FDA approves enfortumab vedotin plus pembrolizumab for MIBC

On July 10, 2026, the FDA approved pembrolizumab (Keytruda) or pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex) each in combination with enfortumab vedotin-ejfv (Padcev) as perioperative regimens for adults with muscle invasive bladder cancer (MIBC) who are candidates for cystectomy.¹

This approval extends the perioperative use of EV plus pembrolizumab—or its subcutaneous formulation pembrolizumab and berahyaluronidase alfa-pmph— to all patients with MIBC, regardless of cisplatin eligibility, building on the November 2025 approval of the combination for cisplatin-ineligible MIBC.²

Data on pembrolizumab plus enfortumab vedotin

The expanded approval is based on data from the phase 3 KEYNOTE-B15/EV-304 trial (NCT04700124),³ which marked the first time in nearly 25 years that a nonplatinum-based regimen surpassed cisplatin-based neoadjuvant chemotherapy in cisplatin-eligible MIBC.

The trial enrolled 808 patients with previously untreated MIBC who were randomly assigned 1:1 to receive perioperative EV plus pembrolizumab and radical cystectomy with pelvic lymph node dissection (n = 405), or to standard neoadjuvant gemcitabine plus cisplatin (n = 403) followed by surgery. The experimental arm received 4 neoadjuvant cycles of EV plus pembrolizumab, followed by 5 adjuvant cycles of EV and 13 adjuvant cycles of pembrolizumab. The control arm underwent observation after surgery.

The trial met its primary end point of event-free survival (EFS). Median EFS was not reached in the EV/pembrolizumab arm vs 48.5 months in the gemcitabine/cisplatin arm (HR, 0.53; 95% CI, 0.41 to 0.70; P < .0001). At 2 years, the estimated EFS rate was 79.4% with EV/pembrolizumab vs 66.2% in the control arm. Overall survival (OS) was also significantly improved, with a 35% reduction in the risk of death (HR, 0.65; 95% CI, 0.48 to 0.89; P = .0029) and a 24-month estimated OS rate of 86.9% in the EV/pembrolizumab arm vs 81.3% in the control arm.

The pathologic complete response (pCR) rate at surgery was 55.8% with EV/pembrolizumab vs 32.5% with gemcitabine/cisplatin—a difference of 23.4 percentage points (P < .0001). Among patients who underwent cystectomy, the pCR rate in the EV/pembrolizumab arm reached 64.4%.

Grade 3 or higher treatment-emergent adverse events occurred in 75.7% of patients in the EV/pembrolizumab arm vs 67.2% in the gemcitabine/cisplatin arm, with 2 treatment-related deaths in the experimental arm and 1 in the control arm. The safety profile was consistent with prior experience with the combination, and no new signals were identified.

“For muscle-invasive bladder cancer, a comprehensive treatment approach is important; the neoadjuvant phase can help shrink the tumor and target undetectable cancer cells early before surgery, while the adjuvant phase can be critical in eliminating residual, undetectable cancer cells following surgery,” explained Christopher Hoimes, DO, Director of the Bladder Cancer Program and Center for Cancer Immunotherapy at Duke Cancer Institute, and an EV-304 principal investigator, in a news release on the approval.⁴ “These data from EV-304 and this approval show that by delivering this regimen across both the neoadjuvant and adjuvant phases, without platinum-based chemotherapy, we can significantly reduce the risk of recurrence and improve overall survival — offering a potential new standard of care for adult patients with muscle-invasive bladder cancer.”

Recommended dose

According to the FDA, the recommended dose for neoadjuvant pembrolizumab is 200 mg IV every 3 weeks or 400 mg IV every 6 weeks. This is administered in combination with enfortumab vedotin 1.25 mg/kg (up to a maximum of 125 mg for patients ≥ 100 kg) IV on days 1 and 8 of a 21-day cycle for 4 cycles. The total duration of neoadjuvant treatment is 12 weeks.

In the adjuvant phase, enfortumab vedotin should be continued for 5 additional cycles, every 3 weeks in combination with pembrolizumab, administered either as 200 mg IV every 3 weeks for 13 cycles or 400 mg IV every 6 weeks for 7 cycles. The combination of pembrolizumab and enfortumab vedotin-ejfv in the adjuvant setting should be continued for 15 weeks.

The overall duration of adjuvant therapy, including pembrolizumab as a single agent, is 39 weeks. Pembrolizumab should be administered after enfortumab vedotin when given on the same day.

REFERENCE

1. FDA approves pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph each with enfortumab vedotin-ejfv for muscle invasive bladder cancer. News release. US Food & Drug Administration. July 10, 2026. Accessed July 10, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-or-pembrolizumab-and-berahyaluronidase-alfa-pmph-each-enfortumab-vedotin

2. FDA approves pembrolizumab with enfortumab vedotin-ejfv for muscle invasive bladder cancer. US Food & Drug Adminstration. November 21, 2025. Accessed July 10, 2026. 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

3. Galsky MD, Pérez-Valderrama B, Maruzzo M, et al. Neoadjuvant and adjuvant enfortumab vedotin plus pembrolizumab for participants with muscle-invasive bladder cancer who are eligible for cisplatin: randomized, open-label, phase 3 KEYNOTE-B15 study. Abstract LBA630. Presented at: 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium; February 26–28, 2026; San Francisco, CA

4. U.S. FDA Approves PADCEV® plus Keytruda® as Neoadjuvant and Adjuvant Treatment for Muscle-Invasive Bladder Cancer Regardless of Cisplatin Eligibility. News release. Pfizer. July 10, 2026. Accessed July 10, 2026. https://www.pfizer.com/news/press-release/press-release-detail/us-fda-approves-padcevr-plus-keytrudar-neoadjuvant-and