Vandetanib in locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 2 trial.
BACKGROUND
No effective standard treatment exists for patients with radioiodine-refractory, advanced differentiated thyroid carcinoma. We aimed to assess efficacy and safety of vandetanib, a tyrosine kinase inhibitor of RET, VEGFR and EGFR signalling, in this setting.


METHODS
In this randomised, double-blind, phase 2 trial, we enrolled adults (aged ≥18 years) with locally advanced or metastatic differentiated thyroid carcinoma (papillary, follicular, or poorly differentiated) at 16 European medical centres. Eligible patients were sequentially randomised in a 1:1 ratio with a standard computerised scheme to receive either vandetanib 300 mg per day (vandetanib group) or matched placebo (placebo group), balanced by centre. The primary endpoint was progression-free survival (PFS) in the intention-to-treat population based on investigator assessment. This study is registered with ClinicalTrials.gov, number NCT00537095.


RESULTS
Between Sept 28, 2007, and Oct 16, 2008, we randomly allocated 72 patients to the vandetanib group and 73 patients to the placebo group. By data cutoff (Dec 2, 2009), 113 (78%) patients had progressed (52 [72%] patients in the vandetanib group and 61 [84%] in the placebo group) and 40 (28%) had died (19 [26%] patients in the vandetanib group and 21 [29%] in the placebo group). Patients who received vandetanib had longer PFS than did those who received placebo (hazard ratio [HR] 0·63, 60% CI 0·54-0·74; one-sided p=0·008): median PFS was 11·1 months (95% CI 7·7-14·0) for patients in the vandetanib group and 5·9 months (4·0-8·9) for patients in the placebo group. The most common grade 3 or worse adverse events were QTc prolongation (ten [14%] of 73 patients in the vandetanib group vs none in the placebo group), diarrhoea (seven [10%] vs none), asthenia (five [7%] vs three [4%]), and fatigue (four [5%] vs none). Two patients in the vandetanib group and one in the placebo group died from treatment-related serious adverse events (haemorrhage from skin metastases and pneumonia in the vandetanib group and pneumonia in the placebo group).


CONCLUSIONS
Vandetanib is the first targeted drug to show evidence of efficacy in a randomised phase 2 trial in patients with locally advanced or metastatic differentiated thyroid carcinoma. Further investigation of tyrosine-kinase inhibitors in this setting is warranted.


BACKGROUND
AstraZeneca.
Institut Gustave Roussy, Université Paris-Sud, Villejuif, France.
Sophie
S
Leboulleux
Lars
L
Bastholt
Thomas
T
Krause
Christelle
C
de la Fouchardiere
Jan
J
Tennvall
Ahmad
A
Awada
José Manuel
JM
Gómez
Françoise
F
Bonichon
Laurence
L
Leenhardt
Christine
C
Soufflet
Muriel
M
Licour
Martin J
MJ
Schlumberger
D018263:Adenocarcinoma, Follicular; D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000556:secondary; D002277:Carcinoma; D002291:Carcinoma, Papillary; D003967:Diarrhea / Q000139:chemically induced; D018572:Disease-Free Survival; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D006329:Heart Conduction System / Q000187:drug effects; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000556:secondary; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D010880:Piperidines / Q000009:adverse effects / Q000627:therapeutic use*; D011799:Quinazolines / Q000009:adverse effects / Q000627:therapeutic use*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D012878:Skin Neoplasms / Q000556:secondary; D016019:Survival Analysis; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000556:secondary*; D055815:Young Adult
D000970:Antineoplastic Agents; D010880:Piperidines; D011799:Quinazolines; D066246:ErbB Receptors; D040262:Receptors, Vascular Endothelial Growth Factor; C452423:vandetanib