure 1A). While our studies were on mice, osimertinib has been shown elsewhere to penetrate the human brain as well [19,[24][25][26][27]. Second, osimertinib is an irreversible inhibitor of EGFR tyrosine kinase, so its inhibition of EGFRvIII signaling is longlasting.…”

“…Thus, in athymic mice, osimertinib has a brain to plasma ratio of >10. Osimertinib also rapidly penetrates the human brain [19] and is effective in lung cancer patients with brain metastases [20].…”

Osimertinib for Patients With Leptomeningeal Metastases Associated With EGFR T790M-Positive Advanced NSCLC: The AURA Leptomeningeal Metastases Analysis

“…23 In a positron emission tomography study in healthy volunteers, microdoses of 11 C-labeled osimertinib were found to cross an intact blood-brain barrier and exhibit widespread exposure in the brain. 24 The AURA program assessed the efficacy and safety of the recommended dose of osimertinib used in clinical practice (80 mg qd) in patients with EGFR T790M-positive advanced NSCLC. Here, we report a retrospective analysis of the efficacy and safety of osimertinib (80 mg qd) in patients with radiologic evidence of LM in the following AURA studies: AURA extension (NCT01802632), AURA2 (NCT02094261), AURA17 (NCT02442349), and AURA3 (NCT02151981).…”

Assessment of Effectiveness and Safety of Osimertinib for Patients With Intracranial Metastatic Disease

“…12 Osimertinib is a third-generation EGFR-TKI that overcomes T790M alteration and is among several targeted therapies that have been considered for use in the prevention and management of IMD because of its ability to penetrate the BBB. 13,14 Multiple trials have demonstrated the effectiveness of osimertinib in primary NSCLC, but only 2 randomized clinical trials (RCTs) to date (AURA3 [AZD9291 vs Platinum-Based Doublet-Chemotherapy in Locally Advanced or Metastatic Non-Small Cell Lung Cancer] 15 19 ) will provide additional information on effectiveness in patients with IMD. Recent review articles 12,20,21 have addressed the role of osimertinib in IMD; however, no study to our knowledge has aggregated CNS effectiveness data across existing RCTs and single-arm studies.…”