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 only achieved in a small, yet uncharacterized patient subset. NECTIN4 located on chromosome 1q23.3, and 1q23.3 gains represent frequent copy number variations (CNVs) cancer. Here, we aimed to evaluate amplifications as genomic biomarker predict EV response mUC. MATERIALS AND METHODS We established NECTIN4-specific fluorescence situ hybridization (FISH) assay assess the predictive value of CNVs multicenter EV-treated mUC cohort (mUC-EV, n = 108). were correlated membranous protein expression, treatment responses, outcomes. also assessed prognostic measured biopsies non–EV-treated (mUC-non-EV, 103). Furthermore, queried Cancer Genome Atlas (TCGA) data sets (10,712 across 32 types) CNVs. RESULTS are events muscle-invasive bladder (TCGA set: approximately 17%) (approximately 26% our cohorts). In mUC-EV, amplification represents stable alteration during progression associates enhanced expression. Ninety-six percent (27 28) demonstrated objective responses compared 32% (24 74) nonamplified subgroup ( P < .001). multivariable Cox analysis adjusted age, sex, Bellmunt risk factors, led 92% reduction death (hazard ratio, 0.08 [95% CI, 0.02 0.34]; mUC-non-EV, not associated TCGA Pan-Cancer that occur frequently other cancers, example, 5%-10% breast lung cancers. CONCLUSION predictors long-term survival