Systemic Therapy in Thyroid Cancer

Abstract

Thyroid cancer is the most common endocrine malignancy. While surgery remains the mainstay of the treatment of all different histologies, for differentiated thyroid cancers, radioactive iodine also plays an important role in management. Once tumor becomes radio-iodine refractory, it needs systemic therapy. Earlier, these tumors had very dismal prognosis. However, with the advancement of technology and research, it has become clear now that thyroid cancer cells are driven by various mutations. Targeting these oncogenic drivers by various molecules have proven to be effective therapeutic strategy in thyroid cancer. Besides, as in other solid tumors, immunotherapy is also being evaluated in thyroid cancer. While these new therapeutic approaches have revolutionized the treatment on advanced/metastatic thyroid cancer, there are definite challenges which limit their use in common clinical practice. These challenges include higher treatment cost and lack of testing to identify the driver mutations. Moreover, there is still need for further research in thyroid cancers to identify oncogenic targets and agent to act upon them.

Thyroid cancer is the most common endocrine malignancy [1]. During the last few decades, the annual incidence has increased mainly due to two reasons: one due to true increase in incidence and second due to improvement in diagnostic techniques. While it can occur at any age, highest incidence is seen between 25 and 60 years. As compared to men, women have a fourfold higher incidence. If we include all stages of differentiated thyroid cancer, the 5-year survival rate exceeds 90% [2].

The cell of origin could be either follicular cell or parafollicular C cells, with majority (nearly 95% cases) derived from thyroid follicular epithelial cells and remaining 3–5% originate from parafollicular C cells [3]. Thyroid cancers are mainly divided into differentiated thyroid cancers and anaplastic thyroid cancers. In between, poorly differentiated thyroid cancers are also there, which were recognized as a distinct entity in 2004 WHO classification of endocrine cancers [4]. Differentiated thyroid cancers are further subdivided into follicular, papillary, and medullary subtypes.

Management of anaplastic thyroid cancers involves surgery, radiotherapy, and/or chemotherapy. Thyroid hormone replacement may be required to maintain euthyroid status. There is no role of radioactive iodine therapy, as these cancer cells are undifferentiated, so unable to show RAI (radioactive iodine) uptake. Medullary thyroid cancers (MTCs) are primarily managed by surgery. In case of metastatic or progressive disease, systemic treatment is required, and treatment options are available in the form of kinase inhibitors and chemotherapy. RAI therapy is not a part of treatment, as these cancers are derived from parafollicular cells.

Surgery is the mainstay of treatment of all differentiated thyroid cancers (DTCs). In case of follicular and papillary subtypes, surgery (which can be total-, near total-, or hemi-thyroidectomy) is followed by adjuvant radioactive iodine therapy with or without adjuvant external beam radiotherapy. Patients are also given thyroid hormone supplementation. The decision for adjuvant treatment is based upon risk of recurrence, which in turn is decided by various tumor characteristics. In case of metastatic disease, radioactive iodine can still be curative in a few patients, and thyroid-stimulating hormone (TSH)-suppressive thyroid hormone therapy can help to slow the pace of the disease. However, patients with metastatic disease, who progress despite the above-mentioned treatment modalities, require and are suitable candidates for systemic therapies. In this review article, we will discuss about the different systemic therapeutic options, which are available currently for the management.

In case of differentiated thyroid cancers, radio-iodine therapy is used as adjuvant treatment in patients who are at high risk of recurrence post thyroidectomy. It is also given in patients with residual and relapsed disease. However, some of these patients become refractory to this treatment and are labelled as radio-iodine refractory differentiated thyroid cancers. This happens probably because over the period, the cells lose their ability for iodine uptake. Nearly 1/5 of differentiated thyroid cancers show/develop RAI resistance or refractoriness at some point in their natural course (either de novo or in the later course) [5]. As per American Thyroid Associations Guideline 2016 [6], a RAI refractory patient can be classified into four different categories (after proper iodine preparation and TSH stimulation):

1. The malignant or metastatic tissue, which has never concentrated iodine in a scan.

2. The tumor tissue loses the ability to concentrate RAI after previous evidence of RAI-avid disease (in the absence of stable iodine contamination).

3. RAI is concentrated in some lesions but not in others.

4. Metastatic disease progresses despite significant concentration of RAI.

Besides these, it has been observed that RAI therapy is ineffective when the thyroid gland is still present and radioactive iodine uptake status cannot be assessed, as most of the RAI will be concentrated in the thyroid itself. This is one of the reasons that thyroidectomy is offered in differentiated thyroid cancer patients even in the presence of metastasis. It has also been observed that patients who have already received 600 mci doses of RAI will not benefit much with further RAI treatment. These patients should be managed as iodine refractory patients [7]. It is important to diagnose RAI refractory patients early so that they can be started on alternative treatment (when indicated) and can be saved from adverse effects of further radio-iodine treatment. These patients also have poor prognosis in terms of overall survival compared to RAI responsive patients.

