The Effects of Variant Allele Frequency for EGFR Mutation on Early Tumor Shrinkage and Deepness of Response to Osimertinib in Patients with Metastatic Non-Small Cell Lung Cancer: An Exploratory Analysis

Background: Several studies evaluated the role of variant allele frequency (VAF) as a clinical decision-making tool for targeted therapies. However, its predictive role for treatment response in epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) remains debated. This study investigates the relationship between VAF and early tumor shrinkage (ETS) and deepness of response (DpR). We also explored the impact of previously undescribed compound uncommon EGFR mutations on osimertinib activity. Methods: We retrospectively analyzed data from patients with advanced EGFR-mutated NSCLC, treated with osimertinib. VAF was obtained through NGS. We calculated corrected VAF (cVAF) based on the percentage of tumor cells. ETS and DpR were assessed according to RECIST 1.1 criteria. Molecular modeling was performed to predict the impact of novel compound EGFR mutations on osimertinib binding and EGFR protein structure. Results: We included 16 patients, who met the eligibility criteria. We found no significant correlation between cVAF and ETS or DpR, suggesting that cVAF may not have a direct effect on early or late tumor response to osimertinib. Median cVAF was 14%. Median progression-free survival and overall survival were longer in patients with higher VAF, even though they were not statistically significant. We identified two previously unreported compound EGFR mutations: N771Y + L858R and L718V + K713R + L858R. Conclusions: This study demonstrates that cVAF of EGFR mutations is not significantly associated with ETS or DpR during osimertinib in mNSCLC patients. Survival does not appear to be influenced by cVAF either. The identification and structural characterization of novel compound EGFR uncommon mutations may explain the benefit experienced by patients.