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

Clinical cancer research : an official journal of the American Association for Cancer Research

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

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.

PMID: 42714834

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