When to Start Treatment in RAI Refractory DTCs

Mere presence of RAI refractory disease does not warrant immediate treatment for all of these patients. As per ATA 2015 guidelines, following patients with RAI refractory disease need to be started on early treatment:

1. Patients who are symptomatic due to disease

2. Patients showing radiological progression

3. Patients who are likely to develop rapidly progressive disease or clinically significant complications

4. Patients with high thyroglobulin levels and short doubling time of thyroglobulin (< 1 year) [6]

Thus, patients (with RAI refractoriness) meeting following criteria can be safely monitored on TSH-suppressive thyroid hormone therapy with close follow-up and serial radiological imaging at regular intervals:

1. Patients who are asymptomatic.

2. Radiological imaging is showing stable disease/maintained responses.

3. Disease is not involving critical structures so that it will not lead to rapid deterioration or significant complications in near future.

4. Thyroglobulin is not rapidly rising.

As per ATA guidelines, there are certain factors which favor use of systemic therapy:

1. Imminently threatening disease progression expected to require intervention and/or to produce morbidity or mortality in < 6 months (e.g., lung or lymph node lesions which can cause airway obstruction, hemorrhage etc.)

2. Symptomatic disease which cannot be managed with local directed therapy (e.g., multiple lung metastases causing breathlessness)

3. Diffuse disease progression, rather than focal progression

For anaplastic and medullary types, RAI is ineffective. So, if these tumors are unamenable to surgery or progressed or metastatic, they do require systemic therapy in the form of targeted therapy or chemotherapy.

Systemic Therapeutic Options in RAI Refractory DTCs, ATCs, and MTCs

Earlier, there were very limited systemic therapeutic options for such patients. However, now newer and effective options are becoming available apart from traditional cytotoxic chemotherapy, which include kinase inhibitors and immunotherapy. These agents can be broadly classified as follows:

1. Targeted agents:

   1. Multikinase inhibitors: e.g., sorafenib, lenvatinib, cabozantinib, vandetanib, pazopanib, axitinib, sunitinib
   2. Specific inhibitors

      • i.
        BRAF inhibitors and combination of BRAF-MEK inhibitors
      • ii.
        mTOR inhibitors
      • iii.
        Selective RET inhibitors

2. Cytotoxic chemotherapeutic agents

3. Immunotherapy: checkpoint inhibitors

4. Tumor agnostic options including pembrolizumab and NTRK fusion inhibitors

Development of these various therapeutic options became possible with the knowledge of different mutations. Genetic predisposition also plays a significant role in thyroid carcinogenesis apart from environmental factors. There are various genetic mutations present in different histological types, and some of them lead to familial predisposition as well. These genetic mutations lead to dysregulation of signaling pathways. Table 1 shows the list of various mutations in different thyroid cancer subtypes [11]. Now, we will discuss each of these agents.

Table 1.

Various mutations in different thyroid cancer subtypes

Mutation	Thyroid cancer type	Somatic/germline	Prevalence
RET [8]	Medullary thyroid cancer	Germline	98–100% in case of hereditary MTCs
		Somatic	40–60% of sporadic MTCs
RAS [9]	Papillary thyroid cancer	Somatic	10–20%
	Poorly differentiated types	Somatic	25%
	Medullary thyroid cancer	Somatic	Nearly 70% of sporadic MTCs subgroup who lack RET mutation [10]
BRAF [11]	Papillary thyroid cancer	Somatic	45%
RET/PTC [12, 13]	Papillary thyroid cancer	Somatic	20–40%

Targeted agents

In cell cycle, various kinases play an important role as signaling molecules, which stimulate various steps of carcinogenesis including tumor cell proliferation, angiogenesis, invasion, and metastasis. So in principle, like many other cancers, in thyroid cancers too, these kinases can be targeted to control the tumor growth. These tyrosine kinase inhibitors (TKIs) target either angiogenesis or oncogenic signaling pathways such as BRAF, RET, or TRK. These kinase inhibitors are disease-modifying agents, usually tumoristatic rather than tumoricidal [14]. Table 2 enlists all the currently available therapeutic options which work against different therapeutic targets in thyroid cancer.

Table 2.

