Background
Randomized open-label phase III trial of 542 patients with advanced urothelial carcinoma that recurred or progressed after platinum-based chemotherapy.
Interventions and follow up
Arm A: Pembrolizumab 200 mg IV q3wk
Arm B: Investigator choice of paclitaxel, docetaxel, or vinflunine
Primary endpoints: Overall survival and progression-free survival
Median follow up: 14.1 mo
Arm B: Investigator choice of paclitaxel, docetaxel, or vinflunine
Primary endpoints: Overall survival and progression-free survival
Median follow up: 14.1 mo
Results
mOS (overall): 10.3 mo vs 7.4 mo (A vs B); HR 0.73, 95% CI 0.59-0.91; P=.002
mOS (PD-L1 CPS ≥10%): 8.0 mo vs 5.2 mo; HR 0.57, 95% CI 0.37-0.88; P=.005
mPFS (overall): 2.1 mo vs 3.3 mo (A vs B)
PFS (PD-L1 CPS ≥10%): No benefit; HR 0.89, 95% CI 0.61-1.28; P=.24
mOS (PD-L1 CPS ≥10%): 8.0 mo vs 5.2 mo; HR 0.57, 95% CI 0.37-0.88; P=.005
mPFS (overall): 2.1 mo vs 3.3 mo (A vs B)
PFS (PD-L1 CPS ≥10%): No benefit; HR 0.89, 95% CI 0.61-1.28; P=.24
Adverse events
Grade 3 or higher events: 15.0% vs 49.4% (A vs B)
Skin/constitutional: Pruritus 19.5% vs 2.7%; fatigue 13.9% vs 27.8%
Gastrointestinal: Nausea 10.9% vs 24.3%; diarrhea 9.0% vs 12.9%
Immune-related: Thyroid disorders 10.2% vs 1.6%; pneumonitis 4.1% vs 0.4%
Skin/constitutional: Pruritus 19.5% vs 2.7%; fatigue 13.9% vs 27.8%
Gastrointestinal: Nausea 10.9% vs 24.3%; diarrhea 9.0% vs 12.9%
Immune-related: Thyroid disorders 10.2% vs 1.6%; pneumonitis 4.1% vs 0.4%
Conclusions
Pembrolizumab significantly prolonged overall survival with fewer high-grade adverse events than chemotherapy as second-line therapy for platinum-refractory advanced urothelial carcinoma, regardless of PD-L1 status.
Key Limitations
Open-label design. PFS did not differ, with early crossing of the curves reflecting delayed immunotherapy benefit. Second-line landscape has since shifted with enfortumab vedotin and earlier immunotherapy use.
Clinical Context
KEYNOTE-045 was the first phase III trial to show an OS benefit for immunotherapy in urothelial carcinoma, supporting FDA/EMA approval of pembrolizumab for platinum-refractory advanced disease and establishing it as an ASCO/ESMO second-line standard.