P2.14-33 An Open-Label PET-MRI Study to Determine Brain Exposure of Osimertinib in Patients with EGFR Mutant NSCLC and CNS Metastases

Abstract

CNS metastases are associated with poor prognosis in patients with advanced NSCLC. Osimertinib is a third-generation, irreversible, oral EGFR-TKI that potently and selectively inhibits both EGFR-TKI sensitising (EGFRm) and EGFR T790M mutations, and has demonstrated efficacy in NSCLC CNS metastases. Osimertinib has also shown superior brain exposure (preclinical/clinical), compared to other EGFR-TKIs. We report preliminary data on brain distribution of 11C-labelled osimertinib ([11C]osimertinib) in patients with NSCLC with brain metastases (BM) using positron emission tomography (PET). Early effects on BM measured by magnetic resonance imaging (MRI) is also presented. This open-label, single-centre Phase I study (NCT03463525) enrolled adult patients with EGFR-mutated advanced NSCLC and BM, as confirmed by MRI. Patients could be EGFR-TKI-naïve or have progressed on a prior EGFR-TKI with confirmed EGFR T790M. Intravenous microdoses of [11C]osimertinib and PET examinations were performed pre-dose on Day1, ∼6hrs post-dose on Day2, and following ≥21 days of once-daily dosing with osimertinib 80mg. Following the 3rd PET scan, patients completed another MRI scan to investigate early effects on tumour size according to RECIST 1.1 criteria. The primary objective was determination of brain exposure of [11C]osimertinib at baseline and following treatment, in the whole brain. During PET examinations, arterial blood samples were collected to measure radioactivity/radiometabolites of [11C]osimertinib. Currently, six patients have been screened. Three enrolled, of whom two completed all imaging visits. PET examinations demonstrated rapid uptake of [11C]osimertinib into the brain and distribution into metastases; MRI scans showed significant decrease in size of brain lesions after 21 treatment days, consistent with partial response according to RECIST 1.1 criteria (Figure). These early outcomes support the CNS efficacy reported in previous osimertinib studies: high brain-uptake and efficacy after a short dosing period. Further data on distribution, efficacy and PET/MRI imaging will be presented.