Axitinib: The evidence of its potential in the treatment of advanced thyroid cancer
Axitinib: The evidence of its potential in the treatment of advanced thyroid cancer
Hari A Deshpande 1
Scott Gettinger 1
Julie Ann Sosa 0
0 Division of Endocrine Surgery, Department of Surgery, Yale University School of Medicine , New Haven, CT , USA
1 Yale Cancer Center, Department of Medical Oncology
s. One phase II study has been published. This included patients with any histological type of thyroid cancer that was not amenable to treatment with radioactive iodine. Clinical potential: To date, in phase II clinical studies axitinib has demonstrated antitumor activity in advanced refractory thyroid cancer. As a monotherapy it resulted in a 30% response rate with another 38% of patients having stable disease. Axitinib appears to have a good tolerability profile, with hypertension being the most common grade 3 or greater side effect.
axitinib; thyroid cancer; vascular endothelial growth factor receptor
open access to scientific and medical research
Potential to use as monotherapy at a dose of 5 mg
twice daily; stable disease achieved in 38% of patients
and progression-free survival of 18.1 months
Evidence of activity with overall response rates of 30%
Decreases levels of soluble vEGFr 2 and 3. Blood
pressure elevation may correlate with response
w ell tolerated, with hypertension, fatigue, and
proteinuria as the most common grade 3 side effects
Abbreviations: vEGFr, vascular endothelial growth factor receptor.
Scope, aims, and objectives
Thyroid cancer is a relatively rare disease with an incidence of 37,340 cases per year.
It retains an excellent prognosis with a mortality of only 1,590 per year.1 However,
its incidence is rising and for men this disease ranks highest overall in the rate of
increase (2.4% annual increase) in cancer deaths.2 Radioactive iodine continues to be
the initial treatment for differentiated thyroid cancer with distant metastatic disease
and can produce five-year overall survival rates of around
50%. The more aggressive variants as well as anaplastic and
medullary subtypes of thyroid cancer however need better
treatments to improve survival, and many agents have now
shown some promise in clinical trials.3
Axitinib is an oral, potent, and selective inhibitor of
vascular endothelial growth factor receptors (VEGFR) 1, 2,
and 3. Axitinib was more than 10-fold less potent in inhibiting
platelet-derived growth factor receptor beta (PDGFR) and
c-KIT in cell-based assays.4 Thyroid cancers have elevated
levels of VEGF compared with normal controls. Axitinib is
one of a number of inhibitors of the VEGF pathway being
studied in the treatment of thyroid cancers. The objective
of this review is to evaluate the potential role of axitinib in
the treatment of advanced thyroid cancers. Current options
for the treatment of thyroid cancer, and the molecular basis
underlying the use of tyrosine kinase inhibitors, are also
rep se Methods
.dow rsona The English language medical literature was searched for
relevant articles related to the use of axitinib in advanced
:tsp oF thyroid cancer. The search terms used were “Axitinib or
th AG-013736,” “thyroid cancer” and the articles published
from covered a period between 1998 to September 2008. The
edd following databases were used:
lnao • PubMed (http://www.ncbi.nlm.nih.gov/entrez)
dow • National Cancer Institute (http://www.cancer.gov/)
cen • Clinical Evidence (BMJ) (http://www.clinicalevidence.
reE • Clinical Trials (http://www.clinicaltrials.com/)
oC The annual scientific sessions from the American Society
of Clinical Oncology (ASCO), European Society of Medical
Oncology (ESMO), American Association of Cancer
Research (AACR), and American Thyroid Association
(ATA; Thyroid) were searched for relevant meeting
abstracts. A total of 27 articles were identified from those
represented by systematic review. Articles were excluded
because they were considered not relevant (Table 1). Two
papers were identified5,6 replacing or supplementing earlier
Few studies were identified for axitinib use specifically
in thyroid cancer, but many references investigated its use
and safety in the treatment of other malignancies with and
No health economics publications were found. One
quality of life publication was found although it was for a
different disease group.
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Thyroid cancer is rare compared with other solid malignancies.
