Next Article in Journal
Genome-Wide Identification and Expression Analyses of the Aquaporin Gene Family in Passion Fruit (Passiflora edulis), Revealing PeTIP3-2 to Be Involved in Drought Stress
Next Article in Special Issue
Sinomenine Hydrochloride Promotes TSHR-Dependent Redifferentiation in Papillary Thyroid Cancer
Previous Article in Journal
Full-Length Transcriptome Sequencing Reveals the Impact of Cold Stress on Alternative Splicing in Quinoa
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 23
Issue 10
10.3390/ijms23105731
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Combination Strategies Involving Immune Checkpoint Inhibitors and Tyrosine Kinase or BRAF Inhibitors in Aggressive Thyroid Cancer

by
Francesca Ragusa
1,
Silvia Martina Ferrari
2,
Giusy Elia
1,
Sabrina Rosaria Paparo
1,
Eugenia Balestri
1,
Chiara Botrini
1,
Armando Patrizio
3,
Valeria Mazzi
1,
Giovanni Guglielmi
4,
Rudy Foddis
5,
Claudio Spinelli
1,
Salvatore Ulisse
6,
Alessandro Antonelli
1,* and
Poupak Fallahi
5
1
Department of Surgical, Medical and Molecular Pathology and Critical Area, University of Pisa, 56126 Pisa, Italy
2
Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
3
Department of Emergency Medicine, Azienda Ospedaliero-Universitaria Pisana, 56124 Pisa, Italy
4
U.O. Medicina Preventiva Del Lavoro, Azienda Ospedaliero-Universitaria Pisana, 56124 Pisa, Italy
5
Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy
6
Department of Surgical Sciences, ‘Sapienza’ University of Rome, 00161 Rome, Italy
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2022, 23(10), 5731; https://doi.org/10.3390/ijms23105731
Submission received: 14 April 2022 / Revised: 10 May 2022 / Accepted: 18 May 2022 / Published: 20 May 2022
(This article belongs to the Special Issue Thyroid Autoimmune Disorders and Cancer)
Versions Notes

Abstract

:
Thyroid cancer is the most common (~90%) type of endocrine-system tumor, accounting for 70% of the deaths from endocrine cancers. In the last years, the high-throughput genomics has been able to identify pathways/molecular targets involved in survival and tumor progression. Targeted therapy and immunotherapy individually have many limitations. Regarding the first one, although it greatly reduces the size of the cancer, clinical responses are generally transient and often lead to cancer relapse after initial treatment. For the second one, although it induces longer-lasting responses in cancer patients than targeted therapy, its response rate is lower. The individual limitations of these two different types of therapies can be overcome by combining them. Here, we discuss MAPK pathway inhibitors, i.e., BRAF and MEK inhibitors, combined with checkpoint inhibitors targeting PD-1, PD-L1, and CTLA-4. Several mutations make tumors resistant to treatments. Therefore, more studies are needed to investigate the patient’s individual tumor mutation burden in order to overcome the problem of resistance to therapy and to develop new combination therapies.

1. Introduction

Thyroid cancer (TC) is the most common (~90%) type of endocrine system tumor [1], accounting for 70% of the deaths from endocrine cancers [2]. Over the past two decades, its incidence has increased [3,4]. Among the risk factors, we find the following: female sex, history of goiter or thyroid nodules, family history of TC, radiation exposure, obesity, and low-iodine diet [5].
Although TC occurs more frequently in women than in men (three to four times more), it is more aggressive in men. In fact, men show more advanced disease and lower survival rates [6]. The main histologic types of TC are the following: (a) differentiated TC of follicular origin (DTC)—papillary (PTC, 80%), follicular (FTC, 11%), and Hürthle cells TC; (b) medullary TC (MTC, ~4%) (developed from C cells); and (c) anaplastic TC (ATC) (2% of all TCs) [7]. Poorly differentiated TC (PDTC) and ATC together represent about 5–10% of all TCs [8] and are responsible of most deaths [9,10,11].
Surgery is the principal therapeutical strategy in patients with DTC and MTC [12]. In DTC patients, after thyroidectomy, radioactive iodine (RAI) is used for the ablation of residual normal thyroid or residual metastatic tissue [13,14]. The subsequent follow-up is important to detect possible persistent/recurrent disease, and it includes neck ultrasound and basal/thyroid-stimulating hormone (TSH)-stimulated thyroglobulin (Tg) dosage, usually every 3–6 months during the first year, and then at different timings, which depend on the initial risk evaluation [15,16,17].
TCs range from indolent cancers, usually with low mortality, to very aggressive ones (for example, ATC) [18]. DTC represents more than 90% of TCs; in these cases, patients have a normal life expectancy [18]. In fact, only about 5% of DTC patients report metastases on lung, bone, or other sites at the diagnosis, and during the follow-up, ~15% of them show relapse in thyroid tissue or lymph nodes. In this case, the survival rate at 10 years decreases from 70% to 50% [19,20]. The progression of DTC causes the thyroid cells to lose the ability to capture iodide, thus becoming RAI-refractory. This affects the prognosis in a negative manner [19,20,21].
In the event of failure of RAI and TSH suppressive thyroid hormone (TH) treatment [22], metastatic DTC patients are treated with other therapeutic strategies, such as surgical resection, chemotherapy, and external beam radiotherapy (EBRT). However, they can lead to significant collateral adverse events (AEs) and actually have a palliative role, without prolonging survival whether used alone or in combination [23].
In recent years, new discoveries have been performed in the knowledge of the molecular/genetic basis of TC progression.
Most TCs are characterized by dysregulations involving the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3 kinase/mammalian target of rapamycin/protein-kinase B (PI3K/mTOR/Akt) signaling pathways that are crucial in the regulation of cellular proliferation [24,25].
MAPK hyperactivation is crucial in PTC initiation through point mutations of the BRAF oncogene. BRAF, a member of the RAF family of serine/threonine protein kinases downstream of RAS, is mutated with a higher prevalence in PTC (29–83%) [26,27,28,29]. PI3K/mTOR/Akt pathway activation has a central role in FTC development. Activating RAS mutations are found more frequently in FTC patients (28–68%), in up to 43% of follicular-variant PTCs (FVPTCs) [30], and in up to 47% of all non-invasive FVPTCs [31].
Additional mutations on other pathways, i.e., p53 and Wnt/β-catenin, have been described in case of TC progression and dedifferentiation to PDTC and ATC. Recent telomerase reverse transcriptase (TERT) promoter mutations have been reported in all histological subtypes of TC, with a significantly higher prevalence in aggressive and undifferentiated tumors, suggesting their role in TC progression [32].
New drugs, such as tyrosine kinase inhibitors (TKIs), have been described as emerging new therapies for progressive, aggressive, and refractory tumors. They are able to inhibit the oncogenic kinases (such as v-Raf murine sarcoma oncogene homolog B (V600EBRAF) and rearranged during transfection (RET)/PTC) or to inhibit the signaling kinases, such as Vascular Endothelial Growth Factor Receptor (VEGFR) or Platelet-Derived Growth Factor Receptor (PDGFR), that are implicated in the cell growth [33,34,35,36,37].
Most of these molecular targets might be new diagnostic/prognostic markers and could be targeted by new oncogenic therapies for TC [33,34,36].
In the last years, high-throughput genomics has been able to identify pathways/molecular targets involved in survival and tumor progression, revolutionizing personalized medicine. In the past, the therapies of TC were based on tumor type and histology; however, since several mutations make tumors resistant to conventional and already known treatments, recent approaches have focused on specific gene mutations and their dysregulation [38].
This inherent cancer heterogeneity contributes to the ever-increasing development of personalized and precision medicine. Personalized therapies may arrest tumor growth, as well as enhance anticancer immunity in a more efficient manner. The synergy between immunotherapies and targeted therapies leads to a personalized treatment. Targeted treatment acts on different oncogenic proteins involved in cancerogenesis, such as those of the MAPK pathways. Inhibitors against these pathways have led to promising results in several types of cancer, such as TC, melanoma, pancreatic cancer, Non-Small-Cell Lung Cancer (NSCLC), and colorectal cancer (CRC). A limitation of these targeted therapies is that, despite the considerable cancer size reduction, clinical responses are usually transient and often lead to cancer relapse after initial treatment. Although immunotherapy induces longer-lasting responses in cancer patients than targeted therapy—in particular, one form of immunotherapy, that is, the checkpoint blockade—its response rate is lower. The checkpoint blockade acts on checkpoint proteins involved in the suppression of the immune system. Individually targeted therapies and immunotherapies have many limitations, which can be overcome by their combination [39]. Indeed, recent evidence of this combination is represented by MAPK-targeted therapies, which can synergize with immune cells.
In this review, we discuss recent findings investigating combination strategies involving immune checkpoint inhibitors (ICIs) and TK or BRAF inhibitors in aggressive TC.

2. Methodology

The PUBMED database was searched by using the following search terms in the English language: thyroid cancer, immunotherapy, new checkpoint inhibitors, tyrosine kinase inhibitors, BRAF, MAPK, MEK, aggressive thyroid cancer, PD-1 inhibitors, PD-L1 inhibitors, and CTLA-4. The reference lists of selected articles were screened for additional relevant studies. Data from eligible studies were extracted and reviewed by the authors.

