Key eligibility criteria
  • Aged 18 years or older
  • Have a histologically confirmed initial diagnosis of non-metastatic MIBC
  • Have not been previously treated with systemic therapy or radiotherapy for bladder cancer
  • Must be eligible for and agree to receive chemoradiotherapy and one of the protocol-specified radiosensitizing chemotherapy regimens.
  • Should be fit for systemic therapy and elect bladder preservation, including participants who are ineligible for or have elected not to undergo cystectomy

Additional requirements apply. Only Principal Investigators can determine eligibility.

Consider a clinical trial for your patients with muscle-invasive bladder cancer who are not eligible for or wish to avoid cystectomy.

Connect with a clinical trial site to learn more and see if your patients may be eligible.

This is a Phase 3, open-label, randomized study evaluating enfortumab vedotin in combination with pembrolizumab in adult participants with muscle-invasive bladder cancer (MIBC) who are ineligible for or have elected not to undergo cystectomy.

Participants will be randomized in a 1:1 ratio to receive either enfortumab vedotin in combination with pembrolizumab (Arm A) or standard-of-care concurrent chemoradiotherapy (Arm B).

Participants in Arm A will receive treatment in 3-week cycles. The first 9 cycles will include IV infusions of enfortumab vedotin and pembrolizumab on Day 1 and enfortumab vedotin alone on Day 8. They will then receive pembrolizumab monotherapy for 8 cycles.

Participants in Arm B will receive standard-of-care concurrent chemoradiotherapy for 4 or 6.5 weeks depending on the institutional radiation protocols. Radiation treatment will be given daily from Monday to Friday each week. Participants will have weekly visits for study assessments, with additional visits depending on the treatment plan.

After treatment ends, both groups will have follow-up visits or phone calls every 12 weeks.

About enfortumab vedotin

Enfortumab vedotin plus pembrolizumab has demonstrated clinical activity and safety in other MIBC settings1,2 supporting ongoing evaluation in bladder‑sparing MIBC.

Enfortumab vedotin is an antibody-drug conjugate (ADC) directed against Nectin-43 and is comprised of a fully human monoclonal antibody, the microtubule disrupting agent monomethyl auristatin E (MMAE), and a protease-cleavable linker. EV’s proposed mechanism of action (see the diagram) is that it delivers MMAE to cells expressing Nectin-4, leading to cell cycle arrest and apoptotic cell death.4

Nectin-4 is a cell adhesion molecule that is expressed in both normal and tumor tissues. It is involved in multiple cellular processes known to be associated with oncogenesis, including cell adhesion, migration, proliferation, differentiation, and survival.5,6

High expression of Nectin-4 in select solid malignancies, including pancreatic, lung, breast, ovarian, and esophageal cancers, is associated with poor prognosis.7-11

The moderate to high expression levels of Nectin-4 in urothelial carcinoma (UC) and other tumors, compared with its low to moderate expression in normal tissues, make it a robust therapeutic target for drug development.12

The safety and efficacy of these investigational compounds, or investigational uses of marketed products, have not been established. For agents whose safety and efficacy have not been established or confirmed, future regulatory approval or commercial availability is not guaranteed.

References
  1. Vulsteke C, et al. Perioperative enfortumab vedotin and pembrolizumab in bladder cancer. N Eng J Med 2026
  2. Galsky MD, et al. Neoadjuvant and adjuvant enfortumab vedotin (EV) plus pembrolizumab (pembro) for participants with muscle-invasive bladder cancer (MIBC) who are eligible for cisplatin: Randomized, open-label, phase 3 KEYNOTE-B15 study; Journal of Clinical Oncology 2026
  3. Liu BA, et al. Additional mechanisms of action of enfortumab vedotin, an anti-Nectin-4 ADC demonstrating bystander effect and immunogenic cell death antitumor activity in models of urothelial carcinoma. Poster presented at: AACR Virtual Annual Meeting II; June 22-24, 2020.
  4. Rosenberg JE, O’Donnell PH, Balar AV, et al. Pivotal trial of enfortumab vedotin in urothelial carcinoma after platinum and anti-programmed death 1/programmed death ligand 1 therapy. J Clin Oncol 2019.
  5. Boylan KLM, Buchanan PC, Manion RD, et al. The expression of Nectin-4 on the surface of ovarian cells alters their ability to adhere, migrate, aggregate, and proliferate. Oncotarget 2017.
  6. Zhang Y, Liu S, Wang L, et al. A novel PI3K/AKT signaling axis mediates nectin-4-induced gallbladder cancer cell proliferation, metastasis and tumor growth. Cancer Lett 2016.
  7. Deng H, Shi H, Chen L, Zhou Y, Jiang J. Over-expression of Nectin-4 promotes progression of esophageal cancer and correlates with poor prognosis of the patients. Cancer Cell Int 2019.
  8. DeRycke MS, Pambuccian SE, Gilks B, et al. Nectin 4 overexpression in ovarian cancer tissues and serum: potential role as a serum biomarker. Am J Clin Pathol 2010.
  9. Nishiwada S, Sho M, Yasuda S, et al. Nectin-4 expression contributes to tumor proliferation, angiogenesis and patient prognosis in human pancreatic cancer. J Exp Clin Cancer Res 2015.
  10. Takano A, Ishikawa N, Nishino R, et al. Identification of nectin-4 oncoprotein as a diagnostic and therapeutic target for lung cancer. Cancer Res 2009.
  11. Zeindler J, Soysal SD, Piscuoglio S, et al. Nectin-4 expression is an independent prognostic biomarker and associated with better survival in triple-negative breast cancer. Front Med 2019.
  12. 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.

Study endpoints

Primary endpoints

  • BI-EFS assessed by BICR
  • OS

Key secondary endpoints

  • BI-EFS assessed by investigator
  • cCR rate assessed by BICR and investigator
  • MFS assessed by BICR and investigator
  • Time to Cystectomy
  • DFS assessed by BICR and investigator
  • CFS

Safety endpoints

  • Type, incidence, relatedness, severity and seriousness of AEs
  • Type, incidence and severity of laboratory abnormalities

This is not a complete list of study endpoints.

AEs, Adverse Events; BI-EFS, Bladder-Intact Event-Free Survival; BICR, Blinded Independent Central Review; cCR, Clinical Complete Response; CFS, Cystectomy-Free Survival; DFS, Disease-Free Survival; MFS, Metastasis-Free Survival; OS, Overall Survival.

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People are often introduced to clinical trials through conversations with their healthcare providers. We appreciate you taking the time to have discussions with your patients and their loved ones who may be interested in contributing to research.

Should any of your patients take part in this clinical trial, they will remain under your medical care for all non-study-related needs.

Thank you for considering your patients for this important clinical trial.