FDA Approves Pembrolizumab Plus Enfortumab Vedotin in MIBC

The FDA has approved pembrolizumab (Keytruda) or pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex) each in combination with enfortumab vedotin-ejfv (Padcev) as neoadjuvant treatment followed by adjuvant treatment following cystectomy in adult patients with muscle-invasive bladder cancer (MIBC).¹

The approval was supported by data from the phase 3 KEYNOTE-B15/EV-304 study (NCT04700124). Findings from KEYNOTE-B15 showed that patients who received neoadjuvant pembrolizumab and enfortumab vedotin (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 gemcitabine and cisplatin (n = 403; HR, 0.53; 95% CI, 0.41-0.70; P < .0001).^1,2 The median overall survival (OS) was NR in either arm (HR, 0.65; 95% CI, 0.48-0.89; P = .0029).

The prescribing information for pembrolizumab includes warnings and precautions for immune-mediated adverse reactions, infusion-related reactions, complications of allogeneic hematopoietic stem cell transplantation, and embryo-fetal toxicity.¹ The prescribing information for enfortumab vedotin includes warnings and precautions for skin reactions, hyperglycemia, pneumonitis/interstitial lung disease, peripheral neuropathy, ocular disorders, infusion site extravasation, and embryo-fetal toxicity.

How was KEYNOTE-B15 designed?

KEYNOTE-B15 enrolled adult patients with MIBC who had clinical stage T2-T4aN0M0 or T10TaN1M0 disease per central assessment.² Patients were also required to have a urothelial histology of at least 50%, be eligible for radical cystectomy and partial lymph node dissection, have an ECOG performance status of 0 or 1, and not meet any Galsky criteria for cisplatin eligibility.

Patients were randomly assigned 1:1 to receive intravenous pembrolizumab at 200 mg every 3 weeks for 4 cycles in combination with enfortumab vedotin at 1.25 mg/kg on days 1 and 8 every 3 weeks for 4 cycles or cisplatin plus gemcitabine prior to radical cystectomy and partial lymph node dissection. After surgery, patients in the investigational arm received pembrolizumab at the same dose plus enfortumab vedotin at 1.25 mg/kg on days 1 and 8 every 3 weeks for 5 cycles; those in the control arm proceeded to observation.

The primary end point was EFS per blinded independent central review. OS and pathologic complete response (pCR) rate represented key secondary end points; safety was also evaluated as a secondary end point.

What further data have been shared from KEYNOTE-B15?

During the 2026 Genitourinary Cancers Symposium, investigators presented additional data from KEYNOTE-B15 which revealed that the 12-month EFS rates in the investigational and control arms were 86.0% and 76.4%, respectively; the respective 24-month EFS rates were 79.4% and 66.2%. The 12-month OS rates were 93.1% and 89.6%, respectively, and the 24-month EFS rates were 86.9% and 81.3%, respectively.

The pCR rate in the investigational arm was 55.8% (95% CI, 50.8%-60.7%) compared with 32.5% (95% CI, 28.0%-37.3%) in the chemotherapy arm. The estimated difference between the 2 arms was 23.4% (95% CI, 16.7%-29.8%; 1-sided P < .001).

In terms of safety, any-grade treatment-emergent adverse effects (TEAEs) occurred in 98.0% of patients in the investigational arm and 98.2% of patients in the chemotherapy arm. Grade 3 or higher (75.7% vs 67.2%), serious (65.3% vs 48.0%), and TEAEs leading to death (4.2% vs 2.8%) were reported in both arms. TEAEs in the neoadjuvant phase that led to treatment discontinuation were reported in 25.1% and 15.4% of patients, respectively; 28.6% of patients in the combination arm experienced TEAEs in the adjuvant phase that led to drug discontinuation.

References

1. FDA approves pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph each with enfortumab vedotin-ejfv for muscle invasive bladder cancer. FDA. 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. Galsky MD, Valderrama RP, 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