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-11]osimertinib brain exposure and distribution in patients with EGFRm NSCLC and BMs. Three dynamic 90-min [C-11]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, similar to 1.5% injected radioactivity reached the brain (IDmax[brain]) 22 min (median, T-max[brain]) after injection. Total volume of distribution (V-T) 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-T in whole brain or BMs. After greater than or equal to 21 days' daily treatment, V-T 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-11]osimertinib crossed the blood-brain and brain-tumor barriers and had a high, homogeneous brain distribution in patients with EGFRm NSCLC and BMs. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Brain metastases (BMs) are associated with poor prognosis in epidermal growth factor receptor mutation-positive (EGFRm) non-small cell lung cancer (NSCLC). Osimertinib has demonstrated efficacy in EGFRm NSCLC, including central nervous system metastases. However, the exposure and exact distribution of osimertinib in whole brain following administration in patients with BMs is unknown. WHAT QUESTION DID THIS STUDY ADDRESS? ODIN-BM was a phase I multimodal imaging study combining positron emission tomography (PET) and magnetic resonance imaging to examine osimertinib brain exposure in patients with EGFRm NSCLC and BMs. The results demonstrated homogenous distribution of radiolabeled osimertinib in the whole brain and BMs. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? These findings corroborate preclinical data and observations in healthy volunteers with an intact blood brain barrier to patients with BMs treated with osimertinib. Notably, our study demonstrated that presence of [C-11]osimertinib exposure in BMs shell and core regions was similar to that in the surrounding brain tissue, suggesting that [C-11]osimertinib passes the blood-brain and blood-tumor barriers. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? Findings of this study offer more information regarding osimertinib brain exposure and its radiologically assessed efficacy in BMs as reported in large clinical trials and recent case study reports. Data suggesting that [C-11]osimertinib passes the blood-brain and brain-tumor barriers has not been reported with any other anticancer treatment to the best of our knowledge. Additionally, this study also illustrates the potential of microdosing PET studies in the development of drugs targeting brain malignancies.

Automated summary

This study investigated the exposure and distribution of osimertinib in the brain of patients with EGFRm NSCLC and BMs using PET and MRI. The results showed that osimertinib can cross the blood-brain and tumor barriers, and had a high and homogeneous distribution in the whole brain and BMs. These findings provide more information on osimertinib's efficacy in BMs and its potential as a treatment for brain malignancies.