3. BRAF in TC

3.1. BRAF

The V600EBRAF mutation, characterized by the substitution of glutamate with valine, is found in about 45% of PTCs (especially tall cell variants and classic papillary) and in 25% of ATCs [11,40]. This mutation, which causes the phosphorylation of a lot of targets (including mitogen activated protein kinase (MEK) and extracellular signal-regulated kinase (ERK)) by the activated BRAF kinase [41], is associated with malignant features, such as cancer aggressiveness and poor prognosis (larger tumoral size, metastases to lymph node, or distant) [42]. Regarding the prognostic role of the V600EBRAF in PTC, there are studies showing contrasting results: (1) after adjustment for different risk factors (age, presence of lymph node or distant metastasis, and extra-thyroidal invasion), a large multicenter retrospective study showed no associated risk [43]; (2) a retrospective study on PTC patients showed different rates of cancer relapse in presence or absence of V600EBRAF mutation (25% vs. 9.6%) [44].

3.2. Sorafenib in Aggressive DTC

Sorafenib (BAY 43–9006) is a multitarget TKI, able to inhibit several kinases, including RAF, RET, VEGFR-2 and -3, PDGFR, and KIT [45,46]. Sorafenib has been shown to exert anticancer effects both in preclinical models of tumor xenograft (such as breast cancer, colon, and non-small-cell lung) and in vitro by inhibiting TPC1 and TT growth, which carry the RET/PTC1 mutation and C634W RET, respectively [47]. It causes antiproliferative and antiangiogenic effects [48]. Its use has been approved by the FDA in the treatment of renal cell and hepatocellular carcinoma, as well as of metastatic DTC. Administration is performed orally (400 mg BID as maximum dosage), with a good patient tolerance.
Several studies have been conducted on sorafenib (Table 1).
An open-label phase II study enrolled 55 metastatic RAI-refractory TC patients (47% with PTC, 36% with FTC/Hürthle Cell, 9% with PDTC/ATC, and 8% with MTC). Progression-free survival (PFS) was better in PTC/FTC patients with the V600EBRAF mutation than in the wild type (84 weeks vs. 54) [49].
A phase II trial investigated sorafenib (400 mg twice daily) to reinduce RAI uptake in 31 patients treated for 26 weeks. It reported partial response (PR) (25%), stable disease (SD) (34%), clinical response (59%), and PFS (58 weeks). No reinduction of RAI uptake was reported [50].
In another study, 13 patients with RAI-refractory PTC or FTC received sorafenib [41]. The remission rate was 20%, with a durable response rate in 66%, and a clinical benefit rate of 80%. Overall survival (OS) was 67% at 2 years, with a PFS of 19 months [51].
In the UPCC 03305 phase II study, 55 patients with advanced TC (85% with DTC/PDTC, 9% with ATC, and 6% with MTC) were enrolled. DTC/PDTC patients had a higher PFS with respect to the other TCs (96 vs. 93.6 weeks); in addition, 38% of them had a PR, and 47% a SD. DTC/PDTC patients (66%) had at least one mutation (in particular, 11% RET, 45% BRAF, 9% PIK3CA, and 19% RAS mutations), whereas 17% of patients had multiple mutations (60% in ATC) [52].
In another phase II trial, 15 patients with aggressive MTC and 19 with RAI-refractory DTC were administered with sorafenib (400 mg twice daily). The radiological response rate was 18%. A patient with a mutated BRAF exon 15 had an important response after 3 months [53].
In a phase II study, 31 RAI-refractory DTC patients received sorafenib (400 mg bid). The 31% of patients achieved a PR and 42% had a SD, after a median follow-up of 25 months. V600EBRAF did not correlate with the progression of the disease [54].
In a phase II trial, 20 ATC patients were treated with sorafenib (400 mg bid), reaching a PR in 10%, and SD in 25%. Only 20% of patients reached a survival of 1-year, suggesting the ineffectiveness of sorafenib in ATC patients [55].
In the double-blinded randomized phase III (DECISION) trial, 417 patients with RAI-refractory, locally advanced, or metastatic DTC were enrolled, of which 207 received sorafenib and 210 received the placebo. PFS was higher in patients treated with the drug than in those treated with the placebo (10.8 vs. 5.8 months). PFS improved in all subgroups, with or without mutations. AEs occurred in 98.6% of sorafenib-treated patients [56].
Further studies have confirmed the results obtained with sorafenib in metastatic and progressive DTC [57,58].
Another phase II trial investigated the effect of sorafenib in patients with aggressive ATC or MTC, reporting the following: (a) in ATC, a median OS of 5.0 months and PFS of 2.8 months; and (b) in MTC, an objective RR of 25% and disease control rate in 75%. It was concluded that sorafenib was effective in MTC, but not in ATC [59].
In a phase II study, sorafenib was administered to 36 patients with metastatic TC (i.e., PTC, Hürthle cell, FTC, or ATC) (200 mg twice daily per os., combined with intravenous temsirolimus (25 mg weekly)), with a 22% PR, 58% SD, and 3% progressive disease (PD) [60].
A meta-analysis investigated the safety and efficacy of sorafenib in RAI-refractory DTC patients, showing that sorafenib improved PFS in comparison to the placebo [61].
A study compared sorafenib or sunitinib in 28 RAI-refractory metastatic DTC patients (26 treated with sorafenib as first-line therapy (eight patients switched successively to sunitinib), and two with sunitinib). The PR rate and mean PFS were 30.7% and 10.8 months, respectively, for sorafenib, and 37.5% and 6 months for sunitinib, as a second-line therapy [62].

3.3. Dabrafenib and Trametinib

Dabrafenib (GSK2118436) is a BRAF kinase inhibitor [63], whose antiproliferative effect has been shown in vitro in V600EBRAF melanoma and in human colon tumor xenografts [69].
Trametinib (trade name Mekinist) is a MEK inhibitor drug with anticancer activity. It inhibits MEK1 and MEK2. Trametinib showed encouraging results for metastatic melanoma carrying the V600EBRAF mutation in a phase III clinical trial.
In 2018, the combination of dabrafenib and trametinib was approved by the FDA for the treatment of locally advanced, unresectable, and metastatic V600EBRAF-mutated ATC, with no possibility of loco-regional treatment.
Trametinib and dabrafenib activity was demonstrated by several studies (Table 1).
In a phase I study, 184 terminal patients with inoperable solid tumors (carrying the V600EBRAF mutation) received dabrafenib (300 mg daily orally). A total of 14/184 patients had PTC, and nine of these survived for all the duration of the study, showing PR in 33% of cases [63]. However, as reported by many other clinical studies, BRAF-positive tumors exhibited resistance to dabrafenib in 6 to 7 months. To circumvent this problem, dabrafenib was used in combination with trametinib [70], a combination that was approved by the FDA in 2014 for the treatment of metastatic melanoma BRAF-V600E/K-positive [71].
Two patients with V600EBRAF-positive ATC were administered with dabrafenib, and it was concluded that BRAF inhibitor monotherapy appears to obtain only temporary clinical improvement in ATC [64].
In a woman with an ATC with V600EBRAF mutation (treated with EBRT, and then with pazopanib when the metastatic disease progressed to the neck and lung, with no benefits) the treatment with dabrafenib (150 mg bid) and trametinib (2 mg/day) led to a PR in 2 weeks. Then the disease progressed, and the patient died upon 6 months [65].
Moreover, another study reported a good clinical effect and a good tolerance in ATC patients with V600EBRAF mutation, showing an overall response rate of 69% (95% CI, 41–89%), with seven ongoing responses [66].
Among 16 ATC patients (10 treated with lenvatinib, and 6 BRAF mutated patients with dabrafenib/trametinib), survival improved in the latter group of patients vs. those treated with lenvatinib [67].
Another study reported the efficacy and safety of dabrafenib plus trametinib in the ATC cohort of the phase II Rare Oncology Agnostic Research (ROAR) basket study. Thirty-six patients with ATC received dabrafenib (150 mg twice daily + trametinib 2 mg once) until disease progression, unacceptable toxicity, or death. The overall response rate was 56%, including three complete responses; the 12-month duration of response rate was 50%. The OS was 14.5 months, while the PFS was 6.7. The OS at 12 months was 43.2%, and at 24 months, it was 31.5% [68].

4. Immune Checkpoint Blockade

The goal of cancer immunotherapy is to improve the immune system ability to destroy cancer cells. The first protocol used involved the use of interleukin 2 (IL-2) for the treatment of metastatic melanoma [72]. IL-2 was able to enhance T-cell activation in a nonspecific way [73]. A high dosage of IL-2 is now not widely used as monotherapy, due to severe toxicity and low response rates [74]; on the contrary, IL-2 has been shown to be more effective when administered at a low dosage together with other treatments (e.g., adoptive cell transfer) [75].
Immune checkpoints, whose main role is to reduce the immune cell activation in order to keep the homeostasis of the immune system and inhibit the autoimmune process, represent an area for which new therapeutic strategies are emerging. Inside the tumor microenvironment, cancer cells upregulate the molecules of immune checkpoint in order to suppress the antitumor immune system response [76]. Specific monoclonal antibodies (mAbs) against immune checkpoints could be used as a strategy to invert the suppression of cancer-specific immune cells, such as T cells and natural killer (NK) cells [77,78]. Recently, Ribas et al. have demonstrated the efficacy of mAbs against immune checkpoint receptors, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death 1 (PD-1), and programmed cell death protein ligand (PD-L1) to treat multiple advanced cancers, such as NSCLC, melanoma, bladder, and head and neck cancers [79].

