Exposure-survival analyses of pazopanib in renal cell carcinoma and soft tissue sarcoma patients: opportunities for dose optimization

• Published in: Cancer chemotherapy and pharmacology Vol. 80; no. 6; pp. 1171 - 1178
• Main Authors: Verheijen, R. B., Swart, L. E., Beijnen, J. H., Schellens, J. H. M., Huitema, A. D. R., Steeghs, N.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.12.2017; Springer Nature B.V
• Subjects: Aged; Angiogenesis; Cancer; Cancer Research; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - mortality; Carcinoma, Renal Cell - pathology; Cell survival; Exposure; Female; Humans; Kidney cancer; Male; Medicine; Medicine & Public Health; Middle Aged; Multivariate analysis; Oncology; Optimization; Original; Original Article; Patients; Pharmacokinetics; Pharmacology; Pharmacology/Toxicology; Pyrimidines - therapeutic use; Renal cell carcinoma; Sarcoma; Sarcoma - drug therapy; Sarcoma - mortality; Sarcoma - pathology; Soft tissue sarcoma; Sulfonamides - therapeutic use; Survival; Survival Analysis; Targeted cancer therapy; Tissues; Treatment Outcome; Tumors; Soft tissue sarcoma; Dose optimization; Pharmacokinetics; Personalized medicine; Renal cell carcinoma; Pazopanib
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-017-3463-x

Background Pazopanib is an angiogenesis inhibitor approved for the treatment of renal cell carcinoma and soft tissue sarcoma. Post hoc analysis of a clinical trial demonstrated a relationship between pazopanib trough concentrations (C min ) and treatment efficacy. The aim of this study was to explore the pharmacokinetics and exposure-survival relationships of pazopanib in a real-world patient cohort. Patients and methods Renal cell cancer and soft tissue sarcoma patients who had at least one pazopanib plasma concentration available were included. Using calculated C min values and a threshold of > 20 mg/L, univariate and multivariate exposure-survival analyses were performed. Results Sixty-one patients were included, of which 16.4% were underexposed (mean C min  < 20 mg/L) using the 800 mg fixed-dosed schedule. In univariate analysis C min  > 20 mg/L was related to longer progression free survival in renal cell cancer patients (34.1 vs. 12.5 weeks, n  = 35, p  = 0.027) and the overall population (25.0 vs. 8.8 weeks, n  = 61, p  = 0.012), but not in the sarcoma subgroup (18.7 vs. 8.8 weeks, n  = 26, p  = 0.142). In multivariate analysis C min  > 20 mg/L was associated with hazard ratios of 0.25 ( p  = 0.021) in renal cancer, 0.12 ( p  = 0.011) in sarcoma and 0.38 ( p  = 0.017) in a pooled analysis. Conclusion This study confirms that pazopanib C min  > 20 mg/L relates to better progression free survival in renal cancer and points towards a similar trend in sarcoma patients. C min monitoring of pazopanib can help identify patients with low C min for whom individualized treatment at a higher dose may be appropriate.