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

• DOI: 10.1200/jco.23.01983
• Publication Date: 2024-04-24T20:02:43Z
• Authors: Niklas Klümper; Ngoc Khanh Tran; Stefanie Zschäbitz; Oliver Hahn; Thomas Büttner; Florian Roghmann; Christian Bolenz; Friedemann Zenger...; Constantin Schwab; Dora Nagy; Marieta Toma; Glen Kristiansen; Hendrik Heers; Philipp Ivanyi; Günter Niegisch; Camilla Marisa Gr...; Christopher Darr; Arian Farid; Katrin Schlack; Mahmoud Abbas; Can Aydogdu; Jozefina Casuscelli; Theresa Mokry; Michael Mayr; Dora Niedersüß-Beke; Steffen Rausch; Dimo Dietrich; Jonas Saal; Jörg Ellinger; Manuel Ritter; Abdullah Alajati; Christoph Kuppe; Joshua Meeks; Francisco E. Vera...; J. Alberto Nakaum...; Joost Boormans; Kerstin Junker; Arndt Hartmann; Viktor Grünwald; Michael Hölzel; Markus Eckstein
• Keywords: Male; Aged, 80 and over; Urologic Neoplasms; DNA Copy Number Variations; Nectins; Medizin; Gene Amplification; Antibodies, Monoclonal; 610; ORIGINAL REPORTS; Middle Aged; SDG 3 - Good Health and Well-being; Urinary Bladder Neoplasms; 616; 617; Biomarkers, Tumor; Humans; Female; Cell Adhesion Molecules; In Situ Hybridization, Fluorescence; Aged

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 = 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. 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.