Annals of Pharmacotherapy
Vandetanib for the Treatment of Medullary Thyroid Carcinoma
© The Author(s) 2013 Reprints and permissions:
sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028013512791 aop.sagepub.com
Maryann R. Cooper, PharmD, BCOP1, Soo Yun Yi1, Wael Alghamdi, BS1, Daniel J. Shaheen, PharmD2, and Michael Steinberg, PharmD, BCOP3
Abstract
Objective: To review the place in therapy of vandetanib for medullary thyroid carcinoma (MTC). Data Sources: Literature searches were performed in Ovid MEDLINE, EMBASE, and Google Scholar using the search terms ZD6474 OR vandetanib OR Caprelsa combined with medullary thyroid carcinoma. Study Selection and Data Extraction: Two phase 2 trials and 1 phase 3 trial were identified. Data Synthesis: Vandetanib is approved for the treatment of unresectable, locally advanced or metastatic MTC in patients with symptomatic or progressive disease. In the phase 3 randomized, double-blind, placebo-controlled trial, vandetanib 300 mg daily (n = 231) was compared with placebo (n = 100). Vandetanib-treated patients experienced a significant improvement in progression-free survival (PFS; hazard ratio [HR] = 0.46; 95% CI = 0.31- 0.69; P < .001). No difference in overall survival (OS) was seen at the time of publication. Most adverse effects were grade
1or 2 and managed by dose interruptions or reductions. The most common grade 3/4 adverse effects were diarrhea, hypertension, QT prolongation, fatigue, and rash. Because of the potential for QT prolongation, torsades de pointes, and sudden death, vandetanib is restricted via a Risk Evaluations and Mitigation Strategy program. Conclusions: Vandetanib prolongs PFS but has not been shown to improve OS. Vandetanib can be considered for patients with unresectable locoregional disease. It is a first-line option for patients with unresectable symptomatic distant metastases as well as an option for advanced disseminated symptomatic metastatic disease. Vandetanib is expected to be an important addition to the formulary of health plans that provide prescription drug benefits.

Keywords
vandetanib, medullary thyroid carcinoma

Introduction
Medullary thyroid carcinoma (MTC) is a rare malignancy that originates in the parafollicular, calcitonin-producing C cells of the thyroid gland.1 MTC accounts for approximately 5% to 8% of thyroid carcinomas and is often characterized by activation of the rearranged-during-transfection (RET) proto-oncogene.1,2 MTC typically presents later in life and is classified as sporadic in 75% of cases and inherited in the remaining 25% of cases.2 Sporadic MTC, which occurs spontaneously, is associated with somatic mutations in RET in 40% to 50% of cases. Inherited MTC can be further clas- sified as either familial (FMTC) or multiple endocrine neo- plasia (MEN) syndromes type 2A and 2B. Activating RET mutations are found in about 90% of patients with inherited MTC. Mutations in RET codon M918T are associated with more aggressive disease and a poorer prognosis.3
Prognosis for patients with local disease is favorable, with 10-year overall survival (OS) rates of 95% and 75% in thyroid bound and regional disease, respectively.2,4 The 10-year survival rate decreases to about 40% in patients with metastatic disease.4 Approximately 35% of patients
initially present with locally advanced disease, and roughly 13% with distant metastases.
The mainstay of treatment for MTC is surgery, with lim- ited options available for patients with unresectable disease. According to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines), options for patients with unresectable locoregional MTC include consideration of vandetanib (category 1), cabozantinib (category 1), or exter- nal beam radiotherapy(which has limited data in MTC).5 Either vandetanib (category 1) or cabozantinib (category 1) may be considered as a first-line option for patients with unresectable symptomatic distant metastases. For second- line therapy in advanced disseminated symptomatic meta- static disease, NCCN Guidelines recommend vandetanib

1MCPHS University, Manchester, NH, USA 2Algeta, Cambridge, MA, USA
3MCPHS University, Worcester, MA, USA
Corresponding Author:
Maryann R. Cooper, PharmD, BCOP, MCPHS University, 1260 Elm Street Manchester, NH 03101, USA.
Email: [email protected]

