Age-related NECTIN4 amplification affects sensitivity and resistance development to the anti-Nectin-4 antibody-drug-conjugate enfortumab vedotin
Final Report Abstract
The anti-NECTIN4 antibody-drug conjugate (ADC) enfortumab vedotin (EV) has been approved for the treatment of metastatic urothelial cancer (mUC). The phase 3 EV-302 trial recently demonstrated the superiority of a combination of EV with pembrolizumab (EV/P) over cisplatinum plus gemcitabine (GC) and established a new standard of care for unselected patients with previously untreated mUC. In our research, we investigated the role of membranous NECTIN-4 expression and amplifications as predictive biomarkers in patients with mUC treated with EV. Initial studies indicated that NECTIN4 expression is widespread mUC, which led to approval of the EV for unselected patients with mUC. However, the recent literature suggests that there has been overestimation of membranous NECTIN4 expression in UC, which is a prerequisite for EV binding. In our study published in Clinical Cancer Research, 2023, we aimed to determine the prevalence of membranous NECTIN-4 protein expression in primary tumors (PRIM) and distant metastases (MET) of mUC patients, and its impact on EV treatment outcomes (1). We found that membranous NECTIN-4 expression significantly decreases during metastatic spread, with a notable absence in 39.4% of MET. Moreover, in a cohort treated with EV, patients with weak or absent NECTIN-4 expression experienced significantly shortened progression-free survival (PFS). These findings underscore the clinical relevance of assessing NECTIN-4 receptor status before initiating EV treatment. In our subsequent study, we delved into NECTIN4 amplifications as genomic biomarkers to predict EV response and outcomes in mUC patients. We developed a fluorescence in-situ hybridization (FISH) assay to evaluate NECTIN4 copy number variations (CNVs) in an EV-treated patient cohort. We found that NECTIN4 amplifications are frequent genomic events in mUC, occurring in approximately 25% of cases, and are associated with enhanced membranous NECTIN-4 protein expression. Importantly, patients with NECTIN4 amplifications demonstrated significantly higher objective response rates to EV and improved long-term survival compared to those without amplifications. These results highlight the potential of NECTIN4 amplifications as predictive markers for EV therapy in mUC patients. Overall, our research emphasizes the importance of understanding NECTIN-4 expression and amplifications in guiding treatment decisions and improving outcomes for mUC patients receiving EV therapy. We recently discussed our biomarker results in the context of the phase 3 EV-302 trial (3) and summarized them in a mini-review.
Publications
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Membranous NECTIN-4 Expression Frequently Decreases during Metastatic Spread of Urothelial Carcinoma and Is Associated with Enfortumab Vedotin Resistance. Clinical Cancer Research, 29(8), 1496-1505.
Klümper, Niklas; Ralser, Damian J.; Ellinger, Jörg; Roghmann, Florian; Albrecht, Julia; Below, Eduard; Alajati, Abdullah; Sikic, Danijel; Breyer, Johannes; Bolenz, Christian; Zengerling, Friedemann; Erben, Philipp; Schwamborn, Kristina; Wirtz, Ralph M.; Horn, Thomas; Nagy, Dora; Toma, Marieta; Kristiansen, Glen; Büttner, Thomas ... & Eckstein, Markus
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Biomarkers of Response to Anti-NECTIN4 Antibody-Drug Conjugate Enfortumab Vedotin in Urothelial Cancer. European Urology Focus, 10(2), 224-226.
Klümper, Niklas & Eckstein, Markus
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Occurrence of NECTIN4 amplification in solid tumors and enfortumab vedotin response in metastatic urothelial cancer.. Journal of Clinical Oncology, 42(4_suppl), 673-673.
Klümper, Niklas; Tran, Ngoc Khanh; Zschaebitz, Stefanie; Hahn, Oliver; Zengerling, Friedemann; Nagy, Dora; Kristiansen, Glen; Ivanyi, Philipp; Grunewald, Camilla Marisa; Darr, Christopher; Schlack, Katrin; Rausch, Steffen; Ritter, Manuel; Junker, Kerstin; Hartmann, Arndt; Grünwald, Viktor; Hölzel, Michael & Eckstein, Markus
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Re: Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. European Urology, 86(3), 280-281.
Klümper, Niklas; Vera-Badillo, Francisco E.; Eckstein, Markus; Hadaschik, Boris & Grünwald, Viktor
