A comparative study of preclinical and clinical molecular imaging response to EGFR inhibition using osimertinib in glioblastoma.

BACKGROUND: To demonstrate the potential value of (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) as a rapid, non-invasive metabolic imaging surrogate for pharmacological modulation of EGFR signaling in EGFR-driven GBM, we synchronously conducted a preclinical imaging study using patient-derived orthotopic xenograft (PDOX) models and validated it in a phase II molecular imaging study in recurrent GBM (rGBM) patients using osimertinib. METHODS: A GBM PDOX mouse model study was performed concurrently with an open-label, single-arm, single-center, phase II study of osimertinib (NCT03732352) that enrolled 12 patients with rGBM with EGFR alterations. Patients received osimertinib daily and 3 (18)F-FDG PET scans: two 24 h apart prior to dosing, and one 48 h after dosing. RESULTS: GBM PDOX models suggest osimertinib has limited impact on both (18)F-FDG uptake (+†9.8%-+25.9%) and survival (+†15.5%; P†=†.01), which may be explained by insufficient exposure in the brain (Kp(uu): 0.30) required to robustly inhibit the EGFR alterations found in GBM. Treatment with osimertinib had subtle, but measurable decreases in the linear rate of change of (18)F-FDG nSUV growth rate averaging -4.5% per day (P†=†.01) and change in (18)F-FDG uptake was correlated with change in tumor growth rate (R(2)†=†0.4719, P†=†.0195). No metabolic (PERCIST) or radiographic (RANO) responses were seen, and no improvements in PFS or OS were observed. CONCLUSIONS: This study demonstrated the feasibility of using FDG PET as a clinically reliable imaging biomarker for assessing EGFR inhibition in GBM, while revealing osimertinib's limited impact on both metabolic activity and tumor growth in GBM, findings that were concordant between preclinical and clinical observations.