Background: The role of gut microbial composition as a determinant of clinical outcomes has been well established in several cancers, including metastatic renal cell carcinoma (mRCC) (Routy et al Science 2018). A growing body of evidence suggests that examining the metabolic function of microbial communities may provide a more insightful understanding of these associations (Helmink et al Nature Medicine 2019). Herein, we aimed to examine the effect of nivolumab/ipilimumab with or without CBM588 on clinical outcomes and gut microbiome functionality. Methods: Treatment naïve mRCC pts with clear cell and/or sarcomatoid histology and IMDC intermediate/high risk disease were enrolled and randomized into receiving nivolumab/ipilimumab or nivolumab/ipilimumab with CBM588 in 1:2 fashion. Whole metagenome sequencing was performed on stool samples collected at baseline and week 12. Generated MetaPhlan 3.0 data was run through HUMAnN 3.0 to identify differentially expressed metabolic pathways between two timepoints in each arm and with respect to treatment response. Results: A total of 30 pts were enrolled and randomized, and 29 pts were eligible for analysis as one patient was excluded as tumor tissue next-generation sequencing revealed genomic alterations pathognomonic for sarcoma after initiation of protocol-based therapy. Median age of the participants was 66 years, 21 pts (72%) were male, 10 pts (34%) had sarcomatoid features, and 29 pts (45%) had prior nephrectomy. Objective response was achieved in 58% and 20% of the pts in nivolumab/ipilimumab/CBM-588 and nivolumab/ipilimumab arm, respectively. Significant changes in 40 metabolic pathways (37 with upregulation and 3 with downregulation) in nivolumab/ipilimumab arm and 52 metabolic pathways (49 with downregulation and 3 with upregulation) in nivolumab/ipilimumab with CBM588 arm were identified. In detail, dTDP-β-L-rhamnose biosynthesis, L-lysine biosynthesis II and superpathway of pyrimidine ribonucleosides degradation pathways were found upregulated while O-antigen building blocks biosynthesis (E. coli) pathway was found downregulated after treatment with nivolumab/ipilimumab and CBM588 (p = 0.001, p = 0.007, p = 0.037, p = 0.005 respectively). Heatmaps detailing the dynamics of metabolic pathway expressions in regard to response in each arm will be presented. Conclusions: We observed an increase in the activity of the pathways associated with butyrate consumption and a resultant decrease in glycolytic dependence. Further, suppression of the pathogenic E. coli function was observed, suggesting a role for CBM588 in protection from pathogenic species. Our findings provide mechanistic evidence for the effect of the addition of CBM588 to nivolumab/ipilimumab on gut microbiome function and resultant improvement in clinical outcomes in mRCC. Clinical trial information: NCT03829111.