1. Introduction

2. Discovery strategy and

preclinical development

3. Clinical development

4. Post-launch

5. Conclusion

6. Expert opinion

Drug Discovery Case History

The discovery and developmentof vandetanib for the treatmentof thyroid cancerMichael W Sim & Mark Steven Cohen†

†University of Michigan Health System, Department of Surgery, Ann Arbor, MI, USA

Introduction: Thyroid cancer represents over 90% of all endocrine malignan-

cies, with medullary thyroid carcinoma (MTC) accounting for 5 -- 9% of

them. Patients with early-stage disease have a favorable prognosis, but once

distant metastasis develops, survival drops to 50% or less. Although surgery

remains effective for early-stage disease, patients with advanced disease

pose a challenge as traditional therapies have not provided long-term bene-

fits. Vandetanib, initially developed to target other receptors, demonstrated

anti-rearranged during transfection (anti-RET) kinase activity. This led to pre-

clinical studies followed by recent human clinical trials, culminating in its FDA

approval in April 2011 for application in the treatment of symptomatic or

progressive MTC in patients with surgically unresectable, locally advanced or

metastatic disease.

Areas covered: The authors provide a review of the discovery strategy and

preclinical development of vandetanib. The authors also provide some insight

into the clinical development and the drug’s post-launch situation.

Expert opinion: Vandetanib has been shown to improve progression-free

survival in MTC patients, but its impact on overall survival is still inconclusive.

Further data analysis will be needed to answer the question of whether it

impacts overall survival in MTC. Despite its advancements, vandetanib still

lacks durable efficacy, carries moderate toxicity and has issues with drug resis-

tance over time, not to mention issues of cost. There is a significant need for

additional research to discover and develop improved therapeutic strategies

for this difficult disease.

Keywords: familial medullary thyroid cancer, medullary thyroid cancer, MEN2A, MEN2B,

thyroid cancer, thyroid cancer treatment, tyrosine kinase inhibitor, vandetanib

Expert Opin. Drug Discov. [Early Online]

1. Introduction

Among human malignancies, thyroid cancer is relatively rare, accounting forapproximately 1% of all human cancers. It is, however, the most common endo-crine malignancy, representing over 90% of all endocrine cancers. Most thyroidcancers present as differentiated subtypes, including papillary and follicular carcino-mas that respond well to surgery followed by radioactive iodine ablation. Otherpoorly differentiated types of thyroid cancer including anaplastic and medullarytumors do not respond well to surgical management or radioactive iodine andremain a challenge to treat clinically. Medullary thyroid carcinoma (MTC) arisesfrom the parafollicular C-cells of the thyroid gland that secrete calcitonin andaccounts for approximately 5% of all thyroid malignancies [1,2]. MTC can be eithersporadic or hereditary, with around 75% of all new cases being sporadic. Theremaining 25% of hereditary cases involve one of three autosomal-dominant hered-itary syndromes: multiple endocrine neoplasia (MEN) 2A, MEN2B and familialMTC. These diagnoses differ in their clinical presentation and in their germline

10.1517/17460441.2014.866942 © 2013 Informa UK, Ltd. ISSN 1746-0441, e-ISSN 1746-045X 1All rights reserved: reproduction in whole or in part not permitted

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mutations of the rearranged during transfection (RET) proto-oncogene that encodes for a transmembrane tyrosine kinasereceptor [3].Germline mutations in the RET proto-oncogene were

found to be the etiologic factors behind hereditary MTC intwo landmark studies in 1993 [4,5]. All MEN2A patientseventually will develop MTC and many will also developpheochromocytomas of the adrenal gland and parathyroidhyperplasia. Patients with MEN2B also present with MTCand pheochromocytoma, but instead of parathyroid abnor-malities, they may develop a marfanoid habitus and mucosalneuromas. These ganglioneuromas of the intestine can leadto multiple gastrointestinal transit difficulties in childhood [6].MTC in MEN2B patients will typically present earlier inlife and is often more aggressive than in MEN2A patients.Familial MTC patients developMTC but lack any of the otherendocrinopathies associated with MEN2 [2]. Patients withearly-stage MTC typically have a favorable prognosis, with10-year survival rates as high as 70 -- 80%. With distant meta-static spread, however, 10-year survival rates drop to 40% [7].Unfortunately, most patients will present with advanceddisease with nearly 70% of patients having regional metastasesto the cervical nodes and 10% having distant metastaticdisease [1,2,8].First-line treatment for early-stage MTC is surgical

resection, which includes a total thyroidectomy and bilateralcentral neck lymph node dissection. More extensive surgeryinvolving a lateral neck compartmental dissection is recom-mended for patients with clinically or radiographically suspi-cious lymph nodes, or those with biopsy-proven metastaticnodes [9], although some surgeons routinely perform a lateralneck lymph node dissection (levels 2, 3, 4, 5) on the side ipsi-lateral to the tumor for larger tumors. Local recurrence rates

can be as high as 27% for sporadic cases and 14% for hered-itary cases. Distant recurrence rates are about 18% in sporadiccases and 14% in hereditary cases at 7 years [10]. With localrecurrence, especially symptomatic nodal disease, reoperationis paramount to achieving adequate disease control andpalliating morbidity.

