NECTIN4

  • NECTIN4 (nectin cell adhesion molecule 4; formerly PVRL4) encodes a single-pass type I transmembrane protein of the nectin family.1
  • Gene Location: Chromosome 1 (1q23.3).1

Biology

  • Nectin-4 mediates cell adhesion through homophilic and heterophilic interactions; a soluble form is released by ADAM17 cleavage. Its high expression on urothelial carcinoma and limited expression in normal tissue make it a target for antibody-drug conjugates.1,2

Etiology and Epidemiology

  • Expression is common: in 2394 specimens, 69% were Nectin-4-positive by IHC, with moderate to strong staining in 60% of bladder tumors.2
  • By stage and histology: 87% of NMIBC and 50 of 86 MIBC were positive in one series; expression was low in sarcomatoid (10%) and absent in small cell (0%) tumors. Expression was lower after neoadjuvant chemotherapy and varied between primary and nodal specimens.3,4
  • NECTIN4 amplification: found in about 26% of metastatic urothelial carcinoma and about 17% of TCGA MIBC; amplification is stable during metastatic progression.5

Testing

When to Test:

  • Nectin-4 testing is not required before enfortumab vedotin. Its indications are defined by disease setting and prior therapy, not by Nectin-4 expression.6

Testing Methodologies:

  • No companion diagnostic: no FDA-approved Nectin-4 assay exists, and no cut point has been clinically validated.6
  • Investigational assays: in a retrospective cohort, NECTIN4 amplification by FISH was associated with a 96% response rate to enfortumab vedotin vs 32% without amplification (HR for death, 0.08). A 2026 scoring system combining amplification with membranous IHC is under study. Cytoplasmic expression was not predictive.5,7

Guideline Recommendations

  • No guideline recommends routine Nectin-4 testing. NCCN designates enfortumab vedotin plus pembrolizumab as the only preferred first-line regimen for locally advanced or metastatic urothelial carcinoma, regardless of cisplatin eligibility, based on clinical setting rather than a Nectin-4 result.8

Targeted Therapy

Approved Agents

Enfortumab Vedotin-ejfv (Padcev)

FDA-Approved Indication:

  • With pembrolizumab (IV or subcutaneous), as neoadjuvant and then adjuvant treatment after cystectomy for adults with MIBC (cisplatin-ineligible, November 21, 2025; all patients, July 10, 2026).6
  • With pembrolizumab for adults with locally advanced or metastatic urothelial cancer (la/mUC).6
  • As a single agent for la/mUC after a PD-1/PD-L1 inhibitor and platinum chemotherapy, or in cisplatin-ineligible patients after 1 or more prior lines.6

Mechanism of Action:

  • Nectin-4-directed antibody conjugated to the microtubule-disrupting agent monomethyl auristatin E (MMAE) through a protease-cleavable linker; after internalization, released MMAE causes cell-cycle arrest and apoptosis.6

Drug Information: Learn more about Enfortumab Vedotin ›

Patient Resources: https://www.padcev.com/

References

  1. NCBI Gene. NECTIN4 nectin cell adhesion molecule 4 [Homo sapiens]. Gene ID 81607. Accessed October 2026.
  2. Challita-Eid PM, Satpayev D, Yang P, et al. Enfortumab vedotin antibody-drug conjugate targeting Nectin-4 is a highly potent therapeutic agent in multiple preclinical cancer models. Cancer Res. 2016;76(10):3003-3013. doi:10.1158/0008-5472.CAN-15-1313
  3. Hoffman-Censits JH, Lombardo KA, Parimi V, et al. Expression of Nectin-4 in bladder urothelial carcinoma, in morphologic variants, and nonurothelial histotypes. Appl Immunohistochem Mol Morphol. 2021;29(8):619-625. doi:10.1097/PAI.0000000000000938
  4. Miyake M, Miyamoto T, Shimizu T, et al. Tumor expression of Nectin-1-4 and its clinical implication in muscle invasive bladder cancer: an intra-patient variability of Nectin-4 expression. Pathol Res Pract. 2022;237:154072. doi:10.1016/j.prp.2022.154072
  5. Klümper N, Tran NK, Zschäbitz S, et al. NECTIN4 amplification is frequent in solid tumors and predicts enfortumab vedotin response in metastatic urothelial cancer. J Clin Oncol. 2024;42(20):2446-2455. doi:10.1200/JCO.23.01983
  6. Padcev (enfortumab vedotin-ejfv) for injection. Prescribing information. Astellas Pharma US, Inc; revised 07/2026. Accessed October 2026.
  7. Klümper N, Büttner T, Rauch S, et al. Integrating NECTIN4 amplification with membranous Nectin-4 expression to develop a scoring system for predicting enfortumab vedotin response in urothelial carcinoma. Clin Cancer Res. Published online September 9, 2026. doi:10.1158/1078-0432.CCR-26-0093
  8. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Bladder Cancer V.2.2026. © National Comprehensive Cancer Network, Inc. 2026. All rights reserved. Accessed October 2026. To view the most recent and complete version of the guideline, go online to NCCN.org.