# NECTIN4 Amplification Is a Frequent Event in Central Nervous System Metastases of Urothelial Carcinoma

## TL;DR

Brain metastases of urothelial carcinoma often have high NECTIN4 gene amplification, suggesting that NECTIN4-targeted therapies may be effective for these patients.

## Contribution

This study is the first to systematically examine NECTIN4 amplification in central nervous system metastases of urothelial carcinoma.

## Key findings

- NECTIN4 amplification was found in 67% of central nervous system metastases cases.
- Membranous NECTIN4 expression was significantly higher in central nervous system metastases compared to non-CNS metastases.
- The findings suggest a biological rationale for using NECTIN4-targeted therapies in brain metastases.

## Abstract

NECTIN4 amplification has emerged as a promising biomarker for predicting the response to anti-NECTIN4 therapies in metastatic urothelial carcinoma (mUC). The anti-NECTIN4 antibody-drug conjugate enfortumab vedotin (EV) combined with pembrolizumab (EV/P) is now the standard of care for mUC, with results demonstrating that it prolongs overall survival in the perioperative setting for patients with muscle-invasive bladder cancer (MIBC). However, data on its effectiveness in patients with active central nervous system (CNS) metastases (MET) are limited, as these patients were excluded from pivotal trials. Recent studies show that NECTIN4 amplification is frequent in mUC (∼15–25%) and predicts the response to single-agent EV and to EV/P. Furthermore, NECTIN4 amplification appears to be a stable genomic feature during metastasis progression. So far, no research has specifically examined NECTIN4 amplification across different metastatic sites, with no systematic study in CNS MET, which is associated with poor outcomes. We compared a CNS MET cohort (n = 18) to two previous comprehensive mUC cohorts (1) non-CNS mUC (n = 128) and (2) EV-treated mUC (n = 108). NECTIN4 gene amplification was found in 67% of CNS MET cases (12/18), which is significantly higher than the 26% in the EV-treated cohort at baseline (28/108). This corresponds to an absolute difference of 41% (95% confidence interval 16–59%; p = 0.002). Consistently, membranous NECTIN4 expression was higher in CNS MET (median H score 175, interquartile range [IQR] 88–260) than in non-CNS mUC (median H score 40, IQR 0–140; p < 0.001). These findings provide a strong biological rationale for extending the use of NECTIN4-targeted therapies such as EV to patients with brain MET.

We found that tumor samples from patients with cancer of the urinary tract that had spread to the brain had higher expression of a gene called NECTIN4 (67%). Our findings suggest that treatments targeting NECTIN4, such as a drug called enfortumab vedotin with or without pembrolizumab, might benefit patients with brain metastases, especially if their tumors have high NECTIN4 levels.