FDA Approves Enfortumab Vedotin Plus Pembrolizumab for Muscle-Invasive Bladder Cancer

Enfortumab vedotin-ejfv (Padcev; Astellas Pharma Inc) has received FDA approval in combination with pembrolizumab (Keytruda; Merck) as a neoadjuvant therapy and after radical cystectomy as adjuvant treatment for patients with muscle-invasive bladder cancer (MIBC) who are ineligible for cisplatin-containing chemotherapy.¹

The approval is based on data from the pivotal phase 3 EV-303 clinical trial (NCT03924895) that evaluated enfortumab vedotin-ejfv in combination with pembrolizumab versus surgery alone, which is the current standard of care. According to data presented at the 2025 European Society of Medical Oncology (ESMO) Congress, the combination reduced the risk of recurrence, progression, or death by 60% and the risk of death by 50% compared to surgery alone.²

What Is Enfortumab Vedotin-ejfv?

Enfortumab vedotin-ejfv is a first-in-class antibody-drug conjugate directed against Nectin-4, which is a protein on the surface of cells and is highly expressed in bladder cancer. According to nonclinical data, the anticancer activity of enfortumab vedotin-ejfv is due to its ability to bind to cells that express Nectin-4, followed by the internalization and release of monomethyl auristatin E into the cell. This causes cell cycle arrest and apoptosis.³

In combination with pembrolizumab, it is approved for adults with locally advanced or metastatic urothelial cancer (la/mUC) regardless of cisplatin eligibility, as well as for use as a single agent for adults with la/mUC who have previously received a PD-1/PD-L1 inhibitor and platinum-containing chemotherapy or are ineligible for cisplatin-containing chemotherapy and have previously received 1 or more prior lines of therapy.³

The EV-303 Trial Design

The EV-303 trial, also known as KEYNOTE-905, was an open-label, multi-arm, controlled, phase 3 trial evaluating pembrolizumab with or without enfortumab vedotin-ejfv versus surgery alone in patients with MIBC who are either not eligible for or declined cisplatin-based chemotherapy. Investigators enrolled 595 patients who were randomized to 1 of 3 arms⁴:

1. Arm A received 3 cycles of preoperative pembrolizumab, followed by radical cystectomy, followed by 14 cycles of postoperative pembrolizumab;
2. Arm B received surgery alone;
3. Arm C received 3 cycles of preoperative pembrolizumab plus enfortumab vedotin-ejfv, followed postoperatively by 6 cycles of pembrolizumab plus enfortumab vedotin-ejfv, and then 8 cycles of pembrolizumab alone.

The primary objective was to compare event-free survival (EFS) between arms C and B, and key secondary objectives were to compare overall survival (OS) and the difference in pathologic complete response (pCR) rates between arms C and B, as well as EFS, OS, and the difference in pCR between arms A and B.⁴

EV-303 Study Findings

According to the findings presented at ESMO in October, the combination of enfortumab vedotin-ejfv and pembrolizumab significantly improved EFS (median not reached [NR] vs 15.7 months; hazard ratio [HR] 0.40; 95% confidence interval [CI] 0.28-0.57; p<0.0001) and OS (NR vs 41.7 months; HR 0.50; 95% CI 0.33-0.74; p=0.0002) when added to standard surgery. The pCR rate was also significantly improved with perioperative use (57.1% vs 8.6%; estimated difference 48.3%; 95% CI 39.5-56.5; p<0.000001).²

“We saw a pCR rate of 57.1%. It’s likely even higher, because patients who achieved very good responses on scans and declined surgery were considered nonresponders but still included in the denominator for transparency,” explained Christof Vulsteke, MD, PhD, head of the Integrated Cancer Centre Ghent in Belgium, in an interview with Pharmacy Times.

What Did the Safety Data Show?

Perioperative enfortumab vedotin-ejfv plus pembrolizumab did not affect patients’ ability to undergo surgery, although grade 3 or higher treatment-emergent adverse events (AEs) occurred more frequently in the combination arm compared with the control arm (71.3% vs 45.9%). The most frequently reported AEs of special interest were skin reactions, peripheral neuropathy, ocular disorders, and hyperglycemia with EV, and hypothyroidism and severe skin reactions with pembrolizumab.²

Conclusion

The FDA’s approval of enfortumab vedotin-ejfv plus pembrolizumab marks a significant advancement in the treatment landscape for patients with muscle-invasive bladder cancer who are ineligible for cisplatin-based chemotherapy. By offering a highly effective neoadjuvant and adjuvant option, the combination has the potential to redefine the standard of care for a population that previously had limited therapeutic avenues.

As clinicians integrate this combination into practice, ongoing real-world evidence and long-term follow-up will help clarify optimal management strategies and safety monitoring in the perioperative setting. Still, the magnitude of benefit observed in EV-303 represents a major step forward for patients with MIBC, providing a more hopeful outlook for those unable to receive cisplatin and reinforcing the expanding role of targeted and immune-based therapies in bladder cancer care.

REFERENCES

1. US FDA approves Padcev plus Keytruda for certain patients with bladder cancer. News release. BusinessWire. 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

2. Perioperative enfortumab vedotin plus pembrolizumab prolongs survival in muscle-invasive bladder cancer. Daily ESMO Reporter. October 18, 2025. Accessed November 11, 2025. https://dailyreporter.esmo.org/esmo-congress-2025/genitourinary-cancers/peri-operative-enfortumab-vedotin-plus-pembrolizumab-prolongs-survival-in-muscle-invasive-bladder-cancer

3. Padcev (enfortumab vedotin-ejfv) plus Keytruda (pembrolizumab) sBLA granted FDA priority review for treatment of certain patients with muscle-invasive bladder cancer. News release. Astellas. October 22, 2025. Accessed November 11, 2025. https://newsroom.astellas.com/2025-10-21-PADCEV-TM-enfortumab-vedotin-ejfv-Plus-KEYTRUDA-R-pembrolizumab-sBLA-Granted-FDA-Priority-Review-for-Treatment-of-Certain-Patients-with-Muscle-Invasive-Bladder-Cancer

4. 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. November 11, 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/