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.
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.
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.
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.
NECTIN4 amplifications are genomic predictors of EV responses and long-term survival in patients with mUC.
Context
Key Objective: Can NECTIN4 amplifications be used as a genomic biomarker to predict the response to the anti-NECTIN4 antibody-drug conjugate (ADC) enfortumab vedotin (EV) in patients with metastatic urothelial cancer (mUC)?
Knowledge Generated: NECTIN4 amplifications were found to be frequent genomic events in mUC, occurring in approximately 25% of cases. In the EV-treated mUC patient cohort, 96% of patients with NECTIN4 amplifications showed objective responses to EV compared with 32% in the nonamplified subgroup. The frequent occurrence of NECTIN4 amplifications in various cancer types, for example, lung and breast cancers, indicates that this biomarker holds promise for tumor-agnostic clinical development of NECTIN4-targeted ADC.
Relevance (M.A. Carducci): This hypothesis generating study requires prospective evaluation as a predictive genomic biomarker for EV responses. Given the target of EV as an anti-NECTIN4 ADC, the results are highly plausible and may represent strong classifier for treatment response and improved clinical outcomes.*
*Relevance section written by JCO Associate Editor Michael A. Carducci, MD, FACP, FASCO.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2024 Apr 24 [Epub ahead of print]
Niklas Klümper, Ngoc Khanh Tran, Stefanie Zschäbitz, Oliver Hahn, Thomas Büttner, Florian Roghmann, Christian Bolenz, Friedemann Zengerling, Constantin Schwab, Dora Nagy, Marieta Toma, Glen Kristiansen, Hendrik Heers, Philipp Ivanyi, Günter Niegisch, Camilla Marisa Grunewald, 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 Badillo, J Alberto Nakauma-González, Joost Boormans, Kerstin Junker, Arndt Hartmann, Viktor Grünwald, Michael Hölzel, Markus Eckstein
Department of Urology and Pediatric Urology, University Hospital Bonn, Bonn, Germany., Department of Medical Oncology, National Center for Tumor Disease (NCT), University Hospital, Heidelberg, Germany., Department of Urology and Pediatric Urology, Julius Maximilians University Medical Center of Würzburg, Würzburg, Germany., BRIDGE-Consortium Germany e.V., Mannheim, Germany., Institute of Pathology, University of Heidelberg, Heidelberg, Germany., Center for Integrated Oncology Aachen/Bonn/Cologne/Düsseldorf (CIO-ABCD), Bonn, Germany., Department of Urology, University Hospital Marburg, Marburg, Germany., Department of Hemostaseology, Oncology and Stem Cell Transplantation, Medical University Hannover, Hannover, Germany., Department of Urology, University Hospital Düsseldorf, Düsseldorf, Germany., Department of Urology, University Hospital Essen, Essen, Germany., Department of Urology, University Medical Center Göttingen, Göttingen, Germany., Department of Urology, University Hospital Münster, Münster, Germany., Department of Pathology, University Hospital Münster, Münster, Germany., Department of Urology, University Hospital, Ludwig Maximilian University of Munich, Munich, Germany., Department of Diagnostic and Interventional Radiology, Heidelberg University Hospital, Heidelberg, Germany., Clinic Ottakring, Institute of Pathology and Microbiology, Wien, Austria., Department of Internal Medicine I, Wilhelminenspital, Wien, Austria., Department of Urology, Eberhard Karls University, Tübingen, Germany., Department of Otorhinolaryngology, University Medical Center Bonn (UKB), Bonn, Germany., Institute of Experimental Oncology, University Medical Center Bonn (UKB), Bonn, Germany., Institute of Experimental Medicine and Systems Biology and Division of Nephrology, RWTH Aachen University, Aachen, Germany., Department of Urology, Feinberg School of Medicine, Chicago, IL., Department of Medical Oncology, Queen's University, Kingston, Ontario, Canada., Department of Urology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands., Department of Urology and Pediatric Urology, Saarland University, Homburg, Germany., Clinic for Internal Medicine (Tumor Research) and Clinic for Urology, Interdisciplinary Genitourinary Oncology at the West-German Cancer Center, Essen University Hospital, Essen, Germany.