Evaluation of thyroid dysfunction as a candidate surrogate marker for efficacy of sunitinib in patients (pts) with advanced renal cell cancer (RCC)

Abstract

5126 Background: Sunitinib is a multi-target tyrosine kinase inhibitor with anti-angiogenic and anti-proliferative activity mediated by signal blockade of VEGFR1/2, KIT, PDGFR α/β, and FLT-3. Sunitinib has recently been approved for the treatment of RCC. Several studies have identified biochemical thyroid function test (TFT) abnormalities in approximately 2/3 of pts under sunitinib treatment. The possible association of the incidence of sunitinib-induced thyroid dysfunction and progression-free (PFS) and overall survival (OS) has not been analyzed yet. Methods: Thyroid function was evaluated prospectively in pts with advanced RCC on days l and 28 of each treatment cycle. Sunitinib was given at a daily oral dose of 50 mg 4 weeks on, 2 weeks off. For the statistical analysis the Kaplan-Meier method was used to construct curves for PFS and OS. The log-rank test was used to compare between pts with and without biochemical thyroid abnormalities. The analysis has been performed with SAS (version 9.1). The alpha-level has been set at 5%. No corrections have been made for multiple testing. Results: From 11/2005 to 12/2007 53 pts received sunitinib and 40 of them [m: 30, f: 10, median age 59 (42–81) years] were evaluable for thyroid function. In total, 28/40 pts (70%) developed TFT abnormalities: 13 pts (32.5%) developed clinical hypothyroidism requiring hormone substitution. Only in 12 pts (30%) no TFT abnormalities were observed. The median PFS was 3.6 mo (95%CI: 2.3 - 6.0) when there was no biochemical thyroid abnormality and 10.3 months (95%CI: 5.0 - 18.4 mo) in presence of biochemical TFT abnormalities (log rank p = 0,047). The median OS was 6.6 mo (95%CI: 3.3 - 7.9) when there was no biochemical thyroid abnormality and 18.2 mo (95%CI: 7.5 - 22.3) in presence of biochemical abnormalities (log rank p = 0,13). Conclusions: In pts with advanced RCC we observed a positive correlation between sunitinib-induced thyroid dysfunction and clinical outcome that requires further prospective evaluation. Understanding the biology and etiology of sunitinib-induced thyroid dysfunction and assessing its correlation with treatment outcome will help to define the role of thyroid dysfunction as a surrogate marker for efficacy of sunitinib in pts with advanced RCC. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pfizer Oncology