Clinical utility of vandetanib in the treatment of patients with advanced medullary thyroid cancer
OncoTargets and Therapy
Clinical utility of vandetanib in the treatment of patients with advanced medullary thyroid cancer
Hari Deshpande 0 2
vicky Marler 0
Julie Ann Sosa 0 1
0 Yale Cancer Center , New Haven, CT , USA
1 Department of Surgery, Yale University School of Medicine
2 Department of Medicine
Vandetanib (ZD6474) became the first systemic agent to be approved for the treatment of metastatic or locally advanced medullary thyroid cancer. It was a proof of principle, because it is an orally bioavailable medication that targets the growth factors felt to be important in the pathogenesis of this disease, ie, the rearranged during transfection proto-oncogene and vascular endothelial growth factor receptor. It was tested initially in two Phase II studies at doses of 100 mg and 300 mg daily. Although activity was seen at both doses, the higher dose was chosen for a randomized, placebo-controlled Phase II study. This trial, which accrued more than 300 patients, showed a statistically significant benefit for the group taking vandetanib compared with those taking placebo medication. Progression-free survival for the vandetanib arm has not been reached, compared with 19 months for the placebo arm. The main toxicity appears to be diarrhea, although some patients experienced significant side effects, including torsades de pointes and sudden cardiac death. Therefore, it is now necessary for practitioners to enroll in a Risk Evaluation Mitigation Strategy before being allowed to prescribe this medication, to reduce the risk of serious side effects occurring.
Chemotherapeutic agents, such as doxorubicin and cisplatin,
have been used in the treatment of unresectable MTC with
limited success, considerable toxicity, and responses lasting
only 9–22 months.10
Recent advances in drug development have led to the
synthesis of many new targeted agents that are inhibitors of
specific growth factors or cell signaling pathways involved
in the pathogenesis of MTC.11
Mutations in specific regions of the rearranged during
transfection (RET) proto-oncogene have been described in
patients with both familial and sporadic forms of MTC. RET
encodes for a transmembrane growth factor receptor that is
involved in cell signaling and ultimately the uncontrolled
growth of malignant MTC cells. Therefore, RET represents
an obvious target for specific drugs to treat unresectable
forms of this disease.
Many cancers rely on angiogenesis or the formation of
new blood vessels to enable growth of the primary tumor
.vdoep lsyeon abnedcomnetrtoasllteadsisbytoa dviasrtiaentty soitfeps.roAtenigniso, gienncelusdisinagppveasacrsultaor
/ww lan endothelial growth factor (VEGF) and its specific receptor
tsp rse (VEGFR) on the cell surface. Because these are often
rom oF overexpressed in thyroid cancers, antiangiogenesis agents
fd have been developed as targeted treatments. Vandetanib
dae (ZD6474, CaprelsaTM, AstraZeneca) targets both the RET
lonw proto-oncogene and the VEGF receptor, and is described in
yod detail in this review.
Targets of vandetanib: RET and
RET was first discovered in patients with MEN syndromes,12
although it was not until 1985 that a new human transforming
gene was detected by transfection of NIH 3T3 cells with a
lymphoma DNA.13 Subsequent work pinpointed mutations on
chromosome 10, followed by the identification of germline
mutations in the RET proto-oncogene, located at 10q11.2, in
patients with MEN 2A, MEN 2B, and familial MTC.6
RET is now felt to be one of a number of receptor tyrosine
kinases which are present on cancer cells. These
glycoproteins, including RET, receive extracellular signals for
processes as diverse as cell growth, differentiation, survival,
and programmed cell death (Figure 1). In response to binding
of extracellular ligands, receptor tyrosine kinases generally
form homodimers or heterodimers. On dimerization,
autophosphorylation occurs, followed by intracellular signal
transduction through effectors that recognize and interact
with the phosphorylated form of the receptor tyrosine kinase.
