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
Cabozantinib (XL184) is an oral inhibitor of MET, VEGFR2, and RET. It was studied in a phase I trial in patients with different malignancies (37 had MTC). A partial response was observed in 10 patients (29%), and 25 patients (68%) had either a partial response or prolonged stable disease ≥ 6 months. Responses have been observed in patients with MTC with and without RET mutations. This study showed promising results to conduct an ongoing randomized phase III study of cabozantinib in MTC.8
Clinical trials of vandetanib
Wells et al presented the results of a double-blind randomized phase III trial of vandetanib in locally advanced or metastatic MTC (the ZETA trial). Vandetanib targets the RET, VEGFR, and epidermal growth factor re ceptor signaling pathways. The researchers randomized 331 patients with 90% sporadic MTC 2:1 to receive vandetanib or placebo. Patients in the placebo arm crossed over after disease progression and also received vandetanib.
Statistically significant prolongation of PFS (the primary objective) was observed for vandetanib compared with placebo (hazard ratio, 0.45; P < 0.0001), as well as improvement in objective response rate, disease control rate, time to worsening of pain, and biochemical response.9 This study was the first phase III trial that showed efficacy of a new multitargeted TKI with extension of PFS and improved quality of life in MTC. Subsequent data showed a median PFS of 16.4 months in the placebo arm and at least 22.6 months in the vandetanib arm; however, there was no significant improvement in overall survival. Based on this new information, the US Food and Drug Administration approved vandetanib as a new treatment for MTC in April 2011