It is the sixth most common cancer in women with an
incidence of about 28,000 cases per year, but in men affects
less than 10,000 individuals per year in the United States.1
Although relatively rare, the incidence of thyroid cancer more
than doubled between 1984 and 2004 in the United States.
Between 1995 and 2004, thyroid cancer was the third fastest
growing cancer diagnosis, behind only peritoneum,
omentum, and mesentery cancers and “other” digestive cancers.
Similarly dramatic increases in thyroid cancer incidence have
also been observed in Canada, Australia, Israel, and several
European countries.7 The factors underlying this epidemic
are not well understood, but may be partly a result of better
screening and diagnosis with fine needle aspirations.8
Thyroid cancers arise from two cell types. The follicular
cells give rise to the differentiated and undifferentiated types.
Differentiated thyroid cancers account for 85%–95% of cases
and consist mainly of papillary and follicular subtypes. The
poorly and undifferentiated category includes anaplastic
thyroid carcinoma, paradoxically one of the most
aggressive and chemotherapy-resistant tumors known in humans.9
Parafollicullar or C cells are the cell of origin for medullary
thyroid carcinoma, which may be familial or sporadic.
The epidemiology of thyroid cancer is unclear in the
majority of cases but environmental and genetic factors
are thought to contribute to an increased risk; these include
environmental goiter, radiation exposure, and, in the case of
medullary thyroid cancer, autosomal dominant inheritance.8
Differentiated thyroid cancers have an excellent
prognosis when treated at an early stage and, even in cases
of metastatic disease, patients can live for many years. The
excellent survival of patients with thyroid cancer as well as
the relatively low incidence of the disease has meant that
it is probably not a significant economic burden on health
care systems, although no published data could be found
to confirm this. However, the incidence of the disease as
mentioned is rising faster than almost any other cancer and
therefore, if more aggressive variants continue to emerge,
the toll on society is also likely to increase.
Current therapy options
Surgery plus radioactive iodine therapy has remained the
standard treatment for early and locally advanced
differentiated thyroid cancer. Several groups have demonstrated
a survival advantage in patients treated with a total or
near-total thyroidectomy followed by radioactive iodine
treatment. The question of neck dissection is not as clear
and probably should be reserved for patients with
clinically positive nodes.10 Advanced metastatic thyroid cancers
that are refractory to radioactive iodine have traditionally
been treated with doxorubicin, platinum agents, taxanes, or
combinations of the above based on little data.11 Cancers that
are refractory to radioiodine have a poor prognosis with a
10-year survival rate of around 15%.12 Currently doxorubicin
is the only systemic agent approved for the treatment of
metastatic thyroid cancer. In a randomized trial comparing
doxorubicin 60 mg/m2 with the same dose of doxorubicin
plus cisplatin 40 mg/m2 administered every three weeks a
complete response was achieved in five of 43 patients. There
was no difference in survival between the arms, but of the
patients who had a complete response, two had a long-term
survival.13 This impressive response rate however, was
unable to be replicated in future studies and it soon became
clear that new approaches to treatment were needed.
As mentioned earlier, thyroid cancers have elevated levels
of VEGF compared with normal controls, and this pathway
has become a target for some of the new small molecule
inhibitors. VEGF proteins are important mediators of
angiogenesis and it was felt that by inhibiting this pathway either
with antibodies, inhibitors of the receptor tyrosine kinase or
downstream proteins, it would be possible to treat resistant
thyroid cancers. The recent explosion of multitargeted
inhibitors in medical oncology has resulted in many of them being
tested in refractory thyroid cancer. Motesanib (AMG 706)
is a novel oral inhibitor of VEGF receptors, platelet-derived
growth factor receptor, and KIT. It was tested in a phase II
study in 93 patients who had progressive, radioiodine
refractory, differentiated thyroid cancer. The authors noted a 14%
response rate with 67% of patients achieving stable disease
(35% for 24 weeks or longer).14 The major side effects appeared
to be hypertension and fatigue. Although this agent is not yet
approved for treatment, it also represents a proof of concept
and should lead to its use in confirmatory clinical trials.
