Clinical trialPhase 3Bladder cancer

Enfortumab Vedotin and Pembrolizumab in Cisplatin-Eligible Bladder Cancer

N Engl J Med · 2026808 patients (405 enfortumab vedotin–pembrolizumab, 403 cisplatin–gemcitabine)

Galsky MD, Valderrama BP, Maruzzo M, et al. N Engl J Med. 2026. 395:338-348

Study type: Clinical trial
Study name: EV-304 (KEYNOTE-B15)
Phase: Phase 3
Design: Randomised, open-label trial
Sample size: 808 patients (405 enfortumab vedotin–pembrolizumab, 403 cisplatin–gemcitabine)
Source: N Engl J Med · 2026
Trial registration: NCT04700124

In plain words

Until now, patients with bladder cancer that has grown into the muscle wall who could take cisplatin were given chemotherapy before surgery. In the EV-304 study, a combination of a "targeted drug linked to chemotherapy" (enfortumab vedotin) and immunotherapy (pembrolizumab), given before and after surgery, was compared with standard chemotherapy. After two years, more patients were free of the disease coming back (about 79 versus 66 out of every 100) and alive (about 87 versus 81), and in more than half of patients no tumour was left in the removed bladder. On the other hand, severe side effects were slightly more common.

Key results

79.4% vs 66.2%

2-year event-free survival

HR for event or death 0.53 (95% CI 0.41 to 0.70); P<0.001

86.9% vs 81.3%

2-year overall survival

HR for death 0.65 (95% CI 0.48 to 0.89); P=0.006 (two-sided)

55.8% vs 32.5%

Pathological complete response

P<0.001

75.7% vs 67.2%

Grade 3 or higher adverse events (any cause)

86.7% vs 89.6%

Cystectomy performed

Median time to data cutoff 33.6 months

Drugs in this study:Cisplatin (Platinol)Gemcitabine (Gemzar)Pembrolizumab (Keytruda)

Dose and schedule cards

Perioperative enfortumab vedotin + pembrolizumab (EV-304 and KEYNOTE-905)

MIBC (cT2 to T4a N0 or T1 to T4a N1, M0), candidate for cystectomy and pelvic lymph node dissection; per the FDA label, in both cisplatin-eligible and cisplatin-ineligible patientsEach drug’s schedule in the tableOn the page “Bladder cancer” · Muscle-invasive cancer (MIBC): perioperative therapy and bladder preservation

MIBC (cT2 to T4a N0 or T1 to T4a N1, M0), candidate for cystectomy and pelvic lymph node dissection; per the FDA label, in both cisplatin-eligible and cisplatin-ineligible patients

Drug	Dose	Route	Schedule
Cisplatin-eligible (EV-304)
Enfortumab vedotin	1.25 mg/kg (maximum 125 mg)	IV over 30 minutes	Days 1 and 8; 4 cycles before and 5 cycles after surgery
Pembrolizumab	200 mg (or 400 mg every 6 weeks)	IV over 30 minutes	Day 1; 4 doses before (or 2 doses of 400 mg) and 13 doses after surgery (or 7 doses of 400 mg)
Cisplatin-ineligible or declining cisplatin (KEYNOTE-905)
Enfortumab vedotin	1.25 mg/kg (maximum 125 mg)	IV over 30 minutes	Days 1 and 8; 3 cycles before and 6 cycles after surgery
Pembrolizumab	200 mg	IV over 30 minutes	Day 1; 3 doses before and 14 doses after surgery (after surgery, alternatively 7 doses of 400 mg every 6 weeks)

Cycle schedule: Every 21 days
Duration: Total treatment about 1 year

Per the FDA label and the KEYNOTE-905 and EV-304 trials.

On the page “Bladder cancer” · Muscle-invasive cancer (MIBC): perioperative therapy and bladder preservation

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Perioperative enfortumab vedotin + pembrolizumab

Neoadjuvant (4 cycles of 21 days): enfortumab vedotin 1.25 mg/kg (maximum 125 mg) IV on days 1 and 8 + pembrolizumab 200 mg IV on day 1 (about 3 months).

Then radical cystectomy with pelvic lymph node dissection (around week 15).

Adjuvant: enfortumab vedotin on days 1 and 8 for 5 cycles and pembrolizumab 200 mg every 3 weeks for 13 cycles (total treatment about 1 year). FDA label equivalent for pembrolizumab: neoadjuvant 200 mg every 3 weeks ×4 or 400 mg every 6 weeks ×2; adjuvant 200 mg ×13 or 400 mg ×7.

2Neoadjuvant cisplatin–gemcitabine (standard)

Cisplatin 70 mg/m² on day 1 with gemcitabine 1000 mg/m² on days 1 and 8, every 3 weeks for 4 cycles; then radical cystectomy.

Source of the regimen details: ClinicalTrials.gov NCT04700124 and FDA labels for PADCEV and KEYTRUDA (DailyMed)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Adults with muscle-invasive bladder cancer (T2 to T4a N0 M0 or T1 to T4a N1 M0) with predominant urothelial histology, eligible for cisplatin-based chemotherapy and radical cystectomy with pelvic lymph node dissection, ECOG performance status 0 or 1 and no prior systemic therapy for muscle-invasive disease (prior intravesical BCG or chemotherapy was allowed).

Endpoints

Primary endpoint: event-free survival. Key secondary endpoints: overall survival and pathological complete response. Safety was also assessed.

Safety and side effects

Grade 3 or higher adverse events of any cause were more frequent with enfortumab vedotin–pembrolizumab (75.7% versus 67.2%). The known toxicities of enfortumab vedotin (skin, peripheral neuropathy, hyperglycaemia) and the immune-mediated adverse events of pembrolizumab require monitoring (details in the full text).

Clinical significance and place in guidelines

Based on this study, on 10 July 2026 the FDA approved enfortumab vedotin with pembrolizumab as neoadjuvant and adjuvant treatment for adults with muscle-invasive bladder cancer, regardless of cisplatin eligibility; this is the first platinum-free regimen approved for all of these patients. This regimen has not been compared directly with durvalumab + gemcitabine–cisplatin (NIAGARA).

Limitations

Open-label design; the control group did not receive perioperative immunotherapy (such as the NIAGARA regimen); severe adverse events were more frequent; long-term overall survival follow-up is ongoing.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.