Introduction
There have been several advances in the treatment of thyroid cancer over the past
couple of decades. This has been possible due to improvements in diagnostic and
therapeutic modalities and the advent of novel molecular targeted therapies. Thyroid
cancers can be broadly classified based on their cell of origin. The cancers that
arise from the endoderm-derived follicular cells comprise of differentiated thyroid
cancer (DTC) [which in turn comprises of papillary thyroid cancer (PTC) and
follicular thyroid cancer (FTC)], anaplastic thyroid cancer (ATC), and poorly
differentiated thyroid cancer [1 ]. Medullary
thyroid cancer (MTC) arises from the neural crest-derived C-cells [1 ]. Thyroid cancers can occur either
sporadically, or as a part of a genetic or a familial condition [such as familial
non-medullary thyroid cancer, multiple endocrine neoplasia (MEN) 2A and 2B, Cowden
syndrome, Carney complex] [2 ]. Classification
of the various forms of thyroid cancer and their genetic hallmarks is provided in
[Table 1 ].
Table 1 Classification of primary thyroid cancers and their
genetic hallmarks.
A. Based on the cell of origin:
I. Endoderm-derived thyroid cancer:
Papillary thyroid cancer (PTC) BRAF V600E (60% of
disease-causing variants), RAS (15% of
disease-causing variants), RET , EIF1AX ,
PPM1D , CHEK2 , NTRK fusion,
ALK fusion, DICER1 .
Follicular thyroid cancer (FTC, including Hurtle cell
cancer) Genetics (disease-causing variants): RAS ,
PAX8-PPARγ fusion gene.
2. Poorly differentiated thyroid cancer Genetics
(disease-causing variants): BRAF , RAS ,
TERT , EIF1AX.
3. Anaplastic thyroid cancer (ATC) Genetics (disease-causing
variants): BRAF , RAS , TERT ,
EIF1AX , TP53 , CTNNB1 ,
PIKC3A , PTEN , AKT1. Other
disease-causing molecular alterations are found in the
SWI/SNF complex and histone
methyltransferases.
II. Neural-crest C-cell derived thyroid cancer:
Medullary thyroid cancer (MTC) Genetics (disease-causing
variants): RET , RAS , STK11.
B. Based on inheritance pattern:
I. Sporadic (non-inheritable).
II. Familial (inheritable):
Familial non-medullary thyroid cancer (DTC)
DICER1 syndrome (DTC)
Carney complex (DTC)
Multiple endocrine neoplasia type 4 (DTC)
Familial adenomatous polyposis (cribriform-morular
variant of PTC)
Werner syndrome (mainly FTC)
PTEN hamartoma syndromes such as Cowden syndrome (mainly
FTC)
Familial MTC
Multiple endocrine neoplasia type 2A (MTC)
Multiple endocrine neoplasia type 2B (MTC, mainly with
RET M918T disease-causing variant)
DTC: Differentiated thyroid cancer. PTC: Papillary thyroid cancer. FTC:
Follicular thyroid cancer. ATC: Anaplastic thyroid cancer. MTC: Medullary
thyroid cancer. Data adapted from [1 ]
[2 ].
The incidence of thyroid cancer has increased significantly in the United States and
worldwide, driven predominantly by the increased annual incidence of DTC. The
incidence of MTC has been relatively stable [3 ]. While increased DTC incidence has been attributed to sonographic
detection of small PTCs, there is evidence of an increase of all stages of DTC [3 ]
[4 ]. Despite this, the mortality rate has
increased only slightly and has ranged from 0.4 to 0.5 per 100 000 people per year
since 1980 [4 ]. Since the compilation of the
American Thyroid Association (ATA) guidelines on the management of thyroid cancer
in
2015, newer studies have focused on risk stratification and optimization of
individualized therapeutic options in these groups of patients. The updated American
Joint Committee on Cancer (AJCC) 8th edition published in 2017 has suggested new
staging definitions to predict disease-specific survival in patients with thyroid
cancer (www.cancerstaging.org) [5 ]. The
application of newer targeted systemic therapies for subjects with advanced disease,
shared decision-making process, and identification of the optimal timing for
initiation of systemic therapy are being actively investigated. This review provides
a comprehensive overview of the most recent updates in the management of thyroid
cancer [6 ]
[7 ]
[8 ].
Differentiated Thyroid Cancer
About 85% of all thyroid cancers are PTCs, while FTC and Hurtle cell
cancers together make up to 5% of all thyroid cancers [1 ]. Histologically, PTC has several
variants, such as classical, tall-cell, follicular, cribriform-morular variants,
among others. The encapsulated forms of follicular variants have been recently
re-classified as noninvasive follicular neoplasms with papillary-like nuclear
features (NIFT-P) in an attempt to replace the term ‘carcinoma’
as this subset of tumors is indolent [1 ]
[9 ]. Due to the indolent course of DTC in
vast majority of patients, the main challenge is to balance the risks and
benefits of therapies offered to these individuals to avoid over-treatment in
low risk individuals and under-treatment in high-risk patients.
The genetic landscape of PTC is heterogeneous, made of mutually exclusive
mutations involving the mitogen-activated kinase (MAPK) pathway [10 ]. Based on the driving somatic
disease-causing variant present in the tumor, PTC can be classified as either
BRAF V600E -like PTCs and RAS -like PTCs [10 ]. BRAF V600E -like PTCs contain
BRAF V600E as the primary driving mutation (60% of all
disease-causing variants in PTC) and are defined as PTCs with classic papillary
morphology and a high MAPK pathway signaling. RAS-like PTC's contain
RAS as the primary disease-causing variant (~15% of
all PTCs) and are defined as PTCs with follicular morphology and low MAP kinase
pathway signaling [1 ]
[10 ]. Other novel driving disease-causing
variants such as NTRK fusion genes, RET , EIF1AX ,
PPM1D , and CHEK2 have been identified [10 ]. FTCs are associated with RAS
and PAX8-PPARγ fusion disease-causing variants [11 ]. With the advent of targeted therapies
with small molecules, several of these molecular pathways are druggable targets
and have been described in the upcoming sections.
Updates on DTC staging
The 8th edition of AJCC published in 2017 has implemented substantial changes
in the staging of DTC. These changes include: (1) increased age cut-off from
45 to 55 years old at diagnosis, stratifying patients with metastatic
disease to lower versus higher risk of death based on age; (2) changing the
definition of T3 disease eliminating lymph node (LN) metastases and the
minimal extra-thyroidal extension reported on histology, as microscopic
extra thyroid extension is not an independent factor increasing the risk of
death; (3) introducing new categories for T3 tumors – namely T3a
(>4 cm tumors confined to the thyroid) and T3b (gross extra
thyroidal extension into strap muscles); (4) N1 (metastasis to regional LN)
disease no longer upstages to stage III or IV in patients over 55 years, all
patients remain in stage II; (5) change in LN levels: level VII LNs are now
classified as central neck LNs (N1a) along with level VI LNs; and (6) the
presence of distant metastases in older patients with DTC is now considered
stage IVB as opposed to stage IVC as per the previous classifications [5 ]
[12 ]. The goal of the new staging
model is to better reflect the DTC biology and to balance the
patients’ quality of life and the delivery of cost-effective
treatments by down-staging of around 29–38% of patients
[13 ]
[14 ]
[15 ]
[16 ]. An online calculator to stratify
patients based on these new recommendations can be found in the following
website:
https://www.thyroid.org/professionals/calculators/thyroid-cancer-staging-calculator/.
