EAU 2024: Membranous NECTIN-4 Expression in Metastasis Versus Matched Primary Tumor More Accurately Predicts Enfortumab Vedotin Response

(UroToday.com) The 2024 European Association of Urology (EAU) annual meeting featured a session on metastatic urothelial cancer, and a presentation by Dr. Thomas Büttner discussing membranous NECTIN-4 expression in metastasis compared to the primary tumor and the outcome of enfortumab vedotin response. Among patients with metastatic urothelial carcinoma, there is a previously uncharacterized subgroup with primary resistance to therapy with enfortumab vedotin. As such, the membranous expression of the enfortumab vedotin target NECTIN-4 expression within the tumor tissue seems to be involved. The objective of this study presented at EAU 2024 was to investigate whether an analysis of the primary tumor is representative of metastatic disease, comparing the predictive value of membranous NECTIN-4 expression in the primary tumor tissue with that of a metastatic urothelial carcinoma distant metastasis sample.

In this retrospective multicenter German cohort, 26 enfortumab vedotin-treated patients with metastatic urothelial carcinoma were identified in whom paired tissue samples from primary tumors and distant metastasis were available. Membrane NECTIN-4 expression was assessed by immunohistochemistry, quantified by H-score, and categorized as negative (H-score 0-15), low (15-99), moderate (100-199), and high (200-300). The endpoints were investigator-reported objective response rate and progression-free.

For this study, the median follow-up was 9 months, with ROC analysis of objective response rate showing an area under the curve of 0.770 for primary tumors and 0.903 for distant metastasis (p = 0.087). In univariate Cox analysis, NECTIN-4 H-score was significantly associated with improved progression-free survival in primary tumors and distant metastasis as a continuous variable (primary tumors: p = 0.008, HR 0.994, 95% CI 0.989 - 0.998; distant metastasis: p < 0.001, HR 0.990, 95% CI 0.984 - 0.996). In Cox regression analysis, an H-score of 100 - 300 compared with 0 - 99 in primary tumors (p = 0.014, HR 0.289, 95% CI 0.108 - 0.775) and distant metastasis (p = 0.001, HR 0.184, 95% CI 0.07 - 0.519) showed a significantly lower risk of progression under enfortumab vedotin. Kaplan-Meier analysis showed significantly prolonged progression-free survival with a NECTIN-4 H-score of 100-300 in primary tumors (log-rank p = 0.024) and distant metastasis (log-rank p = 0.00043):


Dr. Büttner concluded his presentation by discussing membranous NECTIN-4 expression in metastasis compared to the primary tumor and the outcome of enfortumab vedotin response with the following statements:

  • Membranous NECTIN-4 expression is a promising indicator of enfortumab vedotin treatment response and progression-free survival
  • Analyzing distant metastasis seems to be more precise and of higher predictive value compared to primary tumors
  • Given potential new treatment options for metastatic urothelial carcinoma, measurement of NECTIN-4 expression in distant metastases may be helpful in future enfortumab vedotin therapy decision-making

Presented by: Thomas Büettner, MD, University Hospital Bonn, Bonn, Germany

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2024 European Association of Urology (EAU) annual congress, Paris, France, April 5th - April 8th, 2024