Background: Previous treatment with ICI is more common in clinical practice since recent FDA-approval of 5 ICIs in second-line and 2 in first-line for mUC. There is lack of data regarding the use of ICI after progression on a prior ICI. Cabozantinib has been shown to have immunomodulatory properties and may have synergistic effect with ICI. Methods: This is a phase I expansion cohort of mUC pts, who received prior ICI, treated with Cabozantinib 40mg daily and Nivolumab 3mg/kg every 2 weeks until disease progression/unacceptable toxicity. The primary objective was to determine the efficacy and tolerability of CaboNivo. Results: Twenty-nine mUC pts were treated. Median follow-up was 14.1 months (mo). The majority of pts were male (75.8%); 27 were White (93.1%), and 2 were Asian (6.9%). Primary tumor was bladder in 21 pts (72.4%) and upper tract in 8 (27.6%). Twenty-two pts (75.9%) had visceral metastasis (mets), 4 (13.8%) had lymph node only mets and 13 (44.8%) had liver mets. The median number of prior lines of treatment for mUC was 2 (range 0-8) with 17 pts (58.6%) receiving 2 prior lines of treatment. The majority of pts (86.2%) received prior chemotherapy for mUC and all pts received prior ICI. The median number of cycles of prior ICI was 7 (range 1-20) and median time between previous ICI and CaboNivo was 2.5 mo (range 1-18). The best response to previous ICI was partial response (PR) in 1 pt (3.4%), stable disease (SD) in 13 (44.9%), progressive disease (PD) in 14 (48.3%) and one (3.4%) was not evaluable (NE). The overall response rate for CaboNivo was 13.8% with 4 pts achieving PR (13.8%), 15 SD (51.7%), 7 PD (24.2%) and 3 NE (10.3%). Responses were seen in the liver, lung, and lymph nodes. Among 4 pts with PR, 2 were primary refractory to previous ICI and 2 had SD. At cutoff date the median duration of response was not reached and 3 PR were still ongoing: 1 had just began and the other 2 were ongoing at 12.3 and 26.4 mo. Among 15 pts with SD, 4 had SD for more than 6 mo and 2 were still ongoing at 8.1 and 25.1 mo. Median progression-free survival was 3.6 mo (95% CI: 2.1 – 5.3 mo) and median overall survival was 10 mo (95% CI: 5.8 – 16.7 mo). Grade 1/ 2 treatment related adverse events (AEs) occurred in 28 pts (97%) and >Grade 3 (G>3) AEs occurred in 14 pts (48%). The most common G>3 AEs were fatigue (14%), hypophosphatemia (14%), lymphocyte count decrease (14%), hypertension (7%) and hyponatremia (7%). Conclusions: CaboNivo is clinically active and safe in heavily pretreated pts with progressive mUC following ICI. Clinical trial information: NCT02496208.