Treatment for locally advanced and metastatic MTC con-tinues to pose a significant challenge. In this setting, surgeryalone is usually inadequate and these tumors do not concen-trate iodine and, therefore, do not respond to radioiodineablative therapy. Patients with these tumors also cannotundergo thyroid-stimulating hormone (TSH) suppressiontherapy by thyroid hormone administration, as opposed topatients with differentiated thyroid cancer such as papillaryor follicular thyroid cancer, since C cells have no affinity forTSH to begin with [3]. External beam radiotherapy has beenused with limited success on disease control, but does notimpact overall survival, and carries a moderate morbidityrisk from toxicity complications. Conventional chemothera-peutic agents have shown very little efficacy againstMTCs [9,11] clinically and also carry considerable toxicity topatients with this disease. These limitations and gaps in thetreatment of MTC patients provide a fertile opportunity fornovel drug development.

Given these treatment gaps persisting in MTC patients fordecades, there exists a critical need for development of bettertherapeutics that improve efficacy and survival yet carry lim-ited toxicity in these patients. With the approval of imatinibmesylate (Gleevec�, Novartis Pharmaceuticals, Basel Switzer-land) in 2001 as the first targeted drug against chronic mye-loid leukemia, an opportunity developed to explore kinase-targeted therapeutics against RET kinase activity in MTCs.With a growing body of data on RET tyrosine kinase phos-phorylation as a key signaling event in MTC proliferation,early experiments with tyrosine kinase inhibitors (TKIs) dem-onstrated that RET activity could be inhibited leading to inhi-bition of MTC cell proliferation in vitro [12]. Othersconfirmed this mechanism of treatment in MTC as validusing a hammerhead ribozyme, a catalytic RNA enzyme thatspecifically cleaves complementary RNA sequences. Using aribozyme targeting a particular mutation (C634R) of RET,they demonstrated that the function of the kinase proteinscould be inactivated, and that with an even more potentribozyme, MTC cell proliferation could be inhibited [13]. Inanother study, the potential therapeutic implications ofdisrupting RET autophosphorylation were investigatedin vitro and in vivo by transfecting TT medullary thyroid can-cer cells with adenoviral vectors expressing a dominant-negative truncated form of RET [14]. In vitro, the investigatorsfound that compared with the control cells, the treated cellshad decreased cell viability, absence of phosphorylation ofAkt and extracellular signal-regulated kinase, decreased cellcycle progression, and stimulation of apoptosis and concur-rent decrease in the expression of BCL-2. In vivo, they foundthat tumor growth was significantly lower in the group

Article highlights.

. Medullary thyroid cancer, accounting for approximately5% of thyroid cancers, remains a challengingmalignancy to treat in the advanced setting as it doesnot respond well to standard chemotherapy, radioactiveiodine or surgical treatment.

. Vandetanib is the first targeted therapy approved forthe treatment of advanced medullary thyroid cancer.

. Vandetanib treatment in clinical trials improves PFS butnot overall survival in patients with medullarythyroid cancer.

. Vandetanib therapy is associated with several sideeffects, including cardiac QT interval prolongation, skinrashes, diarrhea and endocrine abnormalities of calciumand thyroid hormone function.

. Given the toxicity profile and cost considerations ofvandetanib therapy, patients with advanced medullarythyroid carcinoma must be evaluated individually forrisk/benefit stratification and consideration for the mostappropriate therapy option based on clinical judgment.

This box summarizes key points contained in the article.

M. W. Sim & M. S. Cohen

2 Expert Opin. Drug Discov. (2013) 9 (1)

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inoculated with adenovirus-carrying RET cells compared withthe tumors of control cells.

Through small-molecule library development, other TKIswere soon discovered. Vandetanib (Figure 1) was found tobe an orally active multi-targeted TKI molecule with potenteffects on vascular endothelial growth factor receptor(VEGFR)-2, epidermal growth factor receptor (EGFR) andRET tyrosine kinase receptor [15].

