Background
Phase III, open-label RCT. 886 patients with previously untreated locally advanced or metastatic urothelial carcinoma (mUC), cisplatin-eligible (43%) and cisplatin-ineligible (57%). No restriction on PD-L1 expression. Enfortumab vedotin (EV; anti-Nectin-4 ADC) combined with pembrolizumab tested against platinum-based chemotherapy (GC or MVAC), which was the established first-line standard.
Interventions and follow up
Arm A: Enfortumab vedotin 1.25mg/kg IV D1, D8 q3wk + pembrolizumab 200mg IV q3wk
Arm B: Cisplatin + gemcitabine OR carboplatin + gemcitabine (investigator's choice based on eligibility)
Primary endpoint: PFS and OS (co-primary)
mFollow up: 17.2 mo
Arm B: Cisplatin + gemcitabine OR carboplatin + gemcitabine (investigator's choice based on eligibility)
Primary endpoint: PFS and OS (co-primary)
mFollow up: 17.2 mo
Results
PFS: 12.5 vs 6.3 mo, HR 0.45, P<.001
OS: 31.5 vs 16.1 mo, HR 0.47, P<.001
ORR: 67.7% vs 44.4%
CR rate: 29.1% vs 12.5%
OS: 31.5 vs 16.1 mo, HR 0.47, P<.001
ORR: 67.7% vs 44.4%
CR rate: 29.1% vs 12.5%
Adverse events
Overall grade ≥3: 55.9% vs 69.5% (EV+P lower than chemo)
Dermatologic: skin toxicity grade ≥3 (EV) 7.4% vs 0.4%; rash (any grade) 51.8% vs 10.9%
Neurologic: peripheral neuropathy grade ≥3 5.8% vs 3.0%
Metabolic: hyperglycemia grade ≥3 3.3% vs 0.3%
Immune-mediated (any grade): 40.0% vs 9.4%
Discontinuation: both agents 12.3%; at least one agent 34.5%
Dermatologic: skin toxicity grade ≥3 (EV) 7.4% vs 0.4%; rash (any grade) 51.8% vs 10.9%
Neurologic: peripheral neuropathy grade ≥3 5.8% vs 3.0%
Metabolic: hyperglycemia grade ≥3 3.3% vs 0.3%
Immune-mediated (any grade): 40.0% vs 9.4%
Discontinuation: both agents 12.3%; at least one agent 34.5%
Conclusions
Enfortumab vedotin + pembrolizumab demonstrated unprecedented efficacy versus platinum-based chemotherapy in first-line mUC, roughly doubling OS (31.5 vs 16.1 months) with superior response rates and comparable or lower grade ≥3 toxicity. This combination represents the most practice-changing advance in bladder cancer in decades and has replaced chemotherapy as the standard of care regardless of cisplatin eligibility or PD-L1 status.
Key Limitations
Key Limitations: Open-label design may influence endpoint assessment. Skin toxicity (rash, Stevens-Johnson syndrome risk) and peripheral neuropathy require close monitoring and dose modification experience. Hyperglycemia occurs in diabetic and non-diabetic patients and requires surveillance. The carboplatin + gemcitabine comparator (cisplatin-ineligible subgroup) is the weakest chemotherapy backbone, potentially overstating the benefit in that subgroup. Long-term toxicity data are still maturing. Access and cost of EV + pembrolizumab remain significant global barriers.
Clinical Context
EV-302/KEYNOTE-A39 (NEJM 2024) established enfortumab vedotin + pembrolizumab as the new first-line standard for locally advanced or metastatic UC, regardless of cisplatin eligibility or PD-L1 expression. FDA approved this combination in December 2023. This is one of the largest OS benefit demonstrations in any solid tumor trial: HR 0.47 is extraordinary. Switch maintenance avelumab (JAVELIN Bladder 100, n=138 in DB) for patients who received chemotherapy without EV remains relevant for those who received chemo first-line before EV+P access.
References
References: Powles T et al, NEJM 2024