Response rates of various TKIs in thyroid cancers

S. No	TKI name	Trial name/phase	Type of thyroid cancer	Compared against	Response	Major adverse effects seen	FDA approved or not
1	Sorafenib	DECISION/Phase 3 trial [15]	Differentiated thyroid cancers (DTCs)	Placebo	PFS (progression free survival) 10.8 months vs 5.8 months	Hand foot syndrome (HFS), diarrhea, fatigue, rash, hypertension	Yes, for RAI refractory DTCs
2	Lenvatinib	SELECT/Phase 3 trial [16]	DTCs	Placebo	PFS 18.3 months vs 3.6 months RR 64.8%	Hypertension, diarrhea, proteinuria, fatigue, and weight loss	Yes, for RAI refractory DTCs
3	Vandetanib	ZETA/Phase 3 trial [17]	Medullary thyroid cancers (MTCs)	Placebo	RR (response rate) 43% vs 15% PFS 30.5 months vs 19.3 months	Diarrhea, rash, nausea, hypertension and fatigue	Yes, for unresectable or metastatic medullary thyroid cancer
4	Cabozantinib	EXAM/Phase 3 trial [18]	MTCs	Placebo	PFS 11.2 vs 4.0 months	Diarrhea, weight loss, HFS, hypertension, fatigue, anorexia	Yes, for unresectable or metastatic medullary thyroid cancer
	Cabozantinib	COSMIC-311/Phase 3 trial [19]	RAI refractory DTCs	Placebo	Ongoing	-	-
5	Axitinib	Phase 2 trial [20]	Metastatic or unresectable, locally advanced MTCs or RAI refractory DTC	-	PFS 16.1 months RR 35%	Diarrhea, fatigue, weight loss, and hypertension	No
6	Motesanib	Phase 2 study [21]	RAI refractory DTCs	-	RR 18%	Diarrhea, hypertension, fatigue, weight loss	No
	Motesanib	Phase 2 study [22]	Medullary thyroid cancers	-	RR 2% Stale disease 81%	Diarrhea, fatigue, hypothyroidism, hypertension, anorexia	No
7	Sunitinib	Phase 2 study [23]	RAI refractory DTCs, MTCs, anaplastic thyroid cancers	-	RR: DTC 22% MTC 38.5% anaplastic 0%	Fatigue, HFS, weight loss	No
8	Pazopanib	Phase 2 study [24]	MTCs	-	RR 14.3%	Hypertension, fatigue, abnormal liver function tests	No
9	Vemurafenib	Phase 2 trial [25]	RAI refractory Papillary thyroid cancer, V600E mutated	-	RR 38.5%	Squamous cell carcinoma of skin, lymphopenia	No
10	Dabrafenib (GSK2118436)	Phase 1 study [26]	Advanced thyroid cancer (differentiated and poorly differentiated)	-	RR 29%	Skin papilloma Hyperkeratosis Alopecia	No
11	Dabrafenib and trametinib	Phase 2 trial [27]	BRAF V600E mutant anaplastic thyroid cancer (locally advanced or metastatic)	-	ORR 69%	Fatigue Pyrexia Nausea	No
12	Everolimus	Phase 2 trial [28]	Advanced medullary thyroid cancers	-	No partial response 71.4% stable disease Estimated median PFS 33 weeks	Fatigue Dyslipidemia Hyperglycemia Pneumonitis	No
13	Selumetinib (MEK inhibitor)	Pilot clinical study [29]	Advanced RAI refractory thyroid cancers	-	In 12 out of 20 patients, increase in uptake of iodine 124 was observed	No grade 3 or 4 adverse events
	Selumetinib	ASTRA/Phase 3 study [30]	Non-metastatic DTC patients, post total thyroidectomy Before RAI therapy	Placebo	CR (complete response) rates at 18 months 40% vs 38.5%
14	Selpercatinib (selective RET inhibitor) (LOXO-292)	LIBRETTO-001/Phase 1/2 trial [31]	Advanced or metastatic RET altered thyroid cancers	-	ORR of 69% and 73% in previously treated and treatment naïve RET mutant MTC patients respectively	Dry mouth Hypertension Transaminitis Diarrhea Fatigue	Yes
15	Pralsetinib (BLU-667)	ARROW trial Multi-cohort clinical study [32]	RET mutation positive MTC (in a multi-cohort)	-	ORR of 60% and 74% in previously treated and treatment naïve RET mutant MTC patients respectively	Transaminitis Anemia Constipation Hypertension	Yes

Multikinase Inhibitors

The primary target for all of these effective tyrosine kinase inhibitors is angiogenic signaling in the tumor microenvironment, particularly the vascular endothelial growth factor receptor (VEGFR) family. Two anti-angiogenic agents, lenvatinib and sorafenib, are currently approved by the United States Food and Drug Administration (US FDA) for this indication.

Sorafenib

It is a multikinase inhibitor, which inhibits VEGFR-1, VEGFR-2, and VEGFR-3; RET (including RET/PTC); RAF (including BRAFV600E); and platelet-derived growth factor receptor-ß (PDGFR-B) [33]. Therefore, sorafenib can inhibit the cancer cell growth through both anti-proliferative and anti-angiogenic mechanisms. In one of the initial phase 2 studies, it showed a response rate of 25% at 1 year in patients with medullary thyroid cancers and 18% at 1 year in patients with differentiated thyroid cancers. This study included 34 patients (15 medullary and 19 differentiated). One year OS was 100% and 79% in patients with MTC and DTC respectively [34].

In another phase 2 study by Vandana et al., which included 30 patients with metastatic, iodine refractory thyroid carcinoma, 23% patients showed partial responses which lasted 18–84 weeks. Ninety percent of patients in this study were either follicular or papillary subtypes [35]. Overall clinical benefit rate (partial response + stable disease) was 77%, and median PFS was nearly 18 months in this study.

Further in Phase 3 DECISION trial [15], sorafenib was compared against placebo, and it showed significant improvement in PFS (10.8 months vs 5.8 months, HR = 0.59, 95% CI 0.45–0.76; p < 0.0001). This study included 417 patients, and most of the patients were having metastatic DTCs, and only few (nearly 4%) were having locally advanced disease. All of these patients were RAI refractory and had progressed within the last 14 months. No significant difference was observed in overall survival between the two groups (HR 0.80, 95% CI 0·54–1·19; p = 0.14). Most common adverse events observed were hand foot syndrome (HFS), diarrhea, fatigue, rash, hypertension, etc. Grade 3 HFS was seen in nearly 20% and grade 3 hypertension in approximately 10% patients. So based on these evidences, sorafenib is one of the approved treatment options for patients with radioactive iodine refractory differentiated thyroid cancer.

