Relationships between pazopanib exposure and clinical safety and efficacy in patients with advanced renal cell carcinoma.
Br J Cancer
; 111(10): 1909-16, 2014 Nov 11.
Article
in En
| MEDLINE
| ID: mdl-25349968
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.
Full text:
1
Collection:
01-internacional
Health context:
6_ODS3_enfermedades_notrasmisibles
Database:
MEDLINE
Main subject:
Pyrimidines
/
Sulfonamides
/
Carcinoma, Renal Cell
/
Biomarkers, Tumor
/
Angiogenesis Inhibitors
/
Vascular Endothelial Growth Factor Receptor-2
/
Kidney Neoplasms
Type of study:
Clinical_trials
/
Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
Limits:
Humans
Language:
En
Journal:
Br J Cancer
Year:
2014
Document type:
Article