A randomised, double-blind phase III study of pazopanib in patients with advanced and/or metastatic renal cell carcinoma: final overall survival results and safety update

Eur J Cancer. 2013 Apr;49(6):1287-96. doi: 10.1016/j.ejca.2012.12.010. Epub 2013 Jan 12.

Abstract

Background: In this randomised phase III study (VEG105192; NCT00334282), pazopanib previously demonstrated statistically and clinically meaningful improvement of progression-free survival versus placebo in patients with advanced/metastatic renal cell carcinoma (mRCC). Final overall survival (OS) and updated safety results are now reported.

Methods: Treatment-naive or cytokine-pretreated mRCC patients (n=435) stratified and randomised (2:1) to pazopanib 800 mg daily or placebo, were treated until disease progression, death or unacceptable toxicity. Upon progression, placebo patients could receive pazopanib through an open-label study. Final OS in the intent-to-treat population was analysed using a stratified log-rank test. Rank-preserving structural failure time (RPSFT) and inverse probability of censoring weighted (IPCW) analyses were performed post-hoc to adjust for crossover.

Findings: The difference in final OS between pazopanib- and placebo-treated patients was not statistically significant (22.9 versus 20.5 months, respectively; hazard ratio [HR]=0.91; 95% confidence interval [CI], 0.71-1.16; one-sided P=.224). Early and frequent crossover from placebo to pazopanib and prolonged duration of crossover treatment confounded the OS analysis. In IPCW analyses, pazopanib decreased mortality (HR=0.504; 95% CI, 0.315-0.762; two-sided P=.002). Similar, albeit non-significant, results were obtained in RPSFT analyses (HR=0.43; 95% CI, 0.215-1.388; two-sided P=.172). Since the last cutoff, cumulative exposure to pazopanib increased by 30%. The pazopanib safety profile showed no new safety signals or changes in the type, frequency and severity of adverse events.

Interpretation: Although no significant difference in OS was observed in this study, extensive crossover from placebo to pazopanib confounded final OS analysis. Post-hoc analyses adjusting for crossover suggest OS benefit with pazopanib treatment for mRCC patients.

Publication types

  • Clinical Trial, Phase III
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Angiogenesis Inhibitors / adverse effects
  • Angiogenesis Inhibitors / therapeutic use
  • Carcinoma, Renal Cell / drug therapy*
  • Carcinoma, Renal Cell / pathology
  • Cross-Over Studies
  • Diarrhea / chemically induced
  • Double-Blind Method
  • Drug Administration Schedule
  • Female
  • Humans
  • Hypertension / chemically induced
  • Kaplan-Meier Estimate
  • Kidney Neoplasms / drug therapy*
  • Kidney Neoplasms / pathology
  • Male
  • Middle Aged
  • Neoplasm Metastasis
  • Prognosis
  • Pyrimidines / adverse effects
  • Pyrimidines / therapeutic use*
  • Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors
  • Sulfonamides / adverse effects
  • Sulfonamides / therapeutic use*
  • Treatment Outcome

Substances

  • Angiogenesis Inhibitors
  • Pyrimidines
  • Sulfonamides
  • pazopanib
  • Receptors, Vascular Endothelial Growth Factor

Associated data

  • ClinicalTrials.gov/NCT00334282