FDA Expands Pembrolizumab-Enfortumab for Muscle-Invasive Bladder Cancer

The FDA has approved pembrolizumab (Keytruda; Merck) and the subcutaneous formulation pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex; Merck), each in combination with enfortumab vedotin-ejfv (Padcev; Pfizer/Astellas), as perioperative treatment for adults with muscle-invasive bladder cancer (MIBC), regardless of eligibility for cisplatin-based chemotherapy.¹ The approval expands a previous indication limited to cisplatin-ineligible patients² and makes the combination available to a broader population of patients undergoing curative-intent surgery.¹

Under the expanded indication, patients receive pembrolizumab plus enfortumab vedotin before radical cystectomy and pelvic lymph node dissection, followed by continued treatment after surgery. Keytruda Qlex provides a subcutaneous alternative to intravenous pembrolizumab and may be administered over approximately 1 to 2 minutes.

The approval is supported by results from the phase 3 KEYNOTE-B15 (EV-304) (NCT04700124) trial in cisplatin-eligible patients and builds on previously reported findings from the phase 3 KEYNOTE-905 (EV-303) (NCT03924895) trial in patients who were ineligible for or declined cisplatin-based chemotherapy. The studies were conducted in collaboration with Pfizer and Astellas.

Approval Broadens Perioperative Treatment Options

Cisplatin-based neoadjuvant chemotherapy followed by radical cystectomy has long been the standard perioperative treatment for eligible patients with MIBC. However, many patients cannot receive cisplatin because of renal dysfunction, hearing loss, neuropathy, or other comorbidities, limiting treatment options before surgery. The expanded approval establishes the pembrolizumab-enfortumab vedotin combination as a perioperative option regardless of cisplatin eligibility.

KEYNOTE-B15 Demonstrates Improvements in Survival End Points

KEYNOTE-B15 enrolled 808 previously untreated patients with cisplatin-eligible MIBC who were candidates for radical cystectomy. Participants were randomly assigned to receive perioperative pembrolizumab plus enfortumab vedotin or standard neoadjuvant gemcitabine plus cisplatin chemotherapy.

The combination significantly improved event-free survival (EFS), reducing the risk of disease progression, recurrence, or death by 47% compared with chemotherapy (HR, 0.53; 95% CI, 0.41-0.70; P < .0001). Median EFS was not reached in the pembrolizumab-enfortumab vedotin group compared with 48.5 months in the chemotherapy arm. The regimen also reduced the risk of death by 35% (HR, 0.65; 95% CI, 0.48-0.89; P = .0029). Median overall survival was not reached in either treatment group at the time of analysis.

The trial also met its secondary end point of pathologic complete response (pCR). More than half of patients (55.8%) receiving pembrolizumab plus enfortumab vedotin achieved a pCR at the time of surgery compared with 32.5% of patients treated with gemcitabine and cisplatin.

KEYNOTE-905 Supports Benefit in Cisplatin-Ineligible Disease

Evidence supporting the earlier approval in cisplatin-ineligible patients came from KEYNOTE-905, which enrolled 344 patients with previously untreated MIBC who were candidates for radical cystectomy but were ineligible for or declined cisplatin-based chemotherapy.

Patients treated with perioperative pembrolizumab plus enfortumab vedotin experienced a 60% reduction in the risk of EFS events compared with immediate surgery alone (HR, 0.40; 95% CI, 0.28-0.57; P < .0001). The combination also reduced the risk of death by 50% (HR, 0.50; 95% CI, 0.33-0.74; P = .0002). Pathologic complete response rates were 57.1% with the combination versus 8.6% with surgery alone.

Safety Profile Consistent With Previous Experience

According to the FDA, the safety profile of the regimen was generally consistent with the known safety profiles of pembrolizumab and enfortumab vedotin. Serious adverse reactions occurred during both the neoadjuvant and adjuvant treatment phases, and clinicians should monitor patients for immune-mediated adverse reactions and other known toxicities associated with the agents.

The approval also expands the use of Keytruda Qlex, the subcutaneous formulation of pembrolizumab, which was approved in 2025. Because the injection can be administered in approximately 1 to 2 minutes rather than through a standard intravenous infusion, the formulation may offer additional flexibility for oncology practices while providing the same approved indications as intravenous pembrolizumab.

These approvals establish pembrolizumab plus enfortumab vedotin, administered either with intravenous pembrolizumab or the subcutaneous Keytruda Qlex formulation, as a new perioperative treatment option for adults with resectable MIBC across both cisplatin-eligible and cisplatin-ineligible populations.

References

1. Merck. FDA approves KEYTRUDA (pembrolizumab) and KEYTRUDA QLEX (pembrolizumab and berahyaluronidase alfa-pmph), each with Padcev (enfortumab vedotin-ejfv), as treatment before and after surgery for adults with muscle-invasive bladder cancer (MIBC). News release. July 10, 2026. Accessed July 10, 2026. https://www.businesswire.com/news/home/20260710005432/en/
2. Jeremias S. FDA approves pembrolizumab plus enfortumab vedotim for MIBC. AJMC. November 21, 2025. Accessed July 10, 2026. https://www.ajmc.com/view/fda-approves-pembrolizumab-plus-enfortumab-vedotin-for-mibc