In MIBC, Enfortumab Vedotin Plus Pembro Cuts Risk of Recurrence or Death Nearly in Half for Chemo-Eligible Patients

Combining the antibody drug conjugate enfortumab vedotin (EV; Padcev; Astellas/Pfizer) with the PD-1 inhibitor pembrolizumab (Keytruda; Merck) significantly improved event-free and overall survival (OS) for cisplatin-eligible patients with muscle-invasive bladder cancer (MIBC) in results presented today, answering one question that remained following last fall’s blockbuster results with this drug combination.

Data from the phase 3 EV-304 trial (NCT04700124), presented at the American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU), showed that perioperative use of the combination brought a 47% reduction in the risk of tumor recurrence, progression, or death compared with patients treated with standard of care neoadjuvant (before surgery) gemcitabine and cisplatin, for an HR of 0.53 (95% CI, 0.41-0.70; 1-sided P < .0001).¹

The results follow the unprecedented data presented for EV-303 (NCT03924895) in October 2025 at the European Society for Medical Oncology meeting, which showed that patients with MIBC who cannot or choose not to have cisplatin-based chemotherapy alongside surgery to remove the bladder cut their risk of disease progression or death by 60% when treated with EV plus pembrolizumab alongside surgery. Full data were published this month in the New England Journal of Medicine.²

Investigators said the new results presented today in San Francisco, California, combined with the prior data, show the potential for the EV plus pembrolizumab regimen to become a new standard of care for patients with MIBC, regardless of cisplatin eligibility.

“Approximately half of patients with muscle-invasive bladder cancer experience disease recurrence even after having their bladder removed,” Christopher Hoimes, DO, director of the Bladder Cancer Program and Center for Cancer Immunotherapy at Duke Cancer Institute, and an EV-304 principal investigator, said in a statement emailed to The American Journal of Managed Care^® (AJMC^®).

“The EV-304 results, combined with the EV-303 study, provide compelling evidence that perioperative enfortumab vedotin plus pembrolizumab may offer survival benefits in the curative setting for patients with muscle-invasive bladder cancer, highlighting a potential departure from platinum-based chemotherapy as a cornerstone of care.”

OS, a key secondary end point in EV-304, showed a 35% reduced risk of death in patients who received perioperative EV plus pembrolizumab vs the control regimen of neoadjuvant chemotherapy (HR, 0.65; 95% CI, 0.48-0.89; 1-sided P = .0029). Other results showed:

• EV plus pembrolizumab produced a pathological complete response (pCR) rate of 55.8% compared with a 32.5% pCR rate at the time of surgery (estimated difference 23.4%; 95% CI, 16.7-29.8; 1-sided P <.0001). This shows more than half of patients treated with the combination showed no detectable disease at the time of surgery.
• Event-free survival, OS, and pCR benefits were generally consistent across subgroups, including age, gender, PD-L1 status, clinical stage, and geographic region.
• Safety data for perioperative EV plus pembrolizumab were consistent with prior results with this combination; there were no new safety signals.
• Adverse events of grade 3 or higher due to any cause occurred in 75.7% of patients treated with perioperative EV plus pembrolizumab compared with 67.2% of patients treated with neoadjuvant chemotherapy.

The combination of EV and pembrolizumab previously received full FDA approval in December 2023 for first-line treatment of patients with locally advanced or metastatic urothelial cancer based on EV-302 (NCT04223856). The combination received approval for patients with MIBC who are ineligible for cisplatin-based chemotherapy in November 2025.

In October 2025 at ESMO, which took place in Berlin, Germany, EV-303 principal investigator Christof Vulsteke, MD, PhD, predicted that results for patients who could not receive cisplatin could be transformative and that this regimen might become the standard of care. Asked by AJMC whether this would extend to patients eligible to receive cisplatin, given the recent shortages of the drug that had led to off-label treatment of patients with EV, Vulsteke said that the EV-304 trial would soon answer this question.

“For people with muscle‑invasive bladder cancer, a perioperative approach that avoids the need for platinum‑based chemotherapy has demonstrated significant survival benefits,” Jeff Legos, PhD, MBA, chief oncology officer, Pfizer, said in the statement. “These compelling data, reinforced by the unprecedented EV‑303 results, suggest a transformative opportunity to establish Padcev plus pembrolizumab as the next standard of care if approved, and provide a meaningful step forward for patients and their families.”

“The EV-304 study data further substantiate the role of enfortumab vedotin plus pembrolizumab in bladder cancer and demonstrate its potential to offer patients with muscle-invasive bladder cancer more time with their loved ones,” added Moitreyee Chatterjee-Kishore, PhD, MBA, head of oncology development, Astellas. “We are delighted with these new data and remain committed to investigating therapies for challenging and hard-to-treat cancers, with a goal of bringing renewed hope to patients.”

Bladder cancer is the ninth most common cancer worldwide, diagnosed in more than 614,000 patients each year globally, including an estimated 85,000 people in the US. MIBC represents approximately 30% of all bladder cancer cases. Even after undergoing curative intent surgery, half of patients with MIBC experience disease recurrence.

References

1. Neoadjuvant and adjuvant enfortumab vedotin plus pembrolizumab for participants with muscle-invasive bladder cancer who are eligible for cisplatin: randomized, open-label, phase 3 EV-304/KEYNOTE-B15 study. Presented at: American Society of Clinical Oncology Genitourinary Congress; February 26-28, 2026; San Francisco, CA. Abstract LBA630.
2. Vulsteke C, Adra N, Danchaivijitr P, for the KEYNOTE-905/EV-303 Investigators. Perioperative enfortumab vedotin and pembrolizumab in bladder cancer. N Engl J Med. Published online February 18, 2026. doi:10.1056/NEJMoa2511674