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

ABSTRACT: 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).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 (C?) and sVEGFR2, safety, progression-free survival (PFS), response rate, and tumour shrinkage. Efficacy/safety end points were compared at C? decile boundaries.Strong correlation between increased blood pressure and C? was observed (r(2)=0.91), whereas weak correlation was observed between C? and decline from baseline in sVEGFR2 (r(2)=0.27). C? threshold of >20.5??g?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 C? >20.5??g?ml(-1). However, the association of C? with certain adverse events, particularly hand-foot syndrome, was continuous over the entire C? range.The threshold concentration for efficacy overlaps with concentrations at which toxicity occurs, although some toxicities increase over the entire C? range. Monitoring C? may optimise systemic exposure to improve clinical benefit and decrease the risk of certain adverse events.

SUBMITTER: Suttle AB 

PROVIDER: S-EPMC4229638 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature