Vandetanib in Patients With Locally Advanced or Metastatic Medullary Thyroid Cancer: A Randomized, Double-Blind Phase III Trial

Abstract

A B S T R A C T PurposeThere is no effective therapy for patients with advanced medullary thyroid carcinoma (MTC). Vandetanib, a once-daily oral inhibitor of RET kinase, vascular endothelial growth factor receptor, and epidermal growth factor receptor signaling, has previously shown antitumor activity in a phase II study of patients with advanced hereditary MTC. Patients and MethodsPatients with advanced MTC were randomly assigned in a 2:1 ratio to receive vandetanib 300 mg/d or placebo. On objective disease progression, patients could elect to receive open-label vandetanib. The primary end point was progression-free survival (PFS), determined by independent central Response Evaluation Criteria in Solid Tumors (RECIST) assessments. ResultsBetween December 2006 and November 2007, 331 patients (mean age, 52 years; 90% sporadic; 95% metastatic) were randomly assigned to receive vandetanib (231) or placebo (100). At data cutoff (July 2009; median follow-up, 24 months), 37% of patients had progressed and 15% had died. The study met its primary objective of PFS prolongation with vandetanib versus placebo (hazard ratio [HR], 0.46; 95% CI, 0.31 to 0.69; P Ͻ .001). Statistically significant advantages for vandetanib were also seen for objective response rate (P Ͻ .001), disease control rate (P ϭ .001), and biochemical response (P Ͻ .001). Overall survival data were immature at data cutoff (HR, 0.89; 95% CI, 0.48 to 1.65). A final survival analysis will take place when 50% of the patients have died. Common adverse events (any grade) occurred more frequently with vandetanib compared with placebo, including diarrhea (56% v 26%), rash (45% v 11%), nausea (33% v 16%), hypertension (32% v 5%), and headache (26% v 9%). ConclusionVandetanib demonstrated therapeutic efficacy in a phase III trial of patients with advanced MTC (ClinicalTrials.gov NCT00410761).

Risk of venous thromboembolic events associated with VEGFR‐TKIs: A systematic review and meta‐analysis

“…1 Recently, overall survival benefits gained from small molecule tyrosine kinase inhibitors (TKI) directed against the VEGF receptor (VEGFR) have been observed in several randomized clinical trials (RCTs) among variety of solid tumors. [2][3][4][5][6][7][8][9][10] In addition, the United States Food and Drug Administration (FDA) has approved four VEGF TKIs, sunitinib (Sutent, Pfizer, New York, NY), sorafenib (Nexavar, Bayer Pharmaceuticals, West Haven, CT, and Onyx Pharmaceuticals, Richmond, CA), pazopanib (Votrient, GlaxoSmithKline, Middlesex, UK), and vandetanib (Caprelsa, AstraZeneca, London, UK), for use in cancer therapy. 11 As a result, the use of VEGFR-TKIs is expected to increase in the near future, and an appreciation for the differences in toxicity profiles between traditional cytotoxic agents and targeted agents is therefore urgently needed.…”

Rapid response of hypercortisolism to vandetanib treatment in a patient with advanced medullary thyroid cancer and ectopic Cushing syndrome

“…The study that led to this approval was the ZETA trial which showed a significant longer median progression-free survival (PFS) vs. placebo (30.5 vs. 19.3 months; p = 0.001) in this setting, (HR 0.46; 95% CI 0.31 to 0.69; p < 0.001) with an estimated 11-month prolongation of median PFS (10). Vandetanib also demonstrated significantly higher rates of objective response (45% vs. 13% for placebo; p < 0.001), and calcitonin biochemical response (69% vs. 3% for placebo; p < 0.001) (13).…”

Development of molecular targeted drugs for advanced thyroid cancer in Japan [Review]

“…Vandetanib statistically significantly prolonged progression-free survival in comparison with the placebo (30.5 months vs. 19.3 months, hazard ratio 0.46), and the response rate was higher (45% vs. 13%) [14]. Diarrhea, rashes, nausea, and hypertension were noted in more than 30% of the subjects in the vandetanib group.…”

“…The trial compared vandetanib 300 mg QD with a placebo, and the results were reported with progression-free survival as the primary endpoint [14]. The trial design is shown in Fig.…”

“…Because expression of angiogenesis factors, including vascular endothelial growth factor (VEGF), is increased in thyroid cancer [7], inhibition of signal transduction is expected to have an antitumor effect, and clinical trials of various molecular targeted drugs as a treatment for advanced thyroid cancer have been conducted. Table 1 shows a summary of those trials [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26]. All of molecular targeted drugs are low-molecular-weight compounds that inhibit multiple kinases, including the VEGF receptor.…”