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

Abstract

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. <i>NECTIN4</i> is located on chromosome 1q23.3, and 1q23.3 gains represent frequent copy number variations (CNVs) in urothelial cancer. Here, we aimed to evaluate <i>NECTIN4</i> amplifications as a genomic biomarker to predict EV response in patients with mUC. We established a <i>NECTIN4</i>-specific fluorescence in situ hybridization (FISH) assay to assess the predictive value of <i>NECTIN4</i> 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 <i>NECTIN4</i> 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 <i>NECTIN4</i> CNVs. <i>NECTIN4</i> 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, <i>NECTIN4</i> 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 <i>NECTIN4</i> amplifications demonstrated objective responses to EV compared with 32% (24 of 74) in the nonamplified subgroup (<i>P</i> < .001). In multivariable Cox analysis adjusted for age, sex, and Bellmunt risk factors, <i>NECTIN4</i> amplifications led to a 92% risk reduction for death (hazard ratio, 0.08 [95% CI, 0.02 to 0.34]; <i>P</i> < .001). In the mUC-non-EV, <i>NECTIN4</i> amplifications were not associated with outcomes. TCGA Pan-Cancer analysis demonstrated that <i>NECTIN4</i> amplifications occur frequently in other cancers, for example, in 5%-10% of breast and lung cancers. <i>NECTIN4</i> amplifications are genomic predictors of EV responses and long-term survival in patients with mUC.