2. Discovery strategy and preclinicaldevelopment

Vandetanib was first developed as ‘ZD6474’ by Astra-Zenecato target and inhibit VEGFR tyrosine kinase and demonstratedpotent anti-angiogenesis effects in vitro and in vivo. Subse-quently, its anti-tumor effects via inhibition of EGFR becameapparent. As such, early clinical applications of vandetanibwere to tumors that expressed high proportions of VEGFRand EGFR, including non-small cell lung cancer and colorectalcancer [3]. Vandetanib’s anti-proliferative effects via inhibitionof VEGFR and EGFR kinase-mediated pathways were demon-strated in an in vitro model of VEGF-A-stimulated humanumbilical vein endothelial cells [16]. In this same study, thedrug’s multi-targeted effects were also demonstrated by inhibi-tion of VEGF signaling pathways and angiogenesis in anin vivo rodent model of lung cancer. Vandetanib has alsobeen shown to inhibit cancer cell-proliferation in vitro andtumor growth in xenograft models of prostate, lung, breast,ovarian, vulvar and colorectal cancers, and in syngeneic murinemodels of lung and melanoma [16-19]. In other studies, vandeta-nib’s anti-angiogenic, anti-tumorigenic and anti-metastaticproperties were further defined in orthotopic murine modelsof lung [20], gastric [21], pancreatic [22] and renal [23] cancers.EGFR-dependent growth has also been inhibited in vitro inhuman lung cancer cell lines [24] and in vivo in a human xeno-graft model of lung cancer [25].

Based on these promising results in many cancers in vivo,vandetanib was studied in MTCs and shown to have inhibi-tory effects on RET tyrosine kinase receptor activity. An earlyadvance leading to RET-molecular targeting was the recogni-tion that the molecular structures of RET and VEGFR kin-ases were similar and that inhibitors of VEGFR could alsoinhibit RET tyrosine kinase activity [26]. Vandetanib was,therefore, one of the first multi-targeted TKIs that was inves-tigated for its potential targeting of RET [27]. In this study,vandetanib was found to inhibit autophosphorylation of aRET M918T mutation, found in MEN2B and aggressivestrains of sporadic MTC, as well as other oncogenic RETmutants. In these cells, vandetanib showed high potencywith an IC50 of 100 nmol/l. Further in vitro studies demon-strated vandetanib’s inhibitory activity on wild-type RET aswell as other activated mutant forms of the kinase [28]. Anti-proliferative effects were seen in human MTC cell linesin vitro through inhibition of the RET-dependent cell growthin multiple studies [29,30]. Interestingly, relative drug resistance

was also seen in vitro in rodent fibroblasts expressing theV804 mutation, with nearly a 50-fold increase in IC50

values [28]. This supported the possibility that MTC patientswith V804 mutations (approximately 4% of MEN2 carriers)could demonstrate resistance to vandetanib therapy [31].Despite resistance in V804 mutations, findings from in vivostudies correlated with in vitro findings [29], with demonstra-tion of tumor growth inhibition in a xenograft model ofhuman MTC. In another study, vandetanib exhibited adose-dependent inhibition of tumor growth in a murinexenograft model using implantation of human sporadicMTC cells with the C634R mutation [32]. Given this strongbody of preclinical proof-of-concept studies in MTCs, vande-tanib was moved into human clinical trials for this disease.Moreover, the findings from these preclinical studies canpotentially impact future drug discovery and open new ave-nues for investigation in the treatment of MTC and othertumors as vandetanib has demonstrated the multiplicity ofmechanistic pathways in which response can be effected intumors.

3. Clinical development

Early in its transition to clinical applications, Phase I trials ofvandetanib in patients with various solid tumors demon-strated that oral doses of the drug at 300 mg or less per daywere well-tolerated by patients [33,34]. In these studies, theadverse effects of the treatment were managed successfullywith supportive measures and dose reduction. Following thePhase I study, results of a Phase II trial in patients withadvanced MTC, published in 2010, demonstrated significantanti-tumor activity of vandetanib [35]. In this study, 30 patientswith unresectable, locally advanced or metastatic MTCunderwent vandetanib treatment with a daily oral dose of300 mg. Twenty percent of patients had a partial responseby Response Evaluation Criteria in Solid Tumors (RECIST)criteria (partial response = 30% or more reduction in tumorvolume) for a median duration of 10.2 months, and 53% ofpatients showed stable disease at 24 weeks or more. Moreover,80% of patients had a 50% or more reduction in calcitoninlevels that was maintained for at least 4 weeks and 53% ofpatients had similar rates of reduction in CEA levels. In a sec-ond Phase II trial, a lower dose of vandetanib was used(100 mg daily) [36]. In this study with a similar MTC patientpopulation, 16% of patients showed a partial response to ther-apy and 53% had stable disease. Some of the main adverseevents from both studies included diarrhea and rash, butwere mostly manageable without a hospital admission. Mostnotably, however, QT prolongation attributed to vandetanibwas noted in six patients and in one patient in the twoPhase II trials, respectively.

