Bullet point summary:
What is already known about this subject:
What this study adds:
Data availability statement: The authors confirm that the data supporting the findings of this study are available within the article [and/or] its supplementary materials.
Funding statement : No funding.
Conflict of interest disclosure: On behalf of all authors, the corresponding author states that there is no conflict of interest.
Patient consent statement: Informed consent was obtained from all patients prior to inclusion.
Ethics approval statement & clinical trial registration: The study was approved by institutional review board for non-interventional research (Approval ID 20210429175029).
Permission to reproduce material from other sources: No material from other source.
Abstract :
Background. Pazopanib is an oral angiogenesis inhibitor approved to treat soft tissue sarcoma (STS) but associated with large interpatient pharmacokinetic (PK) variability and narrow therapeutic index. In order to improve its clinical use, this study aimed to define specific threshold of pazopanib trough concentration (Cmin) associated with better progression free survival in STS patients.
Methods. In this observational study, pazopanib Cmin was monitored over the treatment course. For the primary endpoint, the 3-month PFS in STS was analyzed with logistic regression. Secondary, we performed exposure–overall survival (OS) in STS (Cox model plus Kaplan–Meier analysis/ log-rank test) and exposure-toxicity analyses.
Results. One hundred eighteen patients (95 STS and 23 BS) were eligible for PK/PD assessment. In multivariable analysis, pazopanib Cmin < 27 mg/L was independently associated with a risk of progression at 3 months (OR 4.21, 95% CI [1.47-12.12], p = 0.008). OS was not statistically longer between patients with Cmin > 27 mg/L and those with Cmin < 27 mg/L (log-rank p = 0.07). A higher average of PAZ Cmin over the first 3 months of treatment was associated with a higher risk of grades 3-4 toxicities (40.0 vs 30.5 mg/L (OR 1.05, IC95 [1.01-1.09], p = 0.01)
Conclusion. Pazopanib Cmin ≥ 27 mg/L was independently associated with improved 3-month PFS in a large cohort of STS patients. Pharmacokinetically-guided dosing could be helpful to optimize clinical management of STS patients in daily clinical practice.
INTRODUCTION
Soft-tissue sarcomas (STS) are a group of rare mesenchymal cancers that include about 70 histological types, and account for 1% of adult cancers. In Europe, the estimated yearly incidence is five per 100 000 (1). The prognosis of metastatic and unresectable stages remains poor and has been only slightly improved by doxorubicin and ifosfamide in first-line treatment (2).
Pazopanib is an angiogenesis inhibitor that targets the tyrosine kinase domain of vascular endothelial growth factor receptors 1, 2 and 3, platelet-derived growth factor receptors and c-kit (3,4). Pazopanib is approved in the treatment of advanced renal cell carcinoma (RCC) and chemotherapy-pretreated STS (5). In the PALETTE trial, pazopanib showed a clinical benefit with a longer Progression Free Survival (PFS) compared to placebo (median PFS 4.6 (95% CI 3.7–4.8) versus 1.6 months (0.9–1.8), respectively; hazard ratio (HR) 0.31, p<0.0001) but without overall survival improvement (6). Pazopanib have also demonstrated activity for advanced bone sarcoma (BS) (7,8).
Pazopanib is administered orally at a flat-fixed dose despite a large interpatient pharmacokinetic (PK) variability and a low therapeutic index (4,9–12). Pharmacokinetic/pharmacodynamic (PK/PD) studies have reported relationships between exposure and treatment outcomes (efficacy and toxicity) for several TKI suggesting a potential interest of drug monitoring (9,13–16). Regarding pazopanib, a trough plasma concentration (Cmin) ≥ 20.5 mg/L was associated with both improved PFS (19.6 vs. 52.0 weeks, p=0.004) and tumour shrinkage in RCC patients (9). This efficacy threshold was later confirmed in a real-life RCC cohort (10). No threshold value for pazopanib Cmin (PAZ Cmin) has been clearly identified for the occurrence of severe toxicity regardless the tumour type.
From an exploratory study including 34 STS patients, we previously proposed a PAZ Cmin threshold of 27 mg/L for efficacy (17). In the present study, we aimed to confirm this threshold in a larger cohort of unselected STS patients, then to explore the exposure-response relationship for toxicity in an extended cohort including both STS and BS patients.
MATERIEL AND METHODS
Study design and Patients.
Between December 2013 and October 2020, all patients with metastatic or unresectable STS or BS treated with pazopanib in Cochin-Port Royal hospital (Paris, France) were eligible for this observational study. Patients were considered for the main analysis if at least one plasma concentration of pazopanib was available at steady state (after at least 15 days of treatment) (figure 1). Informed consent was obtained from all patients prior to inclusion. The study was approved by institutional review board for non-interventional research (Approval ID 20210429175029).