(category 1), cabozantinib (category 1), clinical trial, dacar- bazine (DTIC)-based chemotherapy, or consideration of other tyrosine kinase inhibitors (TKIs)—such as sorafenib or sunitinib—if vandetanib or cabozantinib are not avail- able. For advanced disseminated symptomatic metastatic disease, external beam radiotherapy may also be used for focal symptoms; bisphosphonates or denosumab may be considered for bone metastases.
Vandetanib is an oral TKI that selectively targets RET, vascular endothelial growth factor receptor 2 (VEGFR-2), and epidermal growth factor receptor (EGFR).6 On April 6, 2011, vandetanib (Caprelsa; AstraZeneca Wilmington, DE) was the first agent to be approved by the United States Food and Drug Administration (FDA) for the treatment of unre- sectable locally advanced or metastatic MTC in patients with symptomatic or progressive disease.7 This article reviews the available data regarding the place in therapy of vandetanib.

Data Selection
Literature searches were performed in Ovid MEDLINE (1996 to October week 1, 2013), EMBASE (1996 to 2013 week 40), and Google Scholar using the search terms ZD6474 OR vandetanib OR Caprelsa combined with medullary thy- roid carcinoma OR thyroid neoplasms. Limits applied to both the Ovid MEDLINE and EMBASE searches included humans and clinical trials. Abstracts presented at the American Society of Clinical Oncology (January 1983 to October 2013) and the European Society for Medical Oncology (January 1990 to October 2013) were reviewed for data from ongoing studies. Two phase 2 and 1 phase 3 trials were identified that examined the safety and efficacy of van- detanib in patients with MTC. Separate searches were con- ducted in Ovid MEDLINE and EMBASE for pharmacological and pharmacokinetic data. The manufacturer’s prescribing information was used to supplement published data.

Pharmacology
Vandetanib (N-(4-bromo-2-fluorophenyl)-6-methoxy-7- [(1-methyl-piperidin-4-yl) methoxy]quinazolin-4-amine) is a potent, small-molecule, multitargeting TKI.8,9 Vandetanib is a competitive inhibitor of VEGFR-2 (half-maximal inhibitory concentration [IC50] = 0.04 µM) that has also demonstrated modest inhibitory activity against EGFR (IC50 = 0.5 µM).9,10 In preclinical studies, vandetanib has demonstrated potent inhibitory activity against wild-type and some mutant strains of RET (IC50 = 0.1 µM).6,11 RET mutations in residues V804 (V804L and V804M) were not found to be inhibited by vandetanib.11 The clinical signifi- cance of this finding is unknown. Vandetanib has also dem- onstrated activity against protein tyrosine kinase 6 (BRK), TIE2, EPH receptor kinases, and Src tyrosine kinases.8
The primary mechanism of action is likely a result of the inhibition of VEGFR-2.9,12 VEGFR-2 inhibition blocks the

Table 1. Pharmacokinetics.

Absorption Tmax: 6 hours (range = 4-10 hours)13
Effect of food: none13 Distribution Vd: 7450 L8
Protein binding: ~90% bound to α-1-acid-
glycoprotein and serum albumin8 Metabolism Liver by CYP 3A4, FMO1, FMO38
Metabolites: N-desmethyl-vandetanib (active),
vandetanib-N-oxide (active)8 Excretion Total body clearance: 13.2 L/h8
Excreted unchanged in urine and feces13 Elimination half-life: 19 days8

Abbreviations: Tmax, time to maximum plasma concentration; Vd, volume
of distribution; CYP 3A4, cytochrome P450 3A4; FMO1, flavine-containing mono-oxygenase 1 (kidney); FMO3, flavine-containing mono-oxygenase 3 (liver).

intracellular signaling cascades that ultimately inhibit angiogenesis.12 In addition, EGFR and RET blockade lead to direct inhibition of tumor growth in cells that are depen- dent on these pathways for survival.12

