Pembrolizumab Plus EV Regimens Receive FDA Approval for Muscle Invasive Bladder Cancer

The FDA approved pembrolizumab (Keytruda; Merck) or pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex; Merck) each in combination with enfortumab vedotin-ejfv (EV, Padcev; Astellas Pharma) as neoadjuvant treatment prior to surgery and followed by adjuvant treatment after cystectomy for adults with muscle invasive bladder cancer (MIBC). According to a news release from the FDA, this approval extends the prior approval for the regimen in this setting from patients who are cisplatin-ineligible to all patients with MIBC who are candidates for cystectomy.¹

What is the Current MIBC Treatment Landscape?

It is estimated that each year, over 614,000 people worldwide are diagnosed with bladder cancer, making it the ninth most common cancer globally. In the MIBC setting specifically, about 117,500 patients received treatment under the established standard of care in 2024—neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy.^2,3

However, significant treatment gaps remain. As many as half of all patients with MIBC are unable to tolerate cisplatin-based therapy, leaving a significant part of the population without access to the most established treatment pathway. Even among those who do undergo radical cystectomy, recurrence remains a persistent threat, occurring in approximately 50% of patients and underscoring the urgent need for more effective perioperative strategies.^2,3

For those with MIBC who are eligible for cisplatin-based chemotherapy, neoadjuvant gemcitabine plus cisplatin followed by radical cystectomy has long been the standard perioperative approach, but results from the randomized phase 3 KEYNOTE-B15/EV-304 trial (NCT04700124)⁴ challenged that standard. EV represents a clinically promising advancement in the treatment of MIBC. An antibody-drug conjugate, EV, targets Nectin-4, a molecule responsible for cell adhesion. Overexpression of this molecule may contribute to tumor cell growth and proliferation; therefore, targeting this molecule can induce cell-cycle arrest and apoptosis.^2,3

The KEYNOTE-B15 Clinical Trial

The approval is based on results from KEYNOTE-B15, a randomized, open-label phase 3 clinical trial evaluating perioperative EV plus pembrolizumab versus neoadjuvant gemcitabine and cisplatin in previously untreated patients with MIBC who are eligible for cisplatin-based chemotherapy. A total of 808 patients were randomly assigned to receive neoadjuvant pembrolizumab and EV followed by surgery followed by adjuvant pembrolizumab and EV (n = 405), or neoadjuvant gemcitabine and cisplatin followed by surgery (n = 403).^1,2,4

KEYNOTE-B15’s major efficacy outcome measure was event-free survival (EFS) assessed by blinded independent central review, and overall survival (OS) was an additional efficacy outcome.^1,4

Pembrolizumab With EV Result in Statistically Significant Improvements in EFS and OS

According to the findings, statistically significant improvements in EFS and OS were observed in patients treated with perioperative pembrolizumab and EV compared with neoadjuvant gemcitabine and cisplatin. Median EFS was not reached (NR; 95% CI, NR-NR) in the pembrolizumab with EV arm and was about 48.5 months (95% CI, 43.3-NR) in the gemcitabine with cisplatin arm (HR, 0.53 [95% CI, 0.41-0.70]; p < .0001). Median OS was not reached in either arm (HR, 0.65 [95% CI, 0.48-0.89]; p = .0029)¹; however, 24-month estimated OS rates were 86.9% and 81.3% in these respective arms.^2,3

Additionally, the pathological complete response rate was nearly double with EV plus pembrolizumab (55.8%) compared with chemotherapy (32.5% [95% CI, 16.7-29.8]; P < .0001), emphasizing the regimen’s ability to eradicate disease prior to surgery.²

The overall safety profile of pembrolizumab with EV in KEYNOTE-B15 was similar to that observed in prior trials of this combination in urothelial cancer. Grade 3 or higher treatment-emergent adverse events (AEs) occurred in approximately 75.7% of patients receiving EV plus pembrolizumab and in 67.2% in the chemotherapy arm. The most common grade 3 or higher drug-related AEs of special interest were skin reactions for both EV (14.1%) and pembrolizumab (13.9%).^2,3

Additional warnings and precautions noted by pembrolizumab’s prescribing information for pembrolizumab include immune-mediated adverse reactions, infusion-related reactions, complications of allogeneic hematopoietic stem cell transplantation, and embryo-fetal toxicity, whereas warnings for EV include skin reactions, hyperglycemia, pneumonitis/interstitial lung disease, peripheral neuropathy, ocular disorders, infusion site extravasation, and embryo-fetal toxicity.¹

For patients who are cisplatin-eligible, the FDA-recommended pembrolizumab dose for neoadjuvant treatment is 200 mg intravenously (IV) every 3 weeks or 400 mg IV every 6 weeks, administered in combination with EV 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 for a total duration of 12 weeks of neoadjuvant treatment.¹

In the adjuvant phase, EV is 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 duration of the combination of pembrolizumab and EV in the adjuvant setting is 15 weeks, and the overall duration of adjuvant therapy—including pembrolizumab as a single agent—is 39 weeks. It is recommended that pembrolizumab be administered after EV when given on the same day.¹

REFERENCES

1. FDA approves pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph each with enfortumab vedotin-ejfv for muscle invasive bladder cancer. FDA. News release. 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. Gerlach A. Phase 3 Data Back a New Perioperative Standard for Cisplatin-Eligible Muscle-Invasive Bladder Cancer. Pharmacy Times. May 29, 2026. Accessed July 10, 2026. https://www.pharmacytimes.com/view/phase-3-data-back-a-new-perioperative-standard-for-cisplatin-eligible-muscle-invasive-bladder-cancer

3. Perioperative Enfortumab Vedotin (EV) Plus Pembrolizumab (MK-3475) Versus Neoadjuvant Chemotherapy for Cisplatin-Eligible Muscle Invasive Bladder Cancer (MIBC) (MK-3475-B15/​ KEYNOTE-B15 /​ EV-304) (KEYNOTE-B15). ClinicalTrials.gov identifier: NCT04700124. Updated June 26, 2026. Accessed July 10, 2026. https://clinicaltrials.gov/study/NCT04700124

4. Gerlach A. Enfortumab Vedotin Plus Pembrolizumab Improves Survival Outcomes While Preserving Surgical Feasibility. Pharmacy Times. February 27, 2026. Accessed July 10, 2026. https://www.pharmacytimes.com/view/enfortumab-vedotin-plus-pembrolizumab-improves-survival-outcomes-while-preserving-surgical-feasibility