In a key multi-center, randomized, placebo-controlledPhase III trial (ZETA) conducted from December of2006 to November of 2007, the efficacy of vandetanib in331 patients with advanced or metastatic MTC was tested

The discovery and development of vandetanib for the treatment of thyroid cancer

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with the hypothesis that progression-free survival (PFS) wouldbe improved with treatment compared with placebo [37].Patients were randomized 2:1 to either the vandetanib300 mg/day arm or to the placebo arm. In this study, 90%of the patients had sporadic MTC, with the remaining 10%of patients having the hereditary form. The study foundstatistically significant findings for its primary endpoint ofPFS, with improvement in PFS seen in the vandetanib armat 30.5 months compared with the placebo arm with a PFSof 19.3 months. Moreover, significant findings were alsofound in the secondary endpoints, which included objectiveresponse rate, disease control rate and biochemical response.Objective response based on RECIST was seen in 45% ofpatients in the vandetanib arm compared with 13% in theplacebo arm. Of note, 12 of the 13 patients in the placeboarm with objective response experienced this after vandetanibtreatment was started for them during the open-label phase ofthe trial. Biochemical response was determined by monitoringcalcitonin and CEA levels, with 69 and 52% of patients in thevandetanib arm experiencing a decrease compared to 3 and2% of patients in the placebo arm, respectively. At the timeof the primary analysis, there was no statistically significantdifference in overall survival, however, observed between thetwo arms. But this is yet to be determined in the long-termfollow-up portion of this study. The investigators also endeav-ored to determine whether RET mutation status affected out-comes, but a large number of the tumor samples wereunsuccessfully genotyped due to insufficient presence ofDNA. Of those tumors analyzed, 52% were positive, 2.7%negative and 45.3% indeterminate. Therefore, this questionremains unanswered.As was seen in the Phase I and II trials, substantial

concentration-dependent QT prolongation was seen inpatients in the ZETA trial. On average, corrected QTprolongation was < 30 ms from week 4 to week 108. Theexpected average increase in QTc is 35 ms for the 300 mg/daydose, 30 ms for the 200 mg/day dose and 21 ms for the100 mg/day dose based on the exposure response relation-ship [38]. QT prolongation was at least 20 ms in 91% ofpatients, 20 -- 49 ms in 46% of patients, 50 -- 99 ms in44% of patients, < 60 ms in 35% of patients and < 100 msin > 2% of patients [39].Vandetanib has also shown cutaneous side effects in

patients [40]. A range of manifestations have been reported,

from a milder rash to more serious reactions, including toxicskin eruptions, epidermolysis and Steven--Johnson syndrome.In the previously mentioned Phase III trial [37], 89% of patientsin the vandetanib arm developed a rash compared with 23% ofpatients in the control group. These effects were seen in amedian time of 2.5 months after starting treatment. Photosen-sitivity reactions were seen in 13% of patients in the vandetanibarm. Patients undergoing vandetanib therapy are thereforerecommended appropriate sun protective measures.

Endocrine effects have also been observed with vandetanibtreatment at a daily dose of 300 mg. Among 35 patients whowere sampled from the Phase III trial, effects on TSH,calcium and phosphate metabolism, adrenal function, andgonadotrope function were noted. An increase in TSH levelwas observed in more patients receiving vandetanib comparedwith placebo (49.3 vs. 17.2%), resulting in increasedadministration of levothyroxine in the vandetanib group [41].Additionally, serum levels 1,25(OH)2 -vitamin D rose signif-icantly during treatment with vandetanib as did levels of para-thyroid hormone, although serum calcium levels remainedunchanged. Although treated patients did require thyroid hor-mone supplementation, as well as calcium and vitamin D sup-plementation, there were no clinically significant short-termconsequences [41]. Based on these observations, however, itmay be beneficial to monitor serum PTH, 1,25(OH)2-vitamin D, and calcium levels closely during vandetanibtherapy.

The pharmacokinetic profile of vandetanib has been wellcharacterized through various studies in both healthy volun-teers as well as those with malignancies and renal and hepaticdysfunction [42,43]. Some of the pharmacokinetic analyses havebeen derived from data collected from the ZETA trial, such assteady-state parameter estimates [39]. In patients receiving a300--mg/day dose, the following parameters were seen in191 of the 231 patients: the maximum plasma concentration(Cmax) was 857 ng/ml, the area under the plasma concentra-tion--time curve from time zero to 24 h (AUC0 -- 24) was19829 ng·h/ml, the accumulation ratio (RAC) was 8.1, thevolume distribution (Vd) was 7450 L, oral clearance (CL)was 13.2 l/h, and terminal elimination half-life (t½) was21 days. Over ranges studied, which included doses of300 --1200 mg [42], the pharmacokinetics of vandetanibseem largely to be in a linear pattern. A two-compartmentmodel sufficiently characterizes the pharmacokinetics, with afirst-order absorption and lag time. With oral administration,vandetanib is absorbed slowly, with Cmax being achieved by amedian time of 6 h after a dose [42]. Cmax and AUC0 -- 24 wasnot significantly affected by a meal high in fat content beforeadministration of the drug at a dose of 300 mg, which onlyincreased the time to achieve Cmax by an additional 2 h [42].Based on these results, the drug may be taken with or withoutfood. It can accumulate up to eight-fold with continueddoses, reaching steady-state concentrations at approximately2 -- 3 months [44]. Vandetanib appears to have a high-affinitybinding (92 -- 94%) to plasma proteins such as albumin [43].

