Brain Exposure of Osimertinib in Patients with Epidermal Growth Factor Receptor Mutation Non-small Cell Lung Cancer and Brain Metastases: A Positron Emission Tomography and Magnetic Resonance Imaging Study

Brain metastases (BMs) are associated with poor prognosis in epidermal growth factor receptor mutation-positive (EGFRm) non-small cell lung cancer (NSCLC). Osimertinib is a third-generation, irreversible, EGFR-tyrosine kinase inhibitor that potently and selectively inhibits EGFR-sensitizing and T790M resistance mutations with efficacy in EGFRm NSCLC including central nervous system (CNS) metastases. The open-label phase I positron emission tomography (PET) and magnetic resonance imaging (MRI) study (ODIN-BM) assessed [ C]osimertinib brain exposure and distribution in patients with EGFRm NSCLC and BMs. Three dynamic 90-min [ C]osimertinib PET examinations were acquired together with metabolite-corrected arterial plasma input functions at: baseline, after first oral osimertinib 80 mg dose, and after greater than or equal to 21 days of osimertinib 80 mg q.d. treatment. Contrast-enhanced MRI was performed at screening and after 25-35 days of osimertinib 80 mg q.d.; treatment effect was assessed per CNS Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and per volumetric changes in total BM using a novel analysis approach. Four patients (aged 51-77 years) completed the study. At baseline, ~1.5% injected radioactivity reached the brain (ID ) 22 min (median, T ) after injection. Total volume of distribution (V ) in whole brain was numerically higher compared with the BM regions. After a single oral osimertinib 80 mg dose, there was no consistent decrease in V in whole brain or BMs. After greater than or equal to 21 days' daily treatment, V in whole brain and BMs were numerically higher versus baseline. MRI revealed 56%-95% reduction in total BMs volume after 25-35 days of osimertinib 80 mg q.d. treatment. The [ C]osimertinib crossed the blood-brain and brain-tumor barriers and had a high, homogeneous brain distribution in patients with EGFRm NSCLC and BMs.