Background: Tucatinib, a highly selective human epidermal growth factor receptor 2 (HER2)-directed tyrosine kinase inhibitor approved in multiple regions for HER2-positive (HER2+) metastatic breast cancer, is being investigated as a novel therapy for metastatic colorectal cancer, gastric cancer, and other solid tumors. In xenograft models of HER2+ and HER2-mutated tumors, dual targeting of HER2 with tucatinib plus trastuzumab showed superior activity to either alone (Kulukian 2020; Peterson 2020). Despite development of several new therapies for metastatic urothelial cancer (UC), most patients are refractory to subsequent therapies and die from the disease, highlighting the need for additional therapeutic approaches. Given that 20%–30% of metastatic UCs have molecular alterations of the ErbB family, tucatinib plus trastuzumab warrants further evaluation. SGNTUC-019 (NCT04579380) is a multi-cohort, open-label, phase 2 study evaluating tucatinib plus trastuzumab in patients with previously treated solid tumors displaying HER2+ or HER2-mutated solid tumors, including a cohort with locally advanced or metastatic UC. Methods: Eligible patients in the UC cohort must have HER2+ locally advanced or metastatic disease, with progression during or after, or intolerance of, the most recent line of systemic therapy. Patients must have an ECOG PS ≤1; adequate hepatic, hematologic, renal, and cardiac function; and no prior exposure to HER2-directed therapy. HER2 alterations can be demonstrated by HER2 overexpression/amplification in tumor tissue by prior IHC/ISH or by HER2 amplification in prior or prescreening NGS assay of ctDNA or prior tissue NGS assay. The HER2 overexpression/amplification UC cohort will enroll 12 response-evaluable patients per RECIST 1.1. If ≥2 responses are observed, the cohort will be expanded to 30. The primary objective is antitumor activity, with confirmed ORR as the primary endpoint and DCR, duration of response, PFS, and OS as secondary efficacy endpoints. Confidence intervals (CIs) will be calculated for confirmed ORR and DCR. For time-to-event endpoints, median survival time will be estimated by the Kaplan-Meier method, and the associated 95% CI will be calculated using complementary log-log transformation. Safety endpoints will be assessed using descriptive statistics. Patients will receive tucatinib 300 mg orally twice daily and trastuzumab 8 mg/kg intravenously on Cycle 1 Day 1 and 6 mg/kg every 21 days from Cycle 2 Day 1. Disease assessments per RECIST 1.1 will occur every 6 weeks for 24 weeks, then every 12 weeks. Trough concentrations of tucatinib will be evaluated in Cycles 2–6, with peak concentration sampled in Cycle 3. Quality of life will be evaluated every second cycle using the EQ-5D-5L. Sites are currently enrolling within the US, EU, and Asia Pacific. Clinical trial information: NCT04579380.