A two-stage phase II trial of sorafenib in metastatic MTC terminated enrolment after the first stage with only one partial tumor response (PR) among 15 patients enrolled [36].

Lenvatinib

Lenvatinib (E7080) is an inhibitor of VEGFR, FGFR (fibroblast growth factor receptor), PDGFR, KIT, and RET [37]. In a phase 2 study [38], 58 patients with RAI refractory DTCs were enrolled. Seventeen out of 58 patients had earlier received prior VEGFR targeted therapy. Fifty percent of patients showed partial responses. In patients who had earlier received VEGFR-directed treatment, response rate was 41%, while it was 54% in patients who had not received anti-VEGFR treatment earlier. Most common adverse events observed were hypertension, diarrhea, fatigue, weight loss, proteinuria, etc.

Further, in the randomized phase 3 SELECT trial [16], 392 patients were randomized in 2:1 fashion to the intervention (Lenvatinib 24 mg once daily D1–D28 cycles) and comparator (placebo) arm. All of these patients were of differentiated thyroid cancers, and all were having metastatic disease. Nearly 25% of patients in the lenvatinib arm had previously been treated with one TKI (including sorafenib). Crossover was allowed on progression from placebo arm to active treatment arm, and nearly 88% patients in placebo arm did so. The median PFS was 18.3 months in the lenvatinib arm and 3.6 months in the placebo group (HR for progression or death, 0.21; 99% CI, 0.14 to 0.31; p < 0.001). Response rate was 64.8% in the lenvatinib group (including CR in 4 patients) and 1.5% in the placebo group. Grade 3 or more adverse events were seen in nearly 75% patients and most common being hypertension, diarrhea, proteinuria, fatigue, and weight loss. Based on these evidences, lenvatinib got the approval from the US FDA in 2015 for patients with RAI refractory differentiated thyroid cancer. Dose of lenvatinib in thyroid cancer is 24 mg once daily compared to its other indications, i.e., renal cell cancer (lenvatinib 18 mg in combination with everolimus 5 mg) and hepatocellular carcinoma (8 mg in < 60 kg and 12 mg daily in ≥ 60 kg body weight).

Vandetanib (RET Kinase Inhibitor)

It is an oral inhibitor of RET (rearranged during transfection) kinase, VEGFR, and EGFR (epidermal growth factor receptor) signaling [39]. Following preclinical studies, which suggested activity of vandetanib by RET kinase inhibition, it was evaluated in patients with locally advanced unresectable or metastatic MTCs in a phase 2 trial by Wells et al. [40]. It showed partial response in 20% and stable disease of more than 24 weeks in 73% of patients.

In Phase 3 Zeta trial [17], 331 patients with locally advanced unresectable or metastatic MTCs were randomized 2:1 to vandetanib arm and placebo arm respectively. Nearly 10% of these patients had hereditary MTC; the rest were all sporadic cases. For all the patients with sporadic MTC, RET mutation testing was done on tumor tissue blocks. It identified RET mutation in 52% of sporadic MTC patients. The study met its primary objective of PFS prolongation with vandetanib versus placebo (hazard ratio [HR], 0.46; 95% CI, 0.31 to 0.69; p = 0.001). There was also statistically significant improvement in objective response rates from 13 to 45% (p < 0.001). Similarly, improvement in calcitonin biochemical response rate and CEA biochemical response rate were also statistically significant. Subgroup analysis of patients with sporadic MTC showed that patients with M918T mutation positive had better response rates compared to M918 mutation negative patients. Diarrhea, rash, nausea, hypertension, and fatigue were the most common adverse events. FDA in 2011 approved vandetanib for patients with adults with unresectable or metastatic MTC.

Cabozantinib

Cabozantinib (XL184) is a multikinase inhibitor of MET, VEGFR2, RET, acting against KIT, AXL, FLT3, and Tie-2. In preclinical and clinical studies, this drug has shown anti-cancer properties against cancers derived from both epithelial and mesenchymal origins like renal cell carcinoma and thyroid cancers [41].

In a phase 3 EXAM trial [18], this drug showed improvement in PFS (11.2 months versus 4.0 months in the placebo group) of patients with MTCs. This observation was seen across all subgroups irrespective of age, bone metastases, RET status, and prior treatment status. Twenty-seven percent of patients showed partial responses, and the median duration of response was 14.7 months. Based on this, FDA in 2012 approved cabozantinib for patients with unresectable or metastatic medullary thyroid cancer (MTC).

Cabozantinib being a multikinase inhibitor has also shown activity in RAI refractory DTCs. In a phase 2 trial by Brose et al. [42], which enrolled 35 patients with metastatic, RAI refractory, unresectable, or locally advanced thyroid cancer, cabozantinib showed 54% response rates.

There is an ongoing phase 3 trial (COSMIC-311) [19], which is a multicenter, randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of cabozantinib in RAI refractory DTCs, who have progressed during or after prior VEGFR targeted therapy (sorafenib or lenvatinib). Crossover has been allowed in this study for patients in placebo arm to cabozantinib arm, after confirmation of progression. Interim analysis showed 78% reduction in the risk of disease progression or death in the cabozantinib arm compared to placebo (HR = 0.22, 96% CI, 0.13–0.36; p < 0.0001).

