Membranous NECTIN-4 Expression Frequently Decreases during Metastatic Spread of Urothelial Carcinoma and Is Associated with Enfortumab Vedotin Resistance

Klümper N, Ralser DJ, Ellinger J, Roghmann F, Albrecht J, Below E, Alajati A, Sikic D, Breyer J, Bolenz C, Zengerling F, Erben P, Schwamborn K, Wirtz RM, Horn T, Nagy D, Toma M, Kristiansen G, Büttner T, Hahn O, Grünwald V, Darr C, Erne E, Rausch S, Bedke J, Schlack K, Abbas M, Zschäbitz S, Schwab C, Mustea A, Adam P, Manseck A, Wullich B, Ritter M, Hartmann A, Gschwend J, Weichert W, Erlmeier F, Hölzel M, Eckstein M (2023)

Publication Type: Journal article

Publication year: 2023

Journal

Clinical Cancer Research American Association for Cancer Research

Book Volume: 29

Pages Range: 1496-1505

Journal Issue: 8

DOI: 10.1158/1078-0432.CCR-22-1764

Abstract

Purpose: The antibody–drug conjugate enfortumab vedotin (EV) releases a cytotoxic agent into tumor cells via binding to the membrane receptor NECTIN-4. EV was recently approved for patients with metastatic urothelial carcinoma (mUC) without prior assessment of the tumor receptor status as ubiquitous NECTIN-4 expression is assumed. Our objective was to determine the prevalence of membranous NECTIN-4 protein expression in primary tumors (PRIM) and patient-matched distant metastases (MET). Experimental Design: Membranous NECTIN-4 protein expression was measured (H-score) by IHC in PRIM and corresponding MET (N ¼ 137) and in a multicenter EV-treated cohort (N ¼ 47). Progression-free survival (PFS) after initiation of EV treatment was assessed for the NECTIN-4–negative/weak (H-score 0–99) versus moderate/strong (H-score 100–300) subgroup. The specificity of the NECTIN-4 IHC staining protocol was validated by establishing CRISPR-Cas9–induced polyclonal NECTIN-4 knockouts. Results: In our cohort, membranous NECTIN-4 expression significantly decreased during metastatic spread (Wilcoxon matched pairs P < 0.001; median H-score ¼ 40; interquartile range, 0–140), with 39.4% of MET lacking membranous NECTIN-4 expression. In our multicenter EV cohort, absence or weak membranous NECTIN-4 expression (34.0% of the cohort) was associated with a significantly shortened PFS on EV (log-rank P < 0.001). Conclusions: Membranous NECTIN-4 expression is frequently decreased or absent in mUC tissue. Of note, the clinical benefit of EV strongly depends on membranous NECTIN-4 expression. Thus, our results are of highest clinical relevance and argue for a critical reconsideration of the current practice and suggest that the NECTIN-4 receptor status should be determined (ideally in a metastatic/progressive lesion) before initiation of EV.

Involved external institutions

Klinikum Ingolstadt DE Germany (DE) Universitätsklinikum Bonn DE Germany (DE) BRIDGE Consortium e.V. (Bladder Cancer Research Initiative for Drug Targets Germany) DE Germany (DE) Bayerisches Zentrum für Krebsforschung (BZKF) DE Germany (DE) Centrum für Integrierte Onkologie Aachen Bonn Köln Düsseldorf (CIO ABCD) DE Germany (DE) Universitätsklinikum Göttingen DE Germany (DE) Universitätsklinikum Essen DE Germany (DE) Eberhard Karls Universität Tübingen DE Germany (DE) Universitätsklinikum Münster DE Germany (DE) Universitätsklinikum Heidelberg DE Germany (DE) Ruprecht-Karls-Universität Heidelberg DE Germany (DE)

How to cite

APA:

Klümper, N., Ralser, D.J., Ellinger, J., Roghmann, F., Albrecht, J., Below, E.,... Eckstein, M. (2023). Membranous NECTIN-4 Expression Frequently Decreases during Metastatic Spread of Urothelial Carcinoma and Is Associated with Enfortumab Vedotin Resistance. Clinical Cancer Research, 29(8), 1496-1505. https://doi.org/10.1158/1078-0432.CCR-22-1764

MLA:

Klümper, Niklas, et al. "Membranous NECTIN-4 Expression Frequently Decreases during Metastatic Spread of Urothelial Carcinoma and Is Associated with Enfortumab Vedotin Resistance." Clinical Cancer Research 29.8 (2023): 1496-1505.

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