While the AJCC 8th edition assesses the risk of death, the ATA risk
stratification system predicts the risk of persistence/recurrent
disease. According to clinical, pathological and molecular characteristics,
thyroid cancer is classified as either low, intermediate or high risk for
recurrence. This risk stratification aids to individualize surveillance and
treatment [17 ]. The modern risk
stratification systems are dynamic and evolve during follow up, based on
ongoing evaluation of the biochemical and structural response to therapy
[6 ]
[18 ]. The utility of newer models
integrating artificial intelligence have been studied. These systems combine
mortality and recurrence risk stratifications to provide optimal treatment
recommendations in patients with DTC. However, software optimization and
prospective data are needed. Retrospective reviews have demonstrated a
suboptimal concordance rate (77%) between artificial
intelligence-based clinical decision systems and clinician-recommended
management of DTC. The performance of this technology varies among various
populations and the standard of practice in different countries [6 ]
[19 ].
Treatment goals in DTC include minimization of the risk of
persistent/recurrent symptomatic disease, reducing the risk of
cancer-related death while maintaining an optimal quality of life and
minimizing treatment-related morbidity. Given the ability of early disease
detection with improved laboratory and imaging techniques, the main goal is
to identify which patients benefit from active surveillance as the best
treatment strategy and which individuals present with actionable disease
requiring either surgical or medical intervention.
Novel laboratory techniques allows the identification of a molecular
signature of thyroid cancer, particularly BRAF V600E somatic
mutation, in circulating cell free DNA (cfDNA), also known as
“liquid biopsy” [20 ].
The pooled analysis of six studies involving a total of 438 thyroid cancer
patients documented that the average proportion of patients who had both
BRAF V600E disease-causing variant in the tumor, as well as
circulating BRAF V600E , was relatively low (16.5%) thus
limiting its diagnostic utility [21 ].
However, some studies suggest an association between the level of BRAF
V600E -mutated cfDNA and tumor aggressiveness [22 ]. This raises the potential of the
peripheral detection of BRAF V600E -mutated cfDNA as a non-invasive
marker of aggressive disease. In fact, the diagnostic and prognostic utility
of liquid biopsy has been proven in the more aggressive MTC and ATC [23 ]
[24 ]. Further understanding of the
tumoral DNA natural history can refine the clinical utility of this
promising non-invasive technique [25 ]
[26 ].
Current standard of care for DTC
Initial DTC treatment usually involves surgery. A personalized surgical
approach is planned based on the disease burden. While surgical alternatives
range from lobectomy/subtotal thyroidectomy for tumors not exceeding
4 cm to near total/total thyroidectomy with or without LN
dissection for more advanced tumors, active surveillance without a surgical
intervention is a reasonable option for very low risk patients with PTC
[6 ]. Age, comorbidities and life
expectancy should be considered when individualizing treatment, as total
thyroidectomy for older adults with low risk PTC has been associated with
higher incidence of complications and hospital readmissions [27 ]. In fact, a significant proportion
of patients, specifically older individuals with low-risk tumors, may
benefit from active surveillance without a surgical intervention.
In a large proportion of patients, PTCs are identified as either a papillary
microcarcinoma (PMC) or a follicular variant thyroid microcarcinoma, both of
which are defined as tumors of <1 cm in diameter with a
favorable prognosis [1 ]
[28 ]. Due to the indolent course of
the disease, active surveillance is a strategy implemented by several
centers for thyroid nodules up to 1.5 cm in diameter, depending on
individual institutional protocols. Tumors larger than 1 cm and less
than 1.5 cm (T1bN0M0) appear to have a similar course than tumors
<1 cm (T1aN0M0) [29 ].
Conversely, a small subset of patients with PMC develop LN and even distant
metastases warranting early surgical intervention.
The Memorial Sloan Kettering Cancer Center (MSKCC) provides a clinical
decision-making framework in individuals with probable or proven PMC [30 ]. Based on this approach, cases are
classified according to thyroid ultrasound findings, candidacy (ideal,
appropriate, inappropriate) and team characteristics. For example, a patient
older than 60 years of age who has a 1 cm thyroid nodule with
well-defined borders with willingness to follow-up with an experienced
multidisciplinary team within their health system at regular intervals would
qualify as an ideal candidate for active surveillance. [Fig. 1 ] provides an algorithmic
approach for clinical decision-making in PMC patients [31 ].
Fig. 1 Risk stratified approach to decision making in
papillary microcarcinoma. Adopted from Brito et al. (2016) [30 ], and Zanocco et al. (2019)
[34 ].
Active surveillance is defined based on the natural history of these tumors.
Most PMCs grow slowly or remain stable over years, while some can even
shrink over time. Disease progression has been inversely correlated with age
at presentation, with younger patients being more likely to progress. None
of the patients with low risk PMC showed distant metastasis or died from
thyroid carcinoma during the active surveillance period [32 ]. Medical costs and adverse events
from surgery (recurrent laryngeal nerve injury, parathyroid gland damage
and/or anesthetic complications) are higher in patients that undergo
immediate resection. Contraindications for active surveillance include high
risk features: presence of clinical LN or distant metastasis at
diagnosis, signs or symptoms of invasion to the trachea or the recurrent
laryngeal nerve and high grade malignancy on cytology, which includes tall
cell variant and poorly differentiated carcinoma [33 ].
Transition from active surveillance to surgery should be considered when a
thyroid nodule size increases in the greatest dimension by at least
>3mm from initial measurement, in cases where a new suspicious
metastatic LN disease shows cytological evidence for thyroid cancer, and
when tumor volume increases by 50% in three-dimensional measurements
[32 ]
[34 ]. The identification of tracheal
invasion can be challenging, as ultrasound as standalone imaging may not
provide a complete evaluation of tumors located at the dorsal side of the
thyroid. Therefore, the use of computerized tomography (CT) can complement
this evaluation. When a lesion is close to the trachea, clinicians should
carefully examine the angle formed by the tumor surface and the tracheal
cartilage. Acute angles are suitable for active surveillance while obtuse
angles require surgical treatment [31 ]. In order to facilitate clinical decision making, “The
Thyroid Cancer Treatment Choice”, an evidence-based tool has been
designed [35 ]. A prototype is being
tested in two health care systems in the United States. The goal is to
understand the impact of this tool in the shared decision-making process and
treatment decisions for patients with PMCs [35 ]. Active surveillance could be potentially advised as first
line therapy in cases of PMC as it is safe, avoids side effects from
surgery, and reflects a cost effective practice in health care systems [36 ]. The longest and largest experience
from Kuma hospital in Japan demonstrated the safety of this conservative
approach as well as a good quality of life of patients undergoing active
surveillance [37 ].
Updates on Radioactive Iodine (RAI) therapy in DTC
RAI treatment is based on the principle of sodium iodide symporter (NIS)
expressed by DTC cells having the ability of trapping RAI. There are 3
identified goals for the administration of RAI: 1. remnant ablation, to
destroy residual presumably benign thyroid tissue, 2. adjuvant therapy, for
suspected but not identified persistent disease, and/or 3. treatment
of known residual or recurrent disease [17 ]
[38 ]. The 2015 ATA guidelines
recommend RAI therapy for all high-risk patients with RAI-avid disease due
to a mortality benefit, for selected cases with intermediate risk disease,
and does not recommend routine use for low risk patients. The selection of
patients for adjuvant therapy needs to be based on careful multidisciplinary
discussion with the patient [38 ]. It
has been estimated that 10% of patients with thyroid cancer develop
advanced disease, which could become resistant to RAI (refractory disease).
