Perioperative EV plus pembrolizumab significantly extends EFS, OS in MIBC

Topline data from the phase 3 EV-303 trial (also known as KEYNOTE-905; NCT03924895) showed that perioperative enfortumab vedotin-ejfv (EV; Padcev) plus pembrolizumab (Keytruda) significantly improved event-free survival (EFS) and overall survival (OS) vs cystectomy alone in patients with muscle-invasive bladder cancer (MIBC), Merck and Pfizer reported in separate news releases.^1,2

The EV-303 study enrolled patients with MIBC who were ineligible for or declined cisplatin-based chemotherapy. The EV plus pembrolizumab regimen was administered as both a neoadjuvant and adjuvant treatment.

“Patients with muscle-invasive bladder cancer who are ineligible for cisplatin-based chemotherapy have not seen any treatment advance beyond surgery and face high rates of disease recurrence and a poor prognosis, even after having their bladder removed,” said principal investigator Christof Vulsteke, MD, PhD, Head of Integrated Cancer Center Ghent (IKG Belgium) and Clinical Trial Unit Oncology Ghent, in the news releases.^1,2 “These EV-303 study results mark the first time a systemic treatment approach, used before and after surgery, significantly extended survival over standard-of-care surgery in this population, demonstrating the potential of this combination to address a critical unmet need.”

Overall, an interim analysis of the data showed that the trial met its primary end point of EFS, as well as the key secondary end points of OS and pathologic complete response (pCR) rate. According to Pfizer and Merck, the safety profiles for EV and pembrolizumab were consistent with the known profiles for each agent.

The companies also reported that data from the EV-303 trial will be shared at an upcoming medical meeting as well as with regulatory authorities.

“These results from EV-303 represent a breakthrough for cisplatin-ineligible patients with muscle-invasive bladder cancer, demonstrating the potential of PADCEV in combination with KEYTRUDA when used before and after surgery as a new standard of care,” said Moitreyee Chatterjee-Kishore, PhD, MBA, Head of Oncology Development, Astellas, in the news release.¹ “We look forward to presenting further details on these data at an upcoming medical congress.”

About the EV-303 trial

In total, the open-label phase 3 study enrolled 595 patients with MIBC who were ineligible for or declined cisplatin-based chemotherapy.³ Patients enrolled in the study were randomly assigned to receive neoadjuvant and adjuvant pembrolizumab (arm A), cystectomy alone (arm B), or neoadjuvant and adjuvant EV plus pembrolizumab (arm C).

The primary end point for the trial was EFS between arms C and B. Key secondary end points include OS, the pCR rate between arms C and B, as well as EFS, OS, and pCR rate between arms A and B. The study remains ongoing to assess EFS, OS, and pCR data as they mature, and specifically to assess the hypotheses between arms A and B.

Final completion of the trial is expected in December 2027.

In addition to the EV-303 trial, EV in combination with pembrolizumab is being explored in cisplatin-eligible patients with MIBC in the phase 3 EV-304 trial (also known as KEYNOTE0B15; NCT04700124).

The combination of EV plus pembrolizumab is currently approved in the US for patients with locally advanced or metastatic urothelial carcinoma. The approval, which was granted in December 2023, was supported by data from the phase 3 EV-302 trial (NCT04223856), which showed that the combination led to significant improvements in OS and progression-free survival compared with chemotherapy in this patient population.⁴

“PADCEV plus KEYTRUDA has already changed the treatment paradigm for patients with locally advanced or metastatic urothelial cancer as standard of care,” concluded Johanna Bendell, MD, Oncology Chief Development Officer, Pfizer, in the news release.¹ “These latest results underscore the practice-changing potential of this combination in earlier stages of bladder cancer, where it has the potential to improve outcomes for even more patients. Thank you to the patients and investigators who participated in this trial.”

REFERENCES

1. PADCEV plus KEYTRUDA significantly improves survival for certain patients with bladder cancer when given before and after surgery. News release. Pfizer, Inc. August 12, 2025. Accessed August 12, 2025. https://www.pfizer.com/news/press-release/press-release-detail/padcevtm-plus-keytrudatm-significantly-improves-survival

2. KEYTRUDA (pembrolizumab) plus Padcev (enfortumab vedotin-ejfv) significantly improved event-free and overall survival and pathologic complete response rate for certain patients with muscle-invasive bladder cancer when given before and after surgery. News release. Merck. August 12, 2025. Accessed August 12, 2025. https://www.merck.com/news/keytruda-pembrolizumab-plus-padcev-enfortumab-vedotin-ejfv-significantly-improved-event-free-and-overall-survival-and-pathologic-complete-response-rate-for-certain-patients-with-muscle/

3. Perioperative pembrolizumab (MK-3475) plus cystectomy or perioperative pembrolizumab plus enfortumab vedotin plus cystectomy versus cystectomy alone in participants who are cisplatin-ineligible or decline cisplatin with muscle-invasive bladder Cancer (MK-3475-905/​KEYNOTE-905/​EV-303). ClinicalTrials.gov. Last updated July 14, 2025. Accessed August 12, 2025. https://clinicaltrials.gov/study/NCT03924895

3. Powles T, Valderrama BP, Gupta S, et al. Enfortumab vedotin and pembrolizumab in untreated advanced urothelial cancer. N Engl J Med. 2024;390(10):875-888. doi:10.1056/NEJMoa2312117