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Extracellular ligands (eg, VEGF)
Growth factor receptor (eg, VEGF, RET)
Growth factor pathways resulting in cell growth, angiogenesis, metastasis, apoptosis
Although the downstream signaling pathways activated
by these steps may be shared by different receptors, the
ligand-receptor interaction itself is very specific. However,
in some cases, high-affinity ligand-receptor tyrosine kinase
interactions can be modulated by the presence of other,
low-affinity, nonsignaling accessory molecules at the cell
The VEGFR pathway is also important in the pathogenesis
of MTC.15 Three transmembrane receptors mediate the
angiogenic and lymphogenic effects of VEGF, ie, VEGFR-1,
VEGFR-2, and VEGFR-3. Of these, VEGFR-2 is believed
to play the primary role in endothelial cell proliferation,
migration, survival, and induction of vascular permeability
characteristic of neovascularization required for tumor
growth and metastasis. VEGF proteins secreted by the
tumor cell act as ligands for the VEGFR, and a complex
feedback loop is involved in the stimulation of angiogenesis
Description of vandetanib
(N-[4-bromo-2-fluorophenyl]-6-methoxy-7[(1-methylpiperidin-4-yl) methoxy] quinazolin-4-amine) is
an oral anilinquinazoline compound with a molecular weight
Pathways involving Src, PI3K, PIP
Cell survival Actin reorganization
VEGFA, VEGFC, VEGFD
Pathways involving Ras, Raf, MEK
Gene expression Cell proliferation Vascular cell permeability
of 475 Da. It competes with ATP binding in the catalytic
domain of several tyrosine kinases. Recombinant enzyme
assays have shown it to be a potent inhibitor of VEGFR-2
(50% inhibitory concentration [IC50] 40 nM), with additional
activity against VEGFR-3 (IC50 110 nM), epidermal growth
factor receptor (IC50 500 nM), and RET (IC50 130 nM)
kinases. Further studies on human umbilical vein
endothelial cells have found vandetanib to be a potent inhibitor of
proliferation of VEGFR-stimulated cells (IC50 60 nM) with
higher doses necessary for epidermal growth factor
receptorstimulated human umbilical vein endothelial cell
proliferation (IC50 170 nM). Vandetanib showed excellent selectivity
for these kinases compared with related receptor tyrosine
kinases, such as platelet-derived growth factor receptor-β and
c-kit.17–19 This activity profile made it an attractive choice as
a treatment for patients with unresectable MTC.
Clinical studies involving vandetanib
Phase i studies
Phase I studies helped to establish the recommended dose
of vandetanib. The first 77 patients were enrolled in the US
and Australia. Adult patients with malignant solid tumors
who were refractory to standard treatments or for whom no
standard treatment existed were treated with a single oral
vandetanib dose ranging from 50 mg to 600 mg, followed
by a 7-day observation period (cycle 0). At the end of this
period, they received once-daily treatment at the same dose
level as cycle 0 for 28 days, and continued to receive further
28-day cycles until evidence of progression or dose-limiting
toxicity. Seventy-six patients had at least one adverse event,
most occurring for the first time during the initial 28-day
treatment period. The most common drug-related adverse
events were diarrhea (n = 29), rash (n = 26), nausea (n = 15),
hypertension (n = 14), fatigue (n = 14), anorexia (n = 10),
acneiform rash (n = 9), and maculopapular rash (n = 8).
Drug-related adverse events that led to treatment
discontinuation were congestive heart failure, follicular rash, folliculitis,
and prolonged QT interval (all n = 1).
There were 43 dose-limiting toxicities reported, 27 of
which occurred during the dose-escalation phase and 16
during the cohort expansion phase. Most of the 14
doselimiting toxicities reported within the first 35 days of the
study (cycles 0 and 1) were at the 500 mg and 600 mg doses;
three of eight patients at each dose experienced four and
seven dose-limiting toxicities, respectively. Asymptomatic
QTc prolongation was seen at the 500 mg and 600 mg dose
levels; consequently, 300 mg was the highest dose used
during the cohort expansion phase of the study. Seven
patients experienced QTc prolongation, although all
occurrences were asymptomatic (n = 1 in the 100 mg, 300 mg,
and 600 mg groups, and n = 2 in the 200 mg and 500 mg
groups). Pharmacokinetic studies in this trial showed
vandetanib to be extensively distributed, with a half-life of
approximately 120 hours and a minimum of 28 days of
continuous oral dosing required to achieve steady-state plasma
concentrations.20 The second Phase I study was conducted
in Japan, and enrolled 18 patients.21 Again, 300 mg daily
was determined to be the recommended dose, with a similar
toxicity profile and pharmacokinetic findings.
