Hypothyroidism may accompany SU11248 therapy in a subset of patients (pts) with metastatic (met) gastrointestinal stromal tumors (GIST) and is manageable with replacement therapy

Abstract

3040 Background: SU11248 is an oral, multitargeted kinase inhibitor with antiangiogenic and antitumor activity due to inhibition of VEGFR, PDGFRα, KIT and FLT3. SU11248 has documented activity in pts with a variety of malignancies, including imatinib-resistant GIST and renal cell carcinoma. Thyroid function was tested serially to assess the tolerability of chronic dosing. Methods: Pts with met GIST treated at a single center with repeat cycles of SU11248 in a phase 1/2 trial underwent serial assessments of TSH levels at the end of each dosing cycle. Comprehensive thyroid function indices (TFTs), including T4, T3, free T4 index, were performed if TSH was abnormal. Results: To date, 64 sequential pts have received 344 dosing cycles of SU11248. 25/64 pts developed abnormal TSH levels (CTC grade (G) 1 = 6; 2 = 19; 3/4 = 0), after a median of 5.4 months of treatment (range 1–24). Of these pts, 13 demonstrated abnormally low T4/T3 levels. 19/25 pts were treated with thyroid hormone replacement (THR) due to persistent elevations of TSH and accompanying fatigue (G 0/1 = 6; 2 = 12; G3/4 = 1). Signs and symptoms of transient myxedema were noted in 5/20 pts. All pts treated with THR had TSH normalization with rapid resolution of fatigue and any other symptoms. 7/25 pts were not treated with THR due to a lack of symptoms (fatigue: G 0/1 = 6; G2 = 1; G3/4 = 0), or disease progression. 5 pts initially had elevated TSH levels prior to developing hypothyroidism, consistent with a thyroidititic process, but with otherwise normal TFTs and no associated clinical symptoms. No pts required cessation or delay of SU11248 treatment as a result of thyroid-related toxicity. Conclusions: A subset of pts may develop thyroid dysfunction, which may account, in part, for fatigue previously described with SU11248. Thyroid dysfunction is not dose-limiting and all pts could be treated effectively with THR, with rapid clinical improvements and resolution of TSH elevation. The mechanism by which SU11248 affects thyroid function is being investigated and may account for documented objective responses to SU11248 which have previously been reported in pts with thyroid cancer (Rosen, Proc ASCO 2003, a765). Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Pfizer Pfizer Pfizer Pfizer