Pharmacokinetics
The pharmacokinetics of vandetanib have been investigated in healthy individuals, patients with renal or hepatic impair- ment, and patients with advanced solid tumors.13-17 These data reveal that vandetanib follows first-order absorption and is best described by a 2-compartment model (Table 1).15
Following oral administration of single doses of 300 to 1200 mg of vandetanib in healthy individuals, absorption was slow and not affected by coadministration with food.13 Vandetanib has been shown to accumulate with repeated dos- ing, and steady state is achieved in approximately 3 months.8
Vandetanib is a highly protein-bound drug.8 Plasma pro- tein binding is similar in patients with renal dysfunction as well as in those with mild, moderate, or severe hepatic impairment (range = 92%-94%).14 It is metabolized to 2 active metabolites: N-desmethyl-vandetanib and vande- tanib-N-oxide.8 N-desmethyl-vandetanib circulates at a con- centration of 7.0% to 17.1% of the parent compound and inhibits VEGFR and EGFR similarly to vandetanib.8,18 Vandetanib-N-oxide circulates at a concentration of 1.4% to 2.2% of vandetanib and is >50-fold less potent than the par- ent compound.8,18 In patients with renal impairment, expo- sure to both metabolites is increased.14 As hepatic function worsens, exposure to N-desmethyl-vandetanib tends to decrease, whereas exposure to vandetanib-N-oxide increases.

Clinical Studies
The efficacy and safety of vandetanib in patients with MTC has been evaluated in 2 phase 2 trials and 1 phase 3 trial.19-21 Both phase 2 studies used an open-label, single-arm design to evaluate the primary outcome of objective response rate

(ORR) in patients with advanced or metastatic hereditary MTC with a documented diagnosis of MEN2A, MEN2B, or FMTC and a germline RET mutation.19,20 Secondary out- comes in both trials included duration of response, disease control rate, progression-free survival (PFS), safety and tol- erability, and changes in serum levels of calcitonin and car- cinoembryonic antigen (CEA).
In the first phase 2 study, patients received vandetanib 300 mg orally once daily until disease progression.19 In the subsequent phase 2 trial, patients initially received vande- tanib 100 mg orally once daily until disease progression, at which time the patient could continue therapy with vande- tanib 300 mg if the investigator felt that the patient was ben- efiting from treatment.20 In both investigations, patients were initially monitored for objective response as defined by Response Evaluation Criteria in Solid Tumors (RECIST) every 12 weeks by investigator-reviewed computed tomog- raphy or magnetic resonance imaging scans.19,20 Patients initially treated with vandetanib 100 mg were monitored in a similar fashion every 24 weeks on switching to the 300- mg dosing schedule.20
A total of 30 patients were enrolled in the first phase 2 trial, including 21 women (70%) and 9 men (30%), with a median age of 49 years (range = 20-77 years).19 Most patients were diagnosed with MEN2A (n = 21; 70%) and had meta- static disease (n = 29; 97%) to the liver (80%), lungs (63%), and lymph nodes (70%). Although no patient achieved a complete response (CR), partial responses (PR) were con- firmed in 20% (n = 6) of patients. Therefore, the ORR (CR + PR) was 20% (95% CI = 8-39). Stable disease for ≥24 weeks (SD) was observed in 53% (n = 16) of patients, making the disease control rate (CR + PR + SD) 73% (n = 22). The median duration of response was 10.2 months (range = 1.9- 16.9 months), and the median PFS was 27.9 months (95% CI = 19.4 to not estimable). At data cutoff, 27% (n = 8) of patients had progressive disease, 67% (n = 20) were alive with no progression, and 7% (n = 2) had died (1 from cardiac failure, 1 from colon cancer). Serum calcitonin levels were decreased ≥50% (biochemical PR) from baseline in 80% (n = 24) of patients, and serum CEA levels decreased similarly in 53% (n = 16) of patients. These was no association between RET mutation and response to treatment.
A total of 19 patients participated in the second phase 2 trial.20 Patient demographics were similar to those of the previous trial: the mean age was 45 years (range = 22-79 years), and the majority of patients had MEN2A (n = 17; 90%) and metastatic disease (n = 18; 95%). In contrast, most enrolled patients were men (n = 13; 68%). The ORR in this evaluation was 16% (95% CI = 3.4-39.6), with no patient achieving a CR and 16% (n = 3) of patients achiev- ing a PR. SD was observed in 53% (n = 10) of patients, making the disease control rate 68% (n = 13). At the data cutoff date, 58% (n = 11) of patients remained on vande- tanib 100 mg daily, and 21% (n = 4) of patients had

