Background
Phase 3 open-label RCT; N=493 muscle-invasive urothelial bladder cancer receiving perioperative chemotherapy — neoadjuvant (NAC, n=437) and adjuvant (n=56); dd-MVAC vs gemcitabine-cisplatin (GC).
Interventions and follow up
Arm A: dd-MVAC (methotrexate 30 mg/m2 d1; vinblastine 3 mg/m2, doxorubicin 30 mg/m2, cisplatin 70 mg/m2 d2; G-CSF d3–9) q2wk x 6 cycles
Arm B: GC (cisplatin 70 mg/m2 d1; gemcitabine 1250 mg/m2 d1 & d8) q3wk x 4 cycles
Primary endpoint: 3yr PFS in ITT and NAC populations
Secondary: pathologic response at surgery, 3yr PFS adjusted for response
Arm B: GC (cisplatin 70 mg/m2 d1; gemcitabine 1250 mg/m2 d1 & d8) q3wk x 4 cycles
Primary endpoint: 3yr PFS in ITT and NAC populations
Secondary: pathologic response at surgery, 3yr PFS adjusted for response
Results
3yr PFS ITT: 64% vs 56%, HR 0.77, 95% CI 0.57–1.02, P=.066 (NS, primary endpoint not met).
3yr PFS NAC: 66% vs 56%, HR 0.70, 95% CI 0.51–0.96, P=.025.
pCR (ypT0pN0): 42% vs 36%, P=.2 (NS).
Organ-confined (<ypT3pN0): 77% vs 63%, P<.001.
3yr PFS by response — pCR vs ypT2N0: HR 2.61, 95% CI 1.38–4.95.
pCR vs ypT≥3 or ypN+: HR 10.3, 95% CI 6.37–16.8.
Dose delivery: GC 84% completed 4 cycles; dd-MVAC 60% completed 6 cycles.
3yr PFS NAC: 66% vs 56%, HR 0.70, 95% CI 0.51–0.96, P=.025.
pCR (ypT0pN0): 42% vs 36%, P=.2 (NS).
Organ-confined (<ypT3pN0): 77% vs 63%, P<.001.
3yr PFS by response — pCR vs ypT2N0: HR 2.61, 95% CI 1.38–4.95.
pCR vs ypT≥3 or ypN+: HR 10.3, 95% CI 6.37–16.8.
Dose delivery: GC 84% completed 4 cycles; dd-MVAC 60% completed 6 cycles.
Adverse events
Hematologic (G≥3): any 52% vs 55% (P=.6); anemia 22% vs 7.8% (P<.0001).
Gastrointestinal/constitutional (G≥3): N/V 9.7% vs 2.9% (P=.003); asthenia 14% vs 4.1% (P<.001).
Renal (G≥3): 6.0% vs 5.3% (P=.9); 4.7% stopped therapy for renal failure (11 dd-MVAC, 12 GC).
Gastrointestinal/constitutional (G≥3): N/V 9.7% vs 2.9% (P=.003); asthenia 14% vs 4.1% (P<.001).
Renal (G≥3): 6.0% vs 5.3% (P=.9); 4.7% stopped therapy for renal failure (11 dd-MVAC, 12 GC).
Conclusions
VESPER did not meet its ITT primary endpoint, but neoadjuvant dd-MVAC improved local control and 3yr PFS in the NAC subgroup vs GC, at the cost of more grade ≥3 anemia, N/V, and asthenia.
Key Limitations
Primary ITT endpoint not met; NAC benefit is a subgroup finding; open-label design; mixed neoadjuvant/adjuvant population; differing cycle numbers between arms; OS data matured later (5yr OS favored dd-MVAC in NAC subgroup).
Clinical Context
Both dd-MVAC and GC are accepted neoadjuvant cisplatin-based regimens for muscle-invasive bladder cancer per ESMO/ASCO; VESPER supports dd-MVAC as a preferred neoadjuvant option in fit patients, though GC remains widely used for tolerability. Neoadjuvant cisplatin-based chemotherapy before radical cystectomy is the established standard.