Axitinib

This drug is a selective multikinase inhibitor of VEGFR-1, VEGFR-2, and VEGFR-3. It was evaluated in the compassionate use program [43] in patients with thyroid cancer. This included a total of 47 patients, which included 34 patients of RAI refractory DTC and 13 patients of MTC. It was given as first-line therapy in 17 patients, as second line in 18 patients, and as 3rd/4th line in 12 patients. ORR was 27.7%, and median PFS was 8.1 months. Response rates and PFS were higher in patients who received axitinib as the first line compared to those who received this in the second line or later. This differential response seen with use of drugs as a different line suggests that there exists cross resistance among different multikinase inhibitors.

In a phase 2 trial by Locati et al. [20], 52 patients with metastatic or unresectable, locally advanced MTC or RAI refractory DTC were given axitinib. ORR was 35% (18 partial responses), median PFS was 16.1 months, and the median OS was 27.2 months. Gd 3 or more adverse events were seen in nearly 80% of patients with diarrhea, fatigue, weight loss, and hypertension being the most common.

Sunitinib

Sunitinib (SU11248) is also one of the oral TKI, which inhibits VEGFR, PDGFR, c-KIT, FMS-related tyrosine kinase 3 (FLT3), and RET. Inhibition of these pathways leads to apoptosis of cancer cells and reduced tumor vascularization, ultimately resulting in tumor shrinkage. Its anti-VEGFR property led to its use in renal cell carcinoma (RCC). Besides RCC, it is also indicated for treatment of gastrointestinal stromal tumor (GIST) after progression on Imatinib, and also in pancreatic neuroendocrine tumors [44].

Sunitinib has shown activity in thyroid cancer (both DTC and MTC) as well in preclinical and in vivo studies [44]. In a phase 2 trial by Ravaud et al. [23], sunitinib was tried as first-line treatment in patients with advanced RAI refractory DTC and advanced MTC and anaplastic thyroid cancer. ORR in DTC was 22% and in MTC was 38.5%, while no objective responses seen in patients with anaplastic thyroid cancer. Most common grade 3 or more adverse events were fatigue, HFS, and weight loss. So far, there is no any phase 3 trial of sunitinib in thyroid cancer patients.

Pazopanib

Pazopanib is an inhibitor of VEGFR-1,-2,-3, PDGFR-α and -β; and c-Kit. It has shown clinical activity against both DTC as well as MTC in preclinical studies. Tumor response rate of 49% has been observed in patients with advanced DTC. In a phase 2 study of patients with MTC, Pazopanib has shown partial response rates of 14.3%. Common and important adverse events were Hypertension, fatigue, abnormal liver function tests [24].

Specific Inhibitors

BRAF and /or MEK Inhibitors

Abnormal activation of the MAPK cascade is seen in nearly 70% of papillary thyroid cancers. It can be due to alterations in RET, RAS, and BRAF genes [45]. BRAF mutations occur in nearly 30–80% of human thyroid cancers, and the most frequent mutation observed is V600E mutation [46]. Apart from thyroid cancers, this mutation is also seen in melanoma, hairy cell leukemia, colorectal cancer, and non-small cell lung cancer. BRAF V600E mutant papillary thyroid cancers are associated with aggressive clinical behavior, higher recurrences, and poor survival rates compared to BRAF wild-type cancers [1]. BRAF mutation leads to alteration in iodine metabolism in follicular cells, so these patients with BRAF mutation show poor response or refractoriness to RAI therapy [47]. While multikinase inhibitors like sorafenib and lenvatinib also inhibit BRAF along with other kinases, there are specific BRAF inhibitors like vemurafenib, dabrafenib, and encorafenib. There is evidence which suggests that BRAF inhibitors help in restoring the iodine responsiveness of the thyroid cancers, probably through reactivation of genes involved in iodine metabolism [48]. As a single agent, BRAF inhibitors showed activity in RAI refractory papillary thyroid cancers. Vemurafenib showed long PFS in a phase 2 study [25] by Brose et al., while dabrafenib achieved partial responses also in nearly 30% of patients in another study [26].

When using BRAF inhibitors as a single agent, cancer cells may develop resistance due to activation of alternate downstream signaling pathways, so these agents may not be effective as a single agent. MAP kinase pathway is one of the downstream pathways. MEK inhibitors block MEK kinase activity within this pathway, so the combination of BRAF and MEK inhibitor is more effective. Moreover, there is decreased risk of adverse events related to paradoxical ERK activation [49]. In a phase 2 trial, combination of dabrafenib and trametinib was evaluated in 16 patients with locally advanced or metastatic BRAF V600E mutant anaplastic thyroid cancer. All of these patients had received prior radiotherapy and/or surgery, and six had received prior systemic therapy as well. In this study, the combination regimen showed an ORR of 69%. Commonly observed adverse events were fatigue, pyrexia, and nausea [27].

