Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial.
OBJECTIVE
There 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.


METHODS
Patients 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.


RESULTS
Between 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 < .001). Statistically significant advantages for vandetanib were also seen for objective response rate (P < .001), disease control rate (P = .001), and biochemical response (P < .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%).


CONCLUSIONS
Vandetanib demonstrated therapeutic efficacy in a phase III trial of patients with advanced MTC (ClinicalTrials.gov NCT00410761).
Medical Oncology Branch, National Cancer Institute, National Institutes of Health, Building 10, Room 13N-240E MSC 1206, 9000 Rockville Pike, Bethesda, MD 20892, USA. wellss@mail.nih.gov
Samuel A
SA
Wells
Bruce G
BG
Robinson
Robert F
RF
Gagel
Henning
H
Dralle
James A
JA
Fagin
Massimo
M
Santoro
Eric
E
Baudin
Rossella
R
Elisei
Barbara
B
Jarzab
James R
JR
Vasselli
Jessica
J
Read
Peter
P
Langmuir
Anderson J
AJ
Ryan
Martin J
MJ
Schlumberger
D018278:Carcinoma, Neuroendocrine; D018450:Disease Progression; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010880:Piperidines / Q000009:adverse effects / Q000627:therapeutic use*; D010919:Placebos; D011799:Quinazolines / Q000009:adverse effects / Q000627:therapeutic use*; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000473:pathology
D010880:Piperidines; D010919:Placebos; D011799:Quinazolines; C452423:vandetanib