In these cases, the 5-year survival rate can be as low as 10% in
comparison with 56% in cases of metastatic RAI-avid disease [39 ].
The standard treatment of empirically administered doses of RAI to treat
metastatic DTC can lead to suboptimal dosing without tumoricidal effects but
with increased risk of adverse effects. RAI-induced adverse effects include
salivary gland damage, lacrimal duct obstruction, myelodysplastic syndrome
and leukemia [6 ]. It is now clear that
effectiveness of RAI therapy correlates with adequate lesional dosing. The
implementation of lesional dosimetry utilizing Iodine-124 positron emission
tomography/computed tomography (I-124 PET/CT) aids to
individualize treatment. Currently, institutions in the United States (MSKCC
and the National Institutes of Health) and in Germany are studying the
utility of I-124 PET/CT in estimating the absorbed dose to
individual tumoral lesions (ClinicalTrials.gov identifiers NCT03647358,
NCT03841617 and NCT01704586).
Treatment of RAI-refractory thyroid cancer
Over the past several years, researchers have developed an interest to
restore and enhance RAI uptake in metastatic lesions in RAI-refractory
metastatic thyroid cancer. These include therapy with lithium carbonate,
retinoic acid, and more recently with MAPK/ERK kinase (MEK)
inhibitors [40 ]
[41 ]
[42 ]. Activation of a MAP kinase
signaling pathway by various oncogenes (RAS, BRAF and RET) reduces NIS
expression, which is paramount in the iodine uptake process [43 ]. Mouse models have shown that
inhibition of MEK signaling restores TSH receptor, thyroglobulin and NIS
expression [44 ]. A landmark study
documented that pretreatment with the MEK 1 and 2 inhibitor selumetinib
induced RAI uptake to thresholds warranting therapeutic intervention as
measured by I-124 PET/CT lesional dosimetry in 8 out of 20 patients
in RAI non-avid DTC [45 ]. Selumetinib
was particularly effective in patients with somatic N-RAS disease-causing
variants in their tumors [45 ]. The
SEL-I-METRY trial is a phase 2 open study, designed to assess the efficacy
of selumetinib followed by RAI therapy in reversing RAI-refractory thyroid
disease in patients with refractory DTC. It is expected that this study will
lead towards defining a dose threshold for successful treatment, to
individualize administered activity and to minimize toxicity [46 ]
[47 ]. Treatment with trametinib, a
second generation MEK inhibitor, followed by RAI therapy guided by I-124
PET/CT lesional dosimetry is also being investigated in a phase 2
clinical trial (NCT02152995). An individualized patient-tailored approach is
being investigated by another trial where trametinib is given as
pre-treatment for RAI in N-RAS-positive tumors and BRAF V600E inhibitor,
dabrafenib, for BRAF-positive tumors (NCT03244956).
The identification of genetic landscapes and molecular pathways in thyroid
cancer cells allowed development of newer therapies that improve
progression-free survival (PFS) [48 ].
The Food and Drug administration (FDA) has approved two tyrosine kinase
inhibitors (TKIs), sorafenib and lenvatinib, in the management of patients
with RAI-refractory progressive DTC [49 ]
[50 ]. The role of newer systemic
agents has been incorporated by the National Comprehensive Cancer Network
guidelines in the treatment of thyroid cancer, published in March 2019.
Molecular testing can guide systemic treatment with novel small-molecule
kinase inhibitors if a clinical trial is not available or if there is a
contraindication to lenvatinib or sorafenib use.
Dabrafenib/trametinib or vemurafenib off-label use in BRAF
V600E positive status have been proposed. In addition, in cases with
a positive neurotrophic tyrosine receptor kinase (NTRK ) 1–3
or anaplastic lymphoma kinase (ALK ) gene fusion, off-label use of
axitinib, everolimus, pazopanib, sunitinib, vandetanib or carbozantinib have
been described [51 ]. Prospective data
describing patient's quality of life and resistance mechanisms can
potentially allow to further establish of first- and second-line salvage
treatments.
The optimal timing of the initiation of targeted therapies might be
challenging. Lenvatinib and sorafenib were approved for progressive
and/or symptomatic RAI-refractory thyroid cancer not amenable to
localized therapies, including but not limited to external beam radiation,
radiofrequency ablation, embolization or metastasectomy. However, the
therapeutic intervention in patients with cancer-related symptoms might be
already too late. Therefore, to identify the ‘best timing’
of systemic therapy initiation in otherwise asymptomatic patients,
estimation of a time point called ‘the inflection point’ has
been proposed [52 ]. The inflection
point is a period of time where the structural disease progression is
clinically significant, and it is the earliest time point where TKIs can be
considered in asymptomatic patients with metastatic disease [52 ]. This time point can be obtained by
integrating the maximal tumor diameter and the rate of doubling time of the
maximal tumor diameter. Tumor volume doubling times can be calculated using
freely available online calculators from either the American Thyroid
Association
(http://www.thyroid.org/professionals/calculators/thyroid-with-nodules/)
or from the Kuma Hospital
(http://www.kuma-h.or.jp/english/about/doubling-time-progression-calculator/)
[52 ]. However, future clinical
trials are required to evaluate whether initiation of TKIs at the inflection
point is better or worse than initiating before or after that time point
[52 ]. Tuttle et al. have proposed
an algorithmic approach on management of metastatic DTC and the timing of
initiation of TKIs based on tumor diameter doubling time and the percentage
change in tumor diameter per year ([Fig.
2 ]) [52 ].
Fig. 2 Practical assessment for cases with metastatic thyroid
cancer and novel concepts for initiating multi-targeted kinase
inhibitors in radioactive iodine refractory differentiated thyroid
cancer. Adopted from Tuttle et al. (2017) [52 ]. RAI: Radioactive iodine;
TKI: Tyrosine kinase inhibitor.
Potential role of immunotherapy in DTC
DTC has been shown to be infiltrated by several immune cells, including
natural killer cells, lymphocytes, and macrophages, with an enrichment in
the expression of CTLA-4 and PD-L1. The intra-tumoral immune cell density
correlates with BRAF V600E mutation and low thyroid differentiation
scores [53 ]. PD-L1 positivity has been
shown to correlate with LN metastasis, extra-nodal invasion, tumor
recurrence and poor survival in thyroid cancer patients [53 ]. Data on utility of immunotherapy
in DTC is currently lacking and there are several on-going clinical trials
evaluating the role of immunotherapy in DTC. Recently, a non-randomized,
phase 1b trial assessed the safety and efficacy of pembrolizumab, a PD-1
inhibitor in patients with advanced, PD-L1 positive DTC [54 ]. Among the 22 enrolled patients,
the median progression-free survival was 7 months and the median overall
survival was not reached. Two patients had confirmed partial response.
