Cabozantinib in Medullary Thyroid Cancer: A Landscape-Shaping New Treatment 


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Medullary thyroid cancer is derived from parafollicular C cells in the thyroid gland. The disease is sporadic in about 75% of cases and hereditary in the remaining 25%.1 Oncogenic mutations in the gene for tyrosine kinase receptor rearranged during transfection (RET) are driver genetic alterations of medullary thyroid cancer that are seen in 60% to 70% of sporadic cases and almost 100% of hereditary cases. Compared with follicular cell–derived thyroid cancer, medullary thyroid cancer is very rare, accounting for only a few percent of all thyroid malignancies.

Nevertheless, medullary thyroid cancer is generally more aggressive than follicular cell–derived thyroid cancer (excluding anaplastic thyroid cancer) and is responsible for a large proportion of thyroid cancer-related mortality. Progressive metastatic medullary thyroid cancer is particularly challenging once the disease becomes surgically inoperable and is the main cause of medullary thyroid cancer–related morbidity and mortality. There have been limited therapeutic options for effective treatment of the disease at this stage.

That said, recent developments in the therapeutic use of small-molecule tyrosine kinase inhibitors have brought unprecedented promise for effective treatment of medullary thyroid cancer. Vandetanib (Caprelsa) was the first tyrosine kinase inhibitor approved by the U.S. Food and Drug Administration (FDA) for the treatment of advanced medullary thyroid cancer, bringing medical treatment of medullary thyroid cancer into a modern era of molecular targeted therapy.2,3 The recent development of cabozantinib (Cometriq), another tyrosine kinase inhibitor, in the treatment of medullary thyroid cancer has added an exciting new dimension to the current treatment landscape of medullary thyroid cancer by providing a new effective therapeutic option for this cancer.4,5

Cabozantinib Trials

Cabozantinib is a triple tyrosine kinase inhibitor known to target three major tyrosine kinases—RET, the hepatocyte growth factor receptor (MET), and vascular endothelial growth factor receptor 2 ­(VEGFR2)—which provides a molecular basis for the strong suppression of metastasis, angiogenesis, and tumor growth observed in preclinical studies.6 Even in the phase I clinical trial, cabozantinib produced remarkable clinical responses in patients with medullary thyroid cancer.4

The subsequent phase III clinical trial confirmed the therapeutic effects of cabozantinib (140 mg/d orally) in progressive metastatic medullary thyroid cancer, which prompted an expedited review and approval of this drug by the FDA for the treatment of patients with advanced medullary thyroid cancer.7 The full report of this phase III clinical trial has now been published by Elisei and colleagues.5

This double-blind trial compared cabozantinib with placebo in 330 patients with documented radiographic progression of metastatic medullary thyroid cancer recruited from 23 countries. The remarkable findings include an estimated median progression-free survival of 11.2 months for cabozantinib vs 4.0 months for placebo (hazard ratio = 0.28, 95% confidence interval = 0.19 to 0.40, P = .001), with progression-free survival similarly prolonged with cabozantinib across many subgroups; a rate of patients alive and progression-free at 1 year of 47.3% for cabozantinib vs 7.2% for placebo; and a response rate of 28% for cabozantinib vs 0% for placebo.

These results unequivocally established the therapeutic effectiveness of cabozantinib for progressive metastatic medullary thyroid cancer. As the overall survival event number had not reached the preset goal at the time of analysis, patient mortality rates cannot be conclusively compared for cabozantinib and placebo at this time. However, with the current remarkable clinical responses, it may be reasonable to be optimistic in expecting a mortality benefit of cabozantinib in medullary thyroid cancer.

Further Considerations

It is important to note that in the phase III trial, radiographically documented tumor progression of medullary thyroid cancer was a major criterion for patient recruitment.5 This represents a feature distinct from the trial of vandetanib, in which tumor progression was not a criterion at study entry and, as a result, patients had less-advanced disease as reflected by the longer median progression-free survival (19.3 months) in the placebo arm.3

Significant therapeutic effects of cabozantinib have recently been demonstrated in clinical trials in other cancers (such as prostate cancer) at advanced stages.8 Several pivotal clinical trials of cabozantinib are currently ongoing in a large number of cancers.9 Given the positive results in medullary thyroid cancer and prostate cancer, it is hoped that cabozantinib will prove to be similarly effective in treating these other cancers.

