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

Cora N Sternberg, Robert E Hawkins, John Wagstaff, Pamela Salman, Jozef Mardiak, Carlos H Barrios, Juan J Zarba, Oleg A Gladkov, Eunsik Lee, Cezary Szczylik, Lauren McCann, Stephen D. Rubin, Mei Chen, Ian D. Davis

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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.

Original languageEnglish
Pages (from-to)1287-1296
Number of pages10
JournalEuropean Journal of Cancer
Volume49
Issue number6
DOIs
Publication statusPublished - Apr 2013
Externally publishedYes

Keywords

  • Inverse probability of censor weighting
  • Overall survival
  • Pazopanib
  • Rank-preserving structural failure time model
  • Renal cell carcinoma

Cite this

Sternberg, C. N., Hawkins, R. E., Wagstaff, J., Salman, P., Mardiak, J., Barrios, C. H., Zarba, J. J., Gladkov, O. A., Lee, E., Szczylik, C., McCann, L., Rubin, S. D., Chen, M., & Davis, I. D. (2013). 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. European Journal of Cancer, 49(6), 1287-1296. https://doi.org/10.1016/j.ejca.2012.12.010