Bullet point summary:
What is already known about this subject:
- The large interpatient pharmacokinetic variability and narrow
therapeutic index of pazopanib are complicated to manage in clinical
practice.
- A through pazopanib concentration of 20 mg/L in renal cancer has been
shown to improve efficacy.
- No consistent cohort of patients treated with pazopanib in sarcoma has
been studied.
What this study adds:
- A through pazopanib concentration of 27 mg/L in soft-tissue sarcoma is
associated with improved progression-free survival (efficacy).
- Toxicity is also associated with the plasma concentration of
pazopanib.
- Therapeutic drug monitoring should be required for all patients
treated with pazopanib.
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).