The B-type Raf kinase (BRAF) in the mitogen-activated
protein signaling pathway plays a key role in thyroid cancer.
One common mutation occurs in about 29%–66% of
papillary thyroid cancers.15 Sorafenib is a multi-tyrosine kinase
inhibitor whose targets include BRAF and VEGFR 1 and 2
and has been studied in patients with advanced papillary
thyroid cancer. Sorafenib activity was studied using
immunohistochemistry (IHC) for pERK, pAKT, and pVEGFR-2.
BRAF mutation status was determined by DNA sequencing.16
Of the first 15 patients treated, five patients achieved a partial
response, three had stable disease, two progressed, and three
patients with stable disease withdrew due to toxicity. Target
lesions decreased on average 31%. Eight of 10 PET scans
showed decreased activity at four weeks. IHC on tissue from
two patients showed 50% decrease in pERK (downstream
of VEGFR2 and BRAF) and 30% decrease in pAKT
(downstream of VEGFR2). In tissue from a patient at 17 months on
sorafenib, the decrease in pERK and pAKT appeared to be
the same or reversed, suggesting compensatory changes in
these pathways in resistant but stable disease. In conclusion,
this study showed the early clinical and biologic activity of
sorafenib in patients with mPTC and the targets of early
suppression. Importantly, it also revealed compensatory
changes in target molecules in cells resistant to therapy.
These cells are the likely source of tumor resistance that has
been seen to develop to other similar targeted agents.16 When
patients with all types of thyroid cancer were treated with
this agent, the results were equally impressive although the
majority of cases had either follicular or papillary subtypes.
Thirty patients were treated with a response rate of 23% and
a stable disease rate of 53%. The median progression-free
survival was 79 weeks.6 Phase II studies are currently still
enrolling patients with other subtypes of thyroid cancer
using this agent.
Targeted therapy with agents similar to the ones mentioned
above appear to be useful in metastatic thyroid cancer treatment.
Axitinib is a multitargeted agent against the VEGF receptors
1, 2, and 3 and will be evaluated further in this paper.
Outcomes achieved in clinical development
Axitinib is one of a number of new targeted therapies being
evaluated in the treatment of many cancers. It inhibits
the VEGF receptors at subnanomolar concentrations and
also inhibits PDGFR-beta and c-Kit in low nanomolar
concentrations. In a phase I trial designed not only to find
the maximum tolerated dose, but also to look at the effect
of food on pharmacokinetics, the planned starting dose
of 30 mg twice daily was found to be too toxic.17 A dose
de-escalation scheme determined the recommended dose for
phase II trials to be 5 mg twice daily. Not surprisingly,
the effect of food was found to decrease both the rate and
018 extent of absorption and there was a median increase of 49%
l-u2 in the plasma exposures of the fasted compared with fed
-J21 state. In the presence of a proton pump inhibitor, rabeprazole,
no2 the rate but not the extent of absorption was decreased, and
.71 so the concurrent use of this group of medications was felt to
.163 be not clinically significant. Twelve-hour urinary collections
.437 obtained on days 1 and 29, demonstrated that less than 1%
y5b of the administered dose appeared as unchanged drug in the
/ urine regardless of dose, indicating that the majority of drug
.cssom l.yno elimination was through systemic metabolism. The primary
rep se dose limiting toxicity was hypertension. This appeared to be
.dow rsona dose-related and was controlled easily with antihypertensive
medications. However, it was occasionally severe, and in the
:tsp oF first cohort at a dose of 30 mg before hypertension guidelines
th were established, two patients suffered seizures although they
from recovered without sequelae. In the 14 patients treated at the
ded recommended phase II dose, six developed hypertension,
ldonoaw abnuttiihtywpaesrtneontsidvoesem-leimdiictiantgioannsd. Iwnatesrceosntitnroglllye,dnboy sshtainftdsaridn
ivcdene trhenatina,xaintigniiobt-einndsiunceIId, hoyrpaeldrtoesntseiroonneiswneorte mseeedni,atseudggbeysttihnigs
reE pathway. One patient who had thyroid cancer had a reduction
oC of tumor burden, but did not meet the RECIST criteria for
Based on these encouraging data, a phase II trial was
performed using axitinib given at a dose of 5 mg twice daily in
patients with all types of aggressive incurable thyroid cancer.5
Patients with hemoptysis and uncontrolled hypertension were
excluded from this study. In total, 60 patients were enrolled, 30
with papillary, 15 with follicular, and 11 with medullary cancer.