5. Immunotherapy and Targeted Therapy Combination in other Solid Cancers

Many cancers are able to evade cell death through the suppression of the immune system. One mechanism is the activation of the expression of PD-L1 by cytokines (e.g., IFN-gamma) released inside tumor-infiltrating lymphocytes (TILs). BRAF inhibitor-resistant melanoma cell lines, in which an increased expression of PD-L1 occurs, have shown the ability to evade the host’s immune system [80]. However, during the initial treatment stages, MAPK and BRAF inhibitors could boost the immune response against cancers, unless the patient develops resistance.
Intratumoral infiltration of T cells can be improved by BRAF and MEK inhibitors. Many studies have demonstrated an increase of T cells in BRAF-mutated melanomas after MAPK-pathway-inhibitors treatment, even if there is a loss of this increase with the progression of the therapy. CD8-effector T cells may be protected against death via stimulation of chronic T-cell receptor by MAPK-pathway inhibitors. The immune-stimulatory effects of MEK inhibitors include the increase of the expression of melanocyte-derived antigen, the increase of T-cell infiltration, and the reduction of the interaction among tumor cells and M2-like macrophages. Increased levels of cancer antigen could enhance antitumoral T-cell responses [80]. Nevertheless, MEK inhibitors can adversely affect the proliferation and viability of naive T cells and the secretion of IFN-gamma.
MAPK inhibitors can stimulate transient responses. It was demonstrated that melanoma patients with BRAF mutation show some short-term advantage after targeted treatments (e.g., MAPK inhibitors). On the contrary, it was suggested that immunotherapies such as immune checkpoint blockades are able to stimulate longer-term responses in about 1/3 of patients [81]. In addition, it was shown that tumor immune infiltration and control could be improved by short-term blockage of MEK and BRAF, together with anti-PD-1/L1 Abs, in a CD8-T cells-dependent way. Monotherapies-related limitations could be bypassed through the combination of MAPK inhibitors and ICIs.
The combination of ICIs (especially anti-PD-1/L1) with MEK and/or BRAF inhibitors are now under evaluation through several clinical trials. The toxicity of each single agent, if used as combined therapy, can only be evaluated with long-term studies. Atkins et al. conducted a phase I study on melanoma, both BRAF-mutated melanoma and BRAF wild type, which showed a tolerable safety profile for an anti-PD-L1 antibody when used together with trametinib and dabrafenib [82]. A phase II study on advanced melanoma patients (NCT02625337) investigated the combination of pembrolizumab with dabrafenib and trametinib, given intermittently or continuously [83,84].
Optimizing the sequence in which ICIs and targeted therapies are given could have potential benefits, as it could reduce the toxicity and costs related to simultaneous treatment strategies used for long periods. Targeted therapies/immunotherapies integration can be useful to overcome the limitations of the single therapeutic approach and to potentiate the response to monotherapy.
Here, we discuss clinical trials conducted in patients with not TC cancers, such as melanoma, NSCLC, and CRC (Table 2).

5.1. Melanoma

Surgery is the primary therapeutic strategy used to treat patients with early stage melanoma, but not in the case of advanced melanoma (because of the high rate of metastasis). Patients with late-stage melanoma are usually treated with conventional chemotherapy, even if the response rate is very poor (~5%) [92,93]. Recently, the strategy of combination therapy (targeted therapies plus immunotherapies) allowed to improve the prognosis of melanoma.
More than 50% of patients with melanoma carry the V600BRAF mutation, which causes constitutive activation of the MAPK signaling [94]. In 2011 the FDA approved the use of vemurafenib, a BRAF inhibitor, for patients with advanced melanoma, as a result of which rates of OS and PFS improved significantly [95]. In 2013, the FDA approved dabrafenib as another BRAF inhibitor; it has an efficacy similar to vemurafenib but with a lower frequency of side effects. Other drugs combination, such as dabrafenib plus trametinib, are expected to be associated with a higher response rate than dabrafenib monotherapy [96]. However, these drugs allow to obtain remarkable clinical responses in the short-term, but only rarely in long-term, due to the acquired resistance [97].
In addition to BRAF inhibitors, MEK inhibitors have been developed, including trametinib. Trametinib was the first FDA-approved MEK inhibitor for the treatment of advanced melanoma. In particular, it inhibits MEK1/2 [98]. For this kind of tumor, recently the FDA also approved the combination of encorafenib (a BRAF inhibitor) and binimetinib (a MEK inhibitor), and this combination is able to improve PFS and OS in patients with BRAF-mutated melanoma [99]. A limitation of these treatments is that, after several months of treatment, the rate of clinical responses tends to decrease [100].
Several clinical trials have investigated the combination of targeted therapies and immunotherapies, specifically ICIs, in order to improve the clinical response (Table 2) [83].

5.2. NSCLC

Lung cancer has a high frequency and is related to mortality regardless of gender. Early stage (stages I, II, and IIIA) NSCLC is usually treated with surgical resection [101], but in 80% of cases, lung cancers are diagnosed when they are already in an advanced stage, and surgery is no longer indicated. Furthermore, tumor relapse may occur a few years after surgical resection [102]. In patients with advanced NSCLC, chemotherapy is, thus, the first-line therapy used [101].
For the treatment of NSCLC patients, immunotherapies have been developed. Several clinical trials have demonstrated the efficacy of anti-PD-1/PD-L1 antibodies, with significant responses and low toxicities [103]. Chemotherapy, which increases the expression of PD-L1 on tumor cells and the number of TILs, has been demonstrated to have few effects in patients characterized by elevated levels of PD-L1 and low levels of causative mutations [104]; thus, the combination between ICIs and chemotherapy could have promising clinical results [105,106].
In recent decades, therapeutic strategies targeting epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutations have made it possible to achieve substantial advances in the treatment of NSCLC patients [107]. Most EGFR mutations, including exon 21 L858R and exon 19 deletions mutations, cause the constitutive activation of downstream pathways, such as MAPK, signal transducer and activator of transcription (STAT), and PI3K [108].
Several clinical trials investigated the combining of MAPK inhibitors and ICIs (Table 2) [83].

5.3. CRC

CRC is the third most common cancer in the world [109]. The OS of metastatic CRC patients is low. Surgery and subsequent adjuvant chemotherapy represent the standard treatment [110,111]. Mutations on BRAF, KRAS, SMAD4, and p53 genes represent the most common mutations, which have an important relevance in the development of CRC metastasis [110].
ICIs which have shown to be effective in many types of cancer (anti-PD-1 mAb (pembrolizumab and nivolumab), anti-PD-L1 Ab (avelumab, durvalumab, and atezolizumab), and anti-CTLA-4 Ab (tremelimumab and ipilimumab)), are not equally effective in treating CRC [111]. Nevertheless, if they are used in combination with MAPK-pathway-targeted therapy, they result in being more efficacious, as demonstrated by several clinical trials (Table 2) [83].

6. Immunotherapy in DTC

As the tumor microenvironment is the primary scenario involved in tumor progression and treatment response, new therapeutic strategies target the TC immune panorama. Immune checkpoints, such as PD-1 and its ligand PD-L1, and CTLA-4 inhibitors work by altering the interaction immune system/cancer cells [112]. Several studies have investigated the PD-1/PD-L1 expression in TC for prognostic and diagnostic purposes [113]. Aghajani et al. have demonstrated the association of PD-L1 in TC with tumor relapse and poor survival [114]. According to the TCGA database analyses, lymph node metastasis, extrathyroid invasion, and shorter disease-specific survival are linked to increased PD-L1 mRNA expression [115], as supported by two studies [116,117]. However, since DTC has few mutations, it is poorly immunogenic. Indeed, it has been demonstrated that TC responds poorly to immunotherapy with checkpoint inhibitors [118,119]. The efficacy of immunotherapy could be improved by combined treatments, as evaluated in several clinical studies conducted on solid tumors, such as TC [56,66,116,118,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149].

7. Immunotherapy and Targeted Therapy in Aggressive TC

ATC is the rarest TC, but the most aggressive one, causing ~50% of the deaths due to TCs. Median survival from the diagnosis is usually about 6 months, because of its aggressiveness and the absence of an efficacious therapy [150].
The standard treatment of ATC includes surgical debulking, accelerated hyperfractionated EBRT, and chemotherapy, which permit patients to reach about 10 months of median survival. It is still challenging to predict the ATC patient clinical therapy responsiveness [150].
ATC shows a high frequency of V600EBRAF mutations, and it is associated with an immunosuppressive microenvironment [151].
Combination therapy is particularly effective in de-differentiated tumors, such as widely invasive Hürthle cell TC and ATC, in which there are a large number of mutations that introduce immunogenicity [152,153], as suggested by some studies described below.

