Integrating NECTIN4 Amplification With Membranous Nectin-4 Expression to Develop a Scoring System for Predicting Enfortumab Vedotin Response in Urothelial Carcinoma

Abstract Purpose: Enfortumab vedotin (EV) is standard therapy for metastatic urothelial carcinoma (mUC), yet the predictive relevance of NECTIN4 expression—especially membranous versus cytoplasmic—remains unclear. Here, we sought to extend previous findings on NECTIN4 gene amplification in parallel with a systematic subcellular evaluation of NECTIN4 expression. Experimental Design: We retrospectively analyzed 179 EV-treated mUC patients. NECTIN4 amplification was assessed by FISH and NECTIN4 protein levels by IHC. A four-tier membranous scoring algorithm (0,1+,2+,3+) adapted from 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) to EV-301 data. Results: Combining membranous and cytoplasmic compartments resulted in a median composite H-score of 260 (78.2% ≥150), closely matching NECTIN4 expression prevalence reported in EV-301 (median 250; 82.6% ≥ 150). A ≥150 cut-off enriched for EV responders in both cohorts; in EV-301 with ORR of 45.8% vs. 20% (P = 0.001). High membranous expression based on the scoring (2+/3+) predicted response (ORR 55.1% vs. 25.5%; P < 0.001), with longer PFS (7.1 vs. 2.9 months; HR 0.45) and 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, non-amplified/high-membranous, and non-amplified/low-membranous—yielded ORRs of 77.2%, 42.9%, and 26.1% and separated survival outcomes. Conclusions: Our NECTIN4 scoring system integrating NECTIN4 amplification with membranous NECTIN4 expression accurately predicts outcomes, supporting combined genomic and membranous assessment as complementary biomarkers for optimizing EV selection.

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Journal
Clinical Cancer Research
Published
2026-09-09
DOI
https://doi.org/10.1158/1078-0432.ccr-26-0093
Primary Topic
Bladder and Urothelial Cancer Treatments
Type
article
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article

Integrating NECTIN4 Amplification With Membranous Nectin-4 Expression to Develop a Scoring System for Predicting Enfortumab Vedotin Response in Urothelial Carcinoma

Viktor Grünwald, Florian Roghmann, Joshua J. Meeks, Michael Hölzel et al.
Clinical Cancer Research
Bladder and Urothelial Cancer Treatments
article

Integrating NECTIN4 Amplification With Membranous Nectin-4 Expression to Develop a Scoring System for Predicting Enfortumab Vedotin Response in Urothelial Carcinoma

Viktor Grünwald, Florian Roghmann, Joshua J. Meeks, Michael Hölzel, Friedemann Zengerling, Kerstin Junker, Hendrik Heers, Manuel Ritter, Can Aydogdu, Thomas Büttner, Philipp Ivanyi, Stefanie Zschäbitz, Marcus Sondermann, Katrin Schlack, Dora Niedersuess‐Beke, Steffen Rausch, Jonas Saal, Arndt Hartmann, Fabienne Lange, Constantin Schwab, Christopher Darr, Jozefina Casuscelli, Christian Bolenz, Pia Paffenholz, Bonnie Choy, Marieta Toma, Susanne Fuessel, Oliver Hahn, Sarmad Sadeghi, Anna Scherping, Nadine Therese Gaisa, Christoph Kuppe, Niklas Klümper, Markus Eckstein, Johannes Brägelmann, Günter Niegisch, Camilla M. Grunewald, Christian Thomas, Parkash S. Gill, Sebastian Rauch, Ulrich Sommer, Patricia Rausch, Richard Weiten
article en

Abstract

Abstract Purpose: Enfortumab vedotin (EV) is standard therapy for metastatic urothelial carcinoma (mUC), yet the predictive relevance of NECTIN4 expression—especially membranous versus cytoplasmic—remains unclear. Here, we sought to extend previous findings on NECTIN4 gene amplification in parallel with a systematic subcellular evaluation of NECTIN4 expression. Experimental Design: We retrospectively analyzed 179 EV-treated mUC patients. NECTIN4 amplification was assessed by FISH and NECTIN4 protein levels by IHC. A four-tier membranous scoring algorithm (0,1+,2+,3+) adapted from 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) to EV-301 data. Results: Combining membranous and cytoplasmic compartments resulted in a median composite H-score of 260 (78.2% ≥150), closely matching NECTIN4 expression prevalence reported in EV-301 (median 250; 82.6% ≥ 150). A ≥150 cut-off enriched for EV responders in both cohorts; in EV-301 with ORR of 45.8% vs. 20% (P = 0.001). High membranous expression based on the scoring (2+/3+) predicted response (ORR 55.1% vs. 25.5%; P < 0.001), with longer PFS (7.1 vs. 2.9 months; HR 0.45) and 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, non-amplified/high-membranous, and non-amplified/low-membranous—yielded ORRs of 77.2%, 42.9%, and 26.1% and separated survival outcomes. Conclusions: Our NECTIN4 scoring system integrating NECTIN4 amplification with membranous NECTIN4 expression accurately predicts outcomes, supporting combined genomic and membranous assessment as complementary biomarkers for optimizing EV selection.

Clinical Cancer Research
Northwestern University (US), University of Southern California (US), Cleveland Clinic (US), LAC+USC Medical Center (US), University of Bonn (DE), TU Wien (AT), Friedrich-Alexander-Universität Erlangen-Nürnberg (DE), Universität Ulm (DE), Heidelberg University (DE), University of Würzburg (DE), University Hospital Bonn (DE), University Hospital Heidelberg (DE), LMU Klinikum (DE), Medizinische Hochschule Hannover (DE), Universitätsklinikum Erlangen (DE), Universitätsklinik Marien Hospital Herne (DE), Augenklinik Universitätsklinikum Würzburg (DE), University Hospital Münster (DE), National Center for Tumor Diseases (DE), Essen University Hospital (DE), Universitätsklinikum Aachen (DE), Universitätsklinikum Würzburg (DE), Northwestern Medicine (US), University Hospital Cologne (DE), University Hospital Ulm (DE), University Hospital Carl Gustav Carus (DE), Heinrich Heine University Düsseldorf (DE), Technische Universität Dresden (DE), University of Tübingen (DE), RWTH Aachen University (DE), Ruhr University Bochum (DE), Saarland University (DE)
Openalex Percentile: Top 8%
Bladder and Urothelial Cancer Treatments
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