Association of NECTIN-4 Expression With Enfortumab Vedotin Resistance in Metastatic Urothelial Carcinoma

Study findings reveal that membranous NECTIN-4 expression in metastatic urothelial carcinoma tissue is often decreased or absent, of which enfortumab vedotin efficacy is highly dependent. As Niklas Klümper, MD, University Medical Center Bonn, Bonn, Germany, and coauthors wrote, “Enfortumab vedotin releases a cytotoxic agent into the urothelial carcinoma tumor cell via binding to the tumor surface protein NECTIN-4.”

This study aimed to discover how membranous NECTIN-4 protein expression changes “in a well-characterized urothelial carcinoma progression cohort by comparison of patients-matched primary tumors and synchronous or metachronous metastases.” The study also sought to determine whether membranous NECTIN-4 expression could predict enfortumab vedotin response in this population of patients. There were 137 urothelial carcinoma specimens, 96 from radical cystectomy and 41 from transurethral resection of bladder tumor (TURBT). NECTIN-4 expression was determined via immunohistochemical staining.

In both the primary tumors and corresponding metastases, there was a heterogeneous expression of NECTIN-4. Of the primary tumors, 19.7% were classified as NECTIN-4-negative, 28.4% showed weak NECTIN-4 expression, and 26.3% showed moderate. During metastatic spread, NECTIN-4 expression was found to decrease significantly: 39.4% of metastases were NECTIN-4-negative and NECTIN-4 expression decreased during metastatic spread in 59.1% of cases.

Histological subtypes of urothelial carcinoma were associated with a lower NECTIN-4 expression, compared with conventional urothelial carcinoma. Additionally, in histological subtypes, there was no significant difference in NECTIN-4 expression during metastatic spread.

In the enfortumab vedotin-treated cohort, all patients had received chemotherapy and most (97.9%) received an immune checkpoint inhibitor prior to the initiation of enfortumab vedotin therapy. Those patients who achieved stable disease, partial or complete responses while on enfortumab vedotin had significantly higher NECTIN-4 expression than those patients with progressive disease.

Dr Klümper et al stated this “indicated that low/absent membranous NECTIN-4 expression predicts [enfortumab vedotin] resistance.” However, 15% of the cohort showed a mixed response on enfortumab vedotin, and there were patients with low tumoral NECTIN-4 expression that achieved disease control.

Limitations of the study include the use of retrospectively collected patient cohorts, and the determination of a NECTIN-4 H-score of 100 as the cutoff between absent/low and moderate/strong expression. Study authors noted the optimal clinical cutoff for enfortumab vedotin therapy stratification would need to be further investigated in prospective studies.

Dr Klümper at al concluded, “Membranous NECTIN-4 expression is frequently decreased or absent in [metastatic urothelial carcinoma] tissue,” adding their results “argue for a critical reconsideration of the current practice and suggest that the NECTIN-4 receptor status should be determined…before initiation of [enfortumab vedotin].”

Source:

Klümper N, Ralser, Ellinger J, et al. Membranous NECTIN-4 expression frequently decreases during metastatic spread of urothelial carcinoma and is associated with enfortumab vedotin resistance. Clin Cancer Res. Published online January 13, 2023. doi:10.1158/1078-0432.CCR-22-1764