Clinical trialPhase 3Bladder cancer

Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer

N Engl J Med · 2024886 patients (442 enfortumab vedotin + pembrolizumab, 444 chemotherapy)

Powles T, Valderrama BP, Gupta S, et al. N Engl J Med. 2024. 390:875-888

A newer report of this study has been published: 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 (2025)

Study type: Clinical trial
Study name: EV-302 (KEYNOTE-A39)
Phase: Phase 3
Design: Randomised, open-label, global, multicentre trial (1:1 randomisation)
Sample size: 886 patients (442 enfortumab vedotin + pembrolizumab, 444 chemotherapy)
Source: N Engl J Med · 2024
Trial registration: NCT04223856

In plain words

For many years, chemotherapy containing platinum was the main treatment for advanced cancer of the bladder and urinary tract. In this large study, the combination of enfortumab vedotin (a "targeted drug carrying chemotherapy" that delivers the drug straight to the cancer cell) and pembrolizumab (an immunotherapy drug) was compared with chemotherapy. The combination almost doubled how long patients lived on average (about 31 months versus 16 months) and also doubled the time the disease was kept under control. Serious side effects were less common than with chemotherapy, but side effects such as skin rashes, numbness in the hands and feet and high blood sugar need careful monitoring.

Key results

31.5 vs 16.1 months

Median overall survival

HR for death 0.47 (95% CI 0.38–0.58); P<0.001; median follow-up 17.2 months

12.5 vs 6.3 months

Median progression-free survival

HR for progression or death 0.45 (95% CI 0.38–0.54); P<0.001

55.9% vs 69.5%

Grade 3 or higher treatment-related adverse events

Enfortumab vedotin + pembrolizumab vs chemotherapy

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

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)”

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)

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 (control group)

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, Clinical Studies section, EV-302/KEYNOTE-A39) 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

Primary endpoints (dual): progression-free survival (PFS) by blinded independent central review, and overall survival (OS).

Secondary endpoints: objective response rate, duration of response and safety.

Safety and side effects

Grade 3 or higher treatment-related adverse events: 55.9% with enfortumab vedotin–pembrolizumab versus 69.5% with chemotherapy. 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

For the first time in decades, this study showed an overall survival advantage over platinum-containing chemotherapy in first-line advanced urothelial cancer. The FDA approved enfortumab vedotin with pembrolizumab for locally advanced or metastatic urothelial cancer in December 2023, and the combination was also approved in the European Union (2024). International guidelines (including ESMO and NCCN) now present this combination as the preferred first-line treatment, regardless of cisplatin eligibility.

Limitations

The trial was open-label (patients and physicians knew the treatment). Avelumab maintenance in the chemotherapy group was used in only some patients. Median follow-up at the first analysis was 17.2 months, and long-term data are given in later reports. Treatment continues until progression, and high cost and cumulative toxicities (neuropathy, skin toxicity) are practical considerations. The study was sponsored by the manufacturers.

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.