Among patients with metastatic differentiated thyroid cancer also, this combination has been evaluated in a phase 2 study, which included total 53 patients with RAI refractory PTCs, and they were randomized into 2 arms. Patients in arm A were given singe agent dabrafenib, while in arm B, combination of dabrafenib and trametinib was given to patients. Objective response rate was 50% and 54%, while median PFS was 11.4 months and 15.1 months in arm A and arm B respectively (p = 0.27) [50].

This combination has also been tried in curative/non-metastatic setting as well. In one case series of 6 patients with locally advanced upfront unresectable BRAF V600E mutated anaplastic thyroid cancer patients, combination of dabrafenib and trametinib given as neoadjuvant therapy leads to responses, and all of these patients later underwent surgery followed by adjuvant chemoradiation [51].

However, in patients with progressive BRAF mutated papillary thyroid carcinoma, single-agent dabrafenib was evaluated against a combination of dabrafenib and trametinib. Both the therapies were well tolerated with similar high response rates (50–54%) [50].

mTOR Inhibitors

Everolimus, which has shown encouraging results in neuroendocrine tumors, has been evaluated in phase 2 trial in patients with advanced MTC. This study included 7 patients, who received everolimus 10 mg daily. Five out of 7 patients showed stable disease; however, no partial responses observed [28].

Selective RET Inhibitors

While multikinase inhibitors like cabozantinib, sunitinib, and lenvatinib also inhibit RET, but being non-specific, they show many off target activity/ adverse effects. So selective RET inhibitors have been studied and now FDA approved for these patients.

Selpercatinib (LOXO-292)

It is one of the selective RET kinase inhibitor. In a phase 1 study, it showed ORR of 45% in RET-mutant MTC patients and 100% ORR in RET fusion PTC patients [52]. In a further phase 1/2 study [31] (LIBRETTO-001), selpercatinib was used in patients with RET mutant MTC. A subset of patients who were previously treated with cabozantinib and/or vandetanib had ORR of 62%, while cabozantinib/vandetanib naive patients showed ORR of 69%. Common grade ≥ 3 adverse events were dry mouth, transaminitis, hypertension, diarrhea, and fatigue. FDA has approved this drug for RET mutant MTC patients and RET fusion positive RAI refractory thyroid cancer patients.

Pralsetinib (BLU-667)

It is also one of the selective RET inhibitors, which showed initial clinical activity in a phase 1 trial. In this phase 1 trial, most of the patients were MTC (29 out of 31) and 2 were PTC. Overall response rate was 40% [32]. In further phase 2 expansion of this trial (ARROW trial), which is a multi-cohort clinical trial, the drug was evaluated in patients with RET mutant MTC and RET fusion positive thyroid cancers. In 79 patients with RET mutation positive MTC, ORR was 65%. For patients who had prior received cabozantinib and/or vandetanib, ORR was 60%, while ORR in treatment naive patients was 74%. Based on the evidence, pralsetinib is also approved by FDA for RET mutant MTC patients and RET fusion positive RAI refractory thyroid cancer patients.

Phenomenon of Reversal of Iodine Refractoriness

MAPK pathway activation results in suppression of iodine uptake by thyroid cells. MEK 1/2 inhibitor can restore this iodine uptake by inhibition of this pathway [53].

Selumetinib

In a pilot clinical study, 20 patients (RAI refractory) were initially given selumetinib, and it resulted in increased I¹²⁴ uptake in 12 patients. Of these 12 patients, 8 reached the dosimetry threshold for RAI therapy. Of these patients, there was partial response in 5 patients and stable disease in 3 patients, after treatment with RAI. No grade ≥ 3 adverse events were observed [29].

In a further Phase 3 ASTRA trial [30], investigators evaluated whether addition of selumetinib prior to RAI therapy will lead to an increase in CR rates in patients with locally advanced DTCs, who had undergone total thyroidectomy (and had indication for RAI therapy due to higher risk of recurrence). However, addition of selumetinib did not show an increase in CR rates compared to addition of placebo. CR rates were 40% and 38.5% for selumetinib and placebo respectively. Even in patients with NRAS/BRAF mutations, the CR rate was 37.4% and 41.2% in the selumetinib and placebo arms, respectively (OR, 0.85; 95% CI, 0.42–1.73; p = 0.65).

Dabrafenib

Dabrafenib was also evaluated in a pilot study, whether it can redifferentiate thyroid tumors and resensitize them to RAI. This study enrolled 10 patients with BRAF V600E mutant RAI refractory thyroid cancers. After giving dabrafenib to these patients, 6 patients (out of total 10 patients) showed RAI uptake, and then they received RAI. Of them, 2 patients achieved PR and 4 patients achieved stable disease [54].

Chemotherapy in Thyroid Cancers

In general, differentiated thyroid cancers, which are refractory to RAI therapy, are not much chemo responsive. However, before the advent of targeted therapeutic options, chemotherapeutic drugs were used as systemic therapy. Common chemotherapeutic drugs used were bleomycin, doxorubicin, paclitaxel, etoposide, platinum agents, and methotrexate. Over the years, doxorubicin has been considered the standard chemotherapeutic option. There is no phase 3 evidence for chemotherapy in thyroid cancers, only phase 1 and phase 2 studies done. Evidence suggests combination of doxorubicin with other agents like cisplatin has survival benefit over single-agent chemotherapy. There is a meta-analysis by Albero et al. [55], which included various prospective and retrospective studies from the 1970s. There were 4 studies which included only patients with RAI refractory DTCs, with a total of 70 patients. Chemotherapy given in 3 of these studies were anthracycline ± platinum. In one study gemcitabine-oxaliplatin regimen was given. Response rates (CR and PR rates) in studies including only RAI refractory DTC were nearly 27% (n = 70), and clinical benefit rate (includes CR + PR + SD) was nearly 61%.