Studies involving vandetanib and MTC
Single-arm Phase ii studies
Germline mutations of RET cause the hereditary forms of
MTC. Because RET is one of the main targets of vandetanib,
two single-arm Phase II clinical trials were developed to
evaluate the clinical utility of this agent in hereditary MTC
(see Table 1). The first of these studies enrolled patients
with unresectable, locally advanced, or metastatic MTC
with a confirmed clinical diagnosis of MEN 2A, MEN 2B,
or familial MTC and a germline RET mutation. They were
treated at an initial dose of 300 mg daily. Inclusion criteria for
this study included at least one measurable lesion according
to Response Evaluation Criteria in Solid Tumors (RECIST)
guidelines, World Health Organization performance status
0–2, and adequate cardiac, hematopoietic, hepatic, and renal
function. This was an open-label Phase II study conducted at
seven centers worldwide, and patients received vandetanib at a
daily dose of 300 mg until progression of disease, withdrawal
of consent, or unacceptable toxicity. The primary endpoint
was objective response by RECIST, and secondary endpoints
included duration of response, disease control,
progression.vdoep lsyeon fsreereumsulrevvievlaslo,fscaafelctyit,oannindatnodletrhaebgilliytyc,opasrowteeinll
/ww lan onic antigen, which are both secreted by MTC cells. Thirty
tsp rse patients were enrolled from November 2004 to August 2006,
rom oF and at the time of data cutoff (February 22, 2008), 17 patients
fd were still continuing on treatment. Four patients had disease
ade progression by RECIST but were reaping clinical benefits and
lnow allowed to remain on study. The remaining patients
disconydo tinued vandetanib because of adverse events (n = 7), disease
rpae progression (n = 4), or withdrawal of consent (n = 2). The
hT majority of patients had MEN 2A disease, and 29 of the 30
and had evidence of metastatic disease at presentation. Twenty
trseg percent of subjects (n = 6) achieved a partial response, and
oaT another 53% had stable disease for more than 24 weeks.
cnO The median duration of response was 10.2 (range 1.9–16.9)
months, confidence interval (CI) 8.0–13.2 months. The
majority of patients (80%) had reductions in calcitonin levels to less
than half their baseline values for at least 4 weeks.22
The second of the two Phase II trials had similar
eligibility criteria. However, in this study, a lower dose of the drug
(100 mg) was chosen as monotherapy in patients with locally
advanced or metastatic familial forms of MTC. The primary
objective again was to assess the objective response rate with
vandetanib, according to RECIST criteria. In this study, if
disease progression was noted on imaging, a post-progression
treatment phase was allowed. If the investigator believed
that there may have been clinical benefit from therapy, then
patients could enter post-progression treatment with
vandetanib at a higher dose of 300 mg/day until objective disease
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progression occurred at this dose, or until another withdrawal
criterion was met. Nineteen patients were recruited between
August 2006 and May 2007; initially, all received 100 mg
daily. At the time of data cutoff, 11 were continuing on this
dose, and the remaining patients had discontinued initial
treatment. Four of these patients had disease progression, and all
entered post-progression treatment with vandetanib 300 mg
daily. There were no complete responses; three (16%) were
partial responders, and 10 patients had stable disease for
24 weeks or longer. In this study, disease control was seen in
68% of all patients (including complete and partial responders
and those who had stable disease for longer than 24 weeks).
Toxicities were manageable in both trials, with the most
common adverse events being diarrhea, rash, and asymptomatic
QTc prolongation on electrocardiogram. Seven patients in the
trial using 300 mg discontinued treatment because of adverse
events, five of which were felt by the investigator to be related
to vandetanib (acne, hemorrhagic diarrhea, QTc prolongation,
abnormal renal function, and nausea).23 Although it could be
seen from both trials that 100 mg and 300 mg daily of
vandetanib had activity in this disease, no direct comparison of
these dose levels has been conducted. The level chosen for
the randomized placebo-controlled study was 300 mg daily.
Phase ii/iii randomized placebo-controlled trial
The encouraging results of these single-arm trials spurred
accrual onto an international randomized Phase II/III trial
known as ZETA (Zactima Efficacy Study versus Tarceva)
comparing ZD6474 (vandetanib) and placebo in patients with
inherited and sporadic forms of MTC.24 In this large trial,
331 adults with unresectable locally advanced or metastatic
MTC were randomized in a 2:1 manner to receive either
ZD6474 at a dose of 300 mg daily, or placebo. Between
December 2006 and November 2007, 231 subjects were
assigned to vandetanib and 100 received placebo. The
majority of patients had sporadic disease (90%), metastatic disease
(95%), and tumors that were positive for a RET mutation
(56%). Patients were followed until disease progression, at
which time they were unblinded and had the option to receive
vandetanib in an open-label trial; if they chose open-label
vandetanib, they were then followed for survival. The median
duration of treatment was 90.1 weeks in the vandetanib arm
and 39.9 weeks in the placebo arm. The primary objective
of the ZETA study was demonstration of improvement in
progression-free survival on vandetanib compared with
placebo. Other endpoints included evaluation of overall
survival and objective response rate.
Two-year follow-up results showed that 37% of the
patients had progression, and 15% had died. The primary
endpoint of the study, ie, progression-free survival, was
met, with the researchers reporting a hazards ratio (HR)
of 0.46 (95% CI: 0.31–0.69). The median progression-free
survival was 19.3 months in the placebo group, and had not
yet been reached in the vandetanib arm at the time of data
presentation at the 14th International Thyroid Congress in
2010. A significant improvement in progression-free survival
was observed for patients randomized to receive vandetanib
(HR: 0.35, 95% CI: 0.24–0.53; P , 0.0001). While the
progression-free survival data led to United States Food and
Drug Administration (FDA) approval, no significant overall
survival difference was noted in the two arms because of the
crossover design of the study.