Eighteen (82%) patients experienced adverse events, diarrhea
occurred in 7 patients and 4 patients experienced fatigue, one patient
experienced a grade 3 adverse event (colitis), and no treatment
discontinuation or treatment-related death occurred. Through large-scale
gene expression profiling of PTC, a recent study classified the canonical
BRAF V600E -like PTCs and RAS -like PTCs into 2 clusters:
immunoreactive PTC (characterized by high immune-related gene expression and
immune cell infiltration of the tumor), and immunodeficient PTC
(characterized by low immune-related gene expression and low immune cell
infiltration of the tumor) [55 ].
Potential future investigations could focus on immunotyping PTCs and
targeting immunoreactive PTCs with immunotherapeutic agents.
On-going clinical trials
As of July 2019, a search for the term ‘differentiated thyroid
cancer’ in ClinicalTrials.gov yielded 51 active clinical trials on
DTC. Some of these trials have been listed in [Table 2 ]. Several TKIs are being
investigated in phase 2 and 3 trials, with lenvatinib being the most studied
TKI (NCT03573960, NCT03506048, NCT02702388, and NCT03139747 among others).
TKIs are being studied either as monotherapy or in combination with
immunotherapy (NCT03914300) or with mTOR inhibitors (everolimus;
NCT01263951), or lenalidomide (NCT01208051). Immunotherapy also continues to
be actively investigated. Some of these agents include pembrolizumab
(NCT02973997), atezolizumab (NCT03170960), nivolumab (NCT03914300), and
ipilimumab (NCT03914300). Several trials continue to investigate the
optimization of RAI treatment either as monotherapy (NCT00415233) or in
combination with TKIs (NCT03506048, NCT02393690), cytotoxic agents
(NCT03387943), and BRAF + MEK inhibitors (NCT03244956). An open,
phase 3, non-inferiority trial is currently comparing total thyroidectomy
alone and a combination of total thyroidectomy and prophylactic central neck
dissection to assess the outcomes in patients with low-risk DTC
(NCT03570021).
Table 2 List of currently investigated drugs in clinical
trials for the treatment of differentiated thyroid cancer
(registered under ClinicalTrials.gov).
Drug
Study phase
Study status
Location
NCT ID Number
I. Tyrosine kinase inhibitors:
1. Vandetanib
Phase 3
Active, not recruiting
Multinational
NCT01876784
2. Apatinib
a. Phase 3
Recruiting
China
NCT03048877
b. Phase 2
Recruiting
China
NCT03167385
3. Donafenib
Phase 3
Recruiting
China
NCT03602495
4. Cabozantinib
a. Phase 3
Recruiting
Multinational
NCT03690388
b. Phase 1
Recruiting
Multinational
NCT03170960
c. Phase 2
Recruiting
USA
NCT03914300
d. Phase 2
Active, not recruiting
USA
NCT02041260
5. Lenvatinib
a. Phase 4
Recruiting
India
NCT03573960
b. Phase 2
Recruiting
USA
NCT03506048
c. Phase 2
Recruiting
Multinational
NCT02702388
d. Phase 2
Recruiting
USA
NCT03139747
e. Phase 2
Recruiting
USA
NCT02973997
f. Phase 2
Recruiting
USA
NCT03630120
g. Phase 2
Not yet recruiting
To be decided
NCT03732495
h. Phase 1
Active, not recruiting
Multinational
NCT02432274
i. Phase 3
Active, not recruiting
China
NCT02966093
6. Anlotinib
Phase 2
Active, not recruiting
China
NCT02586337
7. Sorafenib
a. Phase 2
Recruiting
USA
NCT03630120
b. Phase 2
Active, not recruiting
USA
NCT01263951
8. Nintedanib
Phase 2
Active, not recruiting
Multinational
NCT01788982
9. Sulfatinib
Phase 2
Recruiting
China
NCT02614495
10. Sunitinib
Phase 2
Active, not recruiting
USA
NCT00381641
11. Cediranib
Phase 1
Active, not recruiting
USA, Canada
NCT01208051
12. Pazopanib
a. Phase 2
Active, not recruiting
Multinational
NCT00625846
b. Phase 2
Recruiting
France
NCT01813136
II. Immunotherapy:
1. Pembrolizumab
Phase 2
Recruiting
USA
NCT02973997
2. Ipilimumab
Phase 2
Recruiting
USA
NCT03914300
3. Nivolumab
Phase 2
Recruiting
USA
NCT03914300
4. Atezolizumab
Phase 2
Recruiting
Multinational
NCT03170960
III. mTOR inhibitors:
1. Everolimus
Phase 2
Active, not recruiting
USA
NCT01263951
Phase 2
Recruiting
USA
NCT03139747
2. Sirolimus
Phase 2
Recruiting
USA
NCT03099356
IV. Cytotoxic agents:
1. Liposomal doxorubicin
Phase 2
Recruiting
China
NCT03387943
2. Cisplatin
Phase 2
Recruiting
China
NCT03387943
3. Cyclophosphamide
Phase 2
Recruiting
USA
NCT03099356
V. BRAF inhibitors:
1. Dabrafenib
Phase 2
Recruiting
France
NCT03244956
VI. MEK inhibitors:
1. Trametinib
a. Phase 2
Recruiting
France
NCT03244956
b. Phase 2
Recruiting
USA
NCT02152995
2. Selumetinib
Phase 2
Recruiting
USA
NCT02393690
VII. Radioactive iodine therapy:
1.I-131
a. Phase 3
Recruiting
France
NCT01837745
b. Phase 2
Recruiting
USA
NCT03506048
c. Phase 2/3
Recruiting
UK
NCT01398085
d. Phase 2
Recruiting
France
NCT03244956
e. Phase 2
Recruiting
USA
NCT02393690
f. Phase 2
Recruiting
USA
NCT02152995
g. Unknown
Recruiting
Germany
NCT01704586
h. Phase 2
Active, not recruiting
Korea
NCT02418247
i. Phase 3
Active, not recruiting
UK
NCT00415233
VIII. Combination therapies:
1. Everolimus + Sorafenib
Phase 2
Active, not recruiting
USA
NCT01263951
2. Liposomal doxorubicin + Cisplatin
Phase 2
Recruiting
China
NCT03387943
3. Lenvatinib + I-131
Phase 2
Recruiting
USA
NCT03506048
4. Cabozantinib + Nivolumab +
Ipilimumab
Phase 2
Recruiting
USA
NCT03914300
5. Cyclophosphamide + Sirolimus
Phase 2
Recruiting
USA
NCT03099356
6. Everolimus + Lenvatinib
Phase 2
Recruiting
USA
NCT03139747
7. Trametinib + Dabrafenib + I-131
Phase 2
Recruiting
France
NCT03244956
8. Lenvatinib + Pembrolizumab
Phase 2
Recruiting
USA
NCT02973997
9. Cediranib + Lenalidomide
Phase 1
Active, not recruiting
USA, Canada
NCT01208051
10. Lenvatinib + Sorafenib
Phase 2
Recruiting
USA
NCT03630120
11. Cabozantinib + Atezolizumab
Phase 1/2
Recruiting
Multinational
NCT03170960
12. Selumetinib + I-131
Phase 2
Recruiting
USA
NCT02393690
13. Trametinib + I-131
Phase 2
Recruiting
USA
NCT02152995
Medullary thyroid cancer
Medullary thyroid cancer (MTC) accounts for ~3–5% of all
thyroid malignancies [7 ]. However, based
on the Surveillance, Epidemiology, and End Results (SEER) database, the
prevalence of MTC in the United States is in fact slightly lower
(1–2%), and this is attributed to the relative increase in the
detection of PTC over the past 3 decades [56 ]. About 75% of the cases of MTC are sporadic, while the
remaining 25% are hereditary [57 ].