A partial response was noted in 18 patients giving an overall
response rate of 30%. Stable disease was reported in another
23 (38%) and four patients (7%) had progressive disease as
their best response. With a median follow up of 16.6 months,
the median progression-free survival is 18.1 months which
correlates well with the other small molecule studies
mentioned above. The results were even more impressive as
most of the patients enrolled were men and had metastatic
disease, both poor prognostic factors. The most common
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adverse effects were fatigue, diarrhea, nausea, anorexia, and
hypertension. Of these, hypertension was the most common
grade 3 side effect, occurring in 12% of patients.
The effect of axitinib on soluble proteins as exploratory
pharmacodynamic markers was also studied. Treatment with
axitinib led to a 2.8-fold increase in mean VEGF
concentrations that generally reached a plateau by week 12. In contrast,
there was a 32% decrease in mean sVEGFR-2
concentrations, 35% decrease in mean sVEGFR-3 concentrations,
and 13% decrease in mean sKIT concentrations in blood by
week 12 compared with baseline. The decrease in sVEGFR
reached a plateau within the first 12 weeks of treatment and
was sustained for the duration of therapy in most patients.
Given the paucity of patients with progressive disease, it was
not possible to make a definitive assessment of the potential
correlation of changes in sVEGFR-2 or sVEGFR-3 with
objective response. However, these data demonstrate the
selectivity of axitinib for modulating soluble VEGFRs versus
sKIT in patients with thyroid cancer.
Calcitonin and thyroglobulin were both measured in
subsets of patients in this study. Calcitonin was measured in
seven patients with medullary thyroid cancer: two patients
with progressive disease, three patients with stable disease,
and two patients with partial response. Patients with
progressive disease did not have a change in calcitonin
concentrations; those with partial response had a marked decrease in
calcitonin concentrations and patients with stable disease
had a slight decrease in calcitonin.
Thyroglobulin was measured in two patients with
progressive disease, 11 patients with stable disease, and eight
patients with partial response. The preliminary assessment
demonstrates that most patients, regardless of their clinical
response to therapy, had initial decreases in thyroglobulin.
However, because of the small number of patients with
progressive disease in this trial, no definitive conclusions
could be made for either calcitonin or thyroglobulin with
regard to their utility as potential biomarkers of response
For the most resistant thyroid cancers, monotherapy
with axitinib may not be sufficient to control the disease.
Chemotherapy has been used with some success in earlier
thyroid cancer studies and therefore a combination of axitinib
chemotherapy may represent another possible treatment
option. Although these combinations have not been tested
in the setting of thyroid cancer, they have been evaluated in
other diseases. In two phase I studies reported at the 2008
ESMO meeting, axitinib was combined with a variety of
chemotherapy regimens including FOLFOX and FOLFIRI in
gastrointestinal malignancies and taxane-, capecitabine-, or
gemcitabine-based treatments in a variety of solid
malignancies. In both studies, the pharmacokinetics were not affected
by the addition of chemotherapy and the toxicities were not
increased.18,19 More involved studies have also explored
axitinib chemotherapy combinations with other new agents
including a PDGFR inhibitor CP-868,596 combined with
docetaxel and axitinib. Once again, the combination appeared
safe, pharmacokinetic interactions were not observed, and
antitumor effect was noted.20 Similar results were seen when
axitinib was combined with FOLFOX and bevacizumab.21
In these days of exotic correlative markers, an intriguing
retrospective analysis of the axitinib trials performed to
date noted that patients who developed hypertension with a
diastolic blood pressure of greater than 90 mmHg had a better
survival than those whose did not become hypertensive. This
appeared to be true for all tumor types, and in the case of
thyroid cancer, the difference was 21.9 months survival for
the nonhypertensive group compared with overall survival
not reached for the hypertensive group of responders.22
Axitinib is currently being studied in an ongoing phase II trial
in patients with metastatic thyroid cancers which are
refractory to or ineligible for radioiodine therapy (NCT00176748).