N

N

F

N

HN

O

O

Br

Figure 1. Vandetanib chemical structure.

M. W. Sim & M. S. Cohen

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The excretion and elimination of vandetanib is primarilythrough biliary and urinary routes [42]. Metabolism of vande-tanib to the metabolites N-desmethyl vandetanib and vande-tanib N-oxide is carried out both by the cytochrome P4503A4 isoenzyme and by renal and hepatic flavin-containingmono-oxygenases, respectively [42]. Investigation of thein vitro activity of these metabolites has shown that theN-desmethyl vandetanib is able to inhibit VEGFR andEGFR as potently as vandetanib unmetabolized, whereas van-detanib N-oxide is 50-fold less potent than its parentform [45]. After administration of an 800-mg dose of radio-labeled vandetanib, both metabolites were found in theplasma, urine and feces of healthy volunteer subjects. Approx-imately 44% of drug was recovered in the feces and 25% inthe urine after the 800 mg dose during a 21-day study period.A glucuronide conjugate metabolite of vandetanib was alsofound in the urine and feces of these subjects [42].

The pharmacokinetics of vandetanib did not appear to beaffected by age or gender, and there were no changes in doserequired for patients over 65 years of age [44]. In patientswith renal dysfunction, however, exposure to vandetanib wassignificantly increased in subjects receiving an 800-mgdose [43]. In contrast, patients with liver dysfunction did notdemonstrate significantly increased exposure with an800-mg dose compared with patients with normal liver func-tion. Additional pharmacokinetic interactions of vandetanibwith other drugs have been explored. Since vandetanib is asubstrate of the cytochrome P450 3A4 system, its pharmaco-kinetics may be affected by other drugs that are substrates ofthis cytochrome P450 system. Vandetanib was found to be amoderate inducer of 3A4 in vitro, and therefore, caution iswarranted when being concurrently dosed with notable sub-strates, including immunosuppressants (such as tacrolimus),estroprogestatives and certain chemotherapy agents (doce-taxel). However, long-term clinical studies have not beencarried out for most of these interactions. Vandetanib is aweak inhibitor of the P-glycoprotein efflux pump, and thus,may affect the pharmacokinetics of digoxin. It is also a weakinhibitor of organic cation transporter 2, and may affect met-formin’s metabolism profile. With vandetanib’s adverse effectof QT prolongation being a notable concern, its interactionwith ondansetron (which also prolongs the QT interval) wasinvestigated in a study with 28 healthy volunteer subjects.With a single 700-mg dose of vandetanib and a 32-mg intra-venous dose ondansetron, no change in the pharmacokineticprofile of vandetanib was seen. There was, however, an addi-tive effect on QT prolongation with co-administration of thedrugs [44]. As a result, there is a relative contraindication tousing both of these drugs concurrently in its approvedindications.

4. Post-launch

Based on its improved efficacy and safety profile in MTCpatients in clinical trials, vandetanib received full FDA

approval on April 2011 for use in the treatment of symptom-atic or progressive MTC in patients with surgically unresect-able, locally advanced or metastatic disease [46]. It alsoreceived approval around the same time in Europe, makingit the first chemotherapeutic agent approved internationallyfor the treatment of patients with progressive MTC.A continued concern, however, is the drug’s adverse effecton QT prolongation. In the ZETA trial, QT prolongationwas noted in 14% of patients in the vandetanib arm comparedwith 1% in the placebo group. Furthermore, five patientsexperienced death while undergoing treatment, including asudden death and a cardiopulmonary arrest, which could beattributed to a fatal arrhythmia (torsades de pointes) that isknown to develop from QT prolongation. Unfortunately,QT prolongation as a distinct cause of death with vandetanibwas never clearly documented. Due to these electrocar-diographic findings, however, the FDA issued a warning forQT prolongation, torsades and sudden death, and also limitedthe prescription of the drug to only certified and trainedphysicians and pharmacists [47]. Because it can prolong theQT interval, vandetanib is currently contraindicated for usein patients with serious cardiac complications, including con-genital long QT syndrome, bradyarrhythmias, uncompen-sated heart failure and a history of torsades de pointes [40].

