Patients with radioactive iodine–refractory locally advanced or metastatic differentiated thyroid cancer have a poor prognosis. In the double-blind phase III DECISION trial reported in The Lancet, Marcia S. Brose, MD, PhD, of Abramson Cancer Center of the University of Pennsylvania, and colleagues found that sorafenib (Nexavar) increased progression-free survival in this setting.1 The DECISION trial supported the approval of sorafenib in this indication in November 2013.
RET/PTC translocations, BRAF V600E mutations, RAS mutations, and increased expression of vascular endothelial growth factor (VEGF) and its receptors (VEGFRs) have been implicated in the pathogenesis and poor outcome of thyroid carcinoma. Sorafenib is a kinase inhibitor of VEGFR-1, VEGFR-2, and VEGFR-3, RET (including RET/PTC), RAF (including BRAF V600E), and platelet-derived growth factor receptor–beta.
Study Details
In the trial, 417 patients with radioactive iodine-refractory locally advanced or metastatic differentiated thyroid cancer that had progressed within the past 14 months from 77 centers in 18 countries were randomly assigned to receive sorafenib at 400 mg twice daily (n = 207) or placebo (n = 210). Patients had to have at least one measurable lesion on computed tomography or magnetic resonance imaging, Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, adequate bone marrow, liver, and renal function, and serum thyroid-stimulating hormone concentration < 0.5 mIU/L.
The primary endpoint was progression-free survival assessed every 8 weeks by central independent review. Patients in the placebo group could cross over to sorafenib at disease progression.
The sorafenib and placebo groups were generally balanced for age (median, 63 years in both), sex (50% and 55% female), ethnicity (eg, 59% and 61% white, 23% and 25% Asian), metastases (distant in 97% and 96%), time from diagnosis (median, 66 and 67 months), ECOG performance status (0 in 63% and 62%, 1 in 33% and 35%, 2 in 3% and 3%), histology (eg, papillary in 57% in both, follicular-oncocytic in 18% in both, poorly differentiated in 12% and 8%), metastatic sites (eg, lung in 86% in both, lymph nodes in 55% and 48%, bone in 28% and 27%), FDG uptake (positive in 78% and 76%), and previous treatment (median cumulative radioiodine activity, 400 and 376 mCi; systemic therapy in 3% in both; radiotherapy in 40% and 43%).
Prolonged Progression-Free Survival
Median follow-up was 16.2 months. Median progression-free survival was 10.8 months in the sorafenib group vs 5.8 months in the placebo group (hazard ratio [HR] = 0.59, P < .0001). Progression-free survival was improved with sorafenib in all prespecified clinical and genetic biomarker subgroups, irrespective of mutation status.
Tumor mutation data, available for 60% of patients, showed BRAF mutations in 27.0% of sorafenib patients vs 33.1% of placebo patients and RAS mutations in 19.0% vs 20.0%. BRAF mutation frequency was highest in papillary thyroid carcinoma. Median progression-free survival was prolonged with sorafenib both among patients with BRAF mutations (20.5 vs 9.4 months, HR = 0.46, P = .02) and in those with wild-type BRAF (8.9 vs 3.8 months, HR = 0.55, P < .001) and both in those with RAS mutations (5.5 vs 3.5 months, HR = 0.49, P = .045) and those with wild-type RAS (10.8 vs 5.8 months, HR = 0.60, P = .004). Neither BRAF nor RAS mutation status was predictive of sorafenib benefit (P = .653 and P = .422 for interactions).
Multivariate analyses showed that only histology (papillary vs poorly differentiated), age, and sorafenib treatment were independent predictors of progression-free survival and that mutation status was not an independent predictor when analysis was restricted to papillary tumors. Sorafenib also significantly improved progression-free survival irrespective of high or low thyroglobulin concentration.
Objective response rate (all partial responses) was 12.2% vs 0.5% (P < .0001), and median duration of response in the sorafenib group was 10.2 months. Overall survival did not differ between the groups (HR = 0.80, P = .14), and median overall survival had not been reached at the time of data cutoff. Overal1, 71% of placebo patients crossed over to receive open-label sorafenib at disease progression, and 20% of sorafenib patents and 9% of placebo patients received other anticancer treatment after progression.
Safety Analysis
Most adverse events were mild to moderate and tended to occur early in treatment. The most frequent adverse events of any grade in the sorafenib group were hand-foot skin reaction (76% vs 10% in placebo group), diarrhea (69% vs 15%), alopecia (67% vs 8%), rash or desquamation (50% vs 12%), fatigue (50% vs 25%), weight loss (47% vs 14%), hypertension (41% vs 12%), and anorexia (32% vs 5%). The most common grade 3 or 4 adverse events were hand-foot skin reaction (20% vs 0%), hypertension (10% vs 2%), hypocalcemia (9% vs 2%), weight loss (6% vs 1%), fatigue (6% vs 1%), and diarrhea (6% vs 1%).
Serious adverse events occurred in 37% of sorafenib patients vs 26% of those receiving placebo, with the most common being secondary malignancy (4.3% vs 1.9%), dyspnea (3.4% vs 2.9%), and pleural effusion (2.9% vs 1.9%). The increased serious adverse event rate on the sorafenib arm was likely affected, in part, by the fact that patients received sorafenib twice as long as patients in the other arm received placebo. In patients receiving sorafenib, secondary malignancies included squamous cell carcinoma of the skin in 6 patients, melanoma in 1 patient, and single cases of acute myeloid leukemia and bladder cancer. In patients receiving placebo, single cases of bladder cancer, colon carcinoma, pulmonary carcinoid tumors, and gastric cancer were reported.
Adverse events resulted in dose interruption in 66% vs 26% of patients, reduction in 64% vs 9%, and withdrawal in 19% vs 4%. Hand-foot skin reaction was the most common cause of sorafenib dose interruption (27%), reduction (34%), and withdrawal (5%).
Death occurred in 12 sorafenib patients (due to underlying disease in 7, unknown cause in 2, and lung infection, chronic obstructive lung disease, and myocardial infarction in 1 each) and in 6 placebo patients (due to underlying disease in 4 and pulmonary embolism and subdural hematoma in 1 each). Death from myocardial infarction in a sorafenib patient and from subdural hematoma in a placebo patient were considered related to study drug.
The investigators concluded, “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.” ■
Disclosure: The study was funded by Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals (an Amgen subsidiary). For full disclosures of the study authors, visit www.thelancet.com.
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