Another trial is currently enrolling patients who have
131I-Refractory metastatic or unresectable locally-advanced
papillary, follicular, or Hurthle-cell thyroid cancer who are
also refractory to, or intolerant of, or have clinical
contraindication to, doxorubicin treatment (NCT00389441).
Doxorubicin remains the only US Food and Drug Administration
(FDA)-approved treatment for iodine-refractory metastatic
thyroid cancer and if this study meets its accrual expectations,
it will be the largest study using the new small molecule
inhibitors in this disease to date.23
Thyroid cancers are rising in incidence faster than most other
cancers, and therefore even though they remain a relatively
uncommon disease today, in future their management could
potentially become increasingly important to
endocrinologists and medical oncologists. As the numbers of cancers
increase, so do the numbers of patients who have aggressive
refractory disease. Agents such as axitinib appear to have a
toxicity profile that is much more favorable than the standard
chemotherapy options that are currently available for use
in this disease. Therefore, axitinib and similar compounds
could potentially find themselves in increasing demand if
the current trend of increasing numbers of thyroid cancer
Age and male gender appear to be the two main poor prognostic
factors in patients with thyroid cancers and therefore this is
probably the population who would gain the most benefit from
aggressive treatment of this disease. Younger female patients
can often have a long lifespan often in the presence of widely
metastatic disease. However it is important to take each case
individually and if the disease appears particularly aggressive,
then axitinib should be considered as an option for treatment
when it becomes available. Interestingly, axitinib may also
have a place in the treatment of medullary and anaplastic
thyroid cancers although the numbers of patients with these
subtypes is too small to draw firm conclusions.
Axitinib appears to be a very promising treatment for
patients with aggressive iodine-refractory thyroid cancer.
There are at least two other multitargeted kinase inhibitors
which also have significant activity. It is difficult to compare
these treatments as they have all only been tested in single
arm phase II studies. They all appear to be well tolerated.
Phase III studies will be needed to determine whether these
agents are better than the current standard of care and if they
should be approved for thyroid cancer treatment. Certainly
the toxicity of these agents appears better than that of
traditional chemotherapy, but many of the chemotherapy studies
were performed before modern antiemetics and antibiotics
were widely available.
There have been no quality of life studies with axitinib
when used as a treatment for thyroid cancer. However,
the QLQ-C30 health-related quality of life (HRQOL)
questionnaire was incorporated into a study using axitinib
in patients with renal cell cancer.24 The results were
encouraging and appeared to show that there was an increase
in survival with little or modest change from baseline levels
in the majority of HRQOL domains and symptoms. The one
exception was diarrhea, which appeared to get worse during
treatment, although the average score did not change response
categories to ‘a little’ until 120 weeks, 2.5 years after the
start of treatment, and was still at that approximate level
by 144 weeks. Thyroid cancer and renal cell cancer often
share characteristics of a slowly progressive malignancy
and therefore these results may be applicable when axitinib
is used in the setting of thyroid cancer as well. However,
this may be one of the biggest challenges for the widespread
use of these new small molecule inhibitors, as their initial
cost is likely to be extremely high and many patients are
asymptomatic even with widespread metastatic disease. Any
benefit in survival should also be matched by an improvement
in quality of life, as otherwise the economic burden of the
treatment is likely to be prohibitive. However, the emergence
of axitinib and its fellow compounds as viable options for
treating refractory thyroid cancers represents a remarkable
advance in treating these hitherto resistant tumors.
The authors report no conflicts of interest in this work.
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