7.1. PLX4720

Gunda et al. have assessed the combined treatment of PLX4720 (V600EBRAF inhibitor) and an anti-PD-1/PD-L1 Ab in an immunocompetent murine model of orthotopic ATC. They conducted an immune profiling of myeloid and lymphoid lineage cells at the moment of the maximum response to treatment and tumor regrowth. They demonstrated that the combined treatment results in a significant increase in the mouse survival. At the moment of maximal cancer reduction, a decrease of Ki67 proliferative index, an increase of tumor CD8+ cytotoxic T cells, FoxP3+ Tregs, and NK cells, as well as an increase of granzyme B staining and IFN-gamma production, occur, confirming the increasing of cytotoxicity. However, no complete responses were observed, and tumor regrowth emerged after 2–3 weeks of combination therapy, rapidly causing the mouse to die. Cancer regrowth was associated with decreases in CD8 + T cells and NK cells and loss of granzyme B and IFN-gamma production, confirming the attenuation of inflammation. At the time of maximum tumor shrinkage, there was an increased number and cytotoxicity of CD8 + T cells and NK cells, an increased number of M1 polarized tumor-related macrophages (TAMs) and a decreased number of myeloid-derived suppressor-like cells. On the contrary, at the time of tumor regrowth, there was a decrease in TAMs and an increase in M2 polarization. Hence, the combined treatment drastically decreased tumor volume, prolonging survival and improving the anticancer immune profile in a mouse ATC model, but tumor regrowth was inevitable [151].

7.2. Pembrolizumab

Kinase inhibitors (KIs) have demonstrated a good effectiveness in the ATC treatment; nevertheless, these cancers eventually acquire KI resistance, and patients succumb to their own disease.
KIs targeting BRAF, MEK, and VEGFR have shown promise in managing ATC in a clinical study and in the real world [66,67,116,154]. Although these therapies manage to improve the median OS of ATC patients, the tumors eventually show resistance, with subsequent disease progression and death [12,42]. It is therefore a priority to identify rescue treatments for cancers that progress despite KI treatment.
ATC tumors express the PD-L1 on the tumor surface; there is a diffuse infiltration of the tumor with T-lymphocytes bearing the PD-1 receptor. Pembrolizumab, a mAb against the PD-1 receptor, represents a safe and effective salvage therapy to be added to KI therapy at the time of progression, since the immune microenvironment could be less permissive at the time of progression on KI therapy [155].
Cabanillas et al. reported the case of an unresectable/end-stage/locally advanced ATC patient who was treated at first with trametinib and dabrafenib, and subsequently with pembrolizumab. A PR was reached, allowing surgical resection and chemoradiation [156].
Iyer et al. have explored the effectiveness of pembrolizumab when added to KIs at the moment of ATC progression in patients of MD Anderson Cancer Center between August 2016 and August 2017. BOR was evaluated through the RECIST v1.1 criteria: 42% of patients (5/12) with PR, 33% (4/12) with SD, and 25% (3/12) with PD. Then it was assessed the PFS from the beginning of pembrolizumab, as well as median OS from the beginning of KIs, and from the addition of pembrolizumab: from the start of KIs, the median OS was 10.43 months; after the addition of pembrolizumab, the PFS and median OS were 2.96 months and 6.93 months, respectively. These results suggest that pembrolizumab may represent an effective rescue treatment to add to KIs as cancers progress. Furthermore, the addition of pembrolizumab could occur at any time during KI treatment in order to maximize benefit from the combination treatment. Nevertheless, better therapeutic strategies that include immunotherapy should be investigated for the treatment of patients with ATC [155].
A recent study described six consecutive BRAF-mutated ATC patients with loco-regional advanced disease who received dabrafenib and trametinib, surgical treatment, and adjuvant chemoradiation. Among them, three were also administered with pembrolizumab. At 6 months, the OS was 100%, and it was 83% at 1 year [157].
Sukari et al. [158] recently reported two cases of ATC in order to underline the importance of histopathological diagnosis of tissues, the role of molecular tests, and the potential role of ICIs:
—
Case 1: A 49-year-old man with ATC (diagnosed after a re-review of the histological examination) was treated with concurrent chemotherapy and radiation therapy after surgical resection. A post-treatment PET-CT scan did not highlight residual FDG uptake. The patient was monitored for 14 months, when he suddenly experienced pain in his left arm that later turned out to be a humerus metastasis with a pathological fracture. The histological investigation of metastasis during surgical fixation detected the presence of poorly differentiated malignant cells in line with ATC, so the patient was treated with pembrolizumab (three cycles). Nevertheless, diffuse bone metastases and a new liver injury were later individuated.
—
Case 2: A 61-year-old woman was diagnosed with ATC with extrathyroid expansion and metastasis in lymph nodes and lungs. She was treated with concurrent chemotherapy plus radiation therapy. A post-treatment PET-CT scan highlighted residual FDG uptake in the pulmonary nodules. Lenvatinib was then initiated until the V600EBRAF mutation was identified in the tumor. After that, she was treated with dabrafenib 150 mg PO BID and trametinib 2 mg PO daily. A reduction of the size of the left lung lesion was observed at nine months. Two months later, for the appearance of the metastasis in the right lung, the patient initiated carboplatin, paclitaxel, and pembrolizumab; after four cycles of this therapy, she continued dabrafenib plus trametinib, showing a stability of the disease for 10 months.
Sukari et al. have finally affirmed that ATC immunotherapy with single agent could not be as efficacious (case 1) as in combination (case 2), while other case reports have reported the success of ICIs as single agent [158,159].
Kulkarni et al. reported a case of a 71-year-old ATC man with aggressive metastasis of the lung and V600EBRAF mutation, who initiated dabrafenib 150 mg PO (twice) and trametinib 2 mg PO. After 6 weeks, he presented with fever, and, for this reason, the therapy was stopped and restarted 10 days after with reduced dose of dabrafenib 100 mg PO BID and trametinib 1.5 mg PO that were continued for 6 weeks until the appearance of side effects (recurrent fevers, hearing loss, and uveitis). Since his tumor had a PD-L1 expression of 90%, pembrolizumab was given, but after five cycles, a recurrence of ATC was observed in the right lung and mediastinal lymph nodes [160].

7.3. Spartalizumab

Capdevila et al. conducted a phase I/II study on patients with ATC who were treated with spartalizumab. They enrolled 42 patients with locally advanced and/or metastatic ATC. Patients received 400 mg of spartalizumab intravenously once every 4 weeks. The overall RR was obtained according to RECIST v1.1 criteria.
The overall RR was 19%, with a complete response in three patients and a PR in 5 patients. The RR were higher in PD-L1–positive (8/28; 29%) vs. PD-L1–negative (0/12; 0%) patients. Responses were observed in patients with or without BRAF mutation, with a 1-year survival of 52.1% in patients PD-L1–positive.
Side effects of spartalizumab were similar to those of other PD-1-targeting mAbs [161,162,163].
This was the first clinical trial to show the responsiveness of ATC to PD-1 blockade [164].

7.4. Oncolytic Herpes Simplex Virus

About 30–60% of PDTCs and ATCs show mutations in the BRAF gene; however, specific inhibitors that target oncogenic BRAF have shown a short-lasting therapeutical benefit as single agents. This underlines the necessity for improved treatment strategies, such as new combinations.
Using a V600EBRAF-driven mouse model of ATC, Crespo-Rodriguez et al. assessed the therapeutic effectiveness of combining BRAF inhibition/oncolytic herpes simplex virus (oHSV).
Samples from tumor-bearing mice were analyzed in order to immunologically characterize the effects of various treatments.
The authors characterized the immune landscape in vivo after treatment with BRAF inhibitor and found only few immune modifications. For this reason, they added oncolytic virotherapy to BRAF inhibition in TC to obtain a more favorable tumor immune microenvironment, as well as increase the inflammatory status of cancers and ameliorate BRAF inhibitor therapy. In advance, they demonstrated that TC cells were susceptible to oHSV infection and that this condition was related to the activation of the immune cancer microenvironment in vivo. Subsequently, they demonstrated enhanced therapeutic responses following the combination BRAF inhibition/oHSV in vivo, even if without synergistic effects in vitro, and confirmed that the dominant effect of oHSV in this setting was immune-mediated.
The detected gene and protein expression data increased T-cell and NK-cell activation in the cancer after combined treatment. However, the success of this association was nullified after T cells or NK cells were depleted in vivo. Moreover, an upregulation of PD-L1 and CTLA-4 after combined treatment and an improvement of combination therapy by the blockade of the PD-1/PD-L1 axis or CTLA-4 have been demonstrated [165].

8. Conclusions

TC is the most common type of endocrine-system tumor [1], accounting for 70% of endocrine-cancer deaths [2].
Recent discoveries have been performed in the knowledge of the molecular/genetic basis of TC progression. New drugs, such as TKIs, have been described as emerging new therapies for progressive, aggressive, and refractory tumors, since they are able to block the oncogenic kinases or to block the signaling kinases associated with cell growth [33,34,35,36].
The high-throughput genomics have recently identified pathways/molecular targets involved in survival and tumor progression.
Separately, targeted therapies and immunotherapies have many limitations. Clinical responses to targeted therapy are generally transient and often lead to cancer relapse after initial treatment; and immunotherapy has a low response rate.
These individual limitations can be overcome by combining them. Indeed, combination therapies target signal transduction cascades required for tumor cell survival and maintenance.
Since a lot of different mutations make tumors resistant to treatments, knowing that the patient’s individual tumor mutation burden is important in selecting the optimal personalized combination regimen. This can be an effective strategy to overcome the problem of resistance to therapy and to develop new combination therapies.

