Relationships between pazopanib exposure and clinical safety and efficacy in patients with advanced renal cell carcinoma

Br J Cancer. 2014 Nov 11;111(10):1909-16. doi: 10.1038/bjc.2014.503. Epub 2014 Oct 28.

Abstract

Background: Pazopanib, an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptor (VEGFR)/platelet-derived growth factor receptor (PDGFR)/c-Kit, is approved in locally advanced/metastatic renal cell carcinoma (RCC).

Methods: Data from trials in advanced solid tumours and advanced/metastatic RCC were used to explore the relationships between plasma pazopanib concentrations and biomarker changes, safety, and efficacy. Initially, the relationships between pharmacokinetic parameters and increased blood pressure were investigated, followed by analysis of steady-state trough concentration (Cτ) and sVEGFR2, safety, progression-free survival (PFS), response rate, and tumour shrinkage. Efficacy/safety end points were compared at Cτ decile boundaries.

Results: Strong correlation between increased blood pressure and Cτ was observed (r(2)=0.91), whereas weak correlation was observed between Cτ and decline from baseline in sVEGFR2 (r(2)=0.27). Cτ threshold of >20.5 μg ml(-1) was associated with improved efficacy (PFS, P<0.004; tumour shrinkage, P<0.001), but there was no appreciable benefit in absolute PFS or tumour shrinkage from Cτ >20.5 μg ml(-1). However, the association of Cτ with certain adverse events, particularly hand-foot syndrome, was continuous over the entire Cτ range.

Conclusions: The threshold concentration for efficacy overlaps with concentrations at which toxicity occurs, although some toxicities increase over the entire Cτ range. Monitoring Cτ may optimise systemic exposure to improve clinical benefit and decrease the risk of certain adverse events.

Trial registration: ClinicalTrials.gov NCT00334282.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / pharmacokinetics
  • Angiogenesis Inhibitors / therapeutic use*
  • Biomarkers, Tumor / analysis*
  • Blood Pressure
  • Carcinoma, Renal Cell / drug therapy*
  • Carcinoma, Renal Cell / mortality
  • Carcinoma, Renal Cell / pathology
  • Clinical Trials, Phase I as Topic
  • Clinical Trials, Phase II as Topic
  • Follow-Up Studies
  • Humans
  • Kidney Neoplasms / drug therapy*
  • Kidney Neoplasms / mortality
  • Kidney Neoplasms / pathology
  • Neoplasm Staging
  • Prognosis
  • Pyrimidines / pharmacokinetics
  • Pyrimidines / therapeutic use*
  • Randomized Controlled Trials as Topic
  • Sulfonamides / pharmacokinetics
  • Sulfonamides / therapeutic use*
  • Survival Rate
  • Tissue Distribution
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors
  • Vascular Endothelial Growth Factor Receptor-2 / blood*

Substances

  • Angiogenesis Inhibitors
  • Biomarkers, Tumor
  • Pyrimidines
  • Sulfonamides
  • pazopanib
  • KDR protein, human
  • Vascular Endothelial Growth Factor Receptor-2

Associated data

  • ClinicalTrials.gov/NCT00334282