Enfortumab Vedotin/Pembrolizumab Improved Survival Vs Surgery in MIBC

Patients with cisplatin-ineligible bladder cancer who received enfortumab vedotin plus pembrolizumab and surgery had prolonged survival vs those who received surgery alone.

Positive results from the enfortumab vedotin (Padcev) plus pembrolizumab (Keytruda) combination evaluated in patients with muscle-invasive bladder cancer (MIBC) who are ineligible for or declined cisplatin-based chemotherapy in the phase 3 EV-303/KEYNOTE-905 trial (NCT03924895) were recently announced in a press release from the developers, Pfizer and Astellas Pharma.1

At the first interim efficacy analysis, treatment with neoadjuvant and adjuvant enfortumab vedotin plus pembrolizumab showed a clinically meaningful and statistically significant improvement in event-free survival (EFS) and overall survival (OS) compared with surgery alone. EFS was the trial’s primary end point, and OS was the key secondary end point. The additional secondary end point of pathologic complete response (pCR) rate was also met.

This is the first and only therapy that improved survival when used before and after standard of care surgery in patients who are cisplatin-ineligible with MIBC.

These results will be submitted for presentation at an upcoming medical conference. The developer anticipates discussions with global health authorities regarding these results and the submission processes for potential regulatory filings.

“Patients with MIBC 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,” Christof Vulsteke, MD, PhD, head of Integrated Cancer Center Ghent (IKG, Belgium) and Clinical Trial Unit Oncology Ghent, and principal investigator of the trial, stated in the press release.1 “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.”

EV-303 was a randomized, 3-arm, controlled trial designed to assess the efficacy and safety of enfortumab vedotin plus pembrolizumab vs surgery alone and pembrolizumab alone and enrolled a total of 595 patients.2

In the experimental group, patients received 1.25 mg/kg of intravenous enfortumab vedotin on days 1 and 8 of each 21-day cycle, 200 mg of intravenous pembrolizumab on day 1 of each 21-day cycle, and radical cystectomy plus pelvic lymph node dissection in accordance with regulatory guidelines; therapy was ordered as 3 preoperative cycles of enfortumab vedotin plus pembrolizumab followed by surgery, then 6 cycles of postoperative enfortumab vedotin plus pembrolizumab, then 8 cycles of pembrolizumab alone. In the pembrolizumab plus surgery arm, patients received 3 preoperative cycles of pembrolizumab, followed by surgery, then 14 cycles of postoperative pembrolizumab, and in the surgery alone arm, patients received surgery.

Eligible patients had a histologically confirmed diagnosis of MIBC with predominant urothelial histology, clinically nonmetastatic bladder cancer, eligibility for standard-of-care surgery, ineligibility for or refusal to receive cisplatin, an ECOG performance status of 0 to 2, and adequate organ function.

Those excluded from participating had a known nonurothelial malignancy that is progressing or has required active anticancer treatment 3 years or less prior to study randomization; receipt of prior systemic treatment, chemoradiation, or radiation therapy for MIBC or non-MIBC; ongoing sensory or motor neuropathy of grade 2 or higher; and hypersensitivity to monoclonal antibodies or their excipients, among other reasons.

The trial’s primary end point is EFS between the combination therapy and surgery alone. Key secondary end points were OS and pCR rate between the combination therapy and surgery alone, and EFS, OS, and PCR rate between surgery alone and pembrolizumab plus surgery.

The safety profiles for enfortumab vedotin plus pembrolizumab and pembrolizumab alone were consistent with previously known data for each treatment regimen.

“[Enfortumab vedotin] plus [pembrolizumab] has already changed the treatment paradigm for patients with locally advanced or metastatic urothelial cancer as standard of care,” said Johanna Bendell, MD, oncology chief development officer at Pfizer.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.”

Currently, the combination of enfortumab vedotin plus pembrolizumab is approved as a therapy for patients with locally advanced or metastatic urothelial cancer regardless of cisplatin eligibility in the US, EU, Japan, and several other countries.3

Neoadjuvant and adjuvant enfortumab vedotin plus pembrolizumab is also under evaluation in patients with cisplatin-eligible MIBC in the phase 3 EV-304/KEYNOTE-B15 trial (NCT04700124).

References

1. PADCEV™ plus KEYTRUDA™ significantly improves survival for certain patients with bladder cancer when given before and after surgery. News release. Pfizer and Astellas Pharma. August 12, 2025. Accessed August 12, 2025. https://tinyurl.com/mtnvfvv2
2. 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. August 12, 2025. Accessed August 12, 2025. https://tinyurl.com/3s6wfpjd
3. FDA approves enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer. News release. FDA. December 15, 2023. Accessed August 12, 2025. https://bit.ly/48ls9bi