Author Contributions

All the authors contributed to this paper. Writing, F.R., S.M.F., A.A. and P.F.; Review and editing, G.G., R.F., C.S. and S.U. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Fagin, J.A.; Wells, S.A., Jr. Biologic and Clinical Perspectives on Thyroid Cancer. N. Engl. J. Med. 2016, 375, 1054–1067. [Google Scholar] [CrossRef] [Green Version]
  2. Lim, H.; Devesa, S.S.; Sosa, J.A.; Check, D.; Kitahara, C.M. Trends in Thyroid Cancer Incidence and Mortality in the United States, 1974–2013. JAMA 2017, 317, 1338–1348. [Google Scholar] [CrossRef]
  3. Kilfoy, B.A.; Zheng, T.; Holford, T.R.; Han, X.; Ward, M.H.; Sjodin, A.; Zhang, Y.; Bai, Y.; Zhu, C.; Guo, G.L.; et al. International patterns and trends in thyroid cancer incidence, 1973-2002. Cancer Causes Control 2009, 20, 525–531. [Google Scholar] [CrossRef] [Green Version]
  4. Chen, A.Y.; Jemal, A.; Ward, E.M. Increasing incidence of differentiated thyroid cancer in the United States, 1988–2005. Cancer 2009, 115, 3801–3807. [Google Scholar] [CrossRef]
  5. Carling, T.; Udelsman, R. Thyroid cancer. Ann. Rev. Med. 2014, 65, 125–137. [Google Scholar] [CrossRef]
  6. Nilubol, N.; Zhang, L.; Kebebew, E. Multivariate analysis of the relationship between male sex, disease-specific survival, and features of tumor aggressiveness in thyroid cancer of follicular cell origin. Thyroid 2013, 23, 695–702. [Google Scholar] [CrossRef]
  7. Fallahi, P.; Ferrari, S.M.; Elia, G.; Ragusa, F.; Paparo, S.R.; Ruffilli, I.; Patrizio, A.; Materazzi, G.; Antonelli, A. Evaluating vandetanib in the treatment of medullary thyroid cancer: Patient-reported outcomes. Cancer Manag. Res. 2019, 11, 7893–7907. [Google Scholar] [CrossRef] [Green Version]
  8. Butts, C.A.; Brady, J.J., III; Wilhelm, S.; Castor, L.; Sherwood, A.; McCall, A.; Patch, J.; Jones, P.; Cortes, V.; Ong, A.W. Do simple beside lung function tests predict morbidity after rib fractures? Am. J. Surg. 2017, 213, 473–477. [Google Scholar] [CrossRef]
  9. Besic, N.; Auersperg, M.; Us-Krasovec, M.; Golouh, R.; Frkovic-Grazio, S.; Vodnik, A. Effect of primary treatment on survival in anaplastic thyroid carcinoma. Eur. J. Surg. Oncol. 2001, 27, 260–264. [Google Scholar] [CrossRef]
  10. Molinaro, E.; Romei, C.; Biagini, A.; Sabini, E.; Agate, L.; Mazzeo, S.; Materazzi, G.; Sellari-Franceschini, S.; Ribechini, A.; Torregrossa, L.; et al. Anaplastic thyroid carcinoma: From clinicopathology to genetics and advanced therapies. Nat. Rev. Endocrinol. 2017, 13, 644–660. [Google Scholar] [CrossRef]
  11. Smallridge, R.C.; Marlow, L.A.; Copland, J.A. Anaplastic thyroid cancer: Molecular pathogenesis and emerging therapies. Endocr. Relat. Cancer 2009, 16, 17–44. [Google Scholar] [CrossRef] [Green Version]
  12. Miccoli, P.; Antonelli, A.; Spinelli, C.; Ferdeghini, M.; Fallahi, P.; Baschieri, L. Completion total thyroidectomy in children with thyroid cancer secondary to the Chernobyl accident. Arch. Surg. 1998, 133, 89–93. [Google Scholar] [CrossRef] [Green Version]
  13. Lamartina, L.; Cooper, D.S. Radioiodine remnant ablation in low-risk differentiated thyroid cancer: The “con” point of view. Endocrine 2015, 50, 67–71. [Google Scholar] [CrossRef]
  14. Antonelli, A.; Rotondi, M.; Fallahi, P.; Grosso, M.; Boni, G.; Ferrari, S.M.; Romagnani, P.; Serio, M.; Mariani, G.; Ferrannini, E. Iodine-131 given for therapeutic purposes modulates differently interferon-gamma-inducible alpha-chemokine CXCL10 serum levels in patients with active Graves’ disease or toxic nodular goiter. J. Clin. Endocrinol. Metab. 2007, 92, 1485–1490. [Google Scholar] [CrossRef] [Green Version]
  15. Antonelli, A.; Miccoli, P.; Ferdeghini, M.; Di Coscio, G.; Alberti, B.; Iacconi, P.; Baldi, V.; Fallahi, P.; Baschieri, L. Role of neck ultrasonography in the follow-up of patients operated on for thyroid cancer. Thyroid 1995, 5, 25–28. [Google Scholar] [CrossRef]
  16. Antonelli, A.; Miccoli, P.; Fallahi, P.; Grosso, M.; Nesti, C.; Spinelli, C.; Ferrannini, E. Role of neck ultrasonography in the follow-up of children operated on for thyroid papillary cancer. Thyroid 2003, 13, 479–484. [Google Scholar] [CrossRef] [Green Version]
  17. Cooper, D.S.; Doherty, G.M.; Haugen, B.R.; Kloos, R.T.; Lee, S.L.; Mandel, S.J.; Mazzaferri, E.L.; McIver, B.; Pacini, F.; Schlumberger, M.; et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2009, 19, 1167–1214. [Google Scholar] [CrossRef] [Green Version]
  18. Cabanillas, M.E.; McFadden, D.G.; Durante, C. Thyroid cancer. Lancet 2016, 388, 2783–2795. [Google Scholar] [CrossRef]
  19. Durante, C.; Montesano, T.; Torlontano, M.; Attard, M.; Monzani, F.; Tumino, S.; Costante, G.; Meringolo, D.; Bruno, R.; Trulli, F.; et al. Papillary thyroid cancer: Time course of recurrences during postsurgery surveillance. J. Clin. Endocrinol. Metab. 2013, 98, 636–642. [Google Scholar] [CrossRef] [Green Version]
  20. Gruber, J.J.; Colevas, A.D. Differentiated thyroid cancer: Focus on emerging treatments for radioactive iodine-refractory patients. Oncologist 2015, 20, 113–126. [Google Scholar] [CrossRef] [Green Version]
  21. D’Agostino, M.; Sponziello, M.; Puppin, C.; Celano, M.; Maggisano, V.; Baldan, F.; Biffoni, M.; Bulotta, S.; Durante, C.; Filetti, S.; et al. Different expression of TSH receptor and NIS genes in thyroid cancer: Role of epigenetics. J. Mol. Endocrinol. 2014, 52, 121–131. [Google Scholar] [CrossRef] [Green Version]
  22. Miccoli, P.; Antonelli, A.; Iacconi, P.; Alberti, B.; Gambuzza, C.; Baschieri, L. Prospective, randomized, double-blind study about effectiveness of levothyroxine suppressive therapy in prevention of recurrence after operation: Result at the third year of follow-up. Surgery 1993, 114, 1097–1101. [Google Scholar]
  23. Valerio, L.; Pieruzzi, L.; Giani, C.; Agate, L.; Bottici, V.; Lorusso, L.; Cappagli, V.; Puleo, L.; Mantrone, A.; Viola, D.; et al. Targeted therapy in thyroid Cancer: State of the art. Clin. Oncol. 2017, 29, 316–324. [Google Scholar] [CrossRef]
  24. Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: The next generation. Cell 2011, 144, 646–674. [Google Scholar] [CrossRef] [Green Version]
  25. Cancer Genome Atlas Research Network. Integrated Genomic Characterization of Papillary Thyroid Carcinoma. Cell 2014, 159, 676–690. [Google Scholar] [CrossRef] [Green Version]
  26. Kim, K.H.; Kang, D.W.; Kim, S.H.; Seong, I.O.; Kang, D.Y. Mutations of the BRAF Gene in Papillary Thyroid Carcinoma in a Korean Population. Yonsei Med. J. 2004, 45, 818. [Google Scholar] [CrossRef] [Green Version]
  27. Soares, P.; Trovisco, V.; Rocha, A.S.; Lima, J.; Castro, P.; Preto, A.; Máximo, V.; Botelho, T.; Seruca, R.; Sobrinho-Simões, M. BRAF mutations and RET/PTC rearrangements are alternative events in the etiopathogenesis of PTC. Oncogene 2003, 22, 4578–4580. [Google Scholar] [CrossRef] [Green Version]
