55P EGFR variant allele frequency (VAF) impacts on metastatic NSCLC patients outcome during first-line osimertinib

Epidermal Growth Factor Receptor (EGFR) represents one of the main molecular druggable targets in non-small-cell lung cancer (NSCLC). Osimertinib is an irreversible EGFR-tyrosine kinase inhibitor currently recognised as the standard of care for first-line treatment of EGFR-positive patients with common mutations (L858R or ex19del). Next Generation Sequencing (NGS) is recommended for routine use to detect gene mutation in NSCLC; moreover, NGS can quantitate the proportion of mutant variant reads for each mutation, the variant allele frequency (VAF). EGFR-VAF determined by liquid biopsy is known to be a prognostic factor in NSCLC patients. The role of EGFR-VAF determined on histological specimen in patients receiving first-line osimertinib is unclear. From February 2019 to April 2023 a cohort of 68 patients with diagnosis of advanced EGFR mutated NSCLC started first-line osimertinib at San Raffaele Hospital, in Milan (Italy). We excluded from our analysis patients with VAF value unavailable (n=20). VAF was determined by NGS in pre-treatment baseline tissue samples. 48 NSCLC patients were included in our analysis. Median EGFR-VAF was 31%, mean 35.9%, first quartile 17%, third quartile 52%. Cut-off of 50% was established to distinguish patients in high-VAF group (hVAF) and low-VAF (lVAF). Applying Log Rank test progression-free survival (PFS) was significantly shorter in hVAF patients [HR 0,30 (95% CI 0.12-0.8, p = 0.01)] than in lVAF group. With the limits of a 14.9 months median follow up, overall survival was significantly shorter in patients with high VAF [HR 0.19 (95% CI 0.056-0.648, p = 0.003)]. No correlation with other features (age, sex, smoke status, metastatic sites, PD-L1 expression) was found in covariate analysis, except for the mutation site L858R or ex19del, the latter being more frequently associated with hVAF. High EGFR VAF on tissue seems to be predictive of a reduced response to osimertinib in NSCLC. Our findings must be validated on a greater number of cases, and a longer follow up is needed to confirm the correlation with shorter overall survival.