Hamid Mirshahidi, MD
Loma Linda University School of Medicine, Loma Linda, CA

Medullary thyroid cancer (MTC) is a rare but aggressive disease. Unfortunately, there is not an effective conventional chemotherapy regimen for the disease. New strategies to treat metastatic MTC, including radioimmunotherapy and vaccine-based therapies, have been tested, with no major achievement. 1 Therefore, targeted therapy may offer a novel therapeutic approach for advanced MTC based on the role of mutations in the RET proto- oncogene and vascular endothelial growth factor receptor (VEGFR) activity in the pathogenesis of hereditary and sporadic MTC.2 VEGFR and RET may be common targets among multitargeted tyrosine kinase inhibitors (TKIs), such as sunitinib (Sutent), sorafenib (Nexavar), cabozantinib, motesanib, and vandetanib (Caprelsa).

Early responses with multitargeted TKIs
Sunitinib targets VEGFR 1-2, platelet-derived growth factor receptor (PDGFR), c-KIT, FLT3, and RET. It was tested in 7 patients with metastatic MTC and 28 patients with radioiodine-refractory well-differentiated thyroid carcinoma in a phase II study. Of the 33 evaluable patients, 1 patient with MTC (3%) achieved a complete response, 10 patients (28%) achieved a partial response, and 16 patients (46%) had stable disease, suggesting sunitinib may have activity in MTC.3

Sunitinib was also studied in 25 patients with rapidly progressing MTC in another phase II trial. Partial response was achieved in 8 of 24 patients (33%), with a median duration of response of 37 weeks, and 54 % of patients had SD, with a median duration of 32 weeks. As of May 2010, progression-free survival (PFS) was 49 weeks. Interestingly, patients with and without RET mutations showed a clinical benefit. Patients with the M918T RET mutation have a worse prognosis, and it may be associated with a durable response.4

Sorafenib showed clinical activity in patients with metastatic and radioiodine nonresponsive papillary thyroid carcinomas.5 Sorafenib inhibits the RAF, VEGFR 2-3, PDGFRβ, FLT3, c-KIT, and RET kinases. It also inhibits the growth of RET mutation-positive and wild-type MTC in vitro and in vivo. Therefore, sorafenib was evaluated in a phase II clinical trial to investigate its activity in patients with advanced MTC. Although only one partial response was observed in patients with sporadic MTC, 50% of patients showed stable disease of ≥ 15 months, with tumor shrinkage ranging from 8%–27%. Sorafenib was reasonably well tolerated in this study. The median duration of treatment and PFS were 15 and 17.9 months, respectively. The median overall survival was not reached at the time of data analysis.6

Motesanib is a novel inhibitor of VEGFR 1-2-3, PDGFR, and c-KIT. It has activity in wild-type but not mutant RET. Motesanib was studied in 91 patients with locally advanced or metastatic MTC in a phase II trial. Only two patients (2%) had an objective response, 81% of patients achieved or maintained stable disease, and 76% experienced a decrease from baseline in tumor measurement. In patients who had tumor marker analysis, 83% and 75% had a decrease in circulating concentrations of calcitonin and carcinoembryonic antigen (CEA), respectively. PFS was also 48 weeks. These data were encouraging and suggested the role of VEGF/RET-targeted therapies for MTC, as suggested in other studies.7