Lymphopenia and Circulating Biomarker Dynamics Associated with Clinical Outcome and Toxicity in Pazopanib-Treated Radioiodine-Refractory Thyroid Cancer: Exploratory Analyses from the Pazothyr Trial.

Authors

Céline Rodriguez, Cécile Dalban, Amélie Colombe-Vermorel, Laetitia Odeyer, Livia Lamartina, Yann Godbert, Frederic Illouz, Julien Gautier, Isabelle Treilleux, Sophie Darnis, Christophe Caux, Christelle de la Fouchardière, Christine Ménétrier-Caux

Published in

Thyroid : official journal of the American Thyroid Association. Pages 10507256261500974. Nov 10, 2026. Epub Nov 10, 2026.

Abstract

Pazopanib showed clinical activity in progressive radioiodine-refractory differentiated thyroid carcinoma (RAIR-DTC), although its use is limited by substantial toxicity not reduced by intermittent treatment. We aimed to identify biomarkers associated with outcome and treatment-related toxicity in these patients.
This study reported exploratory results related to the Pazothyr trial (NCT01813136) investigating pazopanib efficacy in RAIR-DTC patients. We evaluated lymphopenia and neutrophil-to-lymphocyte ratio (NLR) from the Pazothyr clinical database (n = 168). Dedicated informed consent for additional plasma and tumor sample collection allowed quantification of plasma angiogenic factors and cytokines at baseline and after one month of pazopanib (n = 111). Immune markers (CD8, FOXP3, CD163, and PDL1) analyzed by immunohistochemistry in archived primary tumors from patients (n = 68) with response or stable disease after 6 months of pazopanib were scored semiquantitatively. Associations with response, progression-free survival (PFS), overall survival (OS), and substantial treatment-related adverse events (TRAEs) were evaluated. Given the exploratory nature of this study, no adjustment for multiple comparisons was performed.
At baseline, moderate and severe lymphopenia were associated with shorter PFS, unlike high NLR. Elevated Vascular Endothelial Growth Factor A (VEGF-A), Interleukin 6 (IL-6), and CXCL8 correlated with poorer PFS. High VEGF-A, hepatocyte growth factor (HGF), IL-6, CXCL8, and CXCL9 were associated with shorter OS. X Early changes in placental growth factor (PlGF), HGF, interleukin 12 subunit p40, and CXCL10 were associated with substantial TRAEs. Multivariable analyses identified baseline severe lymphopenia (hazard ratio [HR] = 2.39 [confidence interval or CI 1.27-4.48], p = 0.007) and high CXCL8 (HR = 2.01 [CI 1.26-3.21], p = 0.004) as independent factors associated with progression. High baseline NLR (HR = 2.26 [CI 1.21-4.22], p = 0.01), HGF (HR = 2.37 [CI 1.33-4.20], p = 0.003), and CXCL8 (HR = 2.20 [CI 1.25-3.87], p = 0.006) were similarly associated with death. One-month increases in PlGF (odds ratio [OR] = 2.49 [CI 1.13-5.50], p = 0.024) and HGF (OR = 2.91 [CI 1.32-6.43], p = 0.008) were independently associated with substantial TRAEs. In patients with tumor samples, Programmed cell Death-Ligand 1 (PDL1)-immune cell score (ICS) >1% (HR = 2.05 [CI 1.15-3.66], p = 0.015) was also associated with progression.
Baseline lymphopenia and inflammatory plasma biomarkers were associated with clinical outcome, whereas early changes in circulating factors were associated with substantial TRAEs. These exploratory results require prospective validation in RAIR-DTC patients treated with pazopanib or other VEGF receptor-targeting multikinase inhibitors. The relevance of PDL1-ICS expression for anti-PD1/PDL1-based therapies requires dedicated prospective trials.

PMID:
43007078
Bibliographic data and abstract were imported from PubMed on 10 Nov 2026.

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