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The availability of molecular agents that target oncogenic signaling pathways now offers the possibility of achieving disease stabilization in a proportion of patients with metastatic medullary thyroid cancer.
Matthew Ringel, MD
The availability of molecular agents that target oncogenic signaling pathways now offers the possibility of achieving disease stabilization in a proportion of patients with metastatic medullary thyroid cancer (MTC), speakers agreed during the annual meeting of the American Thyroid Association.
The more difficult questions are which patients will benefit the most from targeted therapies such as the recently approved vandetanib, and whether response will be durable enough to justify initiating treatment.
“We now have drugs that are active in metastatic MTC, but the selection of who should get the drugs is really the issue, because many of these patients have an excellent quality of life and the drugs do have side effects,” said Matthew Ringel, MD, professor of Medicine at The Ohio State University in Mansfield, Ohio.
With no perfect tool yet to predict which patients will progress, calcitonin doubling time can be valuable. If calcitonin levels take more than 2 years to double, both 5- and 10-year survival rates are 100%. In contrast, if calcitonin takes less than 6 months to double, survival rates at 5 years are only 23%, and they are only 15% at 10 years–“and the faster the calcitonin is rising, the worse the prognosis,” Ringel noted. In general, guidelines indicate that when calcitonin approaches 100 to 150 pg/mL, “that’s about the time where we can find lung and liver metastasis,” he noted.
Historically, chemotherapy, the only available systemic therapy, had only a transient effect, with less than a 20% response rate in metastatic MTC. Somatostatin analogues such as octreotide have not generally been effective in clinical trials, either. Radioimmunotherapy, used largely in Europe with some success, has generated unexpectedly high rates of bone marrow toxicity, Ringel observed. A significant proportion of patients treated with radioimmunotherapy also develop neutralizing antibodies to the regimen, so they can only be treated once.
More recently, investigators have explored the use of tyrosine kinase inhibitors–or what are really multiple kinase inhibitors–in the same MTC metastatic setting. Among the first to be tested was sorefanib. Early trials indicated that sorefanib produced some responses in metastatic MTC but very few partial responses (PRs).
Sunitinib appeared to be slightly more active than sorefanib in metastatic MTC, though it, too, led to few PRs. Side effects requiring either dose reduction or a drug holiday occurred in as many as 50% of patients in these early TKI trials, Ringel added.
The most successful targeted therapy in the treatment of metastatic MTC to date is the multi-kinase inhibitor vandetanib.
Approved in April 2011 for the treatment of unresectable locally advanced or metastatic MTC, the pivotal phase III trial upon which the drug’s approval was based demonstrated a statistically significant 65% reduction in the risk for disease progression with 300 mg of vandetanib a day versus placebo in patients who had progressive disease on enrollment (HR=0.35, 95% CI 0.24-0.53, P<0.0001). Median progression-free survival (PFS) in the active treatment arm was 22.6 months vs 16.4 months in controls.
While there was no difference in overall survival in the study, the majority of patients originally on placebo were allowed to cross over to vandetanib on disease progression, confounding interpretation of this endpoint, speakers agreed.
A phase III study evaluating the activity of cabozantinib in MTC patients indicates that carbozantinib also significantly extends PFS versus placebo. Data on overall survival for the cabozantinib versus placebo trial are not yet available.
Wells SA Jr, Robinson BG, Gagel RF. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol. 2012;30(2):134-141. Published online ahead of print October 24, 2011.