NECTIN4 Amplification Is Frequent in Solid Tumors and Predicts Enfortumab Vedotin Response in Metastatic Urothelial Cancer

Klümper N, Tran NK, Zschäbitz S, Hahn O, Büttner T, Roghmann F, Bolenz C, Zengerling F, Schwab C, Nagy D, Toma M, Kristiansen G, Heers H, Ivanyi P, Niegisch G, Grunewald CM, Darr C, Farid A, Schlack K, Abbas M, Aydogdu C, Casuscelli J, Mokry T, Mayr M, Niedersüß-Beke D, Rausch S, Dietrich D, Saal J, Ellinger J, Ritter M, Alajati A, Kuppe C, Meeks J, Vera Badillo FE, Nakauma-González JA, Boormans J, Junker K, Hartmann A, Grünwald V, Hölzel M, Eckstein M (2024)

Publication Type: Journal article

Publication year: 2024

Journal

Book Volume: 42

Pages Range: 2446-2455

Journal Issue: 20

DOI: 10.1200/JCO.23.01983

Abstract

PURPOSEThe 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 METHODSWe 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.RESULTSNECTIN4 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.CONCLUSIONNECTIN4 amplifications are genomic predictors of EV responses and long-term survival in patients with mUC.

Involved external institutions

Universitätsklinikum Bonn Germany (DE) Universitätsklinikum des Saarlandes (UKS) Germany (DE) BRIDGE Consortium e.V. (Bladder Cancer Research Initiative for Drug Targets Germany) Germany (DE) Universitätsklinikum Essen Germany (DE) Northwestern University United States (USA) (US) Queen's University Canada (CA) Erasmus University Medical Center (MC) Netherlands (NL) Universitätsklinikum Heidelberg Germany (DE) Julius-Maximilians-Universität Würzburg Germany (DE) Ruprecht-Karls-Universität Heidelberg Germany (DE) Centrum für Integrierte Onkologie Aachen Bonn Köln Düsseldorf (CIO ABCD) Germany (DE) Universitätsklinikum Gießen und Marburg (UKGM) Germany (DE) Gottfried Wilhelm Leibniz Universität Hannover Germany (DE) Universitätsklinikum Düsseldorf Germany (DE) Universitätsklinikum Göttingen Germany (DE) Universitätsklinikum Münster Germany (DE) Klinikum der Universität München Germany (DE) Wiener Gesundheitsverbund Kliniken Austria (AT) Wilhelminenspital Austria (AT) Eberhard Karls Universität Tübingen Germany (DE) Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen Germany (DE)

How to cite

APA:

Klümper, N., Tran, N.K., Zschäbitz, S., Hahn, O., Büttner, T., Roghmann, F.,... Eckstein, M. (2024). NECTIN4 Amplification Is Frequent in Solid Tumors and Predicts Enfortumab Vedotin Response in Metastatic Urothelial Cancer. Journal of Clinical Oncology, 42(20), 2446-2455. https://doi.org/10.1200/JCO.23.01983

MLA:

Klümper, Niklas, et al. "NECTIN4 Amplification Is Frequent in Solid Tumors and Predicts Enfortumab Vedotin Response in Metastatic Urothelial Cancer." Journal of Clinical Oncology 42.20 (2024): 2446-2455.

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