Compared with placebo, this multikinase inhibitor nearly doubled PFS in patients with locally advanced, radioiodine-refractory differentiated disease in a phase II trial.

Effective treatments have been lacking for patients with radioiodine-resistant, locally advanced or metastatic differentiated thyroid carcinoma (papillary, follicular, or poorly differentiated). Over the past five years, numerous phase II studies of multitargeted kinase inhibitors such as sorafenib and vascular endothelial growth factor (VEGF) inhibitors such as axitinib have demonstrated clinical efficacy (JW Oncol Hematol Dec 2 2008). However, toxicity has been substantial with these agents, and data is limited because most of these reports are single-arm studies without a control group for comparison. More recently, vandetanib — an inhibitor of VEGF receptor, endothelial growth factor receptor, and RET proto-oncogene kinases — was shown in a phase III trial to significantly prolong progression-free survival (PFS) in patients with unresectable, locally advanced or metastatic medullary thyroid cancer (J Clin Oncol 2012 Jan 10; 30:134).

Now, investigators in Europe have conducted an industry-supported, multicenter, randomized, double-blind, placebo-controlled, phase II study to test the effectiveness and safety of vandetanib in patients with nonmedullary thyroid cancer. A total of 145 patients (age range, 23–87; performance status 2) with unresectable or metastatic undifferentiated thyroid cancer (papillary, follicular, or poorly differentiated without anaplastic features) who were deemed unsuitable for radioiodine therapy received either oral vandetanib (300 mg daily) or placebo until they experienced disease progression, death, or stable disease for 12 months.

PFS (the primary endpoint) was superior with vandetanib versus placebo (11.1 vs. 5.9 months; hazard ratio, 0.63; P=0.017). At 6 months, the disease control rate (including rates of complete response, partial response, and stable disease at 6 months) was also superior with vandetanib. However, overall survival (OS) was not improved. Of note, the PFS benefit was greater for patients with papillary thyroid cancer (16.2 months vs. 7.7 months), but when compared to other histologies, the difference was not statically significant. Grade 3 or greater toxicity was substantially higher in patients treated with vandetanib when compared to placebo. Of note, 74% of patients treated with vandetanib reported diarrhea, and 14% had QTc prolongation. Two treatment-related deaths occurred in the vandetanib group (from pneumonia and skin metastases hemorrhage) and one occurred in the placebo group (from pneumonia).

Comment: The data from this study bring up the ongoing debate regarding the use of pharmaceutical agents that demonstrate a benefit in PFS but fail to demonstrate an improvement in OS. The investigators state that phase III trials are needed to further define the clinical benefits of this agent in differentiated thyroid carcinoma. However, a cautionary note should be sounded. Given the toxicity of vandetanib, off-protocol use of this agent in differentiated thyroid carcinomas should be discouraged.

Source: Journal Watch Oncology and Hematology