Molecularly Targeted Treatment of Thyroid Cancer Rapidly Evolving


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Recent advances in understanding the pathogenesis and altered signaling pathways in thyroid cancer are improving treatment options for this malignancy, especially for the subset of patients with medullary thyroid cancer and those with differentiated thyroid cancer that has metastasized, according to Keith Bible, MD, PhD, of the Mayo Clinic, Rochester, Minnesota. Dr. Bible discussed these molecular targets at an educational session at the 2012 ASCO Annual Meeting.

“There are numerous potential molecular targets in thyroid cancer, and for most of them, we have the means of pharmacologic inhibition. We are entering a whole new realm of thyroid cancer treatment,” Dr. Bible said.

The tyrosine kinase inhibitor vandetanib (Caprelsa) was approved in 2011 for advanced, progressive medullary thyroid cancer, whose activating RET mutations can be inhibited by vandetanib. At this year’s ASCO meeting, the EXAM trial of cabozantinib also met its primary endpoint as a medullary thyroid cancer treatment option, showing median progression-free survival to be 11.2 months with cabozantinib vs 4.0 months with placebo.1 A new drug application under the FDA’s fast track designation has been submitted for the drug, which was granted orphan drug status in January 2011.

Key Molecular Target

The fact that RET is also upregulated in some differentiated thyroid cancers triggered interest in evaluating tyrosine kinase inhibitors in this cancer as well, with the discovery that tyrosine kinase inhibitors are also highly active in this setting, particularly those targeting the vascular endothelial growth factor receptor (VEGF-R).

“VEGF-R, in particular, has emerged as apparently the most important therapeutic molecular target in [differentiated thyroid cancer],” he noted. “Fortuitously, sunitinib [Sutent], sorafenib [Nexavar], pazopanib [Votrient], and axitinib [Inlyta] all target VEGF-R, and all also have clinical activity in [differentiated thyroid cancer].”

In a phase II trial of pazopanib led by Dr. Bible, 18 of 37 patients had confirmed partial responses (49%), “and these responses were remarkably durable, most lasting more than a year,” he said.2 Responses were more frequent and more durable in follicular vs papillary subtypes. “Perhaps histologic differences in mutation carriers can help us individualize therapy with these agents,” he suggested, adding that pharmacogenomics and pharmacokinetics may someday further refine patient selection.

The role of BRAF mutations in papillary thyroid cancer is also of interest, since mutant BRAF is associated with resistance to anti-VEGF therapies. “This gives us a hint that perhaps we can begin to individualize therapy based on mutational status linking to histology,” he said.

Unfortunately, tyrosine kinase inhibitors have been disappointing in the highly aggressive anaplastic thyroid cancer. ■

Disclosure: Dr. Bible reported no potential conflicts of interest.

References

1. Schoffski P, Elisei R, Müller S, et al: An international, double-blind, randomized, placebo-controlled phase III trial (EXAM) of cabozantinib in medullary thyroid carcinoma patients with documented RECIST progression at baseline. 2012 ASCO Annual Meeting. Abstract 5508. Presented June 4, 2012.

2. Bible KC, Suman VJ, Molina JR, et al: Efficacy of pazopanib in progressive, radioiodine-refractory, metastatic differentiated thyroid cancers: Results of a phase 2 consortium study. Lancet Oncol 11:962-972, 2010.


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