BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug conjugates (ADCs) such as disitamab vedotin (DV) and trastuzumab deruxtecan (T-DXd) have emerged as effective treatment options and received regulatory approvals for HER2-expressing locally advanced or metastatic urothelial carcinoma (la/mUC). In addition, ADCs in combination with immunotherapy have demonstrated antitumor activity. The current study aimed to evaluate the combination of DV and toripalimab in patients with la/mUC. PATIENTS AND METHODS: This open-label phase Ib/II study enrolled patients with untreated or chemo-refractory la/mUC. During the dose-escalation phase, DV was administered at escalating doses of 1.5 and 2.0 mg/kg in combination with toripalimab 3.0 mg/kg once every 2 weeks. Primary endpoints were safety and the recommended phase II dose (RP2D). Secondary endpoints included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). RESULTS: From August 2020 to December 2021, a total of 41 patients were enrolled, including 6 in the dose-escalation phase and 35 in the dose-expansion phase. Sixty-one percent of patients were treatment naive. No dose-limiting toxicity was observed. The RP2D was determined as DV (2.0 mg/kg) plus toripalimab (3.0 mg/kg). By the data cut-off date of 1 March 2024, the confirmed ORR was 73.2%. The median PFS was 9.3 months, and the median OS was 33.1 months. The most common treatment-related adverse events (TRAEs) were aspartate aminotransferase increased (65.9%), alanine aminotransferase increased (63.4%), and peripheral sensory neuropathy (63.4%). Grade 3 or higher TRAEs occurred in 51.2% of patients, with the most common being γ-glutamyltransferase increased (12.2%), asthenia (9.8%), and alanine aminotransferase increased (7.3%). One treatment-related death (due to pneumonitis) was reported. CONCLUSIONS: The combination of DV and toripalimab demonstrated promising response rate and OS results with a manageable safety profile in HER2-unselected la/mUC patients. This combination represents a promising first-line option for la/mUC. Randomized phase III study is currently ongoing.