Clinical trialPhase 3Bladder cancer

Enfortumab vedotin plus pembrolizumab in untreated locally advanced or metastatic urothelial carcinoma: 2.5-year median follow-up of the phase III EV-302/KEYNOTE-A39 trial

Ann Oncol · 2025886 patients

Powles TB, Van der Heijden MS, Loriot Y, Bedke J, Valderrama BP, Iyer G, et al. Ann Oncol. 2025. 36:1212-1219

Study type: Clinical trial
Study name: EV-302
Phase: Phase 3
Design: Randomised open-label trial; updated analysis with one additional year of follow-up
Sample size: 886 patients
Source: Ann Oncol · 2025
Trial registration: NCT04223856

In plain words

With one more year of follow-up, the combination of enfortumab vedotin and pembrolizumab in advanced bladder cancer still almost doubled how long patients lived on average compared with chemotherapy (33.8 versus 15.9 months).

Key results

33.8 vs 15.9 months

Median overall survival

Hazard ratio 0.51 (0.43 to 0.61)

12.5 vs 6.3 months

Median progression-free survival

Hazard ratio 0.48 (0.41 to 0.57)

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

Dose and schedule cards

Enfortumab vedotin + pembrolizumab (EV-302)

First-line locally advanced or metastatic urothelial carcinoma, regardless of cisplatin eligibility; in EV-302: ECOG 0 to 2; grade 2 or higher neuropathy and uncontrolled diabetes (HbA1c ≥8%) were exclusion criteriaCycle length: Every 21 daysOn the page “Bladder cancer” · Advanced or metastatic disease: first line

Drug	Dose	Route	Schedule
Enfortumab vedotin	1.25 mg/kg (maximum 125 mg)	IV over 30 minutes	Days 1 and 8
Pembrolizumab	200 mg (or 400 mg every 6 weeks)	IV over 30 minutes; after enfortumab vedotin	Day 1

Cycle length: Every 21 days
Duration: Enfortumab vedotin until progression or toxicity; pembrolizumab up to 2 years

Per the FDA label and the trial. In EV-302, enfortumab vedotin was discontinued because of adverse reactions in 35% of patients (most commonly peripheral neuropathy, 15%).

On the page “Bladder cancer” · Advanced or metastatic disease: first line

Enfortumab vedotin + pembrolizumab (EV-302)

Locally advanced or metastatic urothelial cancerCycle length: Every 21 daysOn the page “Antibody–drug conjugates (ADCs)” · Doses and schedules of the main ADCs (FDA labels)

Locally advanced or metastatic urothelial cancer

Drug	Dose	Route	Schedule
Enfortumab vedotin	1.25 mg/kg (maximum 125 mg)	IV infusion over 30 minutes	Days 1 and 8
Pembrolizumab	200 mg every 3 weeks (or 400 every 6 weeks)	IV over 30 minutes, after enfortumab vedotin	Day 1

Cycle length: Every 21 days
Duration: Until progression or unacceptable toxicity (pembrolizumab at most 24 months)

Avoid enfortumab vedotin in moderate or severe hepatic impairment.

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

EV + pembrolizumab

Advanced urothelial cancer, first lineCycle length: Every 21 daysOn the page “Enfortumab vedotin with pembrolizumab (EV-302)”

Advanced urothelial cancer, first line

Drug	Dose	Route	Schedule
Enfortumab vedotin	1.25 mg/kg (maximum 125 mg)	IV over 30 minutes	Days 1 and 8
Pembrolizumab	200 mg	IV	Day 1

Cycle length: Every 21 days
Duration: Until progression; pembrolizumab up to 35 cycles

Doses as in EV-302.

Dose source:.

On the page “Enfortumab vedotin with pembrolizumab (EV-302)”

Urothelial + enfortumab vedotin

Advanced or metastatic (EV-302); muscle-invasive bladder cancer before and after cystectomyCycle length: Every 3 or 6 weeksOn the page “Pembrolizumab (Keytruda)” · Standard doses and combination regimens (FDA label)

Advanced or metastatic (EV-302); muscle-invasive bladder cancer before and after cystectomy

Drug	Dose	Route	Schedule
Pembrolizumab	200 mg every 3 weeks or 400 mg every 6 weeks	IV infusion over 30 minutes, after enfortumab vedotin on the same day	Day 1
Muscle-invasive, cisplatin-eligible
Pembrolizumab	Before surgery 4 doses of 200 (or 2 doses of 400); after surgery 13 doses of 200 (or 7 doses of 400)	IV	Every 3 (or 6) weeks
Muscle-invasive, cisplatin-ineligible
Pembrolizumab	Before surgery 3 doses of 200; after surgery 14 doses of 200 (or 7 doses of 400)	IV	Every 3 (or 6) weeks

Cycle length: Every 3 or 6 weeks
Duration: Advanced: until progression, toxicity or up to 24 months; muscle-invasive: according to the number of doses

Enfortumab vedotin dose as in its own label. Cisplatin ineligibility: CLcr below 60, ECOG 2 or more, grade 2 or higher hearing loss or neuropathy, or NYHA class III or higher heart failure.

On the page “Pembrolizumab (Keytruda)” · Standard doses and combination regimens (FDA label)

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

Enfortumab vedotin 1.25 mg/kg (maximum 125 mg) IV over 30 minutes on days 1 and 8, and pembrolizumab 200 mg IV over 30 minutes on day 1 (about 30 minutes after enfortumab vedotin), every 21 days; until progression or unacceptable toxicity, pembrolizumab for a maximum of 2 years (442 patients).

2Platinum-containing chemotherapy

Gemcitabine 1000 mg/m² on days 1 and 8 with cisplatin 70 mg/m² or carboplatin (AUC 4.5 or 5) on day 1, every 21 days for up to 6 cycles (according to cisplatin eligibility); avelumab maintenance was allowed per local practice (444 patients).

Source of the regimen details: FDA labels for PADCEV and KEYTRUDA (DailyMed) and ClinicalTrials.gov NCT04223856

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

886 adults with unresectable locally advanced or metastatic urothelial carcinoma with no prior systemic therapy for advanced disease (neoadjuvant/adjuvant chemotherapy was allowed if relapse occurred more than 12 months after completion), eligible for cisplatin-‎ or carboplatin-containing chemotherapy, with measurable disease and ECOG performance status 0 to 2. Exclusion criteria: prior PD-1/PD-L1 inhibitor or MMAE-containing ADC, active brain metastases, grade 2 or higher sensory or motor neuropathy, uncontrolled diabetes (HbA1c ≥8% or ≥7% with symptoms).

Endpoints

Progression-free survival (blinded independent central review) and overall survival in the overall population; safety.

Safety and side effects

Safety data with one additional year of follow-up were consistent with the primary analysis. According to the FDA label (EV-302): serious adverse events 50% and fatal adverse events 3.9% with enfortumab vedotin + pembrolizumab; enfortumab vedotin discontinued because of adverse events in 35% (most common causes peripheral neuropathy 15%, rash 4.1%, pneumonitis 2.3%) and interrupted in 73%.

Clinical significance and place in guidelines

This analysis confirmed the durability of the survival benefit of EV+P, and the authors considered it the first-line standard of care; the EAU guideline regards it as the preferred first-line option for patients eligible for combination therapy.

Limitations

Open-label design; the comparator was chemotherapy without concurrent immunotherapy. Details of subgroups and adverse events are not given in the abstract.

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.