Gut Microbiota in Advanced NSCLC Receiving Chemoimmunotherapy: An Ancillary Biomarker Study From the Phase III Trial...

Immunotherapy has transformed the treatment for NSCLC. Nevertheless, reliable biomarkers for treatment selection remain scarce. Gut microbiota has emerged as a potential biomarker, but its role in chemoimmunotherapy for NSCLC is unclear.

The phase III trial (JCOG2007, NIPPON) compared pembrolizumab plus platinum doublet chemotherapy (PC) with nivolumab and ipilimumab plus platinum doublet chemotherapy (NIC) in treatment-naive patients with advanced NSCLC without driver gene alterations. As an ancillary biomarker study, 270 patients with baseline fecal samples were analyzed for gut microbiota composition from 295 patients enrolled. 16S ribosomal DNA sequencing was performed for the diversity and differential abundance analysis.

The beta diversity analysis of the overall cohort (n = 270) revealed distinct microbial structures between the subpopulations defined by whether overall survival (OS) exceeds 12 or 18 months. Subsequent linear discriminant analysis effect size analysis identified specific bacterial genera that differed between the subpopulations, with Fusicatenibacter, Butyricicoccus, and Blautia being enriched in patients with longer OS. Regarding adverse events (AEs), lower microbial alpha diversity and the presence of certain taxa were linked to a higher risk of serious (≥grade 4) AEs. In addition, favorable genera, including Fusicatenibacter and Butyricicoccus, were associated with a lower risk of serious AEs. Last, regimen-specific analysis demonstrated that higher abundance of Fusicatenibacter and Butyricicoccus was linked to better OS in the NIC arm compared with that in the CP arm (hazard ratio for OS = 0.56 and 0.52, respectively). Conversely, the higher abundance of Prevotellaceae NK3B31 was associated with higher mortality risk in the NIC arm (hazard ratio for OS = 2.33).

Gut microbiota may serve as a biomarker for chemoimmunotherapy in advanced NSCLC. Differences in microbial diversity and specific bacterial genera were associated with prognosis and serious AEs, with potential regimen-specific effects. These findings support integrating gut microbiota profiling into clinical practice to optimize first-line treatment strategies.