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

2025-05-26T11:25:02Z

NECTIN4 Amplification Is Frequent in Solid Tumors and Predicts Enfortumab Vedotin Response in Metastatic Urothelial Cancer Klümper, Niklas; Tran, Ngoc Khanh; Zschäbitz, Stefanie; Hahn, Oliver; Büttner, Thomas; Roghmann, Florian; Bolenz, Christian; Zengerling, Friedemann; Schwab, Constantin; Nagy, Dora; Toma, Marieta; Kristiansen, Glen; Heers, Hendrik; Ivanyi, Philipp; Niegisch, Günter; Grunewald, Camilla Marisa; Darr, Christopher; Farid, Arian; Schlack, Katrin; Abbas, Mahmoud; Aydogdu, Can; Casuscelli, Jozefina; Mokry, Theresa; Mayr, Michael; Niedersüß-Beke, Dora; Rausch, Steffen; Dietrich, Dimo; Saal, Jonas; Ellinger, Jörg; Ritter, Manuel; Alajati, Abdullah; Kuppe, Christoph; Meeks, Joshua; Vera Badillo, Francisco E.; Nakauma-González, J. Alberto; Boormans, Joost; Junker, Kerstin; Hartmann, Arndt; Grünwald, Viktor; Hölzel, Michael; Eckstein, Markus 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 5 108). 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 5 103). 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.

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