In anaplastic thyroid cancer, chemotherapy is still used widely, as part of concurrent chemoradiation or as palliative measure. Chemotherapeutic agents which are active (as alone or in combination) in anaplastic thyroid cancer are paclitaxel, docetaxel, cisplatin, carboplatin, and doxorubicin [56]. For patients with locally advanced ATCs, concurrent chemoradiation (as definitive or adjuvant treatment) is useful. Previously doxorubicin was used for its radiosensitizing effect [57]; however, now other agents like taxanes and platinum agents are preferably used alone or in combination due to more efficacy [56]. For metastatic patients also, same drugs are used. There is no phase 3 evidence available for this setting. In a retrospective, German study, it was observed that chemotherapy is associated with longer overall survival. Chemotherapy protocols in this study were taxane, doxorubicin, and platinum as alone or combination of two drugs. Eight out of 56 patients also received combination of paclitaxel and pemetrexed [58]. In another study, which was non-randomized, open label, and single arm, involving 56 patients, paclitaxel at weekly 80 mg/m² dose was given. Median overall survival was 6.7 months, and partial response was seen in 9 out of 42 patients (21%) with an evaluable lesion [59]. A prospective, placebo-controlled trial of ATC patients by Sosa et al. [60] investigated the efficacy of addition of agent fosbretabulin (Combretastatin A-4 phosphate) to 3 weekly paclitaxel-carboplatin regimen. Study included 80 patients, and of these, 23 patients also received surgical treatment. It was observed that there was no benefit of adding fosbretabulin, in patients who did not undergo surgery. However, there was improvement in OS with addition of fosbretabulin, in patients who underwent surgery.

Role of Immunotherapy

Like other malignancies, immunotherapy is being explored in thyroid cancers as well. Suppression of immune response plays an important role in survival of malignant cells. One of the biomarkers for immunotherapy, PD-L1, is also expressed in DTCs and anaplastic thyroid cancers [61]. Studies have observed that in anaplastic thyroid cancer, PD-L1 is more frequently expressed, thereby suggesting that PD-L1 expression could be a late event in carcinogenesis of thyroid cancers [62]. Tumor mutation burden is considered low in thyroid cancers compared to other solid tumors [63]; however, it is not the only estimate for tumors’ antigenic potential. Antigenicity of thyroid cancers remains largely unknown [61].

In a phase 1b KEYNOTE-028 trial, which included patients of different solid tumors expressing PD-L1, it had 22 patients of differentiated thyroid cancers. Pembrolizumab resulted in partial response in 2 out of 22 such patients. Median PFS was 7 months [64].

A phase 2 trial to evaluate the efficacy of single-agent pembrolizumab in anaplastic or undifferentiated thyroid cancer patients is ongoing (NCT02688608) [65].

However, pembrolizumab is also being investigated in combination with other drugs in different settings in thyroid cancer. In a retrospective study, addition of pembrolizumab as salvage to ongoing TKI was studied in patients with anaplastic thyroid cancer. Data of 12 patients showed partial response in 42% patients and stable disease in another 33% patients [66]. In a prospective phase 2 ATLEP study [67], combination of pembrolizumab and lenvatinib was used in patients with metastatic anaplastic or poorly differentiated thyroid carcinoma. Pembrolizumab 200 mg every 3 weeks was given for up to 36 weeks, and lenvatinib was given in the dose of 20/24 mg. There were a total 20 patients, out of which 16 had anaplastic thyroid cancers. Primary endpoint was ORR and seen in 30% of patients (6 out of 20 patients). Interestingly all these patients had ATCs, so ORR in patients with ATC was 37.5% (6 out of 16 patients). Gd 3 or more toxicities observed were aspergillus pneumonia, bleeding, and fistula formation, seen in 3, 2, and 3 patients respectively. So, this combination looks promising for anaplastic thyroid cancer patients, although needs further validation in studies. Biomarkers observed in this small cohort of good responses included high PD-L1 status and increased tumor mutational burden [67].

In another phase 2 study, Pembrolizumab was given in combination with chemoradiotherapy to patients with anaplastic thyroid cancer as initial treatment. Since combined chemoradiation is one of the treatment options in patients with anaplastic thyroid cancer, it was thought that adding pembrolizumab will add to durability of response. In this study, a 6-month OS was chosen as the primary endpoint; however in its 1st phase itself, all 3 patients died before 6 months despite initial favorable responses, so the study was closed prematurely [68].

As with other solid tumors, pembrolizumab is approved by FDA for use in patients with thyroid cancer any histology who show high microsatellite instability (MSI-high) [69]. Similarly, pembrolizumab is also FDA approved for adult and solid tumors with high tumor mutation burden (defined as presence of 10 or more mutations per mega base) [70]. Pembrolizumab is also being studied in a phase 2 study in patients with recurrent or metastatic medullary thyroid cancers. Studies are also underway to investigate the role and efficacy of other checkpoint inhibitors like nivolumab and ipilimumab.

