PURPOSE: The anti-NECTIN4 antibody-drug conjugate enfortumab vedotin (EV) is approved for patients with metastatic urothelial cancer (mUC). However, durable benefit is only achieved in a small, yet uncharacterized patient subset. NECTIN4 is located on chromosome 1q23.3, and 1q23.3 gains represent frequent copy number variations (CNVs) in urothelial cancer. Here, we aimed to evaluate NECTIN4 amplifications as a genomic biomarker to predict EV response in patients with mUC. MATERIALS AND METHODS: We established a NECTIN4-specific fluorescence in situ hybridization (FISH) assay to assess the predictive value of NECTIN4 CNVs in a multicenter EV-treated mUC patient cohort (mUC-EV, n = 108). CNVs were correlated with membranous NECTIN4 protein expression, EV treatment responses, and outcomes. We also assessed the prognostic value of NECTIN4 CNVs measured in metastatic biopsies of non–EV-treated mUC (mUC-non-EV, n = 103). Furthermore, we queried The Cancer Genome Atlas (TCGA) data sets (10,712 patients across 32 cancer types) for NECTIN4 CNVs. RESULTS: NECTIN4 amplifications are frequent genomic events in muscle-invasive bladder cancer (TCGA bladder cancer data set: approximately 17%) and mUC (approximately 26% in our mUC cohorts). In mUC-EV, NECTIN4 amplification represents a stable genomic alteration during metastatic progression and associates with enhanced membranous NECTIN4 protein expression. Ninety-six percent (27 of 28) of patients with NECTIN4 amplifications demonstrated objective responses to EV compared with 32% (24 of 74) in the nonamplified subgroup ( P < .001). In multivariable Cox analysis adjusted for age, sex, and Bellmunt risk factors, NECTIN4 amplifications led to a 92% risk reduction for death (hazard ratio, 0.08 [95% CI, 0.02 to 0.34]; P < .001). In the mUC-non-EV, NECTIN4 amplifications were not associated with outcomes. TCGA Pan-Cancer analysis demonstrated that NECTIN4 amplifications occur frequently in other cancers, for example, in 5%-10% of breast and lung cancers. CONCLUSION: NECTIN4 amplifications are genomic predictors of EV responses and long-term survival in patients with mUC.

Background: Our study endeavors to elucidate the clinical implications of PD-L1 positivity in individuals afflicted with advanced urothelial carcinoma of the bladder (UCB). Methods: Patients with advanced UCB were prospectively enrolled following a radical cystectomy (RC) performed within January 2017 to December 2022 at our tertiary referral center. The clinical outcome, defined as the progression-free survival (PFS) and overall survival (OS) on systemic treatment, was analyzed using an χ²-test, Mann–Whitney U-test, the Kaplan–Meier method, and a log-rank test. Results: A total of 648 patients were included following an RC performed within January 2017 to December 2022. Their PD-L1 status was analyzed with the primary PD-L1-specific antibody (clone SP263, Ventana) and defined both by the CPS and IC-score in 282 patients (43.5%) with a high risk (pT3–pT4 and/or lymph node involvement) or metastatic UCB. While the median PFS was significantly prolonged 5-fold in PD-L1+ patients, we found no difference in OS, regardless of PD-L1 status, or treatment regimen. Conclusions: While PD-L1 positivity indicates prolonged PFS, the presence of PD-L1 does not influence OS rates, suggesting its limited usefulness as a prognostic biomarker in bladder cancer. However, the positive correlation between an PD-L1 status and a sustained response to ICI treatments indicates its potential role as a predictive biomarker. Further research is required to understand how the predictive value of PD-L1 positivity may extend to the use of ICIs in combination with antibody-drug conjugates.

Immune checkpoint inhibitor (ICI) therapies have been established as the standard-of-care in various uro-oncological cancers. Immune-related adverse events (irAEs) are frequent, but their degree rarely leads to the discontinuation of immunotherapies. Unplanned permanent treatment discontinuation may negatively impact the outcomes of patients, but there are emerging data about a positive correlation between emergence of severe irAEs and therapeutic cancer responses. In this study, a retrospective analysis of patients treated for urothelial carcinoma (UC) with ICI-based immunotherapy was conducted. irAEs were classified according to the Common Terminology Criteria for Adverse Events (CTCAEs) and radiological responses according to the Response Evaluation Criteria In Solid Tumors (RECISTs). Out of 108 patients with metastatic urothelial cancer that underwent immunotherapy, 11 experienced a severe irAE that required permanent discontinuation of ICI therapy. The most frequent irAEs leading to discontinuation were hepatitis (n = 4), pneumonitis (n = 2), and gastritis or colitis (n = 2). Prior to discontinuation (R1), the radiological best response was complete remission (CR) in three patients, partial response (PR) in six, and stable disease (SD) in wo patients. After the discontinuation of ICI therapy (R2), the best responses were CR in six, PR in three, and SD in two patients. Following discontinuation, the majority of these patients showed a sustained treatment response, despite not receiving any cancer-specific treatment. The median time of response after discontinuation of ICI therapy was 26.0 (5.2–55.8) months. We propose accurate counseling and close follow-ups of patients following their discontinuation of ICI therapy due to irAEs, as responses can be durable and deep, and many patients do not require immediate subsequent therapies, even in urothelial cancer. More data are required to find predictors of the length of response to appropriately counsel patients.

