Perioperative Pembrolizumab Plus Enfortumab Vedotin Nets FDA Priority Review in Cisplatin-Eligible MIBC

The FDA has granted priority review to 2 supplemental biologics license applications (sBLAs) seeking the approval of pembrolizumab (Keytruda) or pembrolizumab and berahyaluronidase alfa-pmph (subcutaneous pembrolizumab; Keytruda Qlex), each in combination with enfortumab vedotin-ejfv (Padcev), for the perioperative treatment of patients with muscle-invasive bladder cancer (MIBC) who are eligible for cisplatin-based chemotherapy.¹

The FDA assigned a Prescription Drug User Fee Act target action date of August 17, 2026.

The sBLAs are supported by data from the phase 3 KEYNOTE-B15/EV-304 trial (NCT04700124). Finding from KEYNOTE-B15 presented during 2026 Genitourinary Cancers Symposium (ASCO GU) demonstrated that patients who received enfortumab vedotin plus pembrolizumab (n = 405) experienced a median event-free survival (EFS) that was not reached (NR; 95% CI, NR-NR) compared with 48.5 months (95% CI, 43.3-NR) among patients who received cisplatin plus gemcitabine (n = 403; HR, 0.53; 95% CI, 0.41-0.70; 1-sided P < .0001).² The 24-month EFS rates were 79.4% and 66.2%, respectively; the respective 12-month EFS rates were 86.0% and 75.4%.

“Results from KEYNOTE-B15 challenge long-held expectations for patients with MIBC,” Marjorie Green, MD, senior vice president and head of oncology, global clinical development, at Merck Research Laboratories, stated in a news release.¹ “Even with curative-intent surgery and chemotherapy, patients still experience disease progression or limited survival. These data add to the growing body of evidence demonstrating that [pembrolizumab] and [subcutaneous pembrolizumab], each in combination with [enfortumab vedotin], have the potential to reshape how we approach treatment for these patients and improve outcomes for people facing this aggressive disease.”

Notably, in November 2025, the FDA approved enfortumab vedotin in combination with pembrolizumab or subcutaneous pembrolizumab as neoadjuvant treatment followed by adjuvant treatment after cystectomy for patients with MIBC who are ineligible for cisplatin, based on data from the phase 3 EV-303/KEYNOTE-905 trial (NCT03924895).³ The combination is also approved by the FDA for the treatment of patients with locally advanced or metastatic urothelial cancer, irrespective of cisplatin eligibility.⁴

How was KEYNOTE-B15 designed?

KEYNOTE-B15 enrolled adult patients with clinical stage T2 to T4aN0M0 or T1 to T4aN1M0 MIBC per central assessment.² Patients were also required to have at least 50% urothelial histology, be eligible for radical cystectomy with pelvic lymph node dissection, and have an ECOG performance status of 0 or 1. They could not meet Galsky criteria for cisplatin ineligibility.

Patients were randomly assigned 1:1 to receive neoadjuvant enfortumab vedotin at 1.25 mg/kg on days 1 and 8 plus pembrolizumab at 200 mg on day 1 every 3 weeks for 4 cycles or chemotherapy. In the chemotherapy arm, patients received neoadjuvant cisplatin at 70 mg/m² on day 1 plus gemcitabine at 1000 mg/m² on days 1 and 8 every 3 weeks for 4 cycles. Following radical cystectomy and pelvic lymph node dissection, patients in the experimental arm received enfortumab vedotin at 1.25 mg/kg on days 1 and 8 once every 3 weeks for 5 cycles plus pembrolizumab at 200 mg on day 1 once every 3 weeks for 13 cycles. Those in the control arm underwent observation following surgery.

The primary end point was EFS per blinded independent central review. Overall survival (OS) and pathologic complete response (pCR) rate were the key secondary end points. Safety was also assessed as a secondary end point.

What additional data were shared during ASCO GU?

The median OS was both NR (95% CI, NR-NR) in both the investigational and control arms. Treatment with the combination led to 35% reduction in the risk of death compared with chemotherapy (HR, 0.65; 95% CI, 0.48-0.89; 1-sided P = .0029). The 24-month OS rates were 86.9% and 81.3%, respectively. The pCR rates were 55.8% (95% CI, 50.8%-60.7%) and 32.5% (95% CI, 28.0%-37.3%), respectively, translating to an estimated difference of 23.4% (95% CI, 16.7%-29.8%; 1-sided P < .0001).

In terms of safety, patients in the investigational (n = 403) and chemotherapy (n = 390) arms experienced any-grade treatment-emergent adverse effects (TEAEs) at respective rates of 98.0% and 98.2%. Patients in both arms also experienced grade 3 or higher TEAEs (75.7% vs 67.2%), serious TEAEs (63.3% vs 48.0%), and TEAEs leading to death (4.2% vs 2.8%). The study authors noted that the safety profile of neoadjuvant and adjuvant enfortumab vedotin plus pembrolizumab was consistent with prior experience with the combination regimen.

References

1. FDA grants priority review for Keytruda (pembrolizumab) and Keytruda Qlex (pembrolizumab and berahyaluronidase alfa-pmph), each with Padcev (enfortumab vedotin-ejfv), for cisplatin-eligible patients with muscle-invasive bladder cancer. News release. Merck. April 20, 2026. Accessed April 20, 2026. https://www.merck.com/news/fda-grants-priority-review-for-keytruda-pembrolizumab-and-keytruda-qlex-pembrolizumab-and-berahyaluronidase-alfa-pmph-each-with-padcev-enfortumab-vedotin-ejfv-for-cisplati/
2. Galsky MD, Valderrama BP, Maruzzo M, et al. Neoadjuvant and adjuvant enfortumab vedotin (EV) plus pembrolizumab (pembro) for participants with muscle-invasive bladder cancer (MIBC) who are eligible for cisplatin: randomized, open-label, phase 3 KEYNOTE-B15 study. J Clin Oncol. 2026;44(suppl 7):LBA630. doi: 10.1200/JCO.2026.44.7_suppl.LBA630
3. FDA approves pembrolizumab with enfortumab vedotin-ejfv for muscle invasive bladder cancer. FDA. November 21, 2025. Accessed April 20, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-enfortumab-vedotin-ejfv-muscle-invasive-bladder-cancer
4. FDA approves enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer. FDA. December 15, 2023. Accessed April 20, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic-urothelial-cancer