Emergence of human epidermal growth factor receptor 2 as a key biomarker and therapeutic target in advanced urothelial carcinoma

Figure 1 Proposed clinical algorithm for the management of advanced urothelial carcinoma in the era of human epidermal growth factor receptor 2-directed therapy. This algorithm integrates mandatory human epidermal growth factor receptor 2 (HER2) biomarker testing into the contemporary treatment paradigm for locally advanced or metastatic urothelial carcinoma (la/mUC). First-line treatment selection is primarily guided by HER2 expression status, with disitamab vedotin plus toripalimab representing a new standard for HER2-expressing tumors (immunohistochemistry 1+, 2+, 3+). In contrast, enfortumab vedotin plus pembrolizumab remains the global standard for all patients, particularly those with HER2-negative disease. Alternative options are available depending on cisplatin eligibility, resource availability, and access to clinical trials. Maintenance avelumab following initial platinum-based chemotherapy and subsequent-line therapies is also incorporated. HER2: Human epidermal growth factor receptor 2; IHC: Immunohistochemistry; PD-L1: Programmed death-ligand 1; ADC: Antibody-drug conjugate; DV: Disitamab vedotin; PFS: Progression-free survival; OS: Overall survival; CR: Complete response; QoL: Quality of life; HR: Hazard ratio; FGFR: Fibroblast growth factor receptor.