Background: Non-transitional cell carcinoma of the urothelial tract (non-TCC) includes several distinct histologies and is associated with a poor prognosis. Prospective data regarding management of patients with metastatic non-TCC is scarce. In this single-arm, phase II study, we assessed the activity and safety of durvalumab and tremelimumab in patients with metastatic non-TCC (NCT03430895). Methods: Eligible patients had unresectable/metastatic non-TCC with ECOG PS 0-1 regardless of prior therapy (except for patients with small cell carcinoma who must have progressed after chemotherapy). Patients received treatment with durvalumab 1500 mg and tremelimumab 75 mg IV Q4W for up to 4 cycles, then durvalumab 1500 mg IV Q4W for a total treatment duration of 12 months. The primary endpoint was overall response rate by RECIST 1.1. The study was planned as a Simon’s minimax two-stage design, with 13 patients planned for stage 1. If 1 or more responses were seen in stage 1, an additional 14 patients were planned to be accrued for a total of 27. Results: Thirteen patients were treated (median age 57 years; range, 33-76), including 7 (54%) with small cell carcinoma, 3 (23%) with squamous cell carcinoma, and 3 (23%) with adenocarcinoma. 11 patients (85%) had visceral metastases, and 6 patients (46%) had liver metastases. The study was terminated after stage 1 as no responses were seen; 11 patients (85%) had PD and 2 patients (15%) had SD as their best response. Median PFS was 1.8 months (95% CI 1.25, not reached [NR]) with a median follow-up of 6.8 months (range 4.3 – 18.1 months). Median OS was 6.43 months (95% CI 4.36, NR). Grade 3-4 treatment-related adverse events occurred in 31% of patients. Conclusions: In this poor prognosis cohort of patients with non-TCC, no responses were seen with durvalumab and tremelimumab. Immune correlative studies to help determine mechanisms of resistance will be presented. Novel therapeutic strategies are urgently needed for patients with metastatic non-TCC. Clinical trial information: NCT03430895