experienced disease progression and were switched to the 300-mg dosing regimen. A ≥50% decrease from baseline in calcitonin and CEA was achieved by 16% (n = 3) and 5% (n = 1) of patients, respectively. Similar to the previous trial, there was no association between RET mutation and objec- tive response.
The authors of both trials concluded that vandetanib has sufficient antitumor activity, thus providing an option in patients with advanced or metastatic MTC.19,20 These results, however, are limited by the small sample sizes and lack of a control group.
The Zactima (ZD6474) Efficacy in Thyroid Cancer Assessment (ZETA) was a multinational, phase 3, random- ized, double-blind, placebo-controlled trial.21 Patients with locally advanced or metastatic, unresectable, hereditary, or sporadic MTCs were enrolled in the study. A total of 331 patients were randomly assigned in a 2:1 ratio to receive vandetanib 300 mg daily (n = 231) or matching placebo (n = 100). Treatment continued until investigator-identified disease progression, at which time patients were unblinded and allowed to cross over to open-label vandetanib. The primary objective was PFS, and secondary end points included ORR, disease control rate (CR + PR + SD) at 24 weeks, duration of response, OS, calcitonin and CEA lev- els, and time to worsening of pain. Patients were assessed for response every 12 weeks. Independent central reviews of patient scans using RECIST criteria were used to deter- mine PFS.
Baseline characteristics were well matched between the
2groups.21 The mean age was 50.7 years in the vandetanib group and 53.4 years in the placebo group. The majority of patients were men (58% vandetanib group, 56% placebo group) with sporadic or unknown (88% vandetanib group, 95% placebo group) metastatic disease (94% vandetanib group, 97% placebo group). A total of 39% and 42% of patients in the vandetanib and placebo arms, respectively, received at least 1 prior systemic therapy. Patients were fol- lowed for a median of 2 years, and blinded treatment con- tinued in 139 patients (48% vandetanib group, 28% placebo group). A total of 93 of the 123 patients who experienced disease progression opted for open-label treatment (n = 41/67, 61% vandetanib patients; n = 52/56, 93% placebo patients).
Patients who received vandetanib experienced a signifi- cant improvement in PFS (hazard ratio [HR] = 0.46; 95% CI = 0.31-0.69; P < .001).21 At 6 months, PFS was 83% in the vandetanib group compared with 63% in the placebo group. The median PFS in the placebo group was 19.3 months, which exceeds the 12-month PFS anticipated by the study investigators in the study’s power calculation, possibly reflecting the inclusion of patients with indolent disease. Fitting a Weibull model revealed an anticipated median PFS of 30.5 months in the vandetanib group (actual median was not reached by the time the study was published).

Significant benefits were associated with the use of van- detanib over placebo in terms of the secondary end points.21 The ORR was higher in the vandetanib group than the pla- cebo group (45% vandetanib, 13% placebo [odds ratio = 5.48; 95% CI = 2.99-10.79], P < .001). Vandetanib also sig- nificantly improved the disease control rate (87% vande- tanib patients, 71% placebo patients [odds ratio = 2.64; 95% CI = 1.48 to 4.69], P = .001). In addition, calcitonin (69% vandetanib patients, 3% placebo patients) and CEA (52%

Table 2. Most Commona Adverse Effects.8,21

All Grades (%)
Diarrhea 57
Rash 53
Acne/Dermatitis acneiform 35
Nausea 33
Hypertension 33

Grade 3/4
(%)
11
5
1
1
9

vandetanib patients, 2% placebo patients) biochemical PR rates (≥50% decrease in calcitonin or CEA from baseline) were significantly higher in the vandetanib group compared with the placebo group (P < .001). At the data cutoff date, OS data were nonsignificant (HR = 0.89; 95% CI = 0.48- 1.65); however, a final analysis will occur when 50% of patients have died. Additionally, there was a significant delay in time to worsening of pain in patients who received vandetanib compared with placebo (HR = 0.61; 95% CI =
Headache Fatigue
Upper-respiratory-tract infection Decreased appetite
Abdominal pain QTcF prolongation Calcium decrease ALT increase Glucose decrease
26
24
23
21
21
14
57
51
24
1
6
0
4
3
8
6
2
0

