<em>NECTIN4</em> Amplification Is Frequent in Solid Tumors and Predicts Enfortumab Vedotin Response in Metastatic Urothelial Cancer

Abstract

<strong>PURPOSE</strong> 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. <em>NECTIN4</em> is located on chromosome 1q23.3, and 1q23.3 gains represent frequent copy number variations (CNVs) in urothelial cancer. Here, we aimed to evaluate <em>NECTIN4</em> amplifications as a genomic biomarker to predict EV response in patients with mUC.<br /> <strong>MATERIALS AND METHODS</strong> We established a <em>NECTIN4</em>-specific fluorescence in situ hybridization (FISH) assay to assess the predictive value of <em>NECTIN4</em> CNVs in a multicenter EV-treated mUC patient cohort (mUC-EV, n 5 108). CNVs were correlated with membranous <em>NECTIN4</em> protein expression, EV treatment responses, and outcomes. We also assessed the prognostic value of <em>NECTIN4</em> 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 <em>NECTIN4</em> CNVs.<br /> <strong>RESULTS</strong> <em>NECTIN4</em> 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, <em>NECTIN4</em> 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 <em>NECTIN4</em> 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, <em>NECTIN4</em> 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, <em>NECTIN4</em> amplifications were not associated with outcomes. TCGA Pan-Cancer analysis demonstrated that <em>NECTIN4</em> amplifications occur frequently in other cancers, for example, in 5%-10% of breast and lung cancers.<br /> <strong>CONCLUSION</strong> <em>NECTIN4</em> amplifications are genomic predictors of EV responses and long-term survival in patients with mUC.