Increased thyroid-stimulating hormone (TSH) levels due to lenvatinib treatment in patients with radioactive iodine 131 (¹³¹I)-refractory differentiated thyroid cancer (DTC) were not associated with differences in overall safety, efficacy, or lenvatinib exposure, based on measurement of worst postbaseline TSH levels.

Steven I. Sherman, MD, University of Texas MD Anderson Cancer Center, Houston, Texas, USA, presented data from an exploratory analysis of the SELECT trial [Schlumberger M et al. N Engl J Med. 2015], a randomized phase 3 trial of lenvatinib in ¹³¹I-refractory DTC demonstrating significantly improved progression-free survival (PFS) and response rates compared with placebo. The purpose of this exploratory analysis was to evaluate the effect of thyroid abnormalities on the outcomes observed in the SELECT trial.

Lenvatinib is a tyrosine kinase inhibitor that targets vascular endothelial growth factor receptors 1 through 3, fibroblast growth factor receptors 1 through 4, platelet-derived growth factor receptor α, ret proto-oncogenes, and stem-cell receptors [Okamoto K et al. Cancer Lett. 2013; Matsui J et al. Int J Cancer. 2008]. A common side effect of tyrosine kinase inhibitors with multiple targets is hypothyroidism [Rini B et al. J Natl Cancer Inst. 2007] and exacerbation of postsurgical hypothyroidism [Brose MS et al. Lancet. 2014; Elisei R et al. J Clin Oncol. 2013], which may be associated with response to therapy [Kust D et al. Anticancer Res. 2014; Schmidinger M et al. Cancer. 2011].

In the double-blind, phase 3 SELECT trial, 392 adult patients with ¹³¹I-refractory DTC were randomly assigned 2:1 to receive lenvatinib or placebo until disease progression [Schlumberger M et al. N Engl J Med. 2015]. The primary end point was PFS, and the secondary end points were overall response rate, overall survival, and safety. Patients who were assigned to placebo were able to switch to open-label lenvatinib after disease progression. All patients received concomitant thyroid hormone suppression, primarily via levothyroxine.

In this exploratory analysis, patients in the lenvatinib arm experienced higher TSH levels by cycle 1 that peaked by cycle 2 and steadily declined after cycle 4. In contrast, patients in the placebo arm did not experience consistent changes in TSH levels. In the lenvatinib arm, 28.4% of patients experienced worst postbaseline TSH levels > 5.5 mIU/L compared with 6.2% of patients in the placebo arm.

Worst postbaseline TSH levels were not associated with dose modification of lenvatinib, study drug withdrawal, treatment exposure, or lenvatinib-related adverse events. However, lenvatinib-related thyrotoxicosis and exacerbation of hypothyroidism occurred primarily in patients who had worst postbaseline TSH levels > 5.0 mIU/L. In addition, QTc prolongation occurred more frequently in patients who had worst postbaseline TSH levels of > 5.0 mIU/L (12.5%) compared with patients who had worst postbaseline TSH levels of > 0.5 to 5.0 mIU/L (6.4%) or ≤ 0.5 mIU/L (4%). PFS, overall survival, and overall response rate were not significantly different among the worst postbaseline TSH level categories.

Dr Sherman indicated that the data from this exploratory analysis of the SELECT trial suggest that there is no association between worst postbaseline TSH levels on overall lenvatinib safety or efficacy, as well as lenvatinib exposure. In addition, although increased TSH levels occurred frequently, it was not known if the rise was a result of lenvatinib or modification of TSH-suppression therapy because of patient intolerance to TSH suppression. Dr Sherman stated that a longitudinal analysis of TSH levels may be warranted and could provide further information than this single–time point analysis.