The hereditary forms of MTC can occur as a part of one of the following
syndromes: MEN2A, MEN2B, and hereditary MTC (FTMC) [57 ]. Unlike DTC, MTC is a form of
neuroendocrine tumor which arises from the neural crest-derived parafollicular
C-cells which produce calcitonin, a very specific tumor marker, as well as
smaller quantities of several other peptides among which CEA is used as a
non-specific tumor marker in surveillance of MTC patients [7 ]. The serum levels of both calcitonin and
CEA are usually proportional to the C-cell mass in well differentiated MTC [7 ]. Pathogenic variants of RET
(40–50%), RAS (20%), and STK11
(10–20%) genes are involved in the pathogenesis of sporadic MTC
[58 ]. Interestingly, RET and
RAS (HRAS and KRAS ) disease-causing variants are
usually mutually exclusive [59 ]. The
somatic M918T disease-causing variant in the RET oncogene is the most
common form of mutation seen with sporadic MTCs (>75% of
RET disease-causing variants), and also a main germline
disease-causing variant seen with MEN2B syndrome ([Table 1 ]) [60 ]
[61 ]. The sporadic forms of MTC are
usually observed between the fourth and sixth decades of life [7 ]. In MEN2A patients, MTC can develop
during childhood, but with MEN2B, MTC often develops during infancy and can
follow a highly aggressive clinical course [7 ]. About 1–7% of patients with presumed sporadic MTC
cases in fact have hereditary disease [7 ]
[62 ].
Current standard of care
The latest, revised ATA guidelines for diagnosis and management of MTC from
2015 provide several detailed algorithms for the work-up, treatment, and
follow-up of these tumors [7 ]. Total
thyroidectomy is performed in all patients, and cervical LN dissection is
performed depending on serological, imaging and intra-operative findings
[7 ]. External beam radiotherapy
(EBRT) is provided to the neck if there is evidence of extensive local
disease, residual disease or extra-thyroidal extension [7 ]. Targeted therapy with TKIs
vandetanib or cabozantinib or enrollment into clinical trials is considered
in patients with progressive symptomatic metastatic disease [7 ]. Local cryo-, thermo-, or
chemo-ablation of liver metastases has been also successfully implemented.
The 10-year overall survival in unselected MTC patients is about
75%, but the survival rate is ≤40% among those
patients with locally advanced or metastatic disease [63 ].
The role of tyrosine kinase inhibitors
TKIs are small molecule inhibitors that specifically target and inhibit the
action of tyrosine kinases [64 ]. As
RET is a form of tyrosine kinase receptor, TKIs can inhibit the
phosphorylation of RET protein leading to down-regulation of its downstream
targets and consequent inhibition of tumor growth [64 ]. Over the past couple of decades,
numerous TKIs have been evaluated in the treatment of MTC in phase 1, 2, and
3 clinical trials. Some of the examples include imatinib, gefitinib,
motesanib, sunitinib, sorafenib, axitinib, apatinib, pazopanib, lenvatinib,
vandetanib, and cabozantinib [63 ]
[65 ]
[66 ]
[67 ]
[68 ]
[69 ]
[70 ]
[71 ]
[72 ]
[73 ]
[74 ]
[75 ]
[76 ]
[77 ]
[78 ]
[79 ]. Most of these studies are phase
2 studies, and the partial response rates of these drugs have been variable,
ranging from 0–50%, with many patients demonstrating
prolonged stable disease [7 ]. Two
TKIs, vandetanib (in 2011) and cabozantinib (in 2012) were approved by the
FDA and the European Medicines Agency (EMA) for the treatment of advanced,
progressive, metastatic MTC, based on the evidence of beneficial effects
extending progression-free survival from well-designed phase 3 multicenter
clinical trials [7 ]. As with other
TKIs, the anti-tumor activity of these two drugs stems from their ability to
simultaneously inhibit multiple, but functionally related kinases which
would result in disruption of their associated pathways both in the
parenchymal and stromal components of the thyroid gland [80 ]. The kinases inhibited by these
drugs are: RET, VEGFR, EGFR for vandetanib, and RET, VEGFR, c-KIT and MET
for cabozantinib [80 ].
However, therapy with TKIs is associated with significant adverse effects
most likely due to wide-spread inhibition of RET at
‘off-target’ sites. Moreover, certain forms of RET
disease-causing variants that affect the active enzymatic site of RET, such
as V804L and V804M variants, can render all of the currently known
non-specific RET inhibitors ineffective in treating MTC [80 ]. In fact, the V804 residue in the
RET backbone also corresponds to the gate-keeper position of several other
kinases, including c-KIT, EGFR, PDGFR, and Abl [80 ]. Therefore, utilization of novel
small molecules that selectively target RET rather than multiple kinases has
been investigated in phase 2 clinical trials.
A highly selective, ATP-competitive small molecule RET inhibitor called
LOXO-292 is being studied under phase 2 multinational clinical trials and
patient recruitment is on-going (ClinicalTrials.gov identifiers NCT03157128
and NCT03899792). LOXO-292 demonstrates potent inhibitory effect on a
diverse range of mutated RET proteins even at nanomolar concentrations. In a
proof-of-concept study, orally administered LOXO-292 was utilized to treat a
49-year-old man with metastatic MTC who continued to have progression of
disease in the liver, ascites, and severe tumor-related diarrhea, despite
being on 6 MKI regimens [81 ]. The
patient’s initial surgical tumor specimen contained the founder
M918T RET disease-causing variant, but over time acquired an additional
RET V804M gatekeeper disease-causing variant. After initiation of
the drug at 20 mg twice daily and step-wise escalation of the dose to
160 mg twice daily, the diarrhea, fatigue, and abdominal pain
resolved, serum calcium and CEA levels drastically reduced, and there was up
to 54% radiographic tumor response after 6.9 months of treatment.
Moreover, analysis of circulating cfDNA revealed the suppression of both
RET M918T and V804M variants after treatment. At the conclusion
of the study, the patient continued to be on LOXO-292 and tolerated the
medication well. All of the adverse events were grade 1 and none of these
were attributed to LOXO-292 therapy.
A multi-national, open-label, phase 1/2 study of LOXO-292 is being
carried out in patients with cancers harboring RET activating
mutations (NCT03157128). As of 5th January 2018, the phase 1 study had been
conducted in MTC patients with doses of 20–160 mg of oral
LOXO-292 given in 28-day cycles [82 ].
Although the maximum tolerated dose was not achieved, adverse events were
mainly of grade 1 or 2 (no grade 3 adverse events) and these events were
fatigue, diarrhea, and dyspnea. Radiographic tumor reduction up to
45% was observed in 79% (11 out of 14) of MTC patients,
including 1 patient who was treated previously with 3 TKIs and harbored a
hereditary RET V804M gate-keeper disease-causing variant. A
≥50% decrease in serum calcitonin levels was also observed
in 79% of the patients. Another phase 1/2, multi-center
clinical trial utilizing LOXO-292 is currently recruiting patients aged 6
months to 21 years of age with advanced solid or central nervous system
tumors harboring RET disease-causing variants. Data on MTC patients
is not yet available from this trial (NCT03899792). In addition to the
promising preliminary results, LOXO-292 also possesses several favorable
pharmacokinetic properties, such as high bioavailability, minimal drug
interactions, predictable exposure and attainment of high central nervous
system concentrations, which could potentially make it a powerful, novel
therapy for MTC with RET disease-causing variants [81 ].