Current clinical efforts have attempted to expand the indi-cations for this drug in other thyroid cancers, including itsrole in metastatic differentiated thyroid cancer. A recentreport in Lancet Oncology in 2012 summarized the resultsof a randomized, double-blind Phase II trial evaluating theefficacy of vandetanib in 145 patients with radioiodine-refractory locally advanced or metastatic differentiated thyroidcarcinoma (papillary, follicular or poorly differentiated) at16 European medical centers [48]. In this study, vandetanibsignificantly increased median PFS from 5.9 months in theplacebo arm to 11.1 months (95% CI 7.7 -- 14.0) for patientsin the vandetanib group, which was the primary endpoint ofthe study. Again the most common grade 3 or worse adverseevents were QTc prolongation in 14% of the vandetanibgroup versus 0% in the placebo group. A Phase III trial is cur-rently ongoing in differentiated thyroid cancer whereas aPhase IV trial is being performed to compare the effectivenessof vandetanib 300 versus 150 mg/day in adults with advancedor metastatic MTC [49]. In a recently published Phase I/IItrial, vandetanib application in children (age 5 -- 12 years)and adolescents (age 13 -- 18 years) with locally advanced ormetastatic MTC was investigated [50]. These investigatorsfound that 100 mg/day dosing was well tolerated and effica-cious, with 47% of test subjects with the M918T RET muta-tion (n = 15) having a objective partial response. Diarrhea wasthe most common dose-limiting side effect of the treatment.

Another ongoing Phase I/II trial is evaluating combinationtherapy with vandetanib and the proteosomal inhibitor, bor-tezomib, in patients with advanced solid tumors, includingmedullary thyroid cancer [51]. Given that standard treatmentfor advanced MTC may sometimes involve palliative

The discovery and development of vandetanib for the treatment of thyroid cancer

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resections and external beam radiation, future clinical trialsmay compare or combine these modalities with vandetanibto evaluate PFS and overall survival more closely to define bet-ter its role in standard treatment protocols.Currently, vandetanib is being prescribed to a significant

portion of patients in the U.S. with advanced metastaticMTC who have demonstrated progression of disease and donot have a contraindication to therapy or where the potentialbenefits in PFS outweigh its cost and toxicity profile. Tothis point, cost of therapy is a significant consideration. Inthe U.S., the drug is available only through a restricted pro-gram of distribution by the Biologics pharmacy (Biologics,Inc., Cary, NC). The average wholesale prices for vandetanibare $198 and $396 for a 100- and 300-mg tablet, respec-tively [52]. Extrapolating this cost to a 30-day supply for apatient without insurance would create a monthly drug costof $10,454. Since the earliest PFS benefits in trials havebeen seen after 90 days [37], this would require a cost of$31362 to achieve this PFS benefit and if a patient was kepton drug for a year, they would encumber an annual cost of$125,448 which may be prohibitive for most patients. Suchcost considerations must be included in the decision algo-rithm for effective use of this agent.Although its efficacy is superior to placebo in PFS, there

remains a lack of long-term durable efficacy with vandetanibalong with toxicity and drug-resistance concerns creating aneed for development of drugs with better long-term efficacyand improved toxicity profiles. Since the approval of vandeta-nib, one other multi-targeted TKI, cabozantinib (XL184;Exelixis Corporation, San Francisco, CA) has also been stud-ied in clinical trials and approved for use in patients withadvanced MTC. Similar to vandetanib, cabozantinib was ini-tially studied as a VEGFR inhibitor, as well as a MET-kinaseinhibitor, and its efficacy was demonstrated initially throughin vitro studies [53]. In a Phase I/IIA clinical study [54],37 patients with MTC were treated with cabozantinib, with10 of the patients showing a partial response to treatment.

Another 15 patients showed stable disease for at least6 months. Of note, RET mutational status did not seem toaffect the activity of the drug as responses to treatment wereseen in patients regardless of the type of RET mutation. In arandomized, placebo-controlled Phase III trial (EXAM) [55] inpatients with advanced or metastatic, sporadic or inheritedMTC, subjects were either treated with 140 mg/day of cabo-zantinib or placebo. Similar to the ZETA trial, the primaryendpoint was progression-free survival. In contrast to theZETA trial, however, this study required patients to have con-firmed disease progression, ensuring a more aggressive diseasecohort compared with the placebo arm in the ZETA trial.The study also did not allow placebo patients to crossover tothe treatment arm, thus minimizing confounding variables,unlike the ZETA study. Results from the EXAM trial showedsignificant improvement in PFS in the cabozantinib arm with amedian PFS of 11.2 months compared with 4.0 months in theplacebo arm, but no impact on overall survival, similar tovandetanib.

