The European Commission (EC) has approved pembrolizumab (Keytruda) plus enfortumab vedotin (Padcev) as neoadjuvant treatment and then continued after radical cystectomy as adjuvant treatment for adult patients with resectable muscle-invasive bladder cancer (MIBC), regardless of cisplatin eligibility.1 The approval also extends to pembrolizumab and berahyaluronidase alfa (Keytruda Qlex; subcutaneous pembrolizumab).
Data from the open-label, randomized, phase 3 KEYNOTE-B15/EV-304 trial (NCT04700124) supported the decision. In cisplatin-eligible patients, the perioperative combination was compared with neoadjuvant gemcitabine (Gemzar) plus cisplatin (Platinol) followed by surgery.2 At a median of 33.6 months between randomization and data cutoff, the estimated 2-year event-free survival (EFS) rates were 79.4% with the combination vs 66.2% with chemotherapy (HR, 0.53; 95% CI, 0.41-0.70; P < .0001).1,2
The combination also produced an estimated 2-year overall survival (OS) rate of 86.9% vs 81.3% for chemotherapy (HR, 0.65; 95% CI, 0.48-0.89; P = .006).2 Pathologic complete response (pCR) was achieved by 55.8% vs 32.5% of patients (P < .001).
“Although cisplatin-based chemotherapy has been a standard treatment approach for many patients with MIBC, recurrence remains a significant challenge,” Alfonso Gómez de Liaño, MD, a KEYNOTE-B15 primary investigator at Hospital Universitario Insular de Gran Canaria, stated in a news release.1 “Based on results from the KEYNOTE-B15 trial, [this] approval is a meaningful advance for patients with MIBC in the European Union, extending this chemotherapy-free perioperative treatment option to patients regardless of cisplatin eligibility.”
In July 2026,
The multicenter trial enrolled 808 adults with previously untreated MIBC who were candidates for both cisplatin and radical cystectomy with pelvic lymph node dissection.2,4 To enroll, patients needed predominantly urothelial histology, clinical T2-T4aN0M0 or T1-T4aN1M0 disease, an ECOG performance status of 0 or 1, and adequate organ function.4
Key exclusion criteria included nodal disease of N2 or greater, distant metastases, prior systemic therapy for MIBC, prior exposure to an immune checkpoint inhibitor, grade 2 or higher sensory or motor neuropathy, and uncontrolled diabetes. Patients who had previously received intravesical therapy for non–muscle-invasive disease could enroll.
Patients were randomly assigned 1:1 to the combination or chemotherapy.1 In the investigational arm, patients received 4 neoadjuvant 21-day cycles of intravenous pembrolizumab at 200 mg on day 1 plus enfortumab vedotin at 1.25 mg/kg on days 1 and 8; after surgery, they received 5 adjuvant cycles of enfortumab vedotin and 13 adjuvant cycles of pembrolizumab. The control arm received 4 neoadjuvant cycles of gemcitabine at 1000 mg/m² on days 1 and 8 plus cisplatin at 70 mg/m² on day 1 before surgery.
EFS by blinded independent central review served as the primary end point, and OS and centrally assessed pCR were key secondary end points.4
In the published analysis, grade 3 or higher adverse effects (AEs) of any cause were reported in 75.7% of patients in the combination arm vs 67.2% of those in the chemotherapy arm.2 Cystectomy rates were 86.7% and 89.6%, respectively.
The most common adverse reactions reported in at least 20% of patients (n = 403) treated with pembrolizumab plus enfortumab vedotin during KEYNOTE-B15 comprised rash (63%), fatigue (48%), pruritus (46%), peripheral neuropathy (43%), diarrhea (36%), alopecia (32%), decreased appetite (29%), nausea and dysgeusia (28% each), constipation (27%), urinary tract infection (25%), dry eye (25%), weight loss (22%), and hyperglycemia (20%).1