0.43-0.87; P = .006).
To determine the association between RET mutation and PFS and ORR, the investigators analyzed the DNA of the tumors of 297 of the 298 patients with sporadic MTCs.21 A total of 52% (n = 155) of patients were RET mutation posi-
Abbreviations: QTcF, QT interval, Fridericia; ALT, alanine aminotransferase. aOccurring in ≥20% of patients (all grades). Although rashes are commonly seen in vandetanib-treated patients, severe skin reactions, including Stevens-Johnson Syndrome, have also been observed.8

tive, 2.7% (n = 8) were RET mutation negative, and 45.3% (n = 135) had unknown status. Because of the small number of RET mutation–negative patients, it was difficult to evalu- ate the efficacy of vandetanib in this subgroup. However, the ORR of patients with the M918T mutation was higher compared with that of M918T mutation–negative patients: 54.5% and 30.9%, respectively. The authors concluded that vandetanib is effective in treating locally advanced or meta- static MTC, with a manageable adverse event profile.21 Although vandetanib was shown to significantly improve the primary outcome of PFS, no difference in OS was seen by the end of the evaluation period. In addition, quality-of- life measures other than worsening of pain were not evaluated.

Safety
Adverse Effects
In clinical trials, most adverse effects were grade 1 or 2 and managed by dose interruptions or reductions.19-21 The most common reactions are listed in Table 2.
Mild to moderate skin reactions may be controlled with topical or systemic corticosteroids, antihistamines, and/or topical or systemic antibiotics, depending on severity. Vandetanib treatment must be interrupted or discontinued in the event of grade 3 or higher skin reactions.
Hypothyroidism requiring levothyroxine supplementa- tion was more likely to occur among patients receiving van- detanib than control patients (49.3% vandetanib patients, 17.2% placebo).21 Thyroid-stimulating hormone levels
should be obtained at baseline and during weeks 2 to 4, weeks 8 to 12, and every 3 months thereafter during ther- apy.8 Signs and symptoms of hypothyroidism should also be monitored regularly.
Serious adverse events associated with vandetanib use include QT prolongation, hypertension, interstitial lung dis- ease, ischemic cerebrovascular events, reversible posterior leukoencephalopathy syndrome, and hemorrhage.8 Signs of severe symptoms of these events should prompt discontinu- ation of the therapy. During clinical trials, death occurred in 5 patients receiving vandetanib and resulted from respira- tory failure, respiratory arrest, aspiration pneumonia, car- diac failure with arrhythmia, and sepsis.21 In the placebo arm, 2 patients died secondary to adverse events caused by gastroenteritis and GI hemorrhage.
Key patient counseling points are listed in Table 3.

Contraindications
Vandetanib is contraindicated in patients with congenital long-QT syndrome.8 In addition, vandetanib should be avoided in patients with a history of torsades de pointes (TdP) and should not be initiated in a patient with a baseline QT interval, Fridericia (QTcF interval) >450 ms.

Warnings and Precautions
Vandetanib carries a boxed warning because of the risk of cardiac toxicity, including QT prolongation, TdP, and sud- den death.8 Electrocardiography (ECG) as well as serum levels of calcium, potassium, and magnesium should be

Table 3. Patient Counseling Points.8
•Vandetanib can cause a change in the electrical activity of your heart called QT prolongation. If you feel faint, light headed, or notice an irregular heartbeat contact your health care provider immediately. If you have a history of long-QT syndrome do not take vandetanib
•Your health care provider will perform tests regularly to check for QT prolongation as well as blood levels of potassium, magnesium, and calcium. You will also have
your thyroid stimulating hormone level and blood pressure checked regularly
•Common adverse effects include rash, acne, nausea, feeling tired, loss of appetite, and stomach pain.
•Report skin reactions, new or worsening shortness of breath, symptoms of stroke, bleeding, signs and symptoms of heart failure, diarrhea, headaches, seizures, confusion, or changes in vision to your health care provider right away. These may be signs of a serious adverse effect
•Minimize exposure to the sun while taking vandetanib and for 4 months after stopping treatment
•Vandetanib may be taken with or without food. Do not crush or chew the tablet
•If you miss a dose and it is less than 12 hours to your next dose, skip the missed dose and take your next dose at the regular time. If it is more than 12 hours to the next dose, take the dose as soon as you remember. Take the next dose at the regular time
•Tell your health care provider about all medications you are currently taking, including vitamins, herbals, and prescription drug products. Do not start any new medications without talking to your health care provider
•Use birth control during therapy and for at least 4 months after the last dose of vandetanib
•Breast-feeding women should stop nursing during therapy