  28. Nikiforova, M.N.; Kimura, E.T.; Gandhi, M.; Biddinger, P.W.; Knauf, J.A.; Basolo, F.; Zhu, Z.; Giannini, R.; Salvatore, G.; Fusco, A.; et al. BRAF Mutations in Thyroid Tumors Are Restricted to Papillary Carcinomas and Anaplastic or Poorly Differentiated Carcinomas Arising from Papillary Carcinomas. J. Clin. Endocrinol. Metab. 2003, 88, 5399–5404. [Google Scholar] [CrossRef]
  29. Fugazzola, L.; Mannavola, D.; Cirello, V.; Vannucchi, G.; Muzza, M.; Vicentini, L.; Beck-Peccoz, P. BRAF mutations in an Italian cohort of thyroid cancers. Clin. Endocrinol. 2004, 61, 239–243. [Google Scholar] [CrossRef]
  30. Kimura, E.T.; Nikiforova, M.N.; Zhu, Z.; Knauf, J.A.; Nikiforov, Y.E.; Fagin, J.A. High prevalence of BRAF mutations in thyroid cancer: Genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma. Cancer Res. 2003, 63, 1454–1457. [Google Scholar]
  31. Kim, M.; Jeon, M.J.; Oh, H.S.; Park, S.; Kim, T.Y.; Shong, Y.K.; Kim, W.B.; Kim, K.; Kim, W.G.; Song, D.E. BRAF and RAS Mutational Status in Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features and Invasive Subtype of Encapsulated Follicular Variant of Papillary Thyroid Carcinoma in Korea. Thyroid 2018, 28, 504–510. [Google Scholar] [CrossRef]
  32. Prete, A.; Borges de Souza, P.; Censi, S.; Muzza, M.; Nucci, N.; Sponziello, M. Update on Fundamental Mechanisms of Thyroid Cancer. Front. Endocrinol. 2020, 11, 102. [Google Scholar] [CrossRef]
  33. Ferrari, S.M.; Ruffilli, I.; Centanni, M.; Virili, C.; Materazzi, G.; Alexopoulou, M.; Miccoli, M.; Antonelli, A.; Fallahi, P. Lenvatinib in the therapy of aggressive thyroid cancer: State of the art and new perspectives with patents recently applied. Recent. Pat. Anticancer Drug Discov. 2018, 13, 201–208. [Google Scholar] [CrossRef]
  34. Ferrari, S.M.; Centanni, M.; Virili, C.; Miccoli, M.; Ferrari, P.; Ruffilli, I.; Ragusa, F.; Antonelli, A.; Fallahi, P. Sunitinib in the treatment of thyroid Cancer. Curr. Med. Chem. 2019, 26, 963–972. [Google Scholar] [CrossRef]
  35. Antonelli, A.; Fallahi, P.; Ferrari, S.M.; Ruffilli, I.; Santini, F.; Minuto, M.; Galleri, D.; Miccoli, P. New targeted therapies for thyroid cancer. Curr. Genom. 2011, 12, 626–631. [Google Scholar] [CrossRef] [Green Version]
  36. Ferrari, S.M.; Fallahi, P.; Politti, U.; Materazzi, G.; Baldini, E.; Ulisse, S.; Miccoli, P.; Antonelli, A. Molecular Targeted Therapies of Aggressive Thyroid Cancer. Front. Endocrinol. 2015, 6, 176. [Google Scholar] [CrossRef] [Green Version]
  37. Fallahi, P.; Ferrari, S.M.; Galdiero, M.R.; Varricchi, G.; Elia, G.; Ragusa, F.; Paparo, S.R.; Benvenga, S.; Antonelli, A. Molecular targets of tyrosine kinase inhibitors in thyroid cancer. Semin. Cancer Biol. 2022, 79, 180–196. [Google Scholar] [CrossRef]
  38. Nussinov, R.; Jang, H.; Tsai, C.J.; Cheng, F. Review: Precision medicine and driver mutations: Computational methods, functional assays and conformational principles for interpreting cancer drivers. PLoS Comput. Biol. 2019, 15, e1006658. [Google Scholar] [CrossRef]
  39. Yu, C.; Liu, X.; Yang, J.; Zhang, M.; Jin, H.; Ma, X.; Shi, H. Combination of Immunotherapy with Targeted Therapy: Theory and Practice in Metastatic Melanoma. Front. Immunol. 2019, 10, 990. [Google Scholar] [CrossRef] [Green Version]
  40. Xing, M. BRAF mutation in thyroid cancer. Endocr. Relat. Cancer 2005, 12, 245–262. [Google Scholar] [CrossRef] [Green Version]
  41. Perri, F.; Pezzullo, L.; Chiofalo, M.G.; Lastoria, S.; Di Gennaro, F.; Scarpati, G.D.; Caponigro, F. Targeted therapy: A new hope for thyroid carcinomas. Crit. Rev. Oncol. Hematol. 2015, 94, 55–63. [Google Scholar] [CrossRef]
  42. Zoghlami, A.; Roussel, F.; Sabourin, J.C.; Kuhn, J.M.; Marie, J.P.; Dehesdin, D.; Choussy, O. BRAF mutation in papillary thyroid carcinoma: Predictive value for long-term prognosis and radioiodine sensitivity. Eur. Ann. Otorhinolaryngol. Head Neck Dis. 2014, 131, 7–13. [Google Scholar] [CrossRef] [Green Version]
  43. Cappola, A.R.; Mandel, S.J. Molecular testing in thyroid cancer: BRAF mutation status and mortality. JAMA 2013, 309, 1529–1530. [Google Scholar] [CrossRef]
  44. Xing, M.; Liu, R.; Liu, X.; Murugan, A.K.; Zhu, G.; Zeiger, M.A.; Pai, S.; Bishop, J. BRAF V600E and TERT promoter mutations cooperatively identify the most aggressive papillary thyroid cancer with highest recurrence. J. Clin. Oncol. 2014, 32, 2718–2726. [Google Scholar] [CrossRef] [Green Version]
  45. Fallahi, P.; Ferrari, S.M.; Santini, F.; Corrado, A.; Materazzi, G.; Ulisse, S.; Miccoli, P.; Antonelli, A. Sorafenib and thyroid cancer. BioDrugs 2013, 6, 615–628. [Google Scholar] [CrossRef]
  46. Fassnacht, M.; Shi, Y.; Hadjieva, T.; Bonichon, F.; Gao, M.; Fugazzola, L.; Ando, Y.; Hasegawa, Y.; Park, D.J.; Shong, Y.K. Safety and tolerability of sorafenib in patients with radioiodine-refractory thyroid cancer. Endocr. Relat. Cancer 2015, 22, 877–887. [Google Scholar] [CrossRef] [Green Version]
  47. Carlomagno, F.; Anaganti, S.; Guida, T.; Salvatore, G.; Troncone, G.; Wilhelm, S.M.; Santoro, M. BAY 43-9006 inhibition of oncogenic RET mutants. J. Natl. Cancer Inst. 2006, 98, 326–334. [Google Scholar] [CrossRef] [Green Version]
  48. Wilhelm, S.M.; Carter, C.; Tang, L.; Wilkie, D.; McNabola, A.; Rong, H.; Chen, C.; Zhang, X.; Vincent, P.; McHugh, M.; et al. BAY 43- 9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004, 64, 7099–7109. [Google Scholar] [CrossRef] [Green Version]
  49. Brose, M.S.; Troxel, A.B.; Redlinger, M.; Harlacker, K.; Redlinger, C.; Chalian, A.A.; Flaherty, K.C.; Loevner, L.A.; Mandel, S.J.; O’Dwyer, P.J. Effect of BRAFV600E on response to sorafenib in advanced thyroid cancer patients. J. Clin. Oncol. 2009, 27, 6002. [Google Scholar] [CrossRef]
  50. Hoftijzer, H.; Heemstra, K.A.; Morreau, H.; Stokkel, M.P.; Corssmit, E.P.; Gelderblom, H.; Weijers, K.; Pereira, A.M.; Huijberts, M.; Kapiteijn, E.; et al. Beneficial effects of sorafenib on tumor progression, but not on radioiodine uptake, in patients with differentiated thyroid carcinoma. Eur. J. Endocrinol. 2009, 161, 923–931. [Google Scholar] [CrossRef] [Green Version]
  51. Cabanillas, M.E.; Waguespack, S.G.; Bronstein, Y.; Williams, M.D.; Feng, L.; Hernandez, M.; Lopez, A.; Sherman, S.I.; Busaidy, N.L. Treatment with tyrosine kinase inhibitors for patients with differentiated thyroid cancer: The M. D. Anderson Experience. J. Clin. Endocrinol. Metab. 2010, 95, 2588–2595. [Google Scholar] [CrossRef] [Green Version]
  52. Keefe, S.M.; Troxel, A.B.; Rhee, S.; Puttaswamy, K.; O’Dwyer, P.J.; Loevner, L.A.; Mandel, S.J.; Brose, M.S. Phase II trial of sorafenib in patients with advanced thyroid cancer. J. Clin. Oncol. 2011, 29, 5562. [Google Scholar] [CrossRef]
  53. Ahmed, M.; Barbachano, Y.; Riddell, A.; Hickey, J.; Newbold, K.L.; Viros, A.; Harrington, K.J.; Marais, R.; Nutting, C.M. Analysis of the efficacy and toxicity of sorafenib in thyroid cancer: A phase II study in a UK based population. Eur. J. Endocrinol. 2011, 165, 315–322. [Google Scholar] [CrossRef] [Green Version]
