Relative Dose Intensity of Induction-Phase Pazopanib Treatment of Soft Tissue Sarcoma: Its Relationship with Prognoses of Pazopanib Responders.

Shunji Takahashi,Taisuke Tanizawa,Kenji Nakano,Seiichi Matsumoto,Keisuke Ae,Keiko Hayakawa,Yuki Funauchi

doi:10.3390/jcm8010060

Abstract

The approved standard dose of pazopanib is 800 mg per day, but the appropriate dose of pazopanib to treat soft tissue sarcoma (STS) patients in real-world practice is controversial. Of 124 STS patients treated with pazopanib, we retrospectively analyzed the cases of STS patients who achieved progression-free survival at 12 weeks by pazopanib treatment as pazopanib responders, and we evaluated their relative dose intensity (RDI) in the initial 12 weeks (12W-RDI). We enrolled 78 STS patients in the analyses as pazopanib responders, and 54 patients of the 78 pazopanib responders (69%) were able to maintain 12W-RDI ≥80%. In landmark analyses, patients with 12W-RDI of 80% ≥80% had significantly longer progression-free survival compared to those with 12W-RDI <80% (30.7 weeks vs. 22.0 weeks, hazard ratio [HR]: 0.56 [95%CI: 0.33–0.94], p = 0.026). The most frequently observed reasons of treatment interruption and/or dose reduction of pazopanib during the initial 12 weeks were anorexia and liver function disorders. Liver toxicity was the adverse event most frequently observed in the 12W-RDI <80% patients throughout the treatment periods. Based on our results, it appears that maintaining as high a dose intensity as possible that is tolerable—at least during the initial 12 weeks—is likely to be the better option in pazopanib treatment for STS patients.

Highlights

Pazopanib is an oral multi-target tyrosine kinase inhibitor that is known to inhibit vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR), c-kit, and other growth factors [1]
Based on the randomized clinical trial EORTC 62072 and PALETTE study [2], pazopanib was approved for the treatment of soft tissue sarcoma (STS); it is the first molecular-targeted drug to be used for the treatment of STS other than gastrointestinal stromal tumors (GISTs)
Most oral tyrosine kinase inhibitors approved for malignant diseases are prescribed with a fixed dose, regardless of the patient’s body surface area or body weight; there are exceptions to this, such as lenvatinib treatment for hepatocellular carcinoma (HCC) [13]

Summary

Introduction

Pazopanib is an oral multi-target tyrosine kinase inhibitor that is known to inhibit vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR), c-kit, and other growth factors [1]. In a clinical trial of STS, responses to pazopanib differed when histological subtypes were different [11], which affected the approval of pazopanib to some STS histology, such as liposarcoma. This heterogeneity makes it difficult to evaluate the relationship between the dose intensity or exposure of pazopanib and pazopanib’s efficacy in STS patients, but planning studies based on each histology would be more difficult; STSs account for only 5% of all malignant diseases, and they include many rare histological types (detected in

Patients and Treatments

Analyses

Enrolled Patients in the Analyses

Adverse Events Observed in Pazopanib Responders

Discussion