Enfortumab Vedotin Plus Pembrolizumab Improves Survival in MIBC

A combination of the antibody-drug conjugate enfortumab vedotin (Padcev) and the PD-1 inhibitor pembrolizumab (Keytruda) significantly improved event-free survival (EFS) and overall survival (OS) in patients with muscle-invasive bladder cancer (MIBC), according to topline results from the phase 3 EV-304/KEYNOTE-B15 trial (NCT04700124).¹

The findings mark the first time a nonplatinum-based regimen has demonstrated a survival benefit over standard-of-care chemotherapy in the perioperative setting for patients eligible for cisplatin. The results suggest a potential paradigm shift in the treatment of MIBC, a disease characterized by high rates of recurrence even after surgical resection.

“Despite available treatment options, nearly half of patients with muscle-invasive bladder cancer progress to metastatic disease within 3 years of diagnosis. The EV-304 results represent a key milestone in the new era of urothelial cancer treatment. Together, the EV-303 [NCT03924895] and EV-304 results show that perioperative enfortumab vedotin plus pembrolizumab can positively impact the treatment journey for patients with [MIBC],” said Christopher Hoimes, DO, director of the Bladder Cancer Program and Center for Cancer Immunotherapy at Duke Cancer Institute and EV-304 principal investigator, in a news release.

Full details will be presented at an upcoming medical meeting and discussed with global regulatory authorities.

Trial Design and Outcomes

The phase 3 EV-304 trial (NCT04700124) evaluated the efficacy and safety of perioperative enfortumab vedotin plus pembrolizumab compared with neoadjuvant gemcitabine and cisplatin in patients with MIBC who were eligible for cisplatin-based chemotherapy. The study utilized a randomized, open-label design. Patients in the experimental arm received the combination therapy both before and after radical cystectomy.

The trial met its primary end point of EFS, demonstrating a statistically significant and clinically meaningful improvement compared with the chemotherapy control arm. Furthermore, the combination met its key secondary end point of OS, as well as an additional secondary end point of pathologic complete response rate.

Clinical Significance

Standard treatment for cisplatin-eligible patients with MIBC typically involves neoadjuvant cisplatin-based chemotherapy followed by surgery. Despite this multimodal approach, approximately 50% of patients experience disease recurrence following cystectomy, highlighting a substantial unmet need for more effective therapies.

Mechanism and Safety Profile

Enfortumab vedotin is a Nectin-4–directed antibody-drug conjugate (ADC), while pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor, blocking its interaction with PD-L1 and PD-L2. The combination aims to leverage the direct cytotoxicity of the ADC with the immune-activating properties of the checkpoint inhibitor.

The safety profile of the combination in the EV-304 trial was reported to be consistent with the known profiles of both agents. No new safety signals were identified. Common adverse events associated with enfortumab vedotin in previous studies have included peripheral neuropathy, skin reactions (including severe cases of Stevens-Johnson syndrome and toxic epidermal necrolysis), fatigue, and hyperglycemia. Pembrolizumab is associated with immune-mediated adverse reactions, such as pneumonitis, colitis, and hepatitis.

Future Implications

The positive readout for EV-304 builds upon the recent FDA approval of this combination for patients with locally advanced or metastatic urothelial cancer, supported by the EV-303 trial.² If approved for the perioperative MIBC indication, this regimen would provide a chemotherapy-free alternative for eligible patients, potentially sparing them from the specific toxicities associated with platinum-based agents, such as nephrotoxicity and ototoxicity.

REFERENCES

1. PADCEV® plus Keytruda® significantly improves survival for patients with muscle-invasive bladder cancer regardless of cisplatin eligibility. News release. Pfizer. December 17, 2025. Accessed December 17, 2025. https://tinyurl.com/2mmp6jc2

2. FDA approves pembrolizumab with enfortumab vedotin-ejfv for muscle invasive bladder cancer. News release. FDA. November 21, 2025. Accessed December 17, 2025. https://tinyurl.com/3t7bdzz2