obtained at baseline and during weeks 2 to 4, weeks 8 to 12, and every 3 months thereafter during therapy. Electrolyte imbalances, including hypocalcemia, hypokalemia, and hypomagnesemia should be corrected before initiating ther- apy and maintained within the normal range throughout treatment, specifically with potassium concentrations main- tained above 4 mEq/L. Extra care should be taken in patients experiencing diarrhea to avoid electrolyte imbalances. In addition, patients with renal impairment should receive increased ECG monitoring for QT prolongation.
Because of the potential for QT prolongation, vandetanib is only available through a restricted distribution program. Health care professionals (HCPs), including medical oncol- ogists, surgeons, and endocrinologists, must enroll in the Caprelsa Risk Evaluation and Mitigation Strategy (REMS) Program to be certified by AstraZeneca to prescribe vande- tanib.22 HCPs are required to review the HCP education pamphlet, complete the prescriber training, and agree to review the FDA-approved medication guide with patients. Pharmacies must also be certified by AstraZeneca to dis- pense vandetanib and must also provide the FDA-approved medication guide each time vandetanib is dispensed.

Additional cardiac toxicity, including heart failure and hypertension, has been observed.8 Dose reductions or ther- apy interruptions may be necessary to control hypertension. In the event of refractory hypertension, vandetanib should be discontinued. Vandetanib should not be initiated in patients with bradyarrhythmias, including bradycardia, as well as uncompensated heart failure.
Serious, as well as, fatal hemorrhagic events have also occurred.8 Vandetanib should not be administered to patients with a recent history of hemoptysis exceeding half a tea- spoon of red blood. It should be discontinued if severe hem- orrhage occurs.
Vandetanib is embryotoxic, fetotoxic, and teratogenic in rats.8 The FDA has categorized vandetanib as pregnancy category D. Women should be advised to prevent pregnancy during treatment and for 4 months following therapy. The degree of vandetanib transfer into human breast milk is unknown. Studies in rats have found excretion into milk and detectable plasma levels in pups. Breast feeding is not recommended during treatment with vandetanib.

Drug-Drug Interactions
Vandetanib is a substrate of CYP3A4; therefore, coadminis- tration with a CYP3A4 inducer or inhibitor may lead to drug-drug interactions.14,18 In a phase 1 study, healthy indi- viduals were given a single 300-mg dose of vandetanib on day 1 or 4 of a 24-day course of itraconazole 200 mg daily, a potent CYP3A4 inhibitor.18 A slight increase (9%) in plasma vandetanib concentration was observed. The authors concluded that drug-drug interactions with CYP3A4 inhibi- tors are unlikely to be clinically significant. However, con- tinuous use of vandetanib with a potent CYP3A4 inhibitor has not been studied. In a separate arm of this phase 1 study, healthy individuals were given a single 300-mg dose of vandetanib on day 1 or 10 of a 31-day course of rifampicin 600 mg daily, a potent CYP3A4 inducer.18 A significant reduction of 40% in plasma vandetanib concentration was observed. Thus, concomitant use of vandetanib and potent CYP3A4 inducers should be avoided.8 St John’s wort has been shown to unpredictably decrease vandetanib levels, and the 2 agents should not be used concurrently. In addi- tion, drugs that prolong the QT interval, including antiar- rhythmic drugs, should not be used concurrently with vandetanib.8

Therapeutic and Economic Issues
Vandetanib is not the only currently available agent for management of patients with metastatic MTC, and treat- ment selection requires comparison. On November 29, 2012, the FDA approved cabozantinib (Cometriq, Exelixis, Inc, San Francisco, CA) for the treatment of progressive, metastatic MTC.23 Cabozantinib is an orally administered

