FDA approves pembrolizumab plus enfortumab vedotin for cisplatin-ineligible MIBC

On November 21, 2025, the FDA approved pembrolizumab (Keytruda) and pembrolizumab and berahyaluronidase alfa-pmph (Keytruda QLEX), each in combination with enfortumab vedotin-ejfv (Padcev), as perioperative regimens for patients with muscle-invasive bladder cancer (MIBC) who are ineligible for cisplatin-based chemotherapy.¹

“Pembrolizumab plus enfortumab vedotin is poised to address a critical unmet need. Half of patients with MIBC may experience cancer recurrence even after having their bladder removed, and many of these patients are ineligible to receive cisplatin," said Matthew D. Galsky, MD, professor of medicine and director of genitourinary medical oncology at Mount Sinai Tisch Cancer Center in New York, New York, in a news release on the approval.² "These approvals, based on striking event-free and overall survival benefits, may represent an important practice-changing advance for these patients who’ve had no new options in decades.”

The approval is supported by results from the phase 3 KEYNOTE-905/EV-303 trial (NCT03924895), which were recently presented at the 2025 European Society for Medical Oncology (ESMO) Congress in Berlin, Germany.³ Data from the trial showed that the treatment regimen—consisting of neoadjuvant EV plus pembrolizumab, radical cystectomy plus pelvic lymph node dissection, and adjuvant EV plus pembrolizumab—yielded significant improvements in event-free survival (EFS), overall survival (OS), and pathological complete response (pCR) rate compared with surgery alone.

The 3-arm, open-label trial included 344 patients who were randomly assigned to either neoadjuvant and adjuvant pembrolizumab (arm A), surgery alone (arm B) or neoadjuvant and adjuvant EV plus pembrolizumab (arm C). The primary end point was EFS between arm B and C, as assessed by blinded independent central review. Key secondary end points included OS, pCR, and safety.

Overall, the study met its primary end point, showing that perioperative EV plus pembrolizumab reduced the risk of recurrence, progression, or death by 60% compared with surgery alone. The median EFS was not reached (95% CI, 37.3 to NR) in the EV plus pembrolizumab arm vs 15.7 months (95% CI, 10.3 to 20.5) in the control arm (HR, 0.40; 95% CI, 0.28 to 0.57, one-sided P < .0001). The EFS benefits were observed across subgroups in the study.

Further, the perioperative regimen reduced the risk of death by 50% compared with surgery alone. The median OS was not reached (95% CI, NR to NR) in the EV plus pembrolizumab group vs 41.7 months (95% CI, 31.9 to NR) in the control group (HR, 0.50; 95% CI, 0.33 to 0.74, one-sided P = .0002).

“This is the first trial to show an overall survival benefit in this population,” said presenting author Christof Vulsteke, MD, PhD, during the presentation at ESMO. Like EFS, the OS gains were observed across patient subgroups.

The investigators also reported that 97 patients in the EV plus pembrolizumab group achieved a pCR vs 15 patients in the control group. The pCR rate was 57.1% (95% CI, 49.3 to 64.6) in the EV plus pembrolizumab group vs 8.6% (95% CI, 4.9 to 13.8) in the control group.

Regarding safety, any-grade treatment-emergent adverse events (TEAEs) were reported in 167 (100%) patients in the EV plus pembrolizumab group vs 103 (64.8%) patients in the control group. Grade 3 or higher TEAEs were seen in 119 (71.3%) patients in the EV plus pembrolizumab group vs 73 (45.9%) patients in the control group.

TEAEs leading to dose reduction of EV occurred in 28 (16.8%) patients and TEAEs leading to discontinuation of EV occurred in 69 (41.3%) patients. TEAEs leading to discontinuation of pembrolizumab occurred in 57 (34.1%) patients and TEAEs leading to death occurred in 13 (7.8%) patients in the EV plus pembrolizumab arm vs 9 (5.7%) patients in the control arm.

According to the FDA, the recommended dose for neoadjuvant pembrolizumab is 200 mg IV every 3 weeks administered in combination with enfortumab vedotin-ejfv 1.25 mg/kg (up to a maximum of 125 mg for patients of 100 kg or greater) IV on days 1 and 8 of a 21-day cycle for 3 cycles, totaling 9 weeks of neoadjuvant treatment. For the adjuvant phase, the agency recommends continuing enfortumab vedotin for 6 additional cycles every 3 weeks in combination with pembrolizumab, administered either as 200 mg IV every 3 weeks for 14 cycles or 400 mg IV every 6 weeks for 7 cycles. The total duration of treatment for the adjuvant phase is 42 weeks.

REFERENCES

1. FDA approves pembrolizumab with enfortumab vedotin-ejfv for muscle invasive bladder cancer. US Food & Drug Adminstration. November 21, 2025. Accessed November 21, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-enfortumab-vedotin-ejfv-muscle-invasive-bladder-cancer?utm_medium=email&utm_source=govdelivery 

2. U.S. FDA Approves PADCEV^® plus Keytruda^® for Certain Patients with Bladder Cancer. News relase. Pfizer. November 21, 2025. Accessed November 21, 2025. https://www.businesswire.com/news/home/20251117031627/en/U.S.-FDA-Approves-PADCEV-plus-Keytruda-for-Certain-Patients-with-Bladder-Cancer

3. Perioperative (periop) enfortumab vedotin (EV) plus pembrolizumab (pembro) in participants (pts) with muscle-invasive bladder cancer (MIBC) who are cisplatin-ineligible: The phase III KEYNOTE-905 study. Presented at: 2025 European Society for Medical Oncology Congress. October 17-21, 2025. Berlin, Germany. Abstract LBA2. https://s3.eu-central-1.amazonaws.com/m-anage.com.storage.esmo/static/esmo2025_abstracts/LBA2.html.pdf