PO.ET06.06 · 实验与分子治疗

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

编号 7227 展板 19 时间 4/22 09:00–12:00 区域 Section 18 主讲 Alexander Azizi, BA;MA;MS

分会场 Tumor Diagnostics, Prognostics, and Therapeutic Outcomes

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作者与单位

Alexander Azizi¹, Niklas Klümper², Emma Colliver¹, Alexander Quaas³, Birgid Schoemig-Markiefka³, Arndt Hartmann⁴, Christoph Kuppe⁵, Manuel Ritter², Viktor Grünwald⁶, Michael Hölzel⁷, Chris Bailey¹, Gustavo Arruda Bezerra⁸, Nicholas Guthertz⁸, Sergey Nikolaev⁹, Fabrice Andre⁹, Charles Swanton¹, Johannes Braegelmann³, Markus Eckstein¹⁰

¹The Francis Crick Institute, London, United Kingdom,²University of Bonn, Bonn, Germany,³University of Cologne, Cologne, Germany,⁴Inst. of Pathology, University Hospital Erlangen, Erlangen, Germany,⁵RWTH Aachen, Aachen, Germany,⁶Essen University Hospital, Essen, Germany,⁷University Medical Centre Bonn, Bonn, Germany,⁸Bicycle Therapeutics, Cambridge, United Kingdom,⁹Gustave Roussy, Villejuif, France,¹⁰FAU Erlangen-Nürnberg, Nurnberg, Germany

摘要 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.

利益披露 Disclosure

A. Azizi, WHYZE Health Independent Contractor. Revena Independent Contractor. Nxera Pharma Independent Contractor. N. Klümper, Bicycle Therapeutics Independent Contractor, Stock, ). Astellas Independent Contractor. Novartis Independent Contractor, Travel. Eisai Independent Contractor. Merck Independent Contractor, Travel. MSD Independent Contractor. Ipsen Travel. Johnson & Johnson Travel. A. Quaas, None.. B. Schoemig-Markiefka, None. A. Hartmann, AbbVie Independent Contractor. AstraZeneca Independent Contractor, ). Biocartis Independent Contractor, ). BMS Independent Contractor. Boehringer Ingelheim Independent Contractor. Cepheid Independent Contractor, ). Diaceutis Independent Contractor. Gilead Independent Contractor, ). Illumina Independent Contractor, ). Ipsen Independent Contractor. Janssen Independent Contractor, ). Lilly Independent Contractor. Merck Independent Contractor. MSD Independent Contractor. Novartis Independent Contractor, ). Pfizer Independent Contractor. QUIP GmbH Independent Contractor, ). Owkin ). C. Kuppe, Bayer Independent Contractor. OMAPiX Independent Contractor. InsilicoMedicine Independent Contractor. M. Ritter, Medac Independent Contractor, ), Travel. Janssen Independent Contractor. Procept Biorobotics ). V. Grünwald, Novartis Independent Contractor. Amgen Independent Contractor. Apogepha Independent Contractor. Astellas Independent Contractor. AstraZeneca Independent Contractor, ), Travel. BMS Independent Contractor, ). Eisai Independent Contractor. Ipsen Independent Contractor, Travel. Janssen Independent Contractor. Merck Independent Contractor, Travel. MSD Independent Contractor, ). Novartis Independent Contractor. Oncorena Independent Contractor. PCI Biotech Independent Contractor. Pfizer Independent Contractor. Bicycle Therapeutics Independent Contractor. M. Hölzel, OncoMAGENTx Inc Independent Contractor, Travel. TME Pharma AG Independent Contractor, ), Travel. C. Bailey, None. G. Arruda Bezerra, Bicycle Therapeutics Employment, Stock. N. Guthertz, Bicycle Therapeutics Employment, Stock. S. Nikolaev, None. J. Braegelmann, Bayer ). Merck Travel. M. Eckstein, Bicycle Therapeutics Independent Contractor, Stock, ). Eisai Independent Contractor. MSD Independent Contractor. AstraZeneca Independent Contractor, ). Janssen Independent Contractor, ). Cepheid Independent Contractor, ). Roche Independent Contractor, ). Astellas Independent Contractor. Diaceutics Independent Contractor. Owkin Independent Contractor. BMS Independent Contractor. Merck Independent Contractor. Ferring Independent Contractor. GenomicHealth Independent Contractor. Gilead ). STRATIFYER ). QUIP GmbH ).

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