Background
Open-label phase III trial of 608 patients with locally advanced or metastatic urothelial carcinoma that progressed after platinum-containing chemotherapy and a PD-1 or PD-L1 inhibitor.
Interventions and follow up
Arm A: Enfortumab vedotin 1.25 mg/kg IV on days 1, 8, and 15 of a 28-day cycle
Arm B: Investigator choice of paclitaxel, docetaxel, or vinflunine
Primary endpoint: Overall survival
Median follow up: 11.1 mo
Arm B: Investigator choice of paclitaxel, docetaxel, or vinflunine
Primary endpoint: Overall survival
Median follow up: 11.1 mo
Results
mOS: 12.88 mo vs 8.97 mo (A vs B); HR 0.70, 95% CI 0.56-0.89; P=.001
mPFS: 5.55 mo vs 3.71 mo (A vs B); HR 0.62, 95% CI 0.51-0.75; P<.001
mPFS: 5.55 mo vs 3.71 mo (A vs B); HR 0.62, 95% CI 0.51-0.75; P<.001
Adverse events
Grade 3 or higher events: 51.4% vs 49.8% (A vs B)
Hematologic: Decreased neutrophil count 6.1% vs 13.4%; neutropenia 4.7% vs 6.2%; febrile neutropenia 0.7% vs 5.5%
Skin/constitutional: Maculopapular rash 7.4% vs 0%; fatigue 6.4% vs 4.5%
Hematologic: Decreased neutrophil count 6.1% vs 13.4%; neutropenia 4.7% vs 6.2%; febrile neutropenia 0.7% vs 5.5%
Skin/constitutional: Maculopapular rash 7.4% vs 0%; fatigue 6.4% vs 4.5%
Conclusions
Enfortumab vedotin significantly prolonged overall and progression-free survival versus chemotherapy in urothelial carcinoma previously treated with platinum and a checkpoint inhibitor.
Key Limitations
Open-label design. Characteristic toxicities include peripheral neuropathy, skin reactions (including rare severe cutaneous reactions), and hyperglycemia requiring monitoring. The agent has since moved to first-line use combined with pembrolizumab.
Clinical Context
EV-301 led to full FDA approval and EMA authorization of enfortumab vedotin after platinum and PD-1/PD-L1 therapy in advanced urothelial carcinoma. Building on this, EV-302 established first-line enfortumab vedotin plus pembrolizumab as a new ASCO/ESMO frontline standard.