Benefit-to-Harm Ratio

The adverse effects of cabozantinib, like those of other tyrosine kinase inhibitors, were generally readily manageable in the phase III trial, but some could be potentially serious. Therefore, it is important to respect the principle of individualized medicine in the clinical application of cabozantinib in patients with medullary thyroid cancer. While patients with progressive metastatic disease clearly meet the criteria for cabozantinib and may benefit from the treatment, potential serious adverse effects of this drug may outweigh the benefits in patients with indolent stable disease. Use of cabozantinib in such patients may therefore be precluded.

The role of RET mutations in medullary thyroid cancer, either sporadic or hereditary, in determining the therapeutic effects of cabozantinib was not firmly established in the Elisei et al study.5 The potential predictive value of RAS mutation, another common oncogenic genetic alteration in medullary thyroid cancer,10 was not examined. Thus, whether genetic-guided therapy of medullary thyroid cancer using cabozantinib is feasible is an open issue that needs to be addressed in future, perhaps larger, studies. Specific and detailed clinical indications for the use of cabozantinib need to be accurately defined for the best benefit-to-harm ratio in the treatment of patients with medullary thyroid cancer.

Also, monotherapy with cabozantinib targets only limited molecular targets and is unlikely to cure medullary thyroid cancer because, as in the case of follicular cell–derived thyroid cancer,11 multiple signaling pathways and molecular mechanisms may be involved in the tumorigenesis and progression of medullary thyroid cancer. As for follicular cell–derived thyroid cancer,12 treatments that may result in cure of the disease may require targeting additional key molecular targets in medullary thyroid cancer using combination drug therapies.

Therapeutic Milestone

Cabozantinib represents another milestone in the development of effective treatments for medullary thyroid cancer. Progressive metastatic medullary thyroid cancer is refractory to conventional treatments and is currently associated with the worst prognosis. With its demonstrated therapeutic value in this challenging group of patients, cabozantinib as a valuable new therapeutic option is forcefully shaping the landscape of medical treatment for the disease.

It is exciting to anticipate the new clinical prospects in medullary thyroid cancer to be brought about by this new treatment. It also fills me with great gratitude to think of all those preclinical and clinical investigators who, through their brilliant work and diligent effort in this field, have created this beautiful new landscape for medical treatment of medullary thyroid cancer. ■

Disclosure: Dr. Xing receives royalties as a co-inventor on a licensed patent related to the discovery and clinical characterization of BRAF V600E mutation in thyroid cancer.  He also receives thyroid cancer research funding support from the National Institutes of Health (R01CA134225 and R01CA113507).

Dr. Xing is Professor of Medicine and Oncology, Co-Director of the Johns Hopkins Thyroid Tumor Center, and Chief of the Laboratory for Cellular and Molecular Thyroid Research, Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore.

References

1. Roy M, Chen H, Sippel RS: Current understanding and management of medullary thyroid cancer. Oncologist. September 13, 2013 (early release online).

2. Wells SA Jr, Gosnell JE, Gagel RF, et al: Vandetanib for the treatment of patients with locally advanced or metastatic hereditary medullary thyroid cancer. J Clin Oncol 28:767-772, 2010.

3. Wells SA Jr, Robinson BG, Gagel RF, et al: Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: A randomized, double-blind phase III trial. J Clin Oncol 30:134-141, 2012.

4. Kurzrock R, Sherman SI, Ball DW, et al: Activity of XL184 (cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer. J Clin Oncol 29:2660-2666, 2011.

5. Elisei R, Schlumberger MJ, Müller SP, et al: Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol 31:3639-3646, 2013.

6. Yakes FM, Chen J, Tan J, et al: Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther 10:2298-2308, 2011.

7. National Cancer Institute: FDA approval for cabozantinib s-malate. Available at http://www.cancer.gov/cancertopics/druginfo/fda-cabozantinib-s-malate. Accessed October 9, 2013.

8. Smith DC, Smith MR, Sweeney C, et al: Cabozantinib in patients with advanced prostate cancer: Results of a phase II randomized discontinuation trial. J Clin Oncol 31:412-419, 2013.

9. ClinicalTrials.gov: Studies of cabozantinib. Available at http://clinicaltrials.gov/ct2/results?term=cabozantinib&Search=Search. Accessed October 9, 2013.

10. Agrawal N, Jiao Y, Sausen M, et al: Exomic sequencing of medullary thyroid cancer reveals dominant and mutually exclusive oncogenic mutations in RET and RAS. J Clin Endocrinol Metab 98:E364-E369, 2013.

11. Xing M: Molecular pathogenesis and mechanisms of thyroid cancer. Nat Rev Cancer 13:184-199, 2013.

12. Xing M, Haugen BR, Schlumberger M: Progress in molecular-based management of differentiated thyroid cancer. Lancet 381:1058-1069, 2013.


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