The treatment landscape in thyroid cancer: a focus on cabozantinib

Abstract

Although patients with thyroid cancer generally fare well, there is a subset for which this is not necessarily true. Progress in understanding the molecular aberrations in thyroid cancer has led to a change in the management of these cases. Since 2011, four multikinase inhibitors (MKIs) have been approved by the US Food and Drug Administration for thyroid cancer - cabozantinib and vandetanib for medullary thyroid cancer and sorafenib and lenvatinib for differentiated thyroid cancer. This change in the treatment landscape has raised challenges for practitioners who may not be familiar with the use of MKIs or with the treatment and natural history of advanced thyroid cancer in general. This article reviews the epidemiology, molecular drivers, and initial treatment of patients with thyroid cancer and offers practical guidance to assist with the determination of when to appropriately start an MKI. As an example, cabozantinib and its efficacy are discussed in detail. Close monitoring is required for all patients on targeted agents to assess for adverse effects and response to therapy. An approach to managing drug-related adverse events is detailed. Since these drugs are not curative and have not yet proven to prolong overall survival, it is critical to weigh the risks and benefits of treatment at every visit. The potential value of changing to a different agent following failure of an MKI is also addressed.

Keywords: RET; VEGF; adverse event; chemotherapy; kinase inhibitor; targeted therapy.

Figure 1

Molecular pathways important in MTC and targets relevant to cabozantinib. Notes: Mutations in RET are the most common drivers of MTC; however, there are other important kinases which are upregulated and are targeted by cabozantinib. For example, cabozantinib is a potent inhibitor of MET and VEGFR2. MET and VEGFR cooperate to drive tumor angiogenesis, invasion, and metastasis. Upregulation of MET is associated with the ability of tumors to evade antiangiogenic treatment. Furthermore, osteoblasts and osteoclasts express MET and VEGF receptors. Hepatocyte growth factor, the only known ligand for the MET receptor, may be an important factor directing cross talk between tumor cells and osteoblasts/osteoclasts. Thus, simultaneous inhibition of MET and VEGF receptors may block progression of osteolytic and osteoblastic bone metastases. Abbreviations: MTC, medullary thyroid cancer; RET, rearranged during transfection; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.

Figure 2

Management of locally advanced and/or metastatic differentiated MTCs and the criteria for initiation of kinase inhibitors. Abbreviations: DTC, differentiated thyroid cancer; MTC, medullary thyroid cancer; RAI, radioiodine; RANKL, receptor activator of nuclear factor kappa-B ligand; TSH, thyroid-stimulating hormone.

Figure 3

Factors in the choice of kinase inhibitor for patients with MTC. Notes: Top panel: relative contraindications to consider when choosing vandetanib or cabozantinib for progressive or symptomatic MTC. For patients with MTC who qualify for systemic therapy, the patient’s medical history, medications, electrocardiogram, and tumor characteristics should be reviewed carefully to determine which drug to start. Vandetanib should be avoided in patients who are at risk of prolonged QT interval as a result of their cardiac history, difficulty in managing hypocalcemia, or use of certain medications that cannot be substituted. Cabozantinib should be avoided in patients with a history of peptic ulcer disease, diverticulitis, or a tumor invading the trachea, esophagus, or major vessels because of the risk of perforation or fistula. In patients with these risk factors, vandetanib should be used with caution. Bottom panel: factors that may be taken into consideration when a patient has no relative contraindications to either vandetanib or cabozantinib (top panel). For such patients, a careful review of the medication list, tumor characteristics, and certain personal characteristics is important when selecting which drug to initiate. A list of CYP3A4 inhibitors and inducers can be found at http://www.medicine.iupui.edu/clinpharm/ddis/. Cabozantinib is the only drug proven to be effective in patients with progressive MTC; therefore, the rate of progression may be important when selecting which drug to initiate. Low body mass index and a patient’s willingness to protect himself or herself from sun exposure are additional factors to be considered. Cabozantinib may cause weight loss, whereas vandetanib may cause weight gain. Photosensitivity is an adverse effect of vandetanib. aConcomitant use of a CYP3A4 inhibitor drug may increase the plasma concentration of cabozantinib, resulting in toxicity, whereas CYP3A4 inducers may decrease the plasma concentration of vandetanib, resulting in decreased efficacy. Republished with permission from Cabanillas ME, Hu MI, Jimenez C. Medullary thyroid cancer in the era of tyrosine kinase inhibitors: to treat or not to treat – and with which drug – those are the questions. J Clin Endocrinol Metab. 2014;99(12):4394. Copyright 2014 by The Endocrine Society; permission conveyed through Copyright Clearance Center, Inc. Abbreviations: EBRT, external beam radiation therapy; h/o, history of; MTC, medullary thyroid cancer; PUD, peptic ulcer disease; QTcF, rate-corrected QT interval using the Fridericia formula.

Figure 4

Most often observed nonhematologic adverse events in the Phase III trial of cabozantinib in patients with MTC. Abbreviations: ALT, alanine aminiotransferase; AST, aspartate aminotransferase; MTC, medullary thyroid cancer.

Figure 5

Suggested management of CTCAE AEs of kinase inhibitors. Note: ^a“Dose level” generally refers to a reduction in the daily dose by 20 mg. Abbreviations: AE, adverse event; CTCAE, common terminology criteria for adverse events.

Figure 6

Hand–foot skin reaction. Note: Erythema, hyperkeratosis, and callus formation at sites of friction.