  54. Schneider, T.C.; Abdulrahman, R.M.; Corssmit, E.P.; Morreau, H.; Smit, J.W.; Kapiteijn, E. Long-term analysis of the efficacy and tolerability of sorafenib in advanced radio-iodine refractory differentiated thyroid carcinoma: Final results of a phase II trial. Eur. J. Endocrinol. 2012, 167, 643–650. [Google Scholar] [CrossRef] [Green Version]
  55. Savvides, P.; Nagaiah, G.; Lavertu, P.; Fu, P.; Wright, J.J.; Chapman, R.; Wasman, J.; Dowlati, A.; Remick, S.C. Phase II trial of sorafenib in patients with advanced anaplastic carcinoma of the thyroid. Thyroid 2013, 23, 600–604. [Google Scholar] [CrossRef] [Green Version]
  56. Brose, M.S.; Nutting, C.M.; Jarzab, B.; Elisei, R.; Siena, S.; Bastholt, L.; de la Fouchardiere, C.; Pacini, F.; Paschke, R.; Shong, Y.K.; et al. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: A randomised, double-blind, phase 3 trial. Lancet 2014, 384, 319–328. [Google Scholar] [CrossRef] [Green Version]
  57. Massicotte, M.H.; Brassard, M.; Claude-Desroches, M.; Borget, I.; Bonichon, F.; Giraudet, A.L.; Do Cao, C.; Chougnet, C.N.; Leboulleux, S.; Baudin, E.; et al. Tyrosine kinase inhibitor treatments in patients with metastatic thyroid carcinomas: A retrospective study of the TUTHYREF network. Eur. J. Endocrinol. 2014, 170, 575–582. [Google Scholar] [CrossRef]
  58. Pitoia, F. Response to sorafenib treatment in advanced metastatic thyroid cancer. Arq. Bras. Endocrinol. Metabol. 2014, 58, 37–41. [Google Scholar] [CrossRef] [Green Version]
  59. Ito, Y.; Onoda, N.; Ito, K.I.; Sugitani, I.; Takahashi, S.; Yamaguchi, I.; Kabu, K.; Tsukada, K. Sorafenib in japanese patients with locally advanced or metastatic medullary thyroid carcinoma and anaplastic thyroid carcinoma. Thyroid 2017, 27, 1142–1148. [Google Scholar] [CrossRef] [Green Version]
  60. Sherman, E.J.; Dunn, L.A.; Ho, A.L.; Baxi, S.S.; Ghossein, R.A.; Fury, M.G.; Haque, S.; Sima, C.S.; Cullen, G.; Fagin, J.A.; et al. Phase 2 study evaluating the combination of sorafenib and temsirolimus in the treatment of radioactive iodine-refractory thyroid cancer. Cancer 2017, 123, 4114–4121. [Google Scholar] [CrossRef] [Green Version]
  61. Feng, G.; Luo, Y.; Zhang, Q.; Zeng, F.; Xu, J.; Zhu, J. Sorafenib and radioiodine-refractory differentiated thyroid cancer (RR-DTC): A systematic review and meta- analysis. Endocrine 2020, 68, 56–63. [Google Scholar] [CrossRef]
  62. Sousa Santos, F.; Joana Santos, R.; Leite, V. Sorafenib and sunitinib for the treatment of metastatic thyroid cancer of follicular origin: A 7-year single-centre experience. Eur. Thyroid J. 2019, 8, 262–267. [Google Scholar] [CrossRef]
  63. Falchook, G.S.; Long, G.V.; Kurzrock, R.; Kim, K.B.; Arkenau, T.H.; Brown, M.P.; Hamid, O.; Infante, J.R.; Millward, M.; Pavlick, A.C.; et al. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: A phase 1 dose-escalation trial. Lancet 2012, 379, 1893–1901. [Google Scholar] [CrossRef] [Green Version]
  64. Lim, A.M.; Taylor, G.R.; Fellowes, A.; Cameron, L.; Lee, B.; Hicks, R.J.; McArthur, G.A.; Angel, C.; Solomon, B.; Rischin, D.; et al. BRAF inhibition in BRAFV600E-positive anaplastic thyroid carcinoma. J. Compr. Cancer Netw. 2016, 14, 249–254. [Google Scholar] [CrossRef] [Green Version]
  65. Cabanillas, M.E.; Busaidy, N.L.; Khan, S.A.; Gunn, G.B.; Dadu, R.; Rao, S.N.; Waguespack, S.G. Molecular diagnostics and anaplastic thyroid carcinoma: The time has come to harvest the high hanging fruit. Int. J. Endocr. Oncol. 2016, 3, 221–233. [Google Scholar] [CrossRef]
  66. Subbiah, V.; Kreitman, R.J.; Wainberg, Z.A.; Cho, J.Y.; Schellens, J.; Soria, J.C.; Wen, P.Y.; Zielinski, C.; Cabanillas, M.E.; Urbanowitz, G.; et al. Dabrafenib and trametinib treatment in patients with locally advanced or metastatic BRAF V600-mutant anaplastic thyroid cancer. J. Clin. Oncol. 2018, 36, 7–13. [Google Scholar] [CrossRef] [Green Version]
  67. Iyer, P.C.; Dadu, R.; Ferrarotto, R.; Busaidy, N.L.; Habra, M.A.; Zafereo, M.; Gross, N.; Hess, K.R.; Gule-Monroe, M.; Williams, M.D.; et al. Real-world experience with targeted therapy for the treatment of anaplastic thyroid carcinoma. Thyroid 2018, 28, 79–87. [Google Scholar] [CrossRef]
  68. Subbiah, V.; Kreitman, R.J.; Wainberg, Z.A.; Cho, J.Y.; Schellens, J.; Soria, J.C.; Wen, P.Y.; Zielinski, C.C.; Cabanillas, M.E.; Boran, A.; et al. Dabrafenib plus trametinib in patients with BRAF V600E-mutant anaplastic thyroid cancer: Updated analysis from the phase II ROAR basket study. Ann. Oncol. 2022, 33, 406–415. [Google Scholar] [CrossRef]
  69. Laquerre, S.; Arnone, M.; Moss, K.; Yang, J.; Fisher, K.; Kane-Carson, L.S.; Smitheman, K.; Ward, J.; Heidrich, B.; Rheault, T.; et al. A selective Raf kinase inhibitor induces cell death and tumor regression of human cancer cell lines encoding B-RafV600E mutation. Mol. Cancer Ther. 2009, 8, B88. [Google Scholar] [CrossRef]
  70. Flaherty, K.T.; Infante, J.R.; Daud, A.; Gonzalez, R.; Kefford, R.F.; Sosman, J.; Hamid, O.; Schuchter, L.; Cebon, J.; Ibrahim, N.; et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N. Engl. J. Med. 2012, 367, 1694–1703. [Google Scholar] [CrossRef] [Green Version]
  71. Maverakis, E.; Cornelius, L.A.; Bowen, G.M.; Phan, T.; Patel, F.B.; Fitzmaurice, S.; He, Y.; Burrall, B.; Duong, C.; Kloxin, A.M.; et al. Metastatic melanoma—A review of current and future treatment options. Acta Derm. Venereol. 2015, 95, 516–524. [Google Scholar] [CrossRef] [Green Version]
  72. Rosenberg, S.A.; Packard, B.S.; Aebersold, P.M.; Solomon, D.; Topalian, S.L.; Toy, S.T.; Simon, P.; Lotze, M.T.; Yang, J.C.; Seipp, C.A. Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report. N. Engl. J. Med. 1988, 319, 1676–1680. [Google Scholar] [CrossRef]
  73. Prieto, P.A.; Reuben, A.; Cooper, Z.A.; Wargo, J.A. Targeted Therapies Combined with Immune Checkpoint Therapy. Cancer J. 2016, 22, 138–146. [Google Scholar] [CrossRef]
  74. Rosenberg, S.A. IL-2: The first effective immunotherapy for human cancer. J. Immunol. 2014, 192, 5451–5458. [Google Scholar] [CrossRef]
  75. Amaria, R.N.; Reuben, A.; Cooper, Z.A.; Wargo, J.A. Update on use of aldesleukin for treatment of high-risk metastatic melanoma. Immunotargets Ther. 2015, 4, 79–89. [Google Scholar] [CrossRef] [Green Version]
  76. Ferrari, S.M.; Fallahi, P.; Galdiero, M.R.; Ruffilli, I.; Elia, G.; Ragusa, F.; Paparo, S.R.; Patrizio, A.; Mazzi, V.; Varricchi, G.; et al. Immune and Inflammatory Cells in Thyroid Cancer Microenvironment. Int. J. Mol. Sci. 2019, 20, 4413. [Google Scholar] [CrossRef] [Green Version]
  77. Wei, S.C.; Duffy, C.R.; Allison, J.P. Fundamental Mechanisms of Immune Checkpoint Blockade Therapy. Cancer Discov. 2018, 8, 1069–1086. [Google Scholar] [CrossRef] [Green Version]
  78. Shin, M.H.; Kim, J.; Lim, S.A.; Kim, J.; Kim, S.-J.; Lee, K.-M. NK Cell-Based Immunotherapies in Cancer. Immune Netw. 2020, 20, e14. [Google Scholar] [CrossRef]
