GUT MICROBIOTA (GM) COMPOSITION SIGNATURE AND SHIFT DURING STANDARD THERAPIES IN PATIENTS (PTS) WITH METASTATIC RENAL CELL CARCINOMA (MRCC)

Background: Baseline GM composition is associated with pts outcomes in pts with mRCC treated with immune-checkpoint blockade (ICB). We report IMDC risk and tyrosine kinase inhibitors (TKI)’s GM signatures and GM changes during shift during standard mRCC therapies (ICB and TKI). Methods: We prospectively collected fecal samples of all comers mRCC pts who started ICB or TKI or combinations from 1st line in the NCT04567446 trial at Gustave Roussy. Fecal samples were longitudinally collected before and during treatment (within 1, 3, 6 and 12 months of treatment start). Shot gun metagenomic sequencing (MGS) data were analyzed by multivariate and pair-wise/fold ratio. Patients under TKI were classified as either responders (R) (complete response + partial response (PR) + stable disease (SD) and overall survival (OS)> 12 months) or non-responders (NR) (progressive disease (PD) and OS<12 months by RECIST1.1). Patients under ICB were classified as elite if CR+PR with progression-free survival (PFS) > 12 months and OS > 24 months. Results: From February 2016 to July 2021, 160 mRCC pts were screened for enrollment and 135 met inclusion criteria. The overall response rate of TKI-treated pts was 48% and most of them experienced TKI-related diarrhea. Overall, we observed specific gut MG-fingerprints between IMDC risk groups, where intermediate IMDC harbor immunogenic commensals (Faecalibacterium, Akkermansia spp, Ruminococcaceae), and between TKI R versus NR, NR harboring pro-TH17 bacteria such as Veillonella parvula. Interestingly, both ICB and TKI induced significant and opposite GM shifts during treatment. While TKI induced pro-Treg tolerogenic bacteria (belonging to Enterocloster genus or diarrhea-associated B. intestinalis and Klebsiella), at the expense of health-related Eubacteriaceae and Bifidobacteria in R patients, ICB promoted the loss of tolerogenic Enterocloster gen. in elite pts and the loss of health-related bacteria in NR. Conclusions: In the largest longitudinal MG study in mRCC, we conclude that in contrast to ICB, TKI favor the over-representation of harmful commensals despite treatment success. Indeed, TKI increased bacteria related to carcinogenesis, weight loss, sarcopenia and inflammation as a possible consequence of gastrointestinal toxicity. Our data provide new rationale for decision making in first line and treatment sequencing in mRCC.