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

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.

Figure 1

Pazopanib exposure and blood pressure. Relationship, in patients with solid tumours, between the occurrence of a significant increase in blood pressure (BP) and steady-state plasma pazopanib AUC (A), C_max (B), and Cτ (C); relationship between steady-state AUC and Cτ (D). Open circles represent individual observations (0=no significant increase; 1=significant increase) and closed circles represent the proportion of patients with a significant increase in blood pressure within each plasma pazopanib Cτ quintile range. The thick line represents the plasma pazopanib Cτ quintile range.

Figure 2

Steady-state plasma pazopanib concentration and clinical response. The Kaplan–Meier curves showing PFS (A) and empirical cumulative distribution function (CDF) of maximum decrease from baseline in tumour size (B) for patients with week 4 predose steady-state plasma pazopanib concentration (Cτ) ⩽20.5 μg ml⁻¹ (black) and >20.5 μg ml⁻¹ (red).

Figure 3

Distribution of predose steady-state plasma pazopanib concentrations (Cτ).