BLU-667 is a novel small molecule RET inhibitor that is currently being
evaluated in a global phase I study on MTC and other RET-related solid
tumors (ClinicalTrials.gov NCT03037385). BLU-667 has been designed to target
oncogenic RET alterations, including RET fusions and RET-activating
disease-causing variants such as M918T, C634W, V804L, and V804M [83 ]. When compared with
non-RET-specific TKIs, BLU-667 has demonstrated more potent anti-tumor
activity in in vitro experiments on RET-driven cancer cell lines and in in
vivo murine RET-driven tumor models [83 ].
Clinically, BLU-667 has already demonstrated substantial beneficial effects
in 2 patients with MTC [83 ]. The first
patient was a 27-year-old with highly invasive TKI-naïve MTC which
required emergent tracheostomy, total thyroidectomy, median sternotomy,
total thymectomy and central and bilateral neck dissection from levels I
through IV. TKIs were not considered due to the risk of VEGFR-related
toxicities, predominantly fistula formation. The patient was enrolled in the
BLU-667 clinical trial (NCT03037385) and started on 60mg once daily with an
eventual dose escalation to 300mg once daily. After 28 days of BLU-667
therapy, the serum calcitonin levels dropped by >90%. By 10
months, the patient had confirmed partial response with a 47%
maximal tumor reduction. The clinical status of the patient improved,
resulting in removal of tracheostomy tube and a return to the baseline body
weight. At the time of this report, the patient continued to be on BLU-667
for over 11 months and remained progression free. Only a grade 1 adverse
event of leukopenia was observed which spontaneously resolved. Under the
same trial, another patient, a 56-year-old with MTC that progressed while on
vandetanib was started on BLU-667 at 300 mg once daily dose. After
28 days of starting BLU-667, serum calcitonin and CEA levels were reduced by
>90% and 75% respectively. After 8 weeks, there was
radiographic evidence of tumor reduction by 35% per RECIST 1.1. The
RET 918T circulating cfDNA was undetectable after 56 days. The
medication was well-tolerated with only grade 1 adverse events of nausea and
hyperphosphatemia. At 8 months, a confirmed partial response with
47% maximum reduction was observed and the patient continued to be
on the medication. In an initial data published from the above clinical
trial, a 40% objective response rate was observed in 25 out of 29
MTC patients after a median treatment duration of 4.7 months [84 ]. Most adverse events were grade 1
and included hypertension, peripheral edema, elevated transaminases, fatigue
and constipation [84 ]
[85 ].
The role of immunotherapy in management of MTC
The role of immunotherapy in the treatment of MTC is yet to be fully
explored. Previous studies have identified T-cell infiltration in the MTC
tumors [86 ]. Dendritic cell
vaccination strategies have been previously utilized in the treatment of
MTC. Initial promising results were seen with administration of subcutaneous
injections of calcitonin and CEA loaded dendritic cells into MTC patients
[87 ]. During a mean follow-up of
13.1 months, 43% of the patients (3 out of 7) demonstrated favorable
clinical response with reductions in serum calcitonin and CEA levels, and
one of these patients demonstrated complete regression of liver metastases
and substantial regression of pulmonary metastases. Another study was
performed in a cohort of metastatic MTC patients who were treated with
immunotherapy utilizing autologous dendritic cells loaded with tumor lysates
derived from allogeneic MTC cell lines [88 ]. Three out of 10 patients had stable disease while the
remaining showed progression of disease after a median follow-up of 11
months. In a phase 1 trial, a recombinant yeast-CEA (GI-6207) vaccine was
utilized among patients with metastatic CEA-producing cancers to generate
immune response to CEA resulting in anti-tumor activity [89 ]. However, the only MTC patient in
this study was taken off the study at 3.5 months for a potential toxicity
due to a strong immune response in the areas of metastatic disease.
Currently, several immunotherapy drugs, including pembrolizumab
(NCT03072160, NCT02721732), ipilimumab (NCT03246958), and nivolumab
(NCT03246958) are being evaluated in phase 2 studies for the treatment of
MTC.
Other novel therapeutic options for MTC
MTC, as a neuroendocrine tumor, is known to express somatostatin receptors
(SSTRs) in a subset of tumors and peptide receptor radionuclide therapy may
be of both diagnostic and therapeutic value. A phase 2 clinical trial
evaluated the response, survival and long-term safety of systemic
radiolabeled SSTR-2 analogue Y-90-DOTATOC in patients with metastatic MTC
[90 ]. Out of the 31 patients, only
29% (9 patients) were responders (showed reduction in post-treatment
calcitonin levels). Hematologic toxicity developed in 4 patients
(12.9%) and renal toxicity was seen in 7 patients (22.6%).
Responders had a significantly longer median survival when compared to
non-responders (74.5 months vs. 10.8 months, respectively) from the time of
treatment initiation [90 ]. In another
trial, 7 MTC patients were treated with Lu-177-DOTATATE based on
In-111-DTPA-octreotide uptake, out of which 3 patients had partial response,
3 patients had stable disease, and 1 patient had progressive disease [91 ]. A retrospective study on 10
consecutive patients treated with Lu-177-octreotate revealed stable disease
in 4 patients and progressive disease in 6 patients [92 ]. Those patients with stable disease
had a high uptake on In-111-DTPA-octreotide scan and an immunohistochemical
evidence of SSTR-2 positivity. Radio-immunotherapy with bi-specific
monoclonal antibodies, I-131-labeled bivalent hapten have shown initial
promising results but their efficacy has not been tested in randomized,
placebo-controlled trials [7 ]. The
recent ATA guidelines on MTC recommend utilization of radio-immunotherapy
only in selected patients in the setting of a well-designed clinical trial
[7 ]. Radioisotope therapy with
I-131 MIBG has shown some evidence for partial response or stability of MTC,
but ATA recommends utilization of radioisotope therapy only in the context
of a clinical trial [7 ].
Future directions and on-going clinical trials for MTC
A list of on-going clinical trials for treatment of MTC are listed in [Table 3 ]. Some of the future
considerations in the treatment of MTC include further evaluation of the
utility of TKIs/MKIs and utilization of lower doses, combinations of
these drugs or different administration regimens to minimize systemic
toxicity. Promising areas of research include the examination of the
efficacy of novel therapies, including RET inhibitors such as LOXO-282 and
BLU-667, as well as BOS172738 [93 ],
immunotherapeutic agents such as pembrolizumab, nivolumab, and ipilimumab,
gastrin analogues/cholecystokinin 2 agonists such as 177-Lu-PP-F11N
and 111-In-CP04, CEA-vaccine (GI-6207), and rovalpituzumab, an anti-DLL3
antibody-drug conjugate ([Table
3 ]).
Table 3 List of currently investigated drugs in clinical
trials for the treatment of medullary thyroid cancer (registered
under ClinicalTrials.gov).
