Metastatic Urothelial Cancer: NECTIN4 Amplification and Response to Enfortumab Vedotin

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In a study reported in the Journal of Clinical Oncology, Klümper et al established a fluorescence in situ hybridization (FISH) assay to measure NECTIN4 copy number variations and found that NECTIN4 amplification was associated with high activity of the anti-NECTIN4 antibody-drug conjugate enfortumab vedotin-ejfv in patients with metastatic urothelial carcinoma.

Study Details

The German multicenter study included 108 patients with metastatic urothelial cancer treated with enfortumab vedotin and 103 patients not treated with enfortumab vedotin. Samples were assessed by a NECTIN4-specific FISH to determine presence of NECTIN4 amplification.

Key Points

A total of 28 (26%) of 108 patients in the enfortumab vedotin cohort had NECTIN4 amplifications. Of the 28 with an amplification, 26 (96%) had objective response to enfortumab vedotin treatment, compared with 36% of patients without an amplification (P < .001). Overall survival at 1 year was 90% vs 41%, respectively, and median overall survival was not reached vs 8.8 months. In a multivariate analysis adjusted for age, sex, and Bellmunt risk factors, NECTIN4 amplification vs nonamplification was associated with a significant reduction in mortality (hazard ratio = 0.08, 95% confidence interval [CI] = 0.02–0.34, P < .001).

In the non–enfortumab vedotin cohort, NECTIN4 amplifications were found in 27 (26%) of 103 patients and were not associated with differences in outcomes vs patients without amplifications.

Analysis of The Cancer Genome Atlas datasets (10,712 patients with 32 cancer types) for NECTIN4 copy number variations showed amplifications in 25 cancer types, most commonly bladder cancer (17%), cholangiocarcinoma (14%), hepatocellular carcinoma (12%), breast cancer (9%), and lung adenocarcinoma (7%).

The investigators concluded, “NECTIN4 amplifications are genomic predictors of enfortumab vedotin responses and long-term survival in patients with metastatic urothelial carcinoma.”

Niklas Klümper, MD, of the Institute of Experimental Oncology, University Medical Center Bonn, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was funded by the German Research Foundation and others. For full disclosures of the study authors, visit

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