Background: The antibody-drug conjugate enfortumab vedotin (EV) releases a cytotoxic agent into tumor cells via binding to the membrane receptor NECTIN-4. EV has been recently approved for patients with metastatic urothelial carcinoma (mUC) without prior assessment of the tumor receptor status as ubiquitous NECTIN-4 expression is assumed. Objective: To determine the prevalence of membranous NECTIN-4 protein expression in primary tumors (PRIM) and patient-matched distant metastases (MET). Main Outcomes and Measures: Membranous NECTIN-4 protein expression was measured (H-score) by immunohistochemistry (IHC) in PRIM and corresponding MET (N=137) and in a multicenter EV-treated cohort (N=47). Progression-free survival (PFS) after initiation of EV treatment was assessed for the NECTIN-4 negative/weak (H-score 0-99) versus moderate/strong (H-score 100-300) subgroup. The specificity of the NECTIN-4 IHC staining protocol was validated by establishing CRISPR-Cas9-induced polyclonal NECTIN-4 knockouts. Results: In our cohort, membranous NECTIN-4 expression significantly decreased during metastatic spread (Wilcoxon matched pairs P<0.001, median H-score=40, interquartile range (IQR): 0-140), with 39.4% of MET lacking membranous NECTIN-4 expression. In our multicenter EV cohort, absence or weak membranous NECTIN-4 expression (34.0% of the cohort) was associated with a significantly shortened PFS on EV (Log-rank P<0.001). Conclusion: Membranous NECTIN-4 expression is frequently decreased or absent in mUC tissue. Of note, the clinical benefit of EV strongly depends on membranous NECTIN-4 expression. Thus, our results are of highest clinical relevance and argue for a critical reconsideration of the current practice and suggest that the NECTIN-4 receptor status should be determined (ideally in a metastatic/ progressive lesion) before initiation of EV.
<div>AbstractPurpose:<p>The antibody–drug conjugate enfortumab vedotin (EV) releases a cytotoxic agent into tumor cells via binding to the membrane receptor NECTIN-4. EV was recently approved for patients with metastatic urothelial carcinoma (mUC) without prior assessment of the tumor receptor status as ubiquitous NECTIN-4 expression is assumed. Our objective was to determine the prevalence of membranous NECTIN-4 protein expression in primary tumors (PRIM) and patient-matched distant metastases (MET).</p>Experimental Design:<p>Membranous NECTIN-4 protein expression was measured (H-score) by IHC in PRIM and corresponding MET (<i>N</i> = 137) and in a multicenter EV-treated cohort (<i>N</i> = 47). Progression-free survival (PFS) after initiation of EV treatment was assessed for the NECTIN-4–negative/weak (H-score 0–99) versus moderate/strong (H-score 100–300) subgroup. The specificity of the NECTIN-4 IHC staining protocol was validated by establishing CRISPR-Cas9–induced polyclonal NECTIN-4 knockouts.</p>Results:<p>In our cohort, membranous NECTIN-4 expression significantly decreased during metastatic spread (Wilcoxon matched pairs <i>P</i> < 0.001; median H-score = 40; interquartile range, 0–140), with 39.4% of MET lacking membranous NECTIN-4 expression. In our multicenter EV cohort, absence or weak membranous NECTIN-4 expression (34.0% of the cohort) was associated with a significantly shortened PFS on EV (log-rank <i>P</i> < 0.001).</p>Conclusions:<p>Membranous NECTIN-4 expression is frequently decreased or absent in mUC tissue. Of note, the clinical benefit of EV strongly depends on membranous NECTIN-4 expression. Thus, our results are of highest clinical relevance and argue for a critical reconsideration of the current practice and suggest that the NECTIN-4 receptor status should be determined (ideally in a metastatic/progressive lesion) before initiation of EV.</p><p><i><a href="https://aacrjournals.org/clincancerres/article/doi/10.1158/1078-0432.CCR-22-3882" target="_blank">See related commentary by Aggen et al., p. 1377</a></i></p></div>
<p>Supplementary Figure 1. Expression of membranous NECTIN-4 in UC histology subtypes in PRIM (A) and MET (B). (C) depicts differential NECTIN-4 expression during metastatic spread. Intergroup comparison was calculated by non-parametric Kruskal-Wallis test.</p>
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