Drug
Study phase
Study status
Location
NCT ID Number
I. Tyrosine kinase inhibitors:
1. Cabozantinib
a. Phase 4
Recruiting
Multinational
NCT01896479
b. Phase 2
Recruiting
USA
NCT02867592
c. Phase 2
Recruiting
USA
NCT03630120
d. Phase 4
Active, not recruiting
Multinational
NCT00704730
e. Phase 1
Active, not recruiting
USA, Canada
NCT01709435
2. Regorafenib
Phase 2
Recruiting
USA
NCT02657551
3. Sulfatinib
Phase 2
Recruiting
China
NCT02614495
4. Vandetanib
a. Phase 2
Recruiting
USA
NCT03630120
b. Phase 1/2
Active, not recruiting
USA
NCT00514046
c. Phase 3
Active, not recruiting
Multinational
NCT00410761
d. Phase 4
Active, not recruiting
Multinational
NCT01496313
5. Nintedanib
a. Phase 2
Recruiting
USA
NCT03630120
b. Phase 2
Active, not recruiting
Multinational
NCT01788982
6. Sorafenib
Phase 2
Active, not recruiting
USA
NCT00390325
7. Sunitinib
Phase 2
Active, not recruiting
USA
NCT00381641
8. Pazopanib
Phase 2
Active, not recruiting
Multinational
NCT00625846
9. Ponatinib
Phase 2
Not yet recruiting
To be decided
NCT03838692
II. RET inhibitors:
1. LOXO-292
a. Phase 1/2
Recruiting
Multi-national
NCT03157128
b. Phase 1/2
Recruiting
USA
NCT03899792
2. BLU-667
Phase 1
Recruiting
Multinational
NCT03037385
3. BOS172738
Phase 1
Recruiting
Belgium, France, and Spain
NCT03780517
III. Immunotherapy:
1. Pembrolizumab
a. Phase 2
Recruiting
USA
NCT03072160
b. Phase 2
Recruiting
USA
NCT02721732
2. Ipilimumab
Phase 2
Recruiting
USA
NCT03246958
3. Nivolumab
Phase 2
Recruiting
USA
NCT03246958
5. GI-6207 (CEA vaccine)
Phase 2
Active, not recruiting
USA
NCT01856920
IV. Gastrin analogues/Cholecystokinin-2
receptor agonists:
1. 177Lu-PP-F11N
a. Phase 1
Recruiting
Switzerland
NCT02088645
b. Phase 1
Recruiting
Switzerland
NCT03647657
2. 111In-CP04
Phase 1
Recruiting
Multinational
NCT03246659
IV. Anti-DLL3 antibody-drug conjugate:
1. Rovalpituzumab
Phase 1/2
Active, not recruiting
USA
NCT02709889
VII. Combination therapies:
1. Nivolumab + Ipilimumab
Phase 2
Recruiting
USA
NCT03246958
Anaplastic thyroid carcinoma
Among all the thyroid malignancies, ATC is the most aggressive and carries the
worst prognosis, with a median survival of 5–12 months and a 1 year
survival rate of 20–40% [1 ]
[8 ]
[94 ]. Fortunately, ATC is rare and
accounts for 1.7% of all thyroid malignancies in the United States and
3.6% of all thyroid malignancies world-wide (1.3–9.8%
depending on the geographic region) [8 ].
The last robust set of guidelines for ATC management was generated and published
by the ATA in 2012 and a new set of comprehensive guidelines is currently being
prepared by the ATA [8 ]. The most recent
version (8th edition) of the TNM classification of ATC was provided by the AJCC
in 2017 [5 ]. All cases of ATC, regardless
of the T, N or M, are classified as stage IV disease [5 ]
[8 ]. Typically, ATC has a higher
propensity to occur in a background of a pre-existing goiter or DTC [1 ]
[8 ]. About 50% of the patients
present with widely spread metastatic disease, 40% present with
extrathyroidal extension/LN involvement and only 10% present
with only intrathyroidal involvement [8 ].
About 20% of patients with ATC harbor a coexisting DTC in their thyroid
glands [8 ].
Resectability of these tumors should be carefully assessed through imaging
modalities such as thyroid US, CT, MRI, and PET scans [8 ]. If the tumor is deemed resectable and
if there is no evidence of distant metastasis, the preferred modality of
treatment is surgery followed by local/regional radiation with or
without systemic chemotherapy [8 ]. For ATC
confined to the thyroid, near-total or total thyroidectomy along with
therapeutic LN dissection is performed and for ATC with extra-thyroidal
extension, an en block resection is preferred, with a goal of achieving grossly
negative margins [8 ]. In cases of
unresectable tumors that are of local/regional confinement, the
preferred initial treatment modality is radiation with or without systemic
chemotherapy, and surgery can be considered if these tumors eventually become
resectable [8 ]. Systemic chemotherapy
involves the use of a combination of taxanes, anthracyclines, and platinum-based
cytotoxic agents, but there has been no clear evidence for improvement in
quality of life or survival with their use in ATC [8 ]
[94 ]. Overall, the response rates for ATCs
to standard systemic therapies are suboptimal, typically <15%
[94 ]. Tubulin-binding compounds such
as fosbretabulin, combretastatin, crolibulin, and TKIs/MKIs such as
sorafenib, geftinib, axitinib, and imatinib have been utilized in phase
1/2 studies with highly variable response rates [8 ]
[95 ]. Favorable prognosis is associated
with younger age (usually <60 years), smaller tumor size, female gender,
disease confined to the thyroid gland, absence of distant metastasis, and
complete resection of the primary tumor [8 ]
[96 ]
[97 ]. Due to the aggressive nature of the
disease and poor prognosis, the ATA guidelines emphasize on the importance of
multidisciplinary approach and a thorough discussion with the patients regarding
surrogate decision making, advance directives, and code status [8 ].
The role of the combination of BRAF and MEK inhibitors
Molecular testing in ATC is a field that is being actively investigated. The
2012 ATA guidelines on ATC did not recommend molecular testing, but as more
light is being shed on the commonly occurring molecular alterations in ATC
there is increasing hope for utilization of targeted therapies [98 ]. ATCs harbor mutations in multiple
genes, including BRAF , RAS , TP53 , EIF1AX ,
CTNNB1, as well as genes involved in the AKT-mTOR pathway, the
SWI/SNF complex, and histone methyltransferases ([Table 1 ]). However BRAF and
RAS are usually the main driving mutations. [1 ]
[8 ]. Based on evidence of enhanced
anti-tumor activity with combined inhibition of BRAF and MEK kinases in
mouse models, and its subsequent success in treating melanoma and lung
cancer, the safety and efficacy of combination therapy with dabrafenib (BRAF
inhibitor; 150 mg twice daily) and trametinib (MEK inhibitor;
2 mg once daily) was evaluated in a phase 2, open-label trial, in 16
patients with ATC who had tried prior radiation and/or surgery
and/or systemic therapy [94 ].
After a median follow-up of 47 weeks, the overall response rate was
69%, including 1 complete response. The most common adverse events
(any grade) were fatigue (44%), pyrexia (31%), and nausea
(31%), while anemia (13%) was the most frequent grade 3 and
4 adverse event. The 12-month Kaplan–Meier estimate of duration of
response was 80% and the 12-month Kaplan–Meier estimate of
overall survival was 90% (as compared to previous 12-month overall
survival rates of 20–40% on other modes of therapy [94 ]). In a basket trial for
non-melanoma cancers with BRAFV600 disease-causing variants, among
the 7 enrolled ATC patients who had tried prior systemic therapies, one
patient had a complete response and another patient had a partial response,
and these responses were sustained for more than 12 months [99 ]
[100 ]. Therefore, combination
BRAF/MEK inhibitor therapy holds great promise in the treatment of
ATC and was approved by the FDA for the management of BRAF
V600E -positive ATC. Another BRAF inhibitor, vemurafenib, has also
demonstrated favorable responses in isolated reports of ATC [99 ].
