Background
Phase III RCT (N=1,538) of resected high-risk clear-cell RCC (pT2 grade 3-4 N0, pT3-T4 any grade N0, or any pT/grade N1) post-nephrectomy.
Interventions and follow up
Arm A: Pazopanib 800mg/d x1yr (starting dose later reduced to 600mg/d due to toxicity)
Arm B: Placebo
Primary endpoint: DFS (in the 600mg cohort)
Median follow-up: 2.5yr (primary); ~6.3yr (extended OS analysis)
Arm B: Placebo
Primary endpoint: DFS (in the 600mg cohort)
Median follow-up: 2.5yr (primary); ~6.3yr (extended OS analysis)
Results
DFS (600mg cohort): HR 0.86, 95% CI 0.70-1.06, P=.17
DFS (800mg cohort): HR 0.69, 95% CI 0.51-0.94 (exploratory, not pre-specified primary)
mOS (extended follow-up): HR 1.0, 95% CI 0.80-1.26, P>.9
DFS (800mg cohort): HR 0.69, 95% CI 0.51-0.94 (exploratory, not pre-specified primary)
mOS (extended follow-up): HR 1.0, 95% CI 0.80-1.26, P>.9
Adverse events
Grade 3-4 AEs: 60% with pazopanib vs 21% placebo
Most common: hypertension, diarrhea, and elevated liver enzymes (transaminitis)
Discontinuation due to AEs: 35% with pazopanib
Most common: hypertension, diarrhea, and elevated liver enzymes (transaminitis)
Discontinuation due to AEs: 35% with pazopanib
Conclusions
Adjuvant pazopanib did not improve DFS (primary 600mg cohort) or OS versus placebo in high-risk resected clear-cell RCC.
Key Limitations
Mid-trial reduction of starting dose from 800mg to 600mg altered the primary analysis population; positive exploratory 800mg-cohort signal not confirmed; high discontinuation rate.
Clinical Context
Negative adjuvant TKI trial consistent with ASSURE; reinforced that adjuvant VEGFR TKI is not standard. Adjuvant pembrolizumab (KEYNOTE-564) is the current preferred adjuvant strategy per ASCO/ESMO.