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

Background: 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. Methods: 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. Results: 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. Conclusions: 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.