Background: Nivolumab is an approved standard tretatment for pts with mRCC after one VEGFR-TKI failure. Some reports suggest that Nibolumab provides similar response rate across treatment line. Nevetheless, no comparative data has been reported on the sequence of 2nd line Nivolumab followed by TKI vs TKI followed by Nivolumab in 3rd or later line. Objective: To determine the optimal sequence of Nivolumab monotherapy and anti-VEGFR-TKI in mRCC beginning from the 2nd line. Methods: We included in a French expert center all patients with mRCC who received real-life experienced of anti-PD1 nivolumab monotherapy in 2nd line setting or later were included in a French expert center. Clinical characteristics were prospectively recorded including IDMC prognostic factors. Patients who did not receive TKI on the 1st line were excluded. Survival outcomes and subgroups analysis were performed using log rank test and univariate cox regression analysis. Results: 91 patients with mRCC received Nivolumab between January 2006 and May 2018, 58 pts received nivolumab in 2nde line (63%) and 33 in 3rd line and more. Median follow-up was 18.9 [0.1;143] months starting from the beginning of the 2nd line. All received first line anti-VEGFR TKI, 83%/11% sunitinib/pazopanib. At the beginning of 2^nd line, IMDC prognostic groups were Fav 19%/Int 56%/ Poor 24%, with similar repartition (p=0,8) between pts treated with Nivolumab vs others. PFS at 6 months for 2nd line was in favor of patients treated by targeted treatments with respectively 63% (IC95% [46%;80%]) and 34% (IC95% [23%;49%]), p=0,06. OS at 24 months for 2nd line was significatively higher for patients treated by targeted treatments with 72% (IC95% [56;87%]) and 46% (IC95% [31%;61%]), p=0,007. Conclusions: We report for the first time the optimal timing to sequence Nivolumab – targeted therapy in patients with mRCC. We found better PFS and OS when Nivolumab is given after the 2nde line of treatment. Subgroups analysis including IMDC prognostic groups and duration of fist line TKI will be presented at the meeting.