Urothelial Cancer

P2, N=132, Not yet recruiting, Akeso

P2, N=70, Active, not recruiting, University of Southern California | N=103 --> 70 | Trial completion date: Nov 2026 --> Dec 2030 | Trial primary completion date: Nov 2025 --> Dec 2027

Stage-tailored strategies are emerging, including risk assessment in NMIBC, refining adjuvant decisions in MIBC, and treatment monitoring in mUC. Integration of ctDNA-guided approaches should proceed alongside prospective validation to ensure safe and effective adoption.

P2, N=62, Recruiting, Hoffmann-La Roche | N=362 --> 62

However, interpretation is constrained by small retrospective series, assay discordance, and the absence of standardized HER2 scoring criteria for UC. In the antibody-drug conjugate era, resolving these subtype-specific and methodological uncertainties is essential for refining patient selection and defining the clinical role of HER2-directed therapy across histologic subtypes and divergent histologist.

A 64-year-old man with metachronous metastatic urothelial carcinoma originating from the right renal pelvis underwent nectin-4-targeted [68Ga]Ga-NECT-224 PET/CT prior to initiation of nectin-4-targeted antibody-drug conjugate (ADC) therapy with enfortumab-vedotin (PADCEV), in combination with pembrolizumab. Subsequent [68Ga]Ga-NECT-224 PET/CT restaging revealed multiple new lesions with intense nectin-4 expression. This case illustrates the potential of [68Ga]Ga-NECT-224 PET/CT to visualize heterogeneous nectin-4 expression, its potential in therapy guidance, and highlights the need for theranostic strategies in patients retaining target expression despite cytotoxic therapy resistance.

Using a large-scale Japanese genomic panel dataset, we characterized the molecular alterations associated with S/DD. S/DD frequently exhibits low Nectin-4 expression and basal-like molecular features, which may have implications for treatment selection and inform future therapeutic strategies.

Conventional chemotherapy and first-generation antibody-drug conjugates (ADCs), such as ado-trastuzumab emtansine (T-DM1), were limited by non-specific cytotoxicity, heterogeneous drug-antibody ratios, linker instability, and insufficient bystander killing, yielding modest efficacy in heavily pretreated populations...Clinically, trastuzumab deruxtecan demonstrated meaningful progression-free survival benefit in HER2-low metastatic breast cancer, while enfortumab vedotin reduced mortality risk in platinum- and immunotherapy-refractory urothelial carcinoma, establishing ADC efficacy across solid tumor histologies...Trastuzumab deruxtecan carries a 15.4% incidence of interstitial lung disease, including fatal events, and sacituzumab govitecan is associated with grade 3 or higher neutropenia in approximately 51% of patients. Furthermore, next-generation ADCs are not resistance-proof, with antigen downregulation, payload efflux, and impaired internalization emerging as clinically relevant escape mechanisms. Biomarker-driven patient selection, rigorous toxicity monitoring, and prospective trials addressing resistance will be essential to realizing the full and durable potential of this drug class.

There were no expression differences in TROP2, Nectin4, PDL1, and HER2. However, a subset of GCUC patients might benefit from target therapies (PDL1, Nectin4), warranting more cohort studies.

P2, N=33, Not yet recruiting, University of Washington | Initiation date: Jun 2026 --> Sep 2026

P2, N=10, Not yet recruiting, Haihua Yuan

These findings suggest that NFE2L2-mutated urothelial carcinomas frequently have concomitant squamous and myxoid features, aggressive behaviour and high PD-L1 expression. Recognition of the NFE2L2-mutated urothelial carcinomas may have diagnostic and prognostic utility, particularly with immunotherapy and possible targeted therapy against the NRF2 signalling pathway. Further investigation with larger cohorts is warranted to expand the data surrounding NFE2L2 mutations in urothelial carcinoma.