With two targeted therapies now approved the treatment ofpatients with advanced or metastatic MTC, one lingeringquestion is ‘which drug should be the first-line agent?’ Bothinhibitors demonstrate improved PFS in the clinical setting.Both agents also had similar relative increases in adverseevents in the treatment arms and are reasonably well toleratedoverall by patients with appropriate dose modifications andclinical monitoring. Despite their similarities, the ZETAand EXAM trials were sufficiently different in their studydesign, such that it is not feasible to compare study resultsof the two drugs head-to-head. For example, although thevandetanib arm of the ZETA trial had a longer PFS of30.5 months (compared with 11.2 months in the cabozanti-nib treatment arm) and a greater difference in PFS comparedwith its placebo arm (11.2 months longer vs. 7.2 months lon-ger with cabozantinib) the different eligibility criteria forenrollment in the two studies makes for a very differentcohort of patients in each trial, rendering any direct

Table 1. Comparing ZETA and EXAM trial findings.

Trial ZETA EXAM

Study population Locally advanced or

metastatic MTC

Documented progressive locally

advanced or metastatic MTC

Treatment Vandetanib Placebo Cabozantinib Placebo

Number of patients 231 100 219 111

PFS in months 30.5 19.3 11.2 4Ratio of PFS, treatment: placebo 1.58 2.80Partial response rate % 44 1 27 0QT prolongation % 8 1 0 0Death due to adverse event % 2 2 6 5

Reproduced from [26] with permission of Elsevier.

MTC: Medullary thyroid carcinoma; PFS: Progression-free survival.

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comparisons difficult, if not impossible. An important dis-tinction between the two drugs to note, however, is that sig-nificant QT prolongation was not seen in patients treatedwith cabozantinib, which may simplify patient monitoringduring treatment. To date, however, these two drugs havenot been compared together in a randomized clinical study(Table 1).

5. Conclusion

Medullary thyroid cancer, although relatively rare, poses achallenge to clinicians treating the disease in advanced stages.Vandetanib, first developed as a VEGFR and EGFR inhibi-tor, was eventually shown to inhibit RET kinase activity andlaboratory studies, and in clinical settings, was shown tohave efficacy in various tumors, including MTC. Vandetanibbecame the first targeted therapy approved for the treatmentof advanced MTC, showing in clinical trials to improvePFS. But vandetanib therapy is associated with several sideeffects, including cardiac QT interval prolongation, which ispotentially lethal. Given the toxicity profile and cost consider-ations of vandetanib therapy, patients with advanced MTCmust be evaluated individually for risk/benefit stratificationand consideration for the most appropriate therapy optionbased on clinical judgment.

6. Expert opinion

Since it was first reported by Hazard, Hawk and Crile in1959, MTC has been a challenging malignancy to treat effec-tively. While early-stage disease is amenable to surgical resec-tion, non-surgical therapy for advanced disease has lackedsignificant efficacy for decades. Although patients have beentreated with various cytotoxic agents in the past, none havedemonstrated durable or consistent effects in these patients.External beam radiation has been used for palliation andsome disease control but does not impact overall survivaland carries moderate toxicity. The approval of vandetanibfor the treatment of advanced metastatic medullary thyroidcancer represents the first major advance in adjuvant therapyfor this disease in decades. Using a rational targeted approachhas resulted in significant benefits in PFS for many patients,which has the potential to provide improvements in disease-related morbidity due to tumor progression and organinvolvement. Although the potential benefits are real, thereremain significant barriers to its use that are related to toxic-ity, cost, and long-term efficacy concerns. QT prolongation,observed in 10 -- 14% of treated patients can lead to life-threatening cardiac complications, especially in patients withunderlying cardiac disease as well as those on other medica-tions that can prolong the QTc interval. Other commonside effects have included skin rashes, diarrhea and endocrineabnormalities. Given its toxicity profile, the use of the drughas been restricted by the FDA and its distributor, Biologics,Inc., via the Caprelsa Risk Evaluation and Mitigation Strategy

Program. Costs of therapy are also not trivial at around$10000 per month for a 300 mg/day dose and these cost con-siderations should be weighed into the risk/benefit analysis foreach patient being considered for therapy. Additionally, nostudy with vandetanib to date has demonstrated a significantbenefit in overall survival for these patients, although theZETA trial is still following patients for mortality events.For MTC patients with stable disease or mild progressionthat is not causing significant morbidity, standard observationmay have rational benefit over the potential morbidity andtoxicity of chemotherapy, surgery or radiation. For otherpatients, palliative surgical resection of bulky neck disease ortemporary disease control with external beam radiation stillplay important roles in the adjuvant setting. As such, eachpatient must be evaluated individually for risk/benefit stratifi-cation and consideration for the most appropriate therapybased on clinical judgment.

