Clinical trialPhase 3Bladder cancer

Perioperative Enfortumab Vedotin and Pembrolizumab in Bladder Cancer

N Engl J Med · 2026344 patients (170 enfortumab vedotin + pembrolizumab + surgery, 174 surgery alone)

Vulsteke C, Adra N, Danchaivijitr P, et al. N Engl J Med. 2026. 394:1257-1269

Study type: Clinical trial
Study name: KEYNOTE-905/EV-303
Phase: Phase 3
Design: Randomised, open-label, international multicentre trial; perioperative treatment compared with surgery alone
Sample size: 344 patients (170 enfortumab vedotin + pembrolizumab + surgery, 174 surgery alone)
Source: N Engl J Med · 2026
Trial registration: NCT03924895

In plain words

Patients whose bladder cancer has grown into the muscle of the bladder wall usually have cisplatin chemotherapy before surgery to remove the bladder; but many cannot have this drug because of weak kidneys, hearing problems, heart failure or their general condition, and until now they have had surgery alone. In this study, giving enfortumab vedotin and pembrolizumab before and after surgery left no tumour in the tissue removed at surgery in more than half of patients, almost doubled the chance of staying alive without the disease coming back, and also helped patients live longer. On the other hand, the drugs cause more side effects and need careful follow-up.

Key results

74.7% vs 39.4%

2-year event-free survival

HR for event or death 0.40 (95% CI 0.28–0.57); P<0.001 (two-sided); median follow-up 25.6 months

79.7% vs 63.1%

2-year overall survival

HR for death 0.50 (95% CI 0.33–0.74); P<0.001 (two-sided)

57.1% vs 8.6%

Pathological complete response

Difference 48.3 percentage points (95% CI 39.5–56.5); P<0.001

71.3% vs 45.9%

Grade 3 or higher adverse events

Drug-related grade 3 or higher adverse events in the treatment group: 45.5%

Drugs in this study:Cisplatin (Platinol)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

Perioperative enfortumab vedotin + pembrolizumab (KEYNOTE-905)

Muscle-invasive bladder cancer, cisplatin-ineligibleCycle length: Every 21 daysOn the page “Antibody–drug conjugates (ADCs)” · Doses and schedules of the main ADCs (FDA labels)

Muscle-invasive bladder cancer, cisplatin-ineligible

Drug	Dose	Route	Schedule
Before cystectomy, 3 cycles
Enfortumab vedotin	1.25 mg/kg (maximum 125 mg)	IV infusion over 30 minutes	Days 1 and 8
Before cystectomy
Pembrolizumab	200 mg, 3 doses	IV over 30 minutes, after enfortumab vedotin	Day 1
After cystectomy, 6 cycles
Enfortumab vedotin	1.25 mg/kg (maximum 125 mg)	IV infusion over 30 minutes	Days 1 and 8
After cystectomy
Pembrolizumab	200 mg, 14 doses (or 400 mg, 7 doses)	IV over 30 minutes, after enfortumab vedotin	Day 1

Cycle length: Every 21 days
Duration: For the set number of cycles, or until progression precluding surgery, recurrence or unacceptable toxicity

In cisplatin-eligible patients: enfortumab vedotin 4 cycles before and 5 cycles after surgery; pembrolizumab 4 doses before and 13 doses after surgery.

On the page “Antibody–drug conjugates (ADCs)” · Doses and schedules of the main ADCs (FDA labels)

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

1Enfortumab vedotin + pembrolizumab + surgery

Neoadjuvant: 3 cycles of 21 days of enfortumab vedotin 1.25 mg/kg (maximum 125 mg) IV on days 1 and 8 + pembrolizumab 200 mg IV on day 1; then radical cystectomy and pelvic lymph node dissection; adjuvant: 6 cycles of enfortumab vedotin + pembrolizumab, then 8 cycles of pembrolizumab alone (in total 9 cycles of enfortumab vedotin and 17 cycles of pembrolizumab). FDA-label equivalent for pembrolizumab in cisplatin-ineligible patients: neoadjuvant 200 mg ×3; adjuvant 200 mg every 3 weeks ×14 or 400 mg every 6 weeks ×7.

2Surgery alone (control group)

Radical cystectomy with pelvic lymph node dissection according to standard guidelines, without perioperative drug treatment.

Source of the regimen details: ClinicalTrials.gov NCT03924895 and the 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 (cT2–T4aN0M0 or T1–T4aN1M0) with predominant urothelial histology, candidates for radical cystectomy with pelvic lymph node dissection, who were ineligible for cisplatin-based chemotherapy (for example creatinine clearance 30 to 59 mL/min, ECOG 2, grade 2 or higher hearing loss or class III heart failure) or declined it. The study population was mainly cisplatin-ineligible.

Endpoints

Primary endpoint: event-free survival (EFS).

Key secondary endpoints: overall survival and pathological complete response (no viable tumour after surgical resection). Other secondary endpoints included safety.

Safety and side effects

All participants in the enfortumab vedotin–pembrolizumab group had at least one adverse event (grade 3 or higher: 71.3%; drug-related grade 3 or higher: 45.5%), versus 64.8% in the surgery-alone group (grade 3 or higher: 45.9%). Surgery was performed in 87.6% of the treatment group and 89.7% of the control group.

Clinical significance and place in guidelines

KEYNOTE-905/EV-303 is the first phase 3 trial to show an overall survival improvement with perioperative treatment in patients unable to receive cisplatin. On 21 November 2025 the FDA approved pembrolizumab (or its subcutaneous form) with enfortumab vedotin as neoadjuvant and then adjuvant treatment after cystectomy for adults with muscle-invasive bladder cancer who are ineligible for cisplatin.

Limitations

The trial was open-label and the control group received no drug treatment. Some patients were eligible for cisplatin but declined it, so there was no direct comparison with cisplatin-based chemotherapy. Median follow-up is 25.6 months and grade 3 or higher adverse events were more frequent in the treatment group. Results of the pembrolizumab-alone arm are not reported in this paper.

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.