Neoadjuvant Pembrolizumab and Enfortumab Vedotin Improve Outcomes in MIBC

A recent analysis of the phase 3 KEYNOTE-905/EV-303 (NCT03924895) trial has demonstrated that the combination of pembrolizumab (Keytruda) and enfortumab vedotin-ejfv (Padcev) significantly improved event-free survival (EFS), overall survival (OS), and pathologic complete response (pCR) rates in patients with muscle-invasive bladder cancer (MIBC) who are not eligible for cisplatin-based chemotherapy.¹ These topline results suggest a potential new treatment paradigm for this challenging patient population, offering a systemic therapy option that may improve surgical outcomes.

Merck, the manufacturer of pembrolizumab, and Astellas, the manufacturer of enfortumab vedotin, plan to share these findings with regulatory authorities and will present data at an upcoming medical meeting.

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

About KEYNOTE-905

The phase 3 KEYNOTE-905 study enrolled 595 patients across 242 global sites to assess cystectomy with perioperative enfortumab vedotin and pembrolizumab vs cystectomy alone in patients who are ineligible for or decline cisplatin for the treatment of MIBC.² The study’s primary end point is EFS, and secondary end points include OS, pCR rate, pathologic downstaging, incidence of adverse events, discontinuation due to adverse events, and incidence of perioperative complications.

Patients were required to have confirmed nonmetastatic disease, adequate organ function, and an ECOG performance status of 0 to 2. Those with additional nonurothelial malignancies, who received prior systemic anticancer therapy, who received any prior radiation to the bladder, with hypersensitivity to monoclonal antibodies, with active autoimmune disease, with uncontrolled diabetes, or who have received an allogeneic tissue or solid organ transplant were not eligible for study enrollment.

Safety Pembrolizumab and Enfortumab Vedotin

The safety profile of the combination observed in KEYNOTE-905 was consistent with the known profiles of each agent.¹ When used in combination, the incidence of certain adverse events, including severe events, occurred at a higher rate compared with enfortumab vedotin as a single agent.³

• Skin reactions occurred in 70% of all patients treated with the combination, including 17% experiencing grades 3 to 4 reactions. One patient (0.2%) experienced a fatal reaction of bullous dermatitis.
• Pneumonitis/interstitial lung disease (ILD) occurred in 10% of patients with the combination, with 4% being grades 3 to 4. A fatal event of pneumonitis/ILD occurred in 2 patients (0.4%).
• Peripheral neuropathy occurred in 67% of patients, with 36% experiencing grade 2 and 7% experiencing grade 3 neuropathy.

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://tinyurl.com/2bzuavbh

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://clinicaltrials.gov/study/NCT03924895

3. 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://tinyurl.com/bdmfjcsn