2O TILs and PD-L1 early dynamics in the randomized Neo-CheckRay phase II trial evaluating neo-adjuvant immuno-radiation and adenosine pathway blockade for early-stage, high risk ER+/HER2- breast cancer (BC)

Background: Immunotherapy has transformed treatment for advanced non-small cell lung cancer (NSCLC).However, reliable biomarkers for treatment selection remain scarce.Gut microbiota (GM) has emerged as a potential biomarker, but its role in chemo-immunotherapy for NSCLC is unclear. Methods:The phase III trial (JCOG2007, NIPPON) compared pembrolizumab plus platinum doublet chemotherapy (PC) and nivolumab-ipilimumab plus platinum doublet chemotherapy (NIC) in treatment-nave advanced NSCLC patients without driver gene alterations.As an ancillary biomarker study, 270 patients with baseline fecal samples were analyzed for GM composition out of 295 patients enrolled in JCOG2007.16S rDNA sequencing was performed for the subsequent GM diversity and differential abundance analysis. Results:The beta diversity analysis of the overall cohort (n270) revealed distinct microbial structures between responders and non-responders, categorized by overall survival (OS) at 12 or 18 months.Subsequent LEfSe analysis identified specific bacterial genera that differed between the groups, 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 severe AEs ( grade 4).Additionally, favorable genera, including Fusicatenibacter and Butyricicoccus, were associated with a lower risk of severe AEs.Lastly, regimen-specific analysis showed that higher abundance of Fusicatenibacter and Butyricicoccus in the NIC arm were linked to better OS compared to the CP arm (Hazard Ratio (HR) 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 (HR for OS 2.33).Conclusions: GM may serve as a biomarker for chemo-immunotherapy in advanced NSCLC.Differences in microbial diversity and specific bacterial genera were associated with prognosis and severe AEs, with potential regimen-specific effects.These findings support integrating GM profiling into clinical practice to optimize first-line treatment strategies.