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

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.