Associations between early loss of skeletal muscle and osimertinib trough concentrations in patients with advanced EGFR-mutated NSCLC

INTRODUCTION This study explores the associations between computed tomography (CT)-derived changes in body composition during the first three months of osimertinib monotherapy, systemic osimertinib exposure, and treatment outcomes in patients with advanced EGFR+ NSCLC. MATERIALS AND METHODS Patients initiating osimertinib between January 2016 and January 2022 were selected from the START-TKI biomarker study. Osimertinib trough concentrations (C trough ) were quantified. Body composition was assessed on baseline and three-month CT images using SliceOmatic . Loss of skeletal muscle index (SMI) was defined as a reduction of ≥1.3%. Associations between SMI loss and osimertinib C trough were estimated using linear mixed-effects modeling, while progression-free survival (PFS) and overall survival (OS) were evaluated using Cox proportional hazards models. RESULTS Fifty-three patients were included. Twenty-seven patients (56%) experienced SMI loss after three months. Median osimertinib C trough in the first three months was 212 ng/mL (IQR 159-279 ng/mL). Linear mixed-effects modeling indicated no association between SMI loss and osimertinib C trough over time (β = -17.3; 95% CI, -59.9 to 25.2; P = 0.42). Median follow-up was 53 months (95% CI, 46 – not reached). SMI loss was not associated with PFS (median PFS 11.5 vs. 11.8 months, HR: 0.99 [95% CI, 0.56-1.76]; P = 0.99). Patients in the highest-quartile C trough and those with EGFRexon21 L858R mutations had shorter PFS. SMI loss was an independent predictor of shorter OS (median OS 25.5 vs. 29.8 months, aHR: 2.04 [95% CI, 1.02-4.09]; P = 0.045) after adjusting for C trough and TP53 mutation status. CONCLUSION Early loss of SMI was not associated with osimertinib exposure, yet an independent predictor of shorter OS. Future research should explore whether nutritional interventions to preserve muscle mass improve osimertinib effectiveness.