Data from a multicentre cohort of patients with metastatic urothelial cancer (mUC) highlight NECTIN4 amplifications as genomic biomarkers to predict enfortumab vedotin responses and favourable outcomes. NECTIN4 amplification was strongly associated with enfortumab vedotin sensitivity (best overall response 96%). However, the response rate of 32% in the non-amplified subgroup is comparable with the expected outcomes (best overall response approximately 40%) observed in real-world settings and the pivotal phase III EV-301 study. With a median overall survival of 12 months in mUC cohort treated with enfortumab vedotin, data confirm the clinical activity of enfortumab vedotin in previously treated patients with mUC.
The data are hypothesis-generating and prospective confirmation in larger, biomarker-driven trials is mandatory. Frequent occurrence of NECTIN4 amplifications in other cancer types suggests broader applicability for clinical development of NECTIN4-targeted antibody drug conjugates in a tumour-agnostic context according to Dr. Niklas Klümper of the Department of Urology and Pediatric Urology, University Hospital Bonn; Institute of Experimental Oncology, University Medical Center Bonn; Center for Integrated Oncology Aachen/Bonn/Cologne/Düsseldorf; BRIDGE-Consortium Germany and colleagues who published the findings on 24 April 2024 in the JCO.
The authors wrote in the background that anti-NECTIN4 antibody-drug conjugate enfortumab vedotin is approved for treatment of patients with mUC. However, durable benefitis are only achieved in a small, yet uncharacterised patient subset although there is evidence that NECTIN4 is heterogeneously expressed in UC molecular subtypes. NECTIN4 is located on chromosome 1q23.3, and 1q23.3 gains represent frequent copy number variations (CNVs) in UC.
The study team has recently showed that membranous NECTIN4 expression frequently decreased during metastatic spread and correlates with enfortumab vedotin response in patients with mUC. In light of other effective treatment alternatives such as TROP2- or HER2–directed antibody drug conjugates or FGFR inhibitors, a better understanding of the molecular basis for enfortumab vedotin responses is needed to improve the rational use of this effective drug for patients with mUC and to optimise its ongoing clinical development in earlier UC stages and other solid tumours.
The relationship between CNV, mRNA, and protein expression has been known for decades. Previous reports linked NECTIN4 gene expression to gains/amplifications of 1q23.3, where the NECTIN4 gene is located, occurring in approximately 15-20% of mUC with an enrichment of NECTIN4 amplifications in luminal molecular subtypes of mUC. Despite the frequency of NECTIN4 CNVs in mUC, to date, the link between NECTIN4 CNVs, membranous NECTIN4 protein expression, and especially the clinical potential of NECTIN4 CNVs to predict enfortumab vedotin responses has not been assessed.
In a multicentre cohort of 108 patients with mUC treated with enfortumab vedotin, the study team assessed NECTIN4 CNVs and their association with membranous NECTIN4 protein expression and correlated the results with enfortumab vedotin responses and outcomes. Furthermore, they confirmed the correlation of NECTIN4 CNVs, mRNA, and protein expression in a The Cancer Genome Atlas (TCGA) pan-cancer analysis and explored the prevalence of NECTIN4 CNVs representing a potential tumour-agnostic genomic biomarker to predict enfortumab vedotin response in multiple cancer entities.
They established a NECTIN4-specific fluorescence in situ hybridization assay to assess the predictive value of NECTIN4 CNVs. CNVs were correlated with membranous NECTIN4 protein expression, enfortumab vedotin treatment responses, and outcomes. They also assessed the prognostic value of NECTIN4 CNVs measured in metastatic biopsies of 103 patients with mUC who were not treated with enfortumab vedotin. In addition, they queried TCGA data sets of 10,712 patients across 32 cancer types for NECTIN4 CNVs.
NECTIN4 amplifications are frequent genomic events in muscle-invasive UC with approximately 17% in TCGA bladder cancer data set and approximately 26% in mUC cohorts. In patients with mUC treated with enfortumab vedotin, NECTIN4 amplification represents a stable genomic alteration during metastatic progression and associates with enhanced membranous NECTIN4 protein expression.
A total, 96% of patients with NECTIN4 amplifications demonstrated objective responses to enfortumab vedotin compared with 32% in the non-amplified subgroup (p < 0.001). In multivariable Cox analysis adjusted for age, sex, and Bellmunt risk factors, NECTIN4 amplifications led to a 92% risk reduction for death (hazard ratio 0.08, 95% confidence interval 0.02 to 0.34; p < 0.001).
In the subgroup of patients with mUC who were not treated with enfortumab vedotin, NECTIN4 amplifications were not associated with outcomes suggesting that NECTIN4 amplifications are neither indicating aggressive nor favourable tumour biology, strengthening its potential value as a pure predictive biomarker.
A wide range of surface targets, such as HER2 or TROP2, are present in different types of cancers, and there has been a growing interest to expand the use of antibody drug conjugates beyond specific cancer types in a tumour-agnostic fashion.
TCGA Pan-Cancer analysis demonstrated that NECTIN4 amplifications occur frequently in other cancers, for example, in 5-10% of breast and lung cancers. NECTIN4 amplification is a simple, valuable, and easy-to-implement predictive biomarker for enfortumab vedotin in patients with mUC. The frequent occurrence of NECTIN4 amplifications in other cancer types suggests that this biomarker is a promising candidate with broader applicability for clinical development of NECTIN4-targeted antibody drug conjugates in a tumour-agnostic context.
The study was supported by different grants and the authors acknowledged BioBank initiatives of the participating centres for their support of this study, the NGS Core Facility of the Medical Faculty at the University of Bonn and the TCGA Research Network.
Reference
Klümper N, Tran NK, Zschäbitz S, et al. NECTIN4 Amplification Is Frequent in Solid Tumors and Predicts Enfortumab Vedotin Response in Metastatic Urothelial Cancer. JCO; Published online 24 April 2024. DOI: https://doi.org/10.1200/JCO.23.019838