Tumor Agnostic Options

In this new era of molecular driven therapeutics, basket trial designs are probably the way to go ahead. With this design, tumors of different sites and various histologies, with presence of certain specific mutation/biomarker are studied together. These tumor agnostic options can be useful in patients with otherwise resistant disease or who have failed to other lines of therapy. As mentioned above, pembrolizumab is approved for use in any solid tumors with MSI-high or TMB-high.

Similarly, NTRK fusion inhibitor has also been approved for any solid tumors with presence of this mutation. Larotrectinib (Loxo-101) is Pan-TRK inhibitor and was approved by FDA in 2018. Hong et al. in their pooled analysis of 3 different phase 1 and phase 2 trials had shown objective response rate (ORR) of 79% and complete response rate of 16% with use of larotrectinib. The main adverse effects were raised liver enzymes, anemia, and neutropenia. Overall Gd ≥ 3 adverse events were < 3% [71].

Entrectinib (RXDX-101) was also approved by FDA in 2019 for tumors with NTRK fusion mutation. In a pooled analysis of 3 different phase 1–2 trials, ORR of 57% (n = 31/54) was observed. The major grade ≥ 3 adverse effects were weight gain and anemia, with neurological symptoms in 4% of patients [72].

How to Choose Among Available Options

Despite of having scientific evidence for so many options, factors like feasibility and availability of various mutation testing, availability of drugs, patients performance status, and financial constraints do pose a challenge in adequate management of patients with thyroid cancer. Below, the mentioned flow chart (Table 3) can help in planning the optimal strategy. However, patient’s clinical condition, performance status, comorbidities, and tolerance to any treatment should always be kept in mind before starting or continuing on any treatment.

Table 3.

How to choose and decide systemic t/t in patients with thyroid cancer

	RAI refractory DTC, which requires systemic t/t (criteria mentioned above)	MTC, which is not resectable and progressing by RECIST criteria	ATC, which is not resectable and progressing by RECIST criteria
Mutation testing to be considered at baseline	BRAF mutation testing NTRK fusion mutation MSI/TMB testing RET fusion mutation Can consider next generation sequence (NGS) testing for multiple mutations, to search for possible actionable targets	RET mutation NTRK fusion mutation MSI/TMB testing BRAF mutation Can consider NGS testing	BRAF mutation testing NTRK fusion mutation MSI/TMB testing RET fusion mutation Can consider next generation sequence testing for multiple mutations, to search for possible actionable targets
Preferred agents
If mutation present	NTRK fusion mutation: entrectinib/larotrectinib RET fusion mutation: pralsetinib/selpercatinib	RET fusion mutation: pralsetinib/selpercatinib	BRAF V600E mutation: dabrafenib + trametinib NTRK fusion mutation: entrectinib/larotrectinib RET fusion mutation: pralsetinib/selpercatinib
Mutation is absent or targeted agent against the mutation is not feasible	Lenvatinib (preferred) Sorafenib	Vandetanib Cabozantinib	Chemotherapeutic agents: Paclitaxel-carboplatin Docetaxel-doxorubicin Paclitaxel single agent Doxorubicin single agent
Other options (if already progressed on above drugs or not feasible)
Actionable target present	BRAF mutated: BRAF inhibitors with or without MEK inhibitors	NTRK fusion mutation present: entrectinib/larotrectinib MSI high or TMB-high: pembrolizumab	MSI high or TMB-high: pembrolizumab Any other agent against detected actionable mutation (detected if any)
Can be considered	Other multikinase inhibitors: sorafenib, sunitinib, axitinib mTOR inhibitors Chemotherapeutic agents	Other multikinase inhibitors: sorafenib, sunitinib, axitinib mTOR inhibitors Chemotherapeutic agents	Other multikinase inhibitors
All above mentioned options are exhausted/not feasible
	To enroll in clinical trial	To enroll in clinical trial	To enroll in clinical trial

Conclusion

We have come a long way in management of thyroid cancers from surgery, RAI therapy, and chemotherapy to new era of molecular targets. Despite of these agents being expensive with limited benefit in terms of survival, they have nevertheless opened the door of opportunities. In the future, with further knowledge of molecular mechanisms and research, we will have more and more effective options available for treating metastatic/refractory thyroid cancers.

Author Contribution

All authors contributed in manuscript writing and editing.

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From the previous research papers and reviews.

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Conflict of Interest

Dr. Vanita Noronha has received research funding from Amgen, Sanofi India Ltd., Dr. Reddy’s Laboratories Inc., Intas Pharmaceuticals, and Astra Zeneca Pharma India Ltd. (all research grants paid to the institution). Dr. Kumar Prabhash has received research funding from Dr. Reddy’s Laboratories Inc., Fresenius Kabi India Pvt. Ltd., Alkem Laboratories, Natco Pharma Ltd., BDR Pharmaceuticals Intl. Pvt. Ltd, and Roche Holding AG (all research grants paid to the institution). All other authors report no conflicts of interest.