TY - JOUR
T1 - Sorafenib in radioactive iodine-refractory, locally advanced or metastatic diff erentiated thyroid cancer
T2 - A randomised, double-blind, phase 3 trial
AU - Brose, Marcia S.
AU - Nutting, Christopher M.
AU - Jarzab, Barbara
AU - Elisei, Rossella
AU - Siena, Salvatore
AU - Bastholt, Lars
AU - De La Fouchardiere, Christelle
AU - Pacini, Furio
AU - Paschke, Ralf
AU - Shong, Young Kee
AU - Sherman, Steven I.
AU - Smit, Johannes W.A.
AU - Chung, John
AU - Kappeler, Christian
AU - Peña, Carol
AU - Molnár, István
AU - Schlumberger, Martin J.
N1 - Funding Information:
This study was supported by Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals (an Amgen subsidiary). We thank the patients, their caregivers, and the investigators who participated in this study; the principal investigators are listed in appendix pp 2–5 . We also thank Emma Robinson (7.4 Limited, Oxford, UK), who provided medical writing support, which was funded by Bayer HealthCare Pharmaceuticals.
PY - 2014
Y1 - 2014
N2 - Background Patients with radioactive iodine (131I)-refractory locally advanced or metastatic diff erentiated thyroid cancer have a poor prognosis because of the absence of eff ective treatment options. In this study, we assessed the effi cacy 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 diff erentiated 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. Findings 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 signifi cantly 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 prespecifi ed 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%). Interpretation Sorafenib signifi cantly improved progression-free survival compared with placebo in patients with progressive radioactive iodine-refractory diff erentiated thyroid cancer. Adverse events were consistent with the known safety profi le of sorafenib. These results suggest that sorafenib is a new treatment option for patients with progressive radioactive iodine-refractory diff erentiated thyroid cancer. Funding Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals (an Amgen subsidiary).
AB - Background Patients with radioactive iodine (131I)-refractory locally advanced or metastatic diff erentiated thyroid cancer have a poor prognosis because of the absence of eff ective treatment options. In this study, we assessed the effi cacy 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 diff erentiated 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. Findings 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 signifi cantly 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 prespecifi ed 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%). Interpretation Sorafenib signifi cantly improved progression-free survival compared with placebo in patients with progressive radioactive iodine-refractory diff erentiated thyroid cancer. Adverse events were consistent with the known safety profi le of sorafenib. These results suggest that sorafenib is a new treatment option for patients with progressive radioactive iodine-refractory diff erentiated thyroid cancer. Funding Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals (an Amgen subsidiary).
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U2 - 10.1016/S0140-6736(14)60421-9
DO - 10.1016/S0140-6736(14)60421-9
M3 - Article
C2 - 24768112
AN - SCOPUS:84904855170
SN - 0140-6736
VL - 384
SP - 319
EP - 328
JO - The Lancet
JF - The Lancet
IS - 9940
ER -