Background: RC48-ADC has shown promising data in HER2-positive and even negative patients with metastatic urothelial carcinoma (mUC) who failed with platinum-based chemotherapy. RC48-ADC combined with anti-PD-1 antibody may have a synergistic antitumor effect. Methods: This is an open-label, multicenter, phase 1b/II trial to evaluate the safety and activity of RC48 combined with toripalimab in mUC. Patients received RC48-ADC at 1.5 or 2 mg/kg, in combination with 3mg/kg toripalimab every two weeks in a dose-escalation and expansion cohort until confirmed disease progression, unacceptable toxicity, or voluntary withdrawal. The key primary endpoint was safety; secondary endpoints included efficacy and tumor tissue biomarkers. Results: As of 17 Jan 2022 (data cutoff), 41 la/mUC pts (19 males; median age 66 y [42-76]) were enrolled since 20 Aug 2020. 61% patients were systemic treatment naïve, and 54% had visceral metastases (mets), including 24% with liver mets. The primary site was in upper tract UC in 54%. HER2 expression was positive (IHC 2+ or 3+) in 59% patients, and PD-L1 positive (CPS ≥ 10) in 32%. No dose-limiting toxicity was observed. The recommended dose was RC48-ADC 2mg/kg + toripalimab 3mg/kg every 2 weeks. With a median follow-up of 8.0 mos, 36 patients had at least one tumor assessment, the best ORR was 83.3%, and the confirmed ORR was 76.7% (95%CI: 57.7, 90.1), including 10% CR. The cORR was 82.4% for 1L previously untreated mUC patients, 100% for patients with HER2 IHC (2+ or 3+) & PD-L1 (+), 92.3% for HER2 (2+ or 3+) & PD-L1 (-), 50% for HER2 (0 or 1+) & PD-L1 (+), and 50% HER2 (0 or 1+) & PD-L1 (-). DCR was 96.7% (95%CI: 82.8, 99.9). The median PFS was immature and 9.2 mos (95%CI: 5.49, 10.32) by the time and the median OS was not reached. The most common treatment-related AEs were ALT/AST increase (65.9%), peripheral sensory neuropathy (58.5%), appetite decrease (56.1%), asthenia (56.1%), hypertriglyceridemia (48.8%). Grade ≥3 TRAEs included γ-glutamyl transferase increase (12.2%), ALT/AST increase (7.3%), asthenia (7.3%), hypertriglyceridemia (4.9%), and neutropenia (4.9%). 9 pts had irAEs (22.0%, 7.3% ≥ G3), including immune-related pneumonitis, hepatitis, and myositis. Conclusions: RC48-ADC in combination with toripalimab demonstrated promising efficacy in patients with mUC and a manageable safety profile. A randomized study of RC48-ADC and toripalimab vs. platinum-based chemotherapy in previously untreated la/mUC patients is ongoing. Clinical trial information: NCT04264936.