The last several years of clinical data on vandetanib haveprovided a better understanding of its toxicity profile, espe-cially cardiac QT prolongation, skin rash, diarrhea and endo-crine abnormalities. These toxicity data create a benchmarkby which newer targeted agents can be developed withimproved efficacy and less off-target effects. Cabozantinib’sapproval in 2012 created an opportunity for MTC patientsto have two viable adjuvant options for advanced disease.Although its PFS efficacy and toxicity profile are somewhatsimilar to vandetanib, cabozantinib has not been associatedwith cardiac QT toxicity. Of note, cabozantinib was associ-ated with palmar plantar erythrodysesthesia, mucositis, eleva-tions in AST, ALT, and lipase and mucositis that requiredde-escalation of dosage in some patients in the previouslymentioned Phase I trial [55]. Additionally, some patients mayrespond better to one drug over the other, although thisdata have not been well characterized since both drugs havenever been tested together in the same clinical trial. Sincevandetanib has only thus far been compared with placebo inclinical trials and while a PFS benefit exists, this benefit maychange if compared with palliative/therapeutic surgical resec-tion, radiation or even tumor embolization. Such comparativestudies would further characterize the role of vandetanib inthe adjuvant setting in advanced MTC patients.

It is important to note that neither vandetanib nor cabo-zantinib has demonstrated any impact on overall survival inMTC to date. However, both the ZETA and EXAM trialsare still following patients for mortality events that may betterdefine this impact. Future applications of these RET-targetedinhibitors will also benefit from more in-depth mechanisticstudies in the clinical setting. Although vandetanib and cabo-zantinib have shown potent RET kinase inhibition in vitro,there is still insufficient evidence to suggest that their clinicaleffects are solely through targeting of RET kinase activity.A better mechanistic understanding of tumor RET activityin patients on vandetanib and the effects of the drug on otherkey signaling pathways in the tumor during treatment willprovide significant insight into the mechanisms of drug

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resistance as well as define rational therapeutic strategies toovercome this resistance. Such data will also guide noveldrug development for MTC as well as combination strategiesthat lower the toxicity of vandetanib, while optimally syner-gizing its efficacy with another anticancer agent or therapeuticmodality. This is an area requiring additional exploration toeffectively advance novel therapeutics for patients with pro-gressive MTC. Determining the exact mechanistic effects ofthese targeted drugs on patient tumors will direct futureresearch efforts in their clinical applications and better definepotential drug-resistance pathways.Unlike many other cancers, MTC does not respond well to

standard cytotoxic chemotherapy drugs or radiation. As aresult, combination chemotherapy or chemoradiation proto-cols have not been well explored in this disease and representa future opportunity with vandetanib and cabozantinib. Clini-cal trials to date have evaluated the role of vandetanib as mono-therapy, although an ongoing Phase I/II trial is exploring therole of vandetanib in combination with the proteosomal inhib-itor, bortezomib in patients with advanced solid tumors, with afocus on advanced MTC patients. Other combinations in thefuture may demonstrate synergy or improvements in bothoverall and PFS that are not attainable with vandetanib alone.Through a better mechanistic understanding of vandetanib

resistance as well as its off-target signaling and toxicity,researchers will be able to strategize and test rational combina-tion regimens that add or synergize with vandetanib’s kinaseefficacy but help minimize its toxicity. In the interim, althoughnewer drugs are being discovered and tested in preclinicalmodels of MTC, vandetanib is being explored for alternativeuses in other cancers, including lung, colon and differentiatedthyroid cancer, which in an early-stage trials demonstratedmodest benefit. Regardless of the toxicities and cost concernscomplicating vandetanib therapy, it remains one of the moresignificant advances in the treatment of medullary thyroid can-cer and warrants consideration along with cabozantinib inpatients with advanced, metastatic disease who are appropriatecandidates. Ongoing and future trials will better define the roleof targeted RET kinase inhibitors in the adjuvant treatment ofpatients with advanced medullary thyroid cancer, whereas cur-rent translational efforts continue to develop promising novelagents with potential to improve patient outcomes in thischallenging disease.

Declaration of interest

The authors state no conflict of interest and have received nopayment in preparation of this manuscript.

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AffiliationMichael W Sim1 MD &

Mark Steven Cohen†2 MD FACS†Author for correspondence1University of Michigan Health System,

Department of Otolaryngology -- Head and Neck

Surgery, 1500 E. Medical Center Drive,

1904 Taubman Center, Ann Arbor,

MI 48109-1274, USA2Associate Professor of Surgery,

Director of Endocrine Surgery Research,

University of Michigan Health System,

Department of Surgery,

1500 E Medical Center Dr SPC 5332,

Taubman Center Floor 2 Reception F,

Ann Arbor, MI 48109, USA

Tel: +1 734 936 5738;

Fax: +1 734 936 6927;

E-mail: cohenmar@med.umich.edu

M. W. Sim & M. S. Cohen

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