Baseline gut microbiome and metabolomic profiles associated with durable response to first-line third-generation EGFR-TKIs in patients with advanced EGFR-mutant NSCLC.

Abstract

e20756 Background: First-line third-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs) are standard therapy for EGFR-mutant non–small cell lung cancer (NSCLC); however, clinical outcomes vary among patients with advanced disease. Increasing evidence suggests that the gut microbiome and its metabolites may influence treatment efficacy. This study investigated baseline gut microbiome and metabolomic features associated with durable response to first-line third-generation EGFR-TKIs in stage IV EGFR-mutant NSCLC. Methods: Baseline fecal samples were collected from 29 patients with stage IV EGFR-mutant NSCLC treated with first-line third-generation EGFR-TKIs. Patients were classified as durable responders (R, n = 19; median progression-free survival [PFS], 24 months) or non-responders (NR, n = 10; median PFS, 6 months). Shotgun metagenomic sequencing and untargeted metabolomics were performed, followed by differential abundance, diversity, and integrative microbiome–metabolome analyses. Results: Baseline gut microbiome and metabolomic profiles differed significantly between groups. Species-level α-diversity analysis demonstrated gut microbiome dysbiosis in the NR group, with higher microbial richness and diversity than in the R group (P < 0.05). Alistipes sp. HGB5, Eubacterium sp. AF22_9, and Tyzzerella nexilis were significantly enriched in the R group (all P < 0.05). Metabolomic profiling showed higher levels of chenodeoxycholic acid, testosterone glucuronide, and palmitic acid in responders (all P < 0.05). Integrative analysis identified Tyzzerella nexilis as a key species correlated with lipid and bile acid metabolism. Conclusions: Baseline gut microbiome and metabolomic profiles differed significantly between groups. Species-level α-diversity analysis demonstrated gut microbiome dysbiosis in the NR group, with higher microbial richness and diversity than in the R group (P < 0.05). Alistipes sp. HGB5, Eubacterium sp. AF22_9, and Tyzzerella nexilis were significantly enriched in the R group (all P < 0.05). Metabolomic profiling showed higher levels of chenodeoxycholic acid, testosterone glucuronide, and palmitic acid in responders (all P < 0.05). Integrative analysis identified Tyzzerella nexilis as a key species correlated with lipid and bile acid metabolism.