Other targeted therapies and on-going clinical trials
A list of on-going clinical trials on treatment of ATC is provided in [Table 4 ]. Apart from BRAF
inhibitors and MEK inhibitors, several other classes of drugs have
demonstrated efficacy and safety in the treatment of ATC.
Table 4 List of currently investigated drugs in clinical
trials for the treatment of anaplastic thyroid cancer
(registered under ClinicalTrials.gov).
Drug
Study phase
Study status
Location
NCT ID Number
I. Tyrosine kinase inhibitors:
1. Cabozantinib
Phase 2
Active, not recruiting
USA
NCT02041260
2. Lenvatinib
Phase 2
Active, not recruiting
Japan
NCT02726503
3. Sorafenib
Phase 2
Recruiting
China
NCT03565536
4. Pazopanib
a. Phase 2
Active, not recruiting
Multinational
NCT00625846
b. Phase 2
Active, not recruiting
USA
NCT01236547
II. Immunotherapy:
1. Pembrolizumab
a. Phase 2
Recruiting
USA
NCT02688608
b. Phase 2
Active, not recruiting
USA
NCT03211117
2. Ipilimumab
Phase 2
Recruiting
USA
NCT03246958
3. Nivolumab
Phase 2
Recruiting
USA
NCT03246958
4. Durvalumab
Phase 1
Active, not recruiting
USA
NCT03122496
5. Tremelimumab
Phase 1
Active, not recruiting
USA
NCT03122496
6. Spartalizumab
Phase 1/2
Active, not recruiting
Multinational
NCT02404441
7. Atezolizumab
Phase 2
Recruiting
USA
NCT03181100
III. BRAF inhibitors:
1. Debrafenib
Phase 1
Not yet recruiting
USA
NCT03975231
2. Vemurafenib
Phase 2
Recruiting
USA
NCT03181100
IV. MEK inhibitors:
1. Trametinib
Phase 1
Not yet recruiting
USA
NCT03975231
2. Cobimetinib
Phase 2
Recruiting
USA
NCT03181100
V. Cytotoxic agents:
1. Paclitaxel
a. Phase 1
Recruiting
USA
NCT03085056
b. Phase 2
Active, not recruiting
USA
NCT02152137
c. Phase 2
Active, not recruiting
USA
NCT01236547
d. Phase 2
Recruiting
USA
NCT03181100
2. Docetaxel
Phase 2
Active, not recruiting
USA
NCT03211117
3. Doxorubicin
Phase 2
Active, not recruiting
USA
NCT03211117
VI. m-TOR inhibitors:
1. Sapanisertib
Phase 2
Recruiting
USA
NCT02244463
VII. PPAR γ agonists:
1. Efatutazone
Phase 2
Active, not recruiting
USA
NCT02152137
VIII. ALK inhibitors:
1. Ceritinib
Phase 2
Recruiting
USA
NCT02289144
IX. VEGF inhibitors:
1. Bevacizumab
Phase 2
Recruiting
USA
NCT03181100
X. Combination therapies:
1. Trametinib + Paclitaxel
Phase 1
Recruiting
USA
NCT03085056
2. Durvalumab + Tremelimumab +
Stereotactic Body Radiotherapy
Phase 1
Active, not recruiting
USA
NCT03122496
3. Efatutazone + Paclitaxel
Phase 2
Active, not recruiting
USA
NCT02152137
4. Pembrolizumab + Docetaxel +
Doxorubicin + Intensity-modulated radiotherapy
+ Surgery
Phase 2
Active, not recruiting
USA
NCT03211117
5. Sorafenib + External beam radiation +
Surgery
Phase 2
Recruiting
China
NCT03565536
6. Debrafenib + Trametinib +
Intensity-modulated radiotherapy
Phase 1
Not yet recruiting
USA
NCT03975231
7. Paclitaxel + Pazopanib +
Intensity-modulated radiotherapy
Phase 2
Active, not recruiting
USA
NCT01236547
8. Atezolizumab + Cobimetinib +
Vemurafenib
Phase 2
Recruiting
USA
NCT03181100
9. Atezolizumab + Cobimetinib
Phase 2
Recruiting
USA
NCT03181100
10. Atezolizumab + Bevacizumab
Phase 2
Recruiting
USA
NCT03181100
11. Atezolizumab + Paclitaxel
Phase 2
Recruiting
USA
NCT03181100
The PI3K/AKT/mTOR pathway is activated in about
30–35% of ATCs and is another potential target for therapy
[98 ]. Everolimus is by far the
most extensively studied mTOR inhibitor in thyroid cancers. In a phase 2
clinical trial, everolimus (10 mg once daily) was evaluated in
locally advanced or metastatic thyroid cancers of all histologic subtypes
[101 ]. Among the 6 patients with
ATC, the median progression-free survival was 10 weeks after a median
follow-up of 11 months. Interestingly, one of the ATC patients demonstrated
substantial reduction of tumor size (21% reduction after 4 weeks of
treatment). Another phase 2 open label study evaluated everolimus
(10 mg daily) in various forms of thyroid cancers [102 ]. In this study, (median follow-up
of 10 months), 3 out of 5 ATC patients had disease progression, one patient
had on-going disease stabilization, while another patient had achieved
complete response that lasted for 18 months. Whole-exome sequencing in this
patient revealed a somatic mutation in TSC-2 protein, a negative regulator
of the mTOR pathway.
Analysis of immune markers in ATC samples have revealed extensive expression
of PD-L1 in the tumor cells and PD-1 expression on inflammatory cells, thus
making immunotherapy a potential targeted therapy in ATC [98 ]
[103 ]. Nivolumab was administered
along with vemurafenib to a 62-year-old male patient with ATC
post-thyroidectomy, LN dissection and chemotherapy, who was treated with
vemurafenib after his tumor was found to be PD-L1 positive [104 ]. Two months after nivolumab
initiation, there was substantial regression of supraclavicular LNs and
pulmonary nodules. The patient continued to be in complete remission 20
months into nivolumab therapy. In a retrospective analysis from MD Anderson
Cancer Center, among the 12 patients treated with pembrolizumab and TKIs,
42% achieved partial response, 33% had stable disease, while
25% experienced disease progression [105 ]. Common adverse events encountered with this combination
included fatigue, anemia, and hypertension. Clinical trials are
investigating several immunotherapeutic agents for the treatment of ATC.
Examples include atezolizumab (NCT03181100), nivolumab (NCT03246958),
ipilimumab (NCT03246958), pembrolizumab (NCT03211117), durvalumab
(NCT03122496), tremelimumab (NCT03122496), and spartalizumab (NCT02404441).
Other novel therapies considered for treatment of ATC include ALK inhibitors
(ceritinib, NCT02289144), selective mTOR inhibitors (sapanisertib,
NCT02244463), and efatutazone (PPARγ agonist, NCT02152137). Several
combination therapies consisting of cytotoxic agents, small molecule
targeted therapies, and radiation, are also currently being investigated and
are enlisted in [Table 4 ].
