Intra-Tumoral Pharmacokinetics of Pazopanib in Combination with Radiotherapy in Patients with Non-Metastatic Soft-Tissue Sarcoma

SIMPLE SUMMARY: Pazopanib plasma levels have been associated with treatment efficacy. Since pazopanib targets receptors present on cells in the vicinity of the tumor and on tumor cells themselves, measurement of pazopanib concentrations in tumor tissue might be an even better prognostic biomarker than plasma levels. The aim of our study was to quantify pazopanib concentrations in tumor tissue, correlate this with plasma concentrations, and assess whether this is a better biomarker for efficacy. A modest correlation was found between pazopanib tumor concentrations and plasma concentrations. Additionally, no correlation was found between pazopanib tumor concentrations and efficacy. We provide recommendations for future studies in which pazopanib concentrations are measured. ABSTRACT: There is a lack of understanding whether plasma levels of anticancer drugs (such as pazopanib) correlate with intra-tumoral levels and whether the plasma compartment is the best surrogate for pharmacokinetic and pharmacodynamic evaluation. Therefore, we aimed to quantify pazopanib concentrations in tumor tissue, to assess the correlation between tumor concentrations and plasma concentrations and between tumor concentrations and efficacy. In this clinical trial, non-metastatic STS patients were treated with neo-adjuvant concurrent radiotherapy and pazopanib. Plasma samples and tumor biopsies were collected, and pazopanib concentrations were measured using liquid chromatography-tandem mass spectrometry. Twenty-four evaluable patients were included. The median pazopanib tumor concentration was 19.2 µg/g (range 0.149–200 µg/g). A modest correlation was found between tumor concentrations and plasma levels of pazopanib (ρ = 0.41, p = 0.049). No correlation was found between tumor concentrations and percentage of viable tumor cells (p > 0.05); however, a trend towards less viable tumor cells in patients with high pazopanib concentrations in tumor tissue was observed in a categorical analysis. Possible explanations for the lack of correlation might be heterogeneity of the tumors and timing of the biopsy procedure.