Medullary Thyroid Cancer: Advances and Challenges - Episode 9

Mutations and Targeted Therapies in Advanced MTC

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Several molecular pathways and mutations are implicated in the pathogenesis of medullary thyroid cancer (MTC). In general, somatic RET mutations are present in 40% to 50% of cases of advanced MTC, suggests Steven I. Sherman, MD. Additionally, preclinical studies suggest that targeting RET results in a high-level of tumor control. However, at this point, a pure RET inhibitor is not available, since current agents also inhibit VEGFR. Despite not being purely RET focused, these agents are efficacious in MTC, since VEGF and VEGFR are critical to angiogenesis, Steven Sherman explains. Additionally, these agents are effective in patients with RAS mutations, since RAS signals through the same pathway as RET.

In terms of mutation testing, trials have found that somatic RET M918T mutations produce worse outcomes. Additionally, these tumors also appear to be more sensitive to RET targeted agents. However, Steven Sherman notes, all patients show some level of response to these targeted agents, not just those with RET mutations. As a result, the utility of testing specifically for these somatic mutations remains unclear.

Two targeted agents are currently approved to treat patients with advanced MTC. The first, vandetanib, was approved based on a phase III trial that evaluated the agent in patients with hereditary and nonhereditary MTC, explains Eric J. Sherman, MD. The primary endpoint of the trial was progression-free survival (PFS), due to crossover and the difficulty of assessing overall survival in this setting. The trial found an objective response rate for vandetanib of approximately 44%, notes Eric Sherman. Additionally, the median PFS was prolonged by around 6.2 months in favor of vandetanib compared to placebo (HR = 0.35).

The second agent, cabozantinib, was approved based on a randomized phase III trial that compared the agent to placebo for patients with metastatic MTC, explains Lori J. Wirth, MD. Unlike the vandetanib study, all patients in the study had progressive disease upon enrollment. Due to these different patient populations, a cross-study comparison of the efficacy of these agents is not possible, Wirth advises. The primary endpoint in the cabozantinib trial was also PFS; however, crossover was not allowed in the trial. Overall, the study found a 7.2 month extension in median PFS for patients treated with cabozantinib (HR = 0.28), Wirth notes.

A multidisciplinary team should determine the optimal candidate for these agents. Patients who have been cured, have elevated calcitonin and CEA levels in the absence of structural disease, have small tumor volume, or have small volume distant metastasis should not receive one of these agents, believes R. Michael Tuttle, MD. Treatment with one of these agents should be utilized primarily for patients with symptomatic structurally progressive disease, Tuttle believes.