Background: The NIVOREN GETUG-AFU 26 study reported safety and efficacy of nivolumab in patients with RCC in a “real world setting”. A translational research program was launched to quantify baseline cytokine levels and correlate them with outcomes to nivolumab. Methods: Extreme responder patients (pts) treated with nivolumab as part of the phase II NIVOREN GETUG-AFU 26 were included in this TRAINING cohort. A panel of 14 different plasma cytokines and proteins (VEGF, VCAM-1, IL-6, IL-7, IL-8, IL-10, APRIL, BAFF, 4-1BB, BCA, SDF-1, MDC, IFN-gamma and TNF-alpha) were quantified for each plasma sample using the Elisa-based Meso Scale Discovery electrochemiluminescence assay. The association between baseline cytokine levels and objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) was evaluated. Results: Overall, 80 pts, 40 responders and 40 progressors, were included for cytokine analysis. Baseline characteristics were similar to the overall trial population. The IMDC risk score breakdown was 11.3% good, 56.3% intermediate and 32.5% poor. With a median follow-up of 21.2 months, mOS data was immature at data cut-off. Overall survival rate was 67.3% at 12 months and median PFS was 3.8 months. Increased levels of IL-6 (75^th percentile=P75), IL-7 (P75), IL-8 (P50) and VEGF (P50) were significantly negatively associated with survival (IL-6: HR=2.44, p=0.0112; IL-7: HR=2.38, p=0.0123; IL-8: HR=2.80, p=0.0045, and VEGF: HR=2.43, p=0.0133). 4-1BB (P50) was associated with improved OS (HR=0.39, p=0.0375). Higher levels of IL-8 (P50) and VEGF (P50) were associated with worse PFS (IL-8: HR=2.50, p=0.0133, and VEGF: HR=1.96, p=0.0132) and worse ORR (IL-8: p=0.013, and VEGF: p=0.044). Except for IL-8 and VEGF, no other associations with response were observed. Conclusions: Higher baseline plasma levels of IL-6, IL-7, IL-8 and VEGF were significantly associated with worse survival outcomes in mRCC pts treated with nivolumab within TRAINING cohort of the NIVOREN trial. In contrast, 4-1BB was significantly associated with improved OS. IL-8 and VEGF were also associated with worse PFS and ORR. VALIDATION cohort within the entire NIVOREN study is ongoing.