Vandetanib was also associated with statistically
significant advantages in the secondary endpoints, such as objective
response rate (45% vs 13%; odds ratio [OR]: 5.4); disease
control rate of 24 weeks or more (OR: 2.64); calcitonin
biochemical response (OR: 72.9); carcinoembryonic antigen
biochemical response (OR: 52); and time to worsening of
pain (HR: 0.61). Some of the radiological responses were
dramatic. At this time, it is not known whether any
biochemical, radiological, or clinical parameters significantly predict
response. Data are also not yet available on whether certain
metastatic sites respond better than others. In the placebo arm,
12 of 13 responses occurred after the patients had received
open-label vandetanib. Adverse events were more common
with vandetanib than on placebo, including diarrhea (56%
vs 26%), rash (45% vs 11%), nausea (33% vs 16%),
hypertension (32% vs 5%), and headache (26% vs 9%). The most
severe toxicities were QT prolongation, torsades de pointes,
and sudden death, which are addressed in a boxed warning
in the prescribing information.
Based on these results, Astra Zeneca filed for FDA approval
of the drug in the US and the European Medicines Agency in
Europe late in 2010, receiving an orphan drug designation by
the FDA on December 2, 2010, with final approval granted
on April 6, 2011.25 The approval was specifically for patients
who are ineligible for surgery and have disease that is growing
or causing symptoms. The benefits of the drug in patients
who have occult or micrometastatic disease but with a rapid
calcitonin doubling time are not known.
The severe cardiac side effects mentioned previously are
addressed in a boxed warning in the prescribing information.
Vandetanib has a prolonged half-life of 19 days, so
electrocardiograms and levels of serum potassium, calcium, magnesium,
and thyroid-stimulating hormone are recommended to be
obtained at baseline, at 2–4 weeks, and at 8–12 weeks after
starting treatment, and every 3 months thereafter as long as the
patient remains on treatment. As a result of the FDA concern
about toxicity, only US prescribers and pharmacies certified
through the Vandetanib Risk Evaluation Mitigation Strategy
(REMS) program, ie, a restricted distribution program, are
able to prescribe and dispense vandetanib.
Clinical utility of vandetanib in the treatment of MTC
Vandetanib became the first systemic agent to be approved
for the treatment of locally advanced or metastatic MTC.
Therefore, it represents a new standard of care for these
patients. However, MTC can be an indolent disease, and
subsequent studies have demanded that patients have
radiographic progression of disease prior to enrollment, such as
the randomized Phase III study of XL-184. Some patients
may have a symptom-free existence for many years on
observation alone, and therefore are unlikely to gain much
benefit from the addition of a systemic agent. The potentially
serious cardiac side effects call for caution in prescribing this
medication to otherwise asymptomatic individuals. The less
serious but quality-of-life altering effects, such as acneiform
rash and nausea, also deter some patients and physicians
from starting the drug immediately on signs of
biochemical progression of disease. The high cost of a new tyrosine
kinase inhibitor is also likely to limit the number of patients
who may have access to this medication. However, some
patients could gain significant benefit; these include those
with clear radiographic progression or significant symptoms
related to their disease, those who have no or limited cardiac
histories, and those who are reliable enough to comply with
close follow-up. By closely monitoring of electrolyte levels
and electrocardiograms, the authors have found it possible to
avoid any cardiac events in their patient population to date.
Resistance may also arise in tumors exposed to vandetanib.
The authors speculate that there may be many reasons for
this, including new molecular abnormalities involving RET
or other receptors, such as loss of expression, genomic
amplification, or the activation of alternative downstream
signaling pathways. Further work needs to be done to
elucidate which of these is most important. The combination
of vandetanib and other drugs may help delay or overcome
some resistance mechanisms. Many such drugs have been
evaluated in MTC and other forms of thyroid cancer with
varying degrees of success.26–35
Vandetanib has emerged as an effective targeted therapy in
the treatment of MTC. Its recent FDA approval for patients
with metastatic or unresectable disease is a landmark in
the history of this condition. Its development as a targeted
agent and the results of Phase II and randomized studies
have become a proof of principle. Future studies involving
combinations with other systemic agents are eagerly awaited
and may further improve upon the significant results seen to
date with this agent.
HAD sits on the advisory board for Astra Zeneca (mock
Oncologic Drugs Advisory Committee meeting).
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