TKI that targets VEGFR-2, RET, and the mesenchymal- epithelial transition factor (MET) receptor. MET is postu- lated to be upregulated as a result of VEGF and EGFR inhibition allowing for tumor progression.24,25 FDA approval of cabozantinib was based on the results of an international, double-blind, randomized, placebo-con- trolled, phase 3 trial that compared cabozantinib 140 mg by mouth daily with placebo in 330 patients with progressive, metastatic MTC.26 Similar to the ZETA trial, only patients with unresectable, locally advanced or metastatic disease were included. In contrast to the ZETA trial, patients had to have radiographic evidence of progression within the previ- ous 14 months to be eligible for inclusion. Patient charac- teristics were similar to the ZETA population. A total of 37.0% and 42.3% of cabozantinib and placebo-treated patients, respectively, received prior systemic treatment for MTC, including prior TKI therapy. Median PFS was 11.2 months in the cabozantinib group (n = 219) versus 4 months in the placebo group (n = 111; HR = 0.28; 95% CI = 0.19- 0.40; P < .0001). No difference in OS was observed. Final survival data are not expected for several years because the full impact of treatment is evaluated.
Cabozantinib and vandetanib vary in their inhibitory activity of both VEGFR-2 and RET pathways. An in vitro study of 4 TKIs (axitinib, sunitinib, vandetanib, and cabo- zantinib) found cabozantinib to be the most potent inhibitor in MEN2A MTC, whereas vandetanib was the most potent in MEN2B MTC.27 The clinical significance of this finding is not known. Cabozantinib does not have activity against EGFR.
Both vandetanib and cabozantinib are associated with rare but serious adverse reactions. In general, the side effect profile of both agents is similar, with a few excep- tions. Vandetanib is associated with concentration-depen- dent QT prolongation, with a mean change in QTcF from baseline of 35 ms (90% CI = 33-36).8 Changes of 60 ms from baseline were observed in 36.0% of patients, and 4.3% of patients had a QTcF >500 ms. Changes in QTcF from baseline of 10 to 15 ms have been observed in patients receiving cabozantinib.28 At this time, no cases of TdP or sudden death have been associated with this medication. Both drugs can significantly increase blood pressure and can result in diarrhea and rash.8,28 Cabozantinib carries a boxed warning because of the risk of hemorrhage, perfora- tions, and fistulas.28 These adverse reactions have also been observed with vandetanib.8 Palmar-plantar erythro- dysesthesia syndrome (PPES) was observed in 50% of patients treated with cabozantinib.28 Grade ≥3 PPES was seen in 13% of patients. This adverse reaction is not associ- ated with the use of vandetanib.
Currently, there is a cost difference of about $350 between 1 month’s supply of vandetanib and cabozantinib. The average wholesale prices for each 300 mg and 100 mg vandetanib tablet are $407.88 and $203.94, respectively.29

A one-month supply of the recommended 300-mg daily dose would cost $12 236.40. The average wholesale price of a 1-month supply of the manufacturer-packaged dosing kits of cabozantinib is $11 880.30
Many unanswered questions remain pertaining to the role of vandetanib and cabozantinib in clinical practice. At this time, the 2 agents have not been directly compared, and both carry a category 1 recommendation from the NCCN Guidelines for the treatment of progressive, symptomatic, locally advanced or metastatic MTC.5 Both agents have been shown to significantly improve PFS compared with placebo; however, neither agent has demonstrated a signifi- cant improvement in OS.21,26 Because of the typically slow progression of MTCs, OS data will not be available for some time. In addition, quality-of-life measures as well as pharmacoeconomic evaluations have yet to be conducted.
Currently, there is no clear advantage of one of these TKIs over the other. It is unknown if there are patient char- acteristics, such as over-/underexpression of a gene, that may lead to improved efficacy with either agent. In addi- tion, it is unknown if there is an optimal sequencing of the agents relative to each other or other treatments. Based on the indolent nature of MTCs, it is also unknown if these agents are clinically useful in asymptomatic patients, given the adverse event profiles. It is hopeful that impending sur- vival data will assist in determining the utility of TKIs in this setting. There is also a need for comparative safety and efficacy data of these therapies against other treatment options, such as palliative resection, ablation, and embolization.
The optimal dose of vandetanib is also not known. Currently, there is limited data suggesting efficacy of 100 mg of vandetanib in the treatment of MTCs.20 A phase 4 trial is ongoing to compare the safety and efficacy of vande- tanib 300 mg daily versus 150 mg daily in patients with unresectable, advanced MTC.31
In addition to cabozantinib and vandetanib, several TKIs have undergone phase 2 investigation for MTC, including motesanib (AMG706, Takeda Pharmaceutical Company Ltd. Osaka, Japan), sorafenib (Nexavar, Onyx Pharmaceuticals,Inc,andBayerHealthcarePharmaceuticals, Inc, Wayne, NJ), sunitib (Sutent, Pfizer, Inc, New York, NY), and lenvatinib (E7080, Eisai Co, Ltd. Tokyo, Japan).32-35 The encouraging early results of these drugs and their unique targeted mutations suggest that MTC patients may benefit from pathway-specific therapy.

