Incidence of thyroid dysfunction in renal cell carcinoma (RCC) patients treated with pazopanib in prospective clinical trials.

Abstract

4633 Background: Pazopanib is a small molecule, selective, multi tyrosine kinase inhibitor (TKI), targeting vascular endothelial growth factor receptors (VEGFR)-1, -2 and -3, c-kit and platelet derived growth factor receptor (PDGF-R). Pazopanib is approved for the treatment of advanced RCC and is given by oral daily dosing. Other TKIs for this indication induce thyroid dysfunction in up to 85% of patients (pts) (Rini, B 2007). The incidence and severity of thyroid dysfunction were explored in pazopanib-treated pts participating in 3 trials, where thyroid function tests were systematically assessed. Methods: Thyroid function data from 578 RCC pts participating in trials VEG102616 (phase II), VEG105192 (phase III), and VEG107769 (phase III extension) were analyzed. Serum TSH values were collected at baseline and every 12 weeks. Free T3 and T4 were assessed at baseline and when TSH was abnormal during treatment. Results: In 578 pts, the incidence of elevated TSH at baseline (>5 MU/L) was 37 (6%).167 (29%) pts had a TSH value of >5 MU/L during treatment; 97 (17%) pts had TSH values of >5-10 MU/L during treatment; 45 (8%) pts had TSH values of >10-20 MU/L, and 25 (4%) pts had TSH values of >20 MU/L. Hypothyroidism (TSH >5-10 MU/L and T4 <LLN) was observed in 19 (3%) pts. Hypothyroidism with TSH >10 MU/L and T4<LLN was diagnosed in 15 (3%) pts. Hyperthyroidism, defined as TSH <0.3 MU/L and T4>ULN, was seen in 8 (1%) pts. Thyroid replacement therapy was received by 20 (3%) pts with a TSH elevation. Hypothyroidism was reported as an AE in 26 (4%) pts (15 Grade 1, 10 Grade 2 and 1 unknown grade) by the investigators. Thyroid dysfunction was never reported as a severe adverse event in any pt. Conclusions: In clinical trials, pazopanib, the most recently approved treatment for advanced RCC, lead to a very low incidence of thyroid dysfunction. The low rate of hypothyroidism may partly explain the low incidence of fatigue (19%) and asthenia (14%) with pazopanib (Sternberg 2010), given these conditions can result from hypothyroidism. As fatigue has a profound detrimental effect on HRQoL in RCC pts (Larkin 2010), this data should be considered when making clinical treatment decisions in pts with advanced RCC.