Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial.
BACKGROUND
Patients with radioactive iodine ((131)I)-refractory locally advanced or metastatic differentiated thyroid cancer have a poor prognosis because of the absence of effective treatment options. In this study, we assessed the efficacy and safety of orally administered sorafenib in the treatment of patients with this type of cancer.


METHODS
In this multicentre, randomised, double-blind, placebo-controlled, phase 3 trial (DECISION), we investigated sorafenib (400 mg orally twice daily) in patients with radioactive iodine-refractory locally advanced or metastatic differentiated thyroid cancer that had progressed within the past 14 months. Adult patients (≥18 years of age) with this type of cancer were enrolled from 77 centres in 18 countries. To be eligible for inclusion, participants had to have at least one measurable lesion by CT or MRI according to Response Evaluation Criteria In Solid Tumors (RECIST); Eastern Cooperative Oncology Group performance status 0-2; adequate bone marrow, liver, and renal function; and serum thyroid-stimulating hormone concentration lower than 0·5 mIU/L. An interactive voice response system was used to randomly allocate participants in a 1:1 ratio to either sorafenib or matching placebo. Patients, investigators, and the study sponsor were masked to treatment assignment. The primary endpoint was progression-free survival, assessed every 8 weeks by central independent review. Analysis was by intention to treat. Patients in the placebo group could cross over to open-label sorafenib upon disease progression. Archival tumour tissue was examined for BRAF and RAS mutations, and serum thyroglobulin was measured at baseline and at each visit. This study is registered with ClinicalTrials.gov, number NCT00984282, and with the EU Clinical Trials Register, number EudraCT 2009-012007-25.


RESULTS
Patients were randomly allocated on a 1:1 basis to sorafenib or placebo. The intention-to-treat population comprised 417 patients (207 in the sorafenib group and 210 in the placebo group) and the safety population was 416 patients (207 in the sorafenib group and 209 in the placebo group). Median progression-free survival was significantly longer in the sorafenib group (10·8 months) than in the placebo group (5·8 months; hazard ratio [HR] 0·59, 95% CI 0·45-0·76; p<0·0001). Progression-free survival improved in all prespecified clinical and genetic biomarker subgroups, irrespective of mutation status. Adverse events occurred in 204 of 207 (98·6%) patients receiving sorafenib during the double-blind period and in 183 of 209 (87·6%) patients receiving placebo. Most adverse events were grade 1 or 2. The most frequent treatment-emergent adverse events in the sorafenib group were hand-foot skin reaction (76·3%), diarrhoea (68·6%), alopecia (67·1%), and rash or desquamation (50·2%).


CONCLUSIONS
Sorafenib significantly improved progression-free survival compared with placebo in patients with progressive radioactive iodine-refractory differentiated thyroid cancer. Adverse events were consistent with the known safety profile of sorafenib. These results suggest that sorafenib is a new treatment option for patients with progressive radioactive iodine-refractory differentiated thyroid cancer.


BACKGROUND
Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals (an Amgen subsidiary).
Department of Otorhinolaryngology: Head and Neck Surgery, and Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA, USA. Electronic address: brosem@mail.med.upenn.edu.
Marcia S
MS
Brose
Royal Marsden Hospital, London, UK.
Christopher M
CM
Nutting
Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Gliwice, Poland.
Barbara
B
Jarzab
Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
Rossella
R
Elisei
Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan, Italy.
Salvatore
S
Siena
Department of Oncology, Odense University Hospital, Odense C, Denmark.
Lars
L
Bastholt
Consortium Cancer Thyroïdien, Hospices Civils-Centre Anticancéreux, Lyon, France.
Christelle
C
de la Fouchardiere
Unit of Endocrinology, University of Siena, Siena, Italy.
Furio
F
Pacini
Department for Endocrinology and Nephrology, Leipzig University, Leipzig, Germany.
Ralf
R
Paschke
Division of Endocrinology, Asan Medical Center, Seoul, Korea.
Young Kee
YK
Shong
The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Steven I
SI
Sherman
Radboud University Medical Center, Nijmegen, Netherlands.
Johannes W A
JW
Smit
Bayer HealthCare Pharmaceuticals, Whippany, NJ, USA.
John
J
Chung
Bayer Pharma AG, Berlin, Germany.
Christian
C
Kappeler
Bayer HealthCare Pharmaceuticals, Whippany, NJ, USA.
Carol
C
Peña
Bayer HealthCare Pharmaceuticals, Whippany, NJ, USA.
István
I
Molnár
Gustave Roussy and University Paris Sud, Villejuif, France.
Martin J
MJ
Schlumberger
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000627:therapeutic use*; D000077157:Sorafenib; D016019:Survival Analysis; D013964:Thyroid Neoplasms / Q000188:drug therapy*; D016896:Treatment Outcome; D055815:Young Adult
D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib