Sorafenib inhibits oncogenic RET kinase with an IC50 of < 50 nM and decreased tumor volume of TT cells in athymic mice.Phase I and II clinical trials of at least 15 patients evaluating efficacy of RET TKIs in patients with metastatic MTC are summarized in Table 1.The phase II trial of vandetanib was conducted exclusively in patients with hereditary MTC.Although it showed dramatic suppression of serum Seliciclib selleckchem calcitonin and CEA in 80% of patients, partial responses induced were modest.Responses did not correlate with 618, 620, 634, or 918 codon mutations in RET.The phase II trials for motesanib and sorafenib included patients with sporadic as well as hereditary MTC.Although these trials included mostly sporadic MTC, somatic mutations in RET were present in 70 to 80% of tumors tested; of these, greater than 80% were at codon 918.As indicated in Table 1, partial responses with motesanib and sorafenib were minimal , and overall responses were modest at best.Finally, data for sunitinib and XL-184 are preliminary but reveal modest partial responses and tumor marker responses.Like the sorafenib and motesanib trials, the RET mutation rate in sporadic tumors was also high with predominantly codon 918 mutations.
On the basis of encouraging response and safety data found in early phase clinical trials in MTC, an international multicenter double-blind randomized phase III clinical trial in MTC with vandetanib has been conducted, whereas another with XL-184 is ongoing.Although both trials use placebo as a control group with 2:1 randomization, unblinding and cross-over at time of disease Selumetinib progression was allowed in the vandetanib trial but not in XL-184.The primary endpoint is progression-free survival in the vandetanib trial, whereas overall survival is used in the XL-184 trial.Preliminary results of a phase III trial of vandetanib were reported after 24 months of median duration of followup.A total of 331 patients were enrolled from December 2006 to November 2007, with 231 patients assigned to receive oral vandetanib at a dose of 300 mg daily on an ongoing basis, whereas 100 patients were assigned to receive placebo.Median progression-free survival for the placebo group was 19.3 months, whereas it has not been reached for vandetanib group.The hazard ratio for progression- free survival is 0.46 with a P value of <0.0001.No unexpected adverse events were noted.This phase III trial in sporadic and hereditary MTC is the first to show benefit of RET-targeted TKI in delaying disease progression.