Approved Labeling and Possible Off- Label Uses
Vandetanib is approved for the treatment of symptomatic or progressive unresectable, locally advanced or metastatic MTC.8 A phase 2 trial for vandetanib in combination with chemotherapy demonstrated a possible role for vandetanib

Table 4. Dose Modification Guidelines.8

Dose Modification
Criteria CTCAE Any grade ≥3

Dose Modification Hold until resolved or

study methodology between the 2 phase-3 trials. Adverse reactions are also similar, with the exception of QT prolonga- tion associated with vandetanib and PPES associated with cabozantinib.8,28 In addition, vandetanib use is restricted via a REMS program, whereas cabozantinib is not.22

grade 1, then resume at reduced dosea
QT prolongation QTcF >500 ms Hold until QTcF <450 ms, then resume at reduced dosea
Renal dysfunction CrCl <50 mL/min Reduce dose to 200
Based on the current available data, there does not appear to be a clinical preference for either TKI. Both agents have a different spectrum of targets, and it is unknown if this dif- ference is clinically meaningful.

Hepatic dysfunction Child-Pugh B
or C
mg dailyb
Do not administer
Summary
Vandetanib is a viable treatment option for patients with

Geriatrics
Age >65 years
No dose modifications
neededc
symptomatic, progressive, locally advanced or metastatic MTC. In the phase-3 randomized trial, vandetanib improved

Abbreviations: CTCAE, common toxicity criteria for adverse events; QTcF, QT interval, Fridericia; CrCl, creatinine clearance.
aReduce 300-mg daily dose to 200 mg daily. Reduce 200-mg daily dose to 100 mg daily.
bAdditional monitoring of QT interval recommended. cLimited data in patients older than 75 years.
PFS in MTC patients compared with placebo. Because of the potential for cardiac toxicity, patients and providers must enroll in the Caprelsa REMS program. An analysis of the pharmacoeconomics and comparative data with other treatment options, including the newly approved cabozan- tinib, are necessary in order to determine the place of this agent in therapy.

in maintenance of non-small-cell lung cancer.36 Vandetanib

is also under investigation for the treatment of glioblas- toma, advanced biliary tract cancer, metastatic hormone refractory prostate cancer, metastatic follicular and papil- lary thyroid cancer, and urinary tract cancer.

Dosage and Administration
Vandetanib is available as 100-mg and 300-mg tablets.8 The recommended dose is 300 mg orally once daily. Vandetanib therapy should be continued until unacceptable toxicity occurs or the patient is no longer clinically benefiting from therapy.
Patients who are unable to swallow whole tablets can disperse the tablet in 2 ounces of noncarbonated water.8 The liquid should be stirred for 10 minutes and consumed imme- diately. Any residual drug should be mixed with 4 ounces of water and swallowed. Guidelines for dose modification can be found in Table 4.

Formulary Recommendations
A TKI with activity in progressive, symptomatic, unresect- able MTC is an important formulary consideration for health plans providing prescription drug benefits based on efficacy, adverse reactions, and cost. Both available agents have been shown to prolong PFS, whereas neither can yet claim an improvement in OS at this time.21,26 Cabozantinib improved PFS by 7.2 months compared with placebo, whereas vande- tanib improved PFS by 11.2 months relative to placebo. Because these agents have not been compared head-to-head, a conclusion regarding superiority of one agent cannot be made because of differences in patient characteristics and
Declaration of Conflicting Interests
Daniel J. Shaheen is employed by Algeta. This company does not produce any medications for the treatment of thyroid cancer. The remaining authors have no conflicts of interest.

Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.

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