Phase II Trial of Sorafenib in Advanced Thyroid Cancer

Abstract

A B S T R A C T PurposeGiven the molecular pathophysiology of thyroid cancer and the spectrum of kinases inhibited by sorafenib, including Raf kinase, vascular endothelial growth factor receptors, platelet-derived growth factor receptor, and RET tyrosine kinases, we conducted an open-label phase II trial to determine the efficacy of sorafenib in patients with advanced thyroid carcinoma. Patients and MethodsEligible patients with metastatic, iodine-refractory thyroid carcinoma received sorafenib 400 mg orally twice daily. Responses were measured radiographically every 2 to 3 months. The study end points included response rate, progression-free survival (PFS), and best response by Response Evaluation Criteria in Solid Tumors. ResultsThirty patients were entered onto the study and treated for a minimum of 16 weeks. Seven patients (23%; 95% CI, 0.10 to 0.42) had a partial response lasting 18ϩ to 84 weeks. Sixteen patients (53%; 95% CI, 0.34 to 0.72) had stable disease lasting 14 to 89ϩ weeks. Seventeen (95%) of 19 patients for whom serial thyroglobulin levels were available showed a marked and rapid response in thyroglobulin levels with a mean decrease of 70%. The median PFS was 79 weeks. Toxicity was consistent with other sorafenib trials, although a single patient died of liver failure that was likely treatment related. ConclusionSorafenib has clinically relevant antitumor activity in patients with metastatic, iodine-refractory thyroid carcinoma, with an overall clinical benefit rate (partial response ϩ stable disease) of 77%, median PFS of 79 weeks, and an overall acceptable safety profile. These results represent a significant advance over chemotherapy in both response rate and PFS and support further investigation of this agent in these patients.

An update on molecular biology of thyroid cancers

“…New smallmolecule protein-kinase inhibitors including axitinib [259], sorafenib [260,284,285], motesanib [262] and pazopanib [264] have shown promise in clinical trials on thyroid cancer. PLX4032 (also known as vemurafenib), a BRAF-V600E-specific inhibitor, has been recently approved by the FDA for the treatment of BRAFV600E-positive melanoma [286].…”

Association Between 18F-FDG Avidity and the BRAF Mutation in Papillary Thyroid Carcinoma

“…Our study results might also be pertinent to therapeutic decision-making. There is growing evidence that BRAF mutation-targeted therapy (sorafenib) is effective in metastatic or advanced thyroid cancer [26][27][28]. There was also a report that in iodine-refractory differentiated thyroid cancer, an early 18 F-FDG PET response was useful for identifying sorafenib non-responders, although no BRAF mutation analysis was performed in those patients [29].…”

Phase II Efficacy and Pharmacogenomic Study of Selumetinib (AZD6244; ARRY-142886) in Iodine-131 Refractory Papillary Thyroid Carcinoma with or without Follicular Elements

“…Using prolonged SD measures as reported by other investigators, we observed 36% of patients with SD lasting over 24 weeks which compares favorably with the SD proportions with axitinib (38% over 16 weeks), sorafenib (53% from 14–89+ weeks), and motesanib (35% over 24 weeks; refs. 27–29). Similar to the case for response rates, patients treated with selumetinib showed PFS rates that were shorter than for the 3 comparator studies.…”

“…Only 16% of patients discontinued selumetinib therapy due to adverse events. Reported objective response rates have been greater in recent studies in advanced thyroid cancer of agents (axitinib, motesanib, sorafenib, and sunitinib) that target the vascular endothelial growth factor receptor (VEGFR) compared with agents such as selumetinib and gefitinib that do not target the VEGFR (27–29, 31, 32). This observation suggests that angiogenesis may be more important in progression of disease than signaling pathways known to be activated in the tumor such as RAS/RAF/MAPK activation.…”