Perioperative Enfortumab Vedotin Plus Pembrolizumab Displays Positive Top-Line Data in Muscle-Invasive Bladder Cancer

The antibody-drug conjugate (ADC) enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda) administered before and after surgery demonstrated significant and clinically meaningful improvements in event-free survival (EFS), overall survival (OS), and pathologic complete response (pCR) rates compared with surgery alone in patients with muscle-invasive bladder cancer (MIBC) who were ineligible for cisplatin-based chemotherapy, according to data from the phase 3 KEYNOTE-905 trial (NCT03924895).1

The study evaluated the efficacy and safety of neoadjuvant and adjuvant enfortumab vedotin added to pembrolizumab compared with radical cystectomy alone for the treatment of patients with MIBC who are ineligible for cisplatin-based chemotherapy.

“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 poor prognosis, even after having their bladder removed,” Christof Vulsteke, MD, PhD, head of Integrated Cancer Center Ghent and Clinical Trial Unit Oncology Ghent at AZ Maria Middelares General Hospital in Belgium as well as the principal investigator of the KEYNOTE-905 trial, stated in a news release.1 “The KEYNOTE-905 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.”

The trial is building off the clinical success of enfortumab vedotin plus pembrolizumab for the treatment of patients with locally advanced or metastatic urothelial cancer and is continuing to evaluate EFS as the primary end point and OS and pCR rate as key secondary end points as the data further mature.

Of note, the safety profile of enfortumab vedotin plus pembrolizumab in the study was consistent with previously established profiles for the respective agents, and no new safety signals were observed. Data from the study will be presented at an upcoming medical meeting.1

KEYNOTE-905 Design

KEYNOTE-905 was a randomized, open-label, multicenter study that included patients who were at least aged 18 years, had a histologically confirmed diagnosis of urothelial carcinoma or MIBC with at least 50% or greater urothelial histology confirmed by blinded independent central review, had clinical nonmetastatic bladder cancer as determined by imaging, and were eligible for radical cystectomy plus pelvic lymph node dissection and agreed to undergo curative-intent standard radical cystectomy plus pelvic lymph node dissection. Patients were also required to be ineligible for treatment with cisplatin or be eligible for cisplatin but declined treatment with cisplatin-based chemotherapy. Additionally, eligible patients had a transurethral resection of a bladder tumor, an ECOG performance status of 0 to 2, and adequate organ function.2

In the study, patients were randomly assigned to either arm A, arm B, or arm C. Those in arm A were treated with neoadjuvant intravenous (IV) pembrolizumab 200 mg every 3 weeks for up to 3 cycles, followed by radical cystectomy plus pelvic lymph node dissection and adjuvant IV pembrolizumab 200 mg every 3 weeks for up to 14 cycles. Patients in arm B underwent radical cystectomy plus pelvic lymph node dissection followed by observation. Those in arm C were treated with neoadjuvant enfortumab vedotin at 1.25 mg/kg plus IV pembrolizumab 200 mg every 3 weeks up to 3 cycles, followed by radical cystectomy plus pelvic lymph node dissection and then adjuvant enfortumab vedotin plus pembrolizumab up to 6 cycles plus adjuvant IV pembrolizumab 200 mg every 3 weeks up to 8 cycles.3

“There is a real and pressing need for more effective options for patients with bladder cancer who are ineligible for cisplatin-based treatment,” Marjorie Green, MD, senior vice president and head of oncology, global development, at Merck Research Laboratories, said in the release.1 “The compelling survival results observed in this study reinforce the potential of combining [pembrolizumab] with an ADC to help address a significant unmet need in this vulnerable population.”

References

1. 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/
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. Updated July 14, 2025. Accessed August 12, 2025. https://www.clinicaltrials.gov/study/NCT03924895
3. Necci A, Bedke J, Galsky MD, et al. Phase 3 KEYNOTE-905/EV-303: perioperative pembrolizumab (pembro) or pembro + enfortumab vedotin (EV) for muscle-invasive bladder cancer (MIBC). J Clin Oncol. 2023;41(suppl 6):585. doi:10.1200/JCO.2023.41.6_suppl.TPS585