What question did this study set out to answer?

The aim is to assess NECTIN4 amplification's prevalence and its relationship with targeted therapy effectiveness in breast cancer.

April 5, 2026

Abstract 7227: NECTIN4-a mplified breast cancer targeted by Zelenectide Pevedotin: Amplification and expression are frequent, concordant, and stable

Puntos clave

The aim is to assess NECTIN4 amplification's prevalence and its relationship with targeted therapy effectiveness in breast cancer.
Analyzed public multi-omic BC data from METABRIC, TCGA, and TRANSNEO datasets.
Linked high NECTIN4 copy number to expression levels using proprietary data from the Cologne cohort.
Conducted metastatic analyses on META-PRISM dataset for CN prevalence and expression correlation.
Performed structural studies to evaluate Zelenectide Pevedotin's binding affinity to Nectin-4.
High NECTIN4 copy number was found in 21.1% to 30.8% of breast cancer cases across datasets.
Elevated Nectin-4 mRNA and protein expression correlated with high CN (p < 2 × 10-16).
In the Cologne cohort, high CN strongly correlated with high membranous Nectin-4 expression (H-score 150 vs 0, p = 8.8 × 10-28).
Zelenectide pevedotin showed high affinity for Nectin-4 domain 1 with a binding constant of 2.5 nM.

Resumen

Abstract Background: NECTIN4 amplification (amp) can predict response to Nectin4-targeted therapy. In the Phase I/II Duravelo-1 trial (NCT04561362), NECTIN4-amp breast cancer (BC) showed higher response rates to the Bicycle® Drug Conjugate (BDC™) zelenectide pevedotin (zele, formerly BT8009) versus non-amp tumors (57.1% vs. 6.3%) (Klümper et al, SABCS 2024). These findings led to FDA Fast Track designation and the Phase II Duravelo-3 trial in NECTIN4-amp BC (NCT06840483). To further characterize NECTIN4 and its targetability, we assessed its prevalence, biology across BC datasets, and describe its structure-activity based targeting. Methods: Public, multi-omic primary BC data from METABRIC (n=2173), TCGA (n=1079), and TRANSNEO (n=166) were analyzed. Proprietary primary tissue data (Cologne cohort, n=252) linked high NECTIN4 copy number (CN; amp/polysomy via FISH) with expression and BC subtypes. Metastatic analyses were conducted on META-PRISM (n=59). High NECTIN4 CN was defined as 2× ploidy (amp) or ≥6 copies (polysomy). Structural and biophysical studies (crystallography, SPR) assessed zele’s binding. Results: High NECTIN4 CN was observed in 21.1% (METABRIC), 30.8% (TCGA), and 29.5% (TRANSNEO) of cases, ranking in the 97.5th percentile for amp (TCGA, all genes). By subtype, HR+, HER2+, and TNBC tumors exhibited high CN in 21%, 19%, and 20% (METABRIC) and 30%, 29%, and 36% (TCGA), respectively. CN correlated with elevated mRNA (p 2 × 10-16) and protein expression (p = 2 × 10-6). No differences were observed by immune infiltrate or germline BRCA status. In the Cologne cohort, high NECTIN4 CN (19.1%) strongly correlated with membranous Nectin-4 expression (median H-score 150 vs 0, p = 8.8 × 10-28). In META-PRISM metastases, high CN prevalence was similar (29%) and correlated with RNA expression (r2 = 0.34, p 0.00001). Zelenectide pevedotin binds Nectin-4 domain 1 with high affinity (Kd 2.5 ± 1.5 nM) and minimal conformational change (RMSD 0.435 Å). Its compact bicyclic scaffold (4.2 kDa, surface area 1900 Å2) provides a smaller footprint than conventional antibodies while maintaining strong target engagement, and rapid renal clearance (t½ 1 h), which should support rapid tumor penetration, and efficient delivery of the MMAE payload. Conclusions: NECTIN4 amplification is frequent, concordant with high RNA and protein expression, and stable in frequency between primary and metastatic BC. Nectin-4 can be effectively engaged by the BDC zelenectide pevedotin with high affinity. The frequency and stability of NECTIN4 amplification across breast cancer subtypes supports its evaluation as a biomarker for patient selection in Nectin-4-targeted trials. Citation Format: Alexander Azizi, Niklas Klümper, Emma Colliver, Alexander Quaas, Birgid Schoemig-Markiefka, Arndt Hartmann, Christoph Kuppe, Manuel Ritter, Viktor Grünwald, Michael Hölzel, Chris Bailey, Gustavo Arruda Bezerra, Nicholas Guthertz, Sergey Nikolaev, Fabrice Andre, Charles Swanton, Johannes Braegelmann, Markus Eckstein. NECTIN4-amplified breast cancer targeted by Zelenectide Pevedotin: Amplification and expression are frequent, concordant, and stable abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7227.

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