Treatment Update: Unresectable Medullary Thyroid Cancer

While medullary thyroid cancer (MTC) is an uncommon malignancy, accounting for about 5% of thyroid cancers, progressive forms of the disease are poorly responsive to chemotherapy and radiation.¹

Patients with unresectable MTC are therefore difficult to treat. Since 2011, however, the US Food and Drug Administration (FDA) has approved multiple targeted agents for advanced MTC, and trials are currently under way on additional drugs.

MTC is the result of an autosomal dominant genetic syndrome in about 25% of cases, while the remaining 75% are considered sporadic. The driver mutations in all heritable cases—and approximately half of sporadic cases—of MTC are activating mutations of the rearranged during transfection (RET) proto-oncogene.²RET encodes a receptor tyrosine kinase and the development of tyrosine kinase inhibitors (TKIs) that are effective against this enzyme have yielded the first targeted therapies approved for use in cases of MTC, namely vandetanib and cabozantinib.

Vandetanib

Vandetanib is a multi-TKI that selectively inhibits RET, vascular endothelial growth factor receptor (VEGFR), and epidermal growth factor receptor (EGFR). Vandetanib was approved by the FDA in 2011 for use in patients with unresectable, locally advanced, or metastatic MTC.

Vandetanib has been shown to increase progression free survival (PFS) over placebo (30.5 months vs 19.3) in patients with advanced MTC. A subgroup analysis of the PFS data in patients with sporadic MTC found that patients positive for theM918T RETmutation had a higher response rate to vandetanib than patients who were M918T negative (55% vs 31%). Additionally, vandetanib significantly reduced serum levels of calcitonin (produced in excess in MTC by malignant neuroendocrine parafollicular C cells) and carcinoembryonic antigen (CEA).³

The most common adverse events (AEs) associated with vandetanib are diarrhea, rash, nausea, hypertension, fatigue, and corrected QT interval (QTc) elongation. Most of these side effects can be adequately managed with standard clinical practice alone possibly with a concurrent reduction in vandetanib dosing, although QTc prolongation is of particular concern.⁴

“Prior to starting the treatment we should carefully monitor the existence of QT prolongation by electrocardiogram,” noted Enrique Grande, MD, from the Hospital Universitario Ramón y Cajal, in Madrid, Spain. In dealing with possible AEs associated with vandetanib, Grande said clinicians “should be able to treat them as soon as possible in order to avoid severe toxicities and dose delays or medication withdrawals. The learning curve for dealing with these side effects should always be supervised by a colleague who has experience in the management of tyrosine kinase inhibitors.”

Cabozantinib

Cabozantinib is another multi-TKI approved for use in patients with progressive, metastatic MTC. This drug inhibits RET, VEGFR2, and hepatocyte growth factor receptor (MET). Data from the phase III EXAM trial demonstrated that cabozantinib improves PFS versus placebo (11.2 months vs 4.0) in advanced MTC regardless of RET mutation status, although OS results are still being determined.⁵Additionally, serum calcitonin and CEA levels decreased in patients treated with the drug compared with those in the placebo group.

Serious AEs reported in this trial were similar to vandetanib and other TKIs and included diarrhea, PPE, fatigue, hypocalcemia and hypertension. Notably dangerous QTc prolongation was not observed in any patients enrolled in the EXAM trial.

Treatments Under Investigation

Mark S. Cohen, MD, director of endocrine surgery research at the University of Michigan Hospitals and Health Centers, Ann Arbor, Michigan, noted that “while disease stabilization, partial responses and slight improvement in disease-free progression have been observed with these TKIs in this disease, neither of these drugs have shown definitive improvements in overall survival for advanced MTC patients.” Cohen therefore suggested that clinical trials of new agents and combination therapies should be considered for patients with MTC in addition to approved drugs.

Treatments currently in trials include pazopanib, a TKI that has demonstrated clinical activity in a phase II study,⁶as well the combination of the proteasome inhibitor, bortezomib, with vandetanib in advanced MTC.⁷Another strategy being investigated has employed anti-CEA pretargeted radio-immunotherapy (pRAIT) to enhance the delivery of radionuclides to the tumor, and has produced encouraging efficacy data in a phase II trial.⁸

Parameters of Treatment Remain Under Investigation

Advanced MTC is an uncommon disease that is difficult to treat. Although targeted therapies have become available and continue to be developed, some challenges remain.

“We still need to define who to treat, when to start the treatment, which of these drugs should be offered first, and the optimal treatment sequence,” said Grande. “The absence of an objective molecular biomarker at this time is also crucial.”

References:

1. Marotta V, Sciammarella C, Vitale M, Colao A, Faggiano A. The evolving field of kinase inhibitors in thyroid cancer. [Published online ahead of print September 16, 2014]Crit Rev Oncol Hematol. 2014 pii: S1040-8428(14)00148-6. doi: 10.1016/j.critrevonc.2014.08.007.
2. Krampitz GW, Norton JA. RET gene mutations (genotype and phenotype) of multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma.Cancer. 2014;120(13):1920-1931.
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. 2012;30(2):134-141.
4. Grande E, Kreissl MC, Filetti S, et al. Vandetanib in advanced medullary thyroid cancer: review of adverse event management strategies.Adv Ther. 2013;30(11):945-966.
5. Elisei R, Schlumberger MJ, Müller SP, et al. Cabozantinib in progressive medullary thyroid cancer.J Clin Oncol. 2013;31(29):3639-3646.
6. Bible KC, Suman VJ, Molina JR, et al. A multicenter phase 2 trial of pazopanib in metastatic and progressive medullary thyroid carcinoma: MC057H.J Clin Endocrinol Metab. 2014;99(5):1687-1693.
7. A Targeted Phase I/II Trial of ZD6474 (Vandetanib; ZACTIMA) Plus the Proteasome Inhibitor, Bortezomib (Velcade), in Adults With Solid Tumors With a Focus on Hereditary or Sporadic, Locally Advanced or Metastatic Medullary Thyroid Cancer (MTC). Clinicaltrials.gov.http://clinicaltrials.gov/ct2/show/NCT00923247. Accessed September 28, 2014.
8. Salaun PY, Campion L, Bournaud C, et al. Phase II trial of anticarcinoembryonic antigen pretargeted radioimmunotherapy in progressive metastatic medullary thyroid carcinoma: biomarker response and survival improvement.J Nucl Med. 2012;53(8):1185-1192.

Clinical Pearls

• Since 2011, the FDA has approved multiple targeted agents for advanced MTC, and trials are currently under way on additional drugs.
• Vandetanib is a multi-TKI that selectively inhibits RET, VEGFR, and EGFR. Vandetanib was approved by the FDA in 2011 for use in patients with unresectable, locally-advanced, or metastatic MTC.
• Cabozantinib is another multi-TKI approved for use in patients with progressive, metastatic MTC.
• Treatments currently in trials include pazopanib, a TKI that has demonstrated clinical activity in a phase II study, as well the combination of the proteasome inhibitor, bortezomib, with vandetanib in advanced MTC.