Aumolertinib Versus Osimertinib as First-Line Treatment for EGFR-Mutant Non-Small Cell Lung Cancer: A Retrospective Real-World Multicenter Study.

While third-generation EGFR tyrosine kinase inhibitors (TKIs) improve outcomes in EGFR-mutant NSCLC, optimal selection between these agents remains uncertain. This real-world study compares the efficacy and safety of aumolertinib with those of osimertinib in the first-line treatment setting. We retrospectively analyzed 109 EGFR-mutant (exon 19del/L858R) NSCLC patients treated with first-line aumolertinib (n = 53) or osimertinib (n = 56) across four tertiary hospitals (2016-2023). The primary end points included progression-free survival (PFS) and safety; secondary end points encompassed overall survival (OS), objective response rate (ORR), and predictive biomarker identification through subgroup analyses. Aumolertinib demonstrated superior median PFS compared to osimertinib (34.4 vs. 26.9 months; HR 0.52, 95% CI 0.29-0.92, p = 0.031), with comparable OS (HR 0.76, 95% CI 0.27-2.15, p = 0.60). No significant differences emerged in primary lesion ORR (33.96%, 18/53 vs. 42.86%, 24/56) or adverse event (AE) rates (37.7%, 20/53 vs. 39.3%, 22/56). Subgroup analyses confirmed enhanced PFS benefit with aumolertinib in exon 19del-mutant (HR 0.43, 95% CI 0.21-0.87, p = 0.02) and co-mutation-negative (HR 0.53, 95% CI 0.25-1.14, p = 0.08) populations. Subgroup analysis identified age < 65 years (HR 0.46, 95% CI 0.22-0.99, p = 0.046), brain metastases (HR 0.24, 95% CI 0.09-0.66, p = 0.006), and exon 19del status (HR 0.43, 95% CI 0.2-0.89, p = 0.023) as independent PFS predictors. Regarding safety, aumolertinib showed a lower overall incidence of liver dysfunction compared to osimertinib (9.43%, 5/53 vs. 14.29%, 8/56), with Grade ≥ 3 events being rare (1.89%, 1/53). Given that liver function is a critical determinant of prognosis, the manageable hepatic safety profile of aumolertinib supports its long-term clinical utility. Our study demonstrated a clinically meaningful PFS advantage of aumolertinib over osimertinib in treatment-naïve EGFR-mutant NSCLC, particularly for exon 19del-driven and co-mutation-negative disease, while maintaining equivalent safety. These findings provide valuable real-world evidence supporting the use of aumolertinib as a first-line therapy, contributing to the optimization of treatment selection and AE management. While these subgroup-specific results offer hypothesis-generating insights into potential biomarkers for therapeutic individualization, these preliminary findings require further validation in larger, prospective cohorts.