Background
Phase 3 RCT; N=405 locally advanced (T4b, N2, N3) or metastatic urothelial carcinoma; gemcitabine-cisplatin (GC) vs MVAC, first line.
Interventions and follow up
Arm A: GC (gemcitabine 1000 mg/m2 d1, d8, d15; cisplatin 70 mg/m2 d2) q28d x up to 6 cycles
Arm B: MVAC (methotrexate 30 mg/m2 d1, d15, d22; vinblastine 3 mg/m2 d2, d15, d22; doxorubicin 30 mg/m2 d2; cisplatin 70 mg/m2 d2) q28d x up to 6 cycles
Primary endpoint: Overall survival
Secondary: response, DOR, time to progression, toxicity, QoL
mFollow up: 19 mo
Arm B: MVAC (methotrexate 30 mg/m2 d1, d15, d22; vinblastine 3 mg/m2 d2, d15, d22; doxorubicin 30 mg/m2 d2; cisplatin 70 mg/m2 d2) q28d x up to 6 cycles
Primary endpoint: Overall survival
Secondary: response, DOR, time to progression, toxicity, QoL
mFollow up: 19 mo
Results
mOS: 13.8 mo vs 14.8 mo, HR 1.04, 95% CI 0.82–1.32, P=.75 (NS).
mPFS: 7.4 mo vs 7.4 mo, HR 1.05, 95% CI 0.85–1.30, P=.66 (NS).
Time to treatment failure: 5.8 mo vs 4.6 mo, HR 0.89, 95% CI 0.72–1.10, P=.27.
ORR: 49.4% vs 45.7%, P=.51.
DOR: 9.6 mo vs 11.0 mo, P=.48.
Weight loss ≥5%: 8% vs 16%, P=.02.
mPFS: 7.4 mo vs 7.4 mo, HR 1.05, 95% CI 0.85–1.30, P=.66 (NS).
Time to treatment failure: 5.8 mo vs 4.6 mo, HR 0.89, 95% CI 0.72–1.10, P=.27.
ORR: 49.4% vs 45.7%, P=.51.
DOR: 9.6 mo vs 11.0 mo, P=.48.
Weight loss ≥5%: 8% vs 16%, P=.02.
Adverse events
Hematologic (G3–4): anemia 27% vs 18%; thrombocytopenia 57% vs 21%; neutropenia 71% vs 82%.
Infectious: neutropenic fever 2% vs 14%; neutropenic sepsis 1% vs 12%, P<.001.
Mucosal/other: mucositis 1% vs 22%, P=.001; toxic deaths 1% vs 3%.
Infectious: neutropenic fever 2% vs 14%; neutropenic sepsis 1% vs 12%, P<.001.
Mucosal/other: mucositis 1% vs 22%, P=.001; toxic deaths 1% vs 3%.
Conclusions
GC achieved similar survival, response, and DOR as MVAC in advanced urothelial carcinoma with a markedly better tolerability profile (less febrile neutropenia, sepsis, mucositis), establishing GC as a first-line standard.
Key Limitations
Designed/powered for superiority rather than non-inferiority (no formal non-inferiority margin); pre-immunotherapy era; classic (not dose-dense) MVAC comparator; modest follow-up.
Clinical Context
Landmark trial that made GC a long-standing first-line cisplatin-based standard for advanced urothelial carcinoma per ESMO/ASCO, given equivalent efficacy and better tolerability than MVAC. Frontline standard has since shifted to enfortumab vedotin + pembrolizumab, with GC reserved for selected/alternate use.