Front Mol Biosci. 2026 Jun 24;13:1878152. doi: 10.3389/fmolb.2026.1878152. eCollection 2026.
ABSTRACT
BACKGROUND: Osimertinib is an approved first-line therapy for epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). However, beyond the identification of common EGFR mutations, additional pathological or molecular factors that predict treatment response, survival outcomes, or toxicity remain limited.
MATERIALS AND METHODS: This retrospective study analyzed data from a registry of NSCLC patients with EGFR mutations treated with first-line osimertinib between March 2017 and December 2024. Variant allele frequency (VAF) was evaluated as a potential predictive factor for overall survival (OS), progression-free survival (PFS), and adverse events (AEs).
RESULTS: Among 147 eligible patients, the mean OS was 25.5 months and the mean PFS was 21.4 months. Patients with VAF ≥30% exhibited improved outcomes compared to those with VAF <30%, with mean OS of 31.4 months versus 19.7 months (p = 0.022), and mean PFS of 25.0 months versus 18.2 months (p = 0.234). Similar trends were observed across EGFR exon 19 deletion and exon 21 L858R subgroups (p = 0.056). When comparing toxicity profiles, the overall AE rates were similar between high-VAF and low-VAF patients. However, several statistically significant differences were noted: diarrhea (21.3% vs. 5.7%, p = 0.005) and dyspnea (16.4% vs. 3.4%, p = 0.0085) were more frequent in the high-VAF group, while anemia (9.2% vs. 3.3%, p = 0.03) and creatinine elevation (5.7% vs. 1.6%, p = 0.01) occurred more commonly in the low-VAF group.
CONCLUSION: Higher EGFR VAF was significantly associated with improved overall survival in patients with EGFR-mutated NSCLC treated with first-line osimertinib and showed a numerical trend toward longer progression-free survival. Similar patterns were observed across key molecular subgroups. Additionally, this study is the first to report potential VAF-related differences in adverse event patterns, suggesting that VAF may have relevance not only for efficacy but also for toxicity characterization. These findings support the potential role of VAF as a prognostic biomarker in EGFR-mutant NSCLC and warrant further prospective validation.
PMID:42422880 | PMC:PMC13342395 | DOI:10.3389/fmolb.2026.1878152