Purpose: Enfortumab vedotin (EV) is standard therapy for metastatic urothelial carcinoma (mUC), yet the predictive relevance of Nectin cell adhesion molecule 4 (NECTIN4) expression—especially membranous versus cytoplasmic—remains unclear. In this study, we sought to extend previous findings on NECTIN4 gene amplification in parallel with a systematic subcellular evaluation of Nectin-4 expression. Experimental Design: We retrospectively analyzed 179 EV-treated patients with mUC. NECTIN4 amplification was assessed by fluorescence in situ hybridization (FISH) and Nectin-4 protein levels by immunohistochemistry (IHC). A four-tier membranous scoring algorithm (0, 1+, 2+, and 3+) adapted from the College of American Pathologists (CAP) HER2 gastric guidelines was benchmarked against H-score. We integrated amplification status with membranous staining to refine predictive stratification and compared associations with objective response rate (ORR) with those observed in EV-301 data. Results: Combining membranous and cytoplasmic compartments resulted in a median composite H-score of 260 (78.2% ≥ 150), closely matching Nectin-4 expression prevalence reported in EV-301 (median, 250; 82.6% ≥ 150). A ≥150 cutoff enriched for EV responders in both cohorts, with an ORR of 45.8% versus 20% (P = 0.001) in EV-301. High membranous expression based on the scoring (2+/3+) predicted response (ORR, 55.1% vs. 25.5%; P < 0.001), with longer progression-free survival [PFS; 7.1 vs. 2.9 months; hazard ratio (HR) = 0.45] and overall survival (OS; 12.3 vs. 6.9 months; HR = 0.57), whereas cytoplasmic expression lacked predictive value. NECTIN4-amplified tumors showed particularly favorable outcomes (PFS, 12.2 months; OS, 30.1 months). An integrated three-tier model—amplified, nonamplified/high-membranous, and nonamplified/low-membranous—yielded ORRs of 77.2%, 42.9%, and 26.1% and separated survival outcomes. Conclusions: Our Nectin-4 scoring system integrating NECTIN4 amplification with membranous Nectin-4 expression accurately predicts outcomes, supporting combined genomic and membranous assessment as complementary biomarkers for optimizing EV selection. See related article by YYY, p. XX .

Objectives: To evaluate whether a simplified risk model preserves the prognostic performance of the International Bladder Cancer Group (IBCG) five‐factor risk stratification model in intermediate‐risk (IR) non‐muscle‐invasive bladder cancer (NMIBC). Patients and Methods: We performed a multicentre retrospective analysis of 2822 patients with IR NMIBC treated with transurethral resection of bladder tumour and intravesical therapy between 2005 and 2025. Multivariable Cox regression identified independent predictors of recurrence and progression. A simplified risk model was constructed using significant variables and compared with the full IBCG model using recurrence and progression rates, area under the curve analysis, and likelihood ratio testing. Results: A total of 2822 patients with IR NMIBC were included. When classified using the full IBCG model, 1143 (41%) were in the IR‐low, 1535 (54%) IR‐intermediate, and 144 (5%) IR‐high‐risk groups. On multivariable analysis, only multifocality, early recurrence, and failure of intravesical therapy independently predicted oncological outcomes. Using these factors, patients were stratified as IR‐low (no factors), IR‐intermediate (one factor), or IR‐high (two or more factors). Under the simplified model, 1535 (54%) patients were classified as IR‐low, 906 (32%) as IR‐intermediate, and 381 (14%) as IR‐high. The 3‐year recurrence and progression rates increased stepwise across simplified risk groups. Discriminative performance of the simplified model was comparable to the full model across all metrics, with no meaningful loss of discrimination. Conclusion: Three variables captured the most prognostic signal in this cohort without loss of discrimination compared with the full model. This simplified model is an internally validated refinement, with planned external validation to confirm generalisability and to ensure that simplified thresholds do not alter the clinically important IR‐high subgroup used in care and trials.