FDA Grants Priority Review to Perioperative Enfortumab Vedotin Plus Pembrolizumab in Cisplatin-Ineligible MIBC

The FDA has accepted and granted priority review to 2 supplemental biologics license applications (sBLAs) seeking the approval of enfortumab vedotin-ejfv (Padcev) in combination with pembrolizumab (Keytruda) or pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex) as a neoadjuvant treatment, and then continued after surgery as adjuvant treatment, for patients with muscle-invasive bladder cancer (MIBC) who are ineligible for cisplatin-containing chemotherapy.^1,2

The FDA has set a Prescription Drug User Fee Act target action date of April 7, 2026, for both indications. Notably, this is the first time that pembrolizumab and pembrolizumab plus berahyaluronidase alfa-pmph are under concurrent review for the same novel indication.²

The applications were supported by findings from the phase 3 EV-303 trial (KEYNOTE-905; NCT03924895), which evaluated the Nectin-4–directed antibody-drug conjugate enfortumab vedotin plus the PD-1 inhibitor pembrolizumab as perioperative therapy compared with radical cystectomy plus pelvic lymph node dissection (RC + PLND) alone, the current standard of care.^1,2

Data from EV-303 presented at the 2025 ESMO Congress showed that enfortumab vedotin plus pembrolizumab (n = 170) generated a median event-free survival (EFS) that was not reached(NR; 95% CI, 37.3-NR) vs 15.7 months (95% CI, 10.3-20.5) with RC + PLND (n = 174; HR, 0.40; 95% CI, 0.28-0.57; 1-sided P < .0001).³ The respective 12-month EFS rates were 77.8% vs 55.1%, and the 24-month rates were 74.7% vs 39.4%, respectively.

Similarly, median overall survival (OS) was NR (95% CI, NR-NR) in the enfortumab vedotin plus pembrolizumab arm vs 41.7 months (95% CI, 31.8-NR) with in the control arm (HR, 0.50; 95% CI, 0.33-0.74; 1-sided P = .0002). The 12- and 24-month OS rates were 86.3% and 79.7% with the combination vs 75.7% and 63.1% with the control, respectively. The pathologic complete response (pCR) rate was 57.1% (95% CI, 49.3%-64.6%) with enfortumab vedotin plus pembrolizumab vs 8.6% (95% CI, 4.9%-13.8%) with RC + PLND alone, corresponding to an estimated difference of 48.3% (95% CI, 39.5%-56.5%; 1-sided P < .000001).

“New options for MIBC are vital—patients who are ineligible for chemotherapy have not seen a treatment advance beyond surgery in decades,” Marjorie Green, MD, senior vice president and head of oncology and global clinical development at Merck Research Laboratories, stated in a news release.² “With the FDA’s priority review, we are one step closer to offering [pembrolizumab] or [pembrolizumab and berahyaluronidase alfa-pmph] plus [enfortumab vedotin] as a potential treatment option to these patients with MIBC who are ineligible for cisplatin-containing chemotherapy and have such high unmet medical need.”

Notably, in December 2023, the FDA approved enfortumab vedotin in combination with pembrolizumab for patients with locally advanced or metastatic urothelial cancer.⁴

What was the design of the EV-303 trial?

EV-303 was an open-label, randomized, three-arm, controlled study designed to evaluate the efficacy and safety of neoadjuvant and adjuvant therapy with enfortumab vedotin in combination with pembrolizumab in patients with MIBC who were ineligible for or have declined cisplatin-based chemotherapy.^1,2 Patients needed to have clinical stage T2-T4aN0M0 or T1-T4aN1M0 disease and a urothelial histology of at least 50%.² An ECOG performance status of 0 to 2 was required.

Eligible patients were randomly assigned to one of three treatment arms:

• Arm A: Neoadjuvant and adjuvant pembrolizumab monotherapy and RC + PLND
• Arm B: RC +PLND
• Arm C: Neoadjuvant and adjuvant enfortumab vedotin plus pembrolizumab and RC + PLND

In the combination arm, neoadjuvant therapy comprised enfortumab vedotin at 1.25 mg/kg on days 1 and 8 every 3 weeks of each cycle, plus pembrolizumab at 200 mg once every 3 weeks for a total of 3 cycles. Following RC + PLND, patients received the agents at the same doses, with enfortumab vedotin given on days 1 and 8 every 3 weeks for a total of 6 cycles, plus pembrolizumab once every 3 weeks for 14 cycles.

The primary end point of the trial is EFS, comparing enfortumab vedotin plus pembrolizumab vs surgery alone. EFS was defined as the time from randomization to the first occurrence of disease progression precluding RC, failure to undergo RC in patients with residual disease, gross residual disease following surgery, local or distant recurrence as determined by imaging or biopsy, or death from any cause.¹

Secondary end points included OS, pCR rate, and safety; EFS by pCR status was an exploratory end point.²

What was the safety profile observed in EV-303?

The safety profile of enfortumab vedotin plus pembrolizumab was consistent with the known safety profiles of both agents, and no new safety signals were identified.¹

Any-grade treatment-emergent adverse effects (TEAEs) occurred in all patients who received the combination (n = 167) and in 64.8% of those treated with RC + PLND alone (n = 159).² Grade 3 or higher TEAEs were reported in 71.3% and 45.9% of patients, respectively, and serious effects occurred in 58.1% and 40.9%, respectively. Surgery delays occurred in 4.0% of patients in the combination arm and 0.6% in the control arm.

Dose reductions or discontinuations of enfortumab vedotin occurred in 16.8% and 41.3% of patients, respectively, and pembrolizumab was discontinued in 34.1%. AEs leading to death occurred in 7.8% of patients in the combination arm and 5.7% in the control arm.

Note From the Editor: This story was originally published on October 22, 2025 and was updated and republished on October 23, 2025.

References

1. Padcev (enfortumab vedotin-ejfv) plus Keytruda (pembrolizumab) sBLA granted FDA priority review for treatment of certain patients with muscle-invasive bladder cancer. Astellas. News release. October 21, 2025. Accessed October 22, 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
2. Vulsteke C, Kaimakliotis HZ, Danchaivijitr P, et al. Perioperative enfortumab vedotin plus pembrolizumab in participants with muscle-invasive bladder cancer who are cisplatin-ineligible: phase 3 KEYNOTE-905 study. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA2.
3. FDA approves enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer. FDA. December 15, 2023. Accessed October 22, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic-urothelial-cancer