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

The FDA has approved pembrolizumab (Keytruda; Merck) or pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex; Merck), each in combination with enfortumab vedotin-ejfv (EV, Padcev; Astellas Pharma US, Inc/Seagen Inc), as neoadjuvant treatment before surgery followed by adjuvant treatment after cystectomy for adults with muscle-invasive bladder cancer (MIBC). According to an FDA news release, this approval extends prior approval of the regimen in this setting from cisplatin-ineligible patients 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, approximately 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 and therefore lack access to the most established treatment pathway. Even among those who do undergo radical cystectomy, recurrence is 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 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 involved in cell adhesion. Overexpression of this molecule may contribute to tumor cell growth and proliferation; therefore, targeting this molecule may induce cell-cycle arrest and apoptosis.^2,3

KEYNOTE-B15

The approval is based on results from KEYNOTE-B15, a randomized, open-label phase 3 clinical trial evaluating perioperative EV plus pembrolizumab vs 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, then surgery, then 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 Improves EFS and OS

According to the findings, statistically significant improvements in EFS and OS were observed among patients treated with perioperative pembrolizumab and EV compared with those treated with neoadjuvant gemcitabine and cisplatin. Median EFS was not reached (NR; 95% CI, NR-NR) in the pembrolizumab with EV arm and was 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, estimated 24-month OS rates were 86.9% and 81.3%, respectively.^2,3

Additionally, the pathological complete response rate was nearly double with EV plus pembrolizumab (55.8%) compared with chemotherapy, 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 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 in pembrolizumab’s prescribing information include immune-mediated adverse reactions, infusion-related reactions, complications of allogeneic hematopoietic stem cell transplantation, and embryo-fetal toxicity. 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 IV (up to a maximum of 125 mg for patients weighing ≥100 kg) on days 1 and 8 of a 21-day cycle for 4 cycles for a duration of 12 weeks.¹

In the adjuvant phase, EV is continued for 5 additional cycles, every 3 weeks in combination with pembrolizumab, which is 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. 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. 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