Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial

Abstract

Background Patients with radioactive iodine (131I, RAI)-refractory locally advanced or metastatic differentiated thyroid cancer (DTC) have a poor prognosis due to the lack of effective treatment options. Methods This multicentre, randomized (1:1), double-blind, placebo-controlled, phase 3 study (DECISION; NCT00984282) investigated sorafenib (400 mg orally twice-daily) in patients with RAI-refractory locally advanced or metastatic DTC progressing within the past 14 months. The primary endpoint was progression-free survival (PFS) by central independent review. Patients receiving placebo could crossover to open-label sorafenib upon progression. Archival tumour tissue was examined for BRAF and RAS mutations. Serum thyroglobulin was measured at baseline and each visit. Findings A total of 417 patients were randomized to sorafenib (n=207) or placebo (n=210). Sorafenib treatment significantly improved PFS compared with placebo (hazard ratio, 0·59; 95% confidence interval, 0·45–0·76; P<0·0001; median 10·8 vs. 5·8 months, respectively). PFS improvement was seen in all pre-specified clinical and genetic biomarker subgroups irrespective of mutation status. There was no statistically significant difference in overall survival (hazard ratio, 0·80; 95% confidence interval, 0·54–1·19; P=0·14); median overall survival had not been reached and 150 (71%) patients receiving placebo crossed over to sorafenib upon progression. Response rates (all partial responses) were 12·2% (24/196; sorafenib) and 0·5% (1/201; placebo; p<0·0001). Median thyroglobulin levels increased in the placebo group, and decreased, then paralleled treatment responses in the sorafenib group. Most adverse events were grade 1 or 2. The most common treatment-emergent adverse events in the sorafenib arm were hand–foot skin reaction (76·3%), diarrhoea (68·6%), alopecia (67·1%), and rash/desquamation (50·2%). Interpretation Sorafenib significantly improved PFS compared with placebo in patients with progressive RAI-refractory DTC. Adverse events were consistent with the known sorafenib safety profile. These results suggest that sorafenib represents a new treatment option for patients with progressive RAI-refractory DTC.

Lenvatinib induces early tumor shrinkage in patients with advanced thyroid carcinoma

“…Lenvatinib is a new treatment option approved for RAI-refractory metastatic or recurrent thyroid carcinoma patients, which achieved outstanding results in comparison with other previous TKIs such as sorafenib [2], vandetanib, and pazopanib. It is an oral multikinase inhibitor of vascular endothelial growth factor (VEGF) receptor (VEGFR)1-3, fibroblast growth factor receptor (FGFR)1-4, platelet-derived growth factor receptor alpha (PDGFR-α), ret proto-oncogene (RET), and KIT proto-oncogene [3][4][5].…”

Partial response to sorafenib treatment associated with transient grade 3 thrombocytopenia in a patient with locally advanced thyroid cancer

“…In none of the patients who presented this AE it was grade 3 (between 50,000 and 25,001 x 10 3 /mm 3 ) or grade 4 (< 25,000 x 10 3 /mm 3 ). Thrombocytopenia was not an AE which led to a dose decreasing or dose interruption in any patient of the DECI-SION trial (10). Nevertheless, in this patient, it seems that this AE was dose dependent because the patient resumed her platelet count to normal after dose reduction to 400 mg/day.…”

“…In vitro, it has shown to inhibit multiple kinases thought to be involved in both cell proliferation and angiogenesis. Sorafenib was recently approved in US, Europe and some other countries for the treatment of RAIrefractory and progressive advanced thyroid cancer after the presentation of the DECISION trial which showed that progression-free survival was significantly improved with sorafenib (n = 207) compared with placebo (n = 210) (HR 0.587; 95% CI 0.454-0.758; p < 0.0001; median 10.8 versus 5.8 months, respectively) (10).…”

2016 Russian clinical practice guidelines for differentiated thyroid cancer diagnosis and treatment

“…Таргетная терапия [1, [229][230][231][232][233][234][235][236][237] Рекомендация 47. Системная таргет-ная терапия препаратами, зарегистрирован-ными в РФ по данным медицинским показа-ниям (сорафениб и ленватиниб), показана при неэффективности РЙТ и доказанном про-грессировании опухоли в течение 3-12 мес согласно критериям RECIST 1.1 в случаях:…”