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

• Published in: British journal of cancer Vol. 111; no. 10; pp. 1909 - 1916
• Main Authors: Suttle, A B, Ball, H A, Molimard, M, Hutson, T E, Carpenter, C, Rajagopalan, D, Lin, Y, Swann, S, Amado, R, Pandite, L
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.11.2014; Nature Publishing Group
• Subjects: 631/92/436/108; 692/699/67/1059/99; 692/699/67/589/1588/1351; Angiogenesis; Angiogenesis Inhibitors - pharmacokinetics; Angiogenesis Inhibitors - therapeutic use; Biological and medical sciences; Biomarkers; Biomarkers, Tumor - analysis; Biomedical and Life Sciences; Biomedicine; Blood Pressure; Cancer Research; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - mortality; Carcinoma, Renal Cell - pathology; Clinical Study; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Drug dosages; Drug Resistance; Epidemiology; Follow-Up Studies; Humans; Hypertension; Indazoles; Kidney cancer; Kidney Neoplasms - drug therapy; Kidney Neoplasms - mortality; Kidney Neoplasms - pathology; Kidneys; Kinases; Medical research; Medical sciences; Metastasis; Molecular Medicine; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasm Staging; Nephrology. Urinary tract diseases; Oncology; Pharmacokinetics; Plasma; Prognosis; Pyrimidines - pharmacokinetics; Pyrimidines - therapeutic use; Randomized Controlled Trials as Topic; Response rates; Sulfonamides - pharmacokinetics; Sulfonamides - therapeutic use; Survival Rate; Tissue Distribution; Tumors; Tumors of the urinary system; Vascular endothelial growth factor; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; Vascular Endothelial Growth Factor Receptor-2 - blood; United States > US; blood pressure; renal cell carcinoma; pazopanib; progression-free survival; trough concentration; Antineoplastic agent; Carcinoma; Cancerology; Progression free survival; Grawitz tumor; Arterial pressure; Advanced stage; Blood pressure; Protein-tyrosine kinase; Pazopanib; Kidney disease; Human; Urinary system disease; Enzyme; Tyrosine kinase inhibitor; Transferases; Treatment efficiency; Enzyme inhibitor; Exposure; Malignant tumor; Concentration; Kidney cancer; Hemodynamics; Cancer
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2014.503

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