  79. Ribas, A.; Wolchok, J.D. Cancer immunotherapy using checkpoint blockade. Science 2018, 359, 1350–1355. [Google Scholar] [CrossRef] [Green Version]
  80. Hughes, P.E.; Caenepeel, S.; Wu, L.C. Targeted Therapy and Checkpoint Immunotherapy Combinations for the Treatment of Cancer. Trends Immunol. 2016, 37, 462–476. [Google Scholar] [CrossRef]
  81. Karachaliou, N.; Gonzalez-Cao, M.; Sosa, A.; Berenguer, J.; Bracht, J.W.P.; Ito, M.; Rosell, R. The combination of checkpoint immunotherapy and targeted therapy in cancer. Ann. Transl. Med. 2017, 5, 388. [Google Scholar] [CrossRef] [Green Version]
  82. Atkins, M.B.; Larkin, J. Immunotherapy Combined or Sequenced with Targeted Therapy in the Treatment of Solid Tumors: Current Perspectives. J. Natl. Cancer Inst. 2016, 108, djv414. [Google Scholar] [CrossRef]
  83. ClinicalTrials.gov. Available online: https://clinicaltrials.gov/ (accessed on 10 May 2022).
  84. Wang, M.; Liu, Y.; Cheng, Y.; Wei, Y.; Wei, X. Immune checkpoint blockade and its combination therapy with small-molecule inhibitors for cancer treatment. Biochim. Biophys. Acta Rev. Cancer 2019, 1871, 199–224. [Google Scholar] [CrossRef]
  85. Ackerman, A.; Klein, O.; McDermott, D.F.; Wang, W.; Ibrahim, N.; Lawrence, D.P.; Gunturi, A.; Flaherty, K.T.; Hodi, F.S.; Kefford, R. Outcomes of patients with metastatic melanoma treated with immunotherapy prior to or after BRAF inhibitors. Cancer 2014, 120, 1695–1701. [Google Scholar] [CrossRef]
  86. Ludlow, S.P.; Pasikhova, Y. Cumulative dermatologic toxicity with ipilimumab and vemurafenib responsive to corticosteroids. Melanoma Res. 2013, 23, 496–497. [Google Scholar] [CrossRef]
  87. Mandalà, M.; Voit, C. Targeting BRAF in melanoma: Biological and clinical challenges. Crit. Rev. Oncol. Hematol. 2013, 87, 239–255. [Google Scholar] [CrossRef]
  88. Amin, A.; Lawson, D.H.; Salama, A.K.; Koon, H.B.; Guthrie, T., Jr.; Thomas, S.S.; O’Day, S.J.; Shaheen, M.F.; Zhang, B.; Francis, S.; et al. Phase II study of vemurafenib followed by ipilimumab in patients with previously untreated BRAF-mutated metastatic melanoma. J. Immunother. Cancer 2016, 4, 44. [Google Scholar] [CrossRef] [Green Version]
  89. Dummer, R.; Lebbé, C.; Atkinson, V.; Mandalà, M.; Nathan, P.D.; Arance, A.; Richtig, E.; Yamazaki, N.; Robert, C.; Schadendorf, D.; et al. Combined PD-1, BRAF and MEK inhibition in advanced BRAF-mutant melanoma: Safety run-in and biomarker cohorts of COMBI-i. Nat. Med. 2020, 26, 1557–1563. [Google Scholar] [CrossRef]
  90. Dummer, R.; Long, G.V.; Robert, C.; Tawbi, H.A.; Flaherty, K.T.; Ascierto, P.A.; Nathan, P.D.; Rutkowski, P.; Leonov, O.; Dutriaux, C.; et al. Randomized Phase III Trial Evaluating Spartalizumab Plus Dabrafenib and Trametinib for BRAF V600-Mutant Unresectable or Metastatic Melanoma. J. Clin. Oncol. 2022, 40, 1428–1438. [Google Scholar] [CrossRef]
  91. Zimmer, L.; Livingstone, E.; Krackhardt, A.; Schultz, E.S.; Göppner, D.; Assaf, C.; Trebing, D.; Stelter, K.; Windemuth-Kieselbach, C.; Ugurel, S.; et al. Encorafenib, binimetinib plus pembrolizumab triplet therapy in patients with advanced BRAFV600 mutant melanoma: Safety and tolerability results from the phase I IMMU-TARGET trial. Eur. J. Cancer 2021, 158, 72–84. [Google Scholar] [CrossRef]
  92. Shain, A.H.; Bastian, B.C. From melanocytes to melanomas. Nat. Rev. Cancer 2016, 16, 345–358. [Google Scholar] [CrossRef]
  93. Cerezo, M.; Lehraiki, A.; Millet, A.; Rouaud, F.; Plaisant, M.; Jaune, E.; Botton, T.; Ronco, C.; Abbe, P.; Amdouni, H.; et al. Compounds Triggering ER Stress Exert Anti-Melanoma Effects and Overcome BRAF Inhibitor Resistance. Cancer Cell 2016, 29, 805–819. [Google Scholar] [CrossRef] [Green Version]
  94. Ascierto, P.A.; Kirkwood, J.M.; Grob, J.J.; Simeone, E.; Grimaldi, A.M.; Maio, M.; Palmieri, G.; Testori, A.; Marincola, F.M.; Mozzillo, N. The role of BRAF V600 mutation in melanoma. J. Transl. Med. 2012, 10, 85. [Google Scholar] [CrossRef] [Green Version]
  95. Chapman, P.B.; Hauschild, A.; Robert, C.; Haanen, J.B.; Ascierto, P.; Larkin, J.; Dummer, R.; Garbe, C.; Testori, A.; Maio, M.; et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N. Engl. J. Med. 2011, 364, 2507–2516. [Google Scholar] [CrossRef] [Green Version]
  96. Menzies, A.M.; Long, G.V.; Murali, R. Dabrafenib and its potential for the treatment of metastatic melanoma. Drug Des. Dev. Ther. 2012, 6, 391–405. [Google Scholar] [CrossRef] [Green Version]
  97. Xue, Z.; Vis, D.J.; Bruna, A.; Sustic, T.; van Wageningen, S.; Batra, A.S.; Rueda, O.M.; Bosdriesz, E.; Caldas, C.; Wessels, L.F.A.; et al. MAP3K1 and MAP2K4 mutations are associated with sensitivity to MEK inhibitors in multiple cancer models. Cell Res. 2018, 28, 719–729. [Google Scholar] [CrossRef]
  98. Eroglu, Z.; Ribas, A. Combination therapy with BRAF and MEK inhibitors for melanoma: Latest evidence and place in therapy. Ther. Adv. Med. Oncol. 2016, 8, 48–56. [Google Scholar] [CrossRef] [Green Version]
  99. Brighton, H.E.; Angus, S.P.; Bo, T.; Roques, J.; Tagliatela, A.C.; Darr, D.B.; Karagoz, K.; Sciaky, N.; Gatza, M.L.; Sharpless, N.E.; et al. New Mechanisms of Resistance to MEK Inhibitors in Melanoma Revealed by Intravital Imaging. Cancer Res. 2018, 78, 542–557. [Google Scholar] [CrossRef] [Green Version]
  100. Shirley, M. Encorafenib and Binimetinib: First Global Approvals. Drugs 2018, 78, 1277–1284. [Google Scholar] [CrossRef]
  101. Zappa, C.; Mousa, S.A. Non-small cell lung cancer: Current treatment and future advances. Transl. Lung Cancer Res. 2016, 5, 288–300. [Google Scholar] [CrossRef] [Green Version]
  102. Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2018. CA Cancer J. Clin. 2018, 68, 7–30. [Google Scholar] [CrossRef]
  103. Herbst, R.S.; Baas, P.; Kim, D.W.; Felip, E.; Perez-Gracia, J.L.; Han, J.Y.; Molina, J.; Kim, J.H.; Arvis, C.D.; Ahn, M.J.; et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): A randomised controlled trial. Lancet 2016, 387, 1540–1550. [Google Scholar] [CrossRef]
  104. Janjigian, Y.Y.; Park, B.J.; Zakowski, M.F.; Ladanyi, M.; Pao, W.; D’Angelo, S.P.; Kris, M.G.; Shen, R.; Zheng, J.; Azzoli, C.G. Impact on disease-free survival of adjuvant erlotinib or gefitinib in patients with resected lung adenocarcinomas that harbor EGFR mutations. J. Thorac. Oncol. 2011, 6, 569–575. [Google Scholar] [CrossRef] [Green Version]
  105. Zhong, W.Z.; Wang, Q.; Mao, W.M.; Xu, S.T.; Wu, L.; Shen, Y.; Liu, Y.Y.; Chen, C.; Cheng, Y.; Xu, L.; et al. Gefitinib versus vinorelbine plus cisplatin as adjuvant treatment for stage II-IIIA (N1-N2) EGFR-mutant NSCLC (ADJUVANT/CTONG1104): A randomised, open-label, phase 3 study. Lancet. Oncol. 2018, 19, 139–148. [Google Scholar] [CrossRef]
  106. Lim, S.M.; Hong, M.H.; Kim, H.R. Immunotherapy for Non-small Cell Lung Cancer: Current Landscape and Future Perspectives. Immune Netw. 2020, 20, e10. [Google Scholar] [CrossRef] [PubMed]
  107. Miller, K.D.; Siegel, R.L.; Lin, C.C.; Mariotto, A.B.; Kramer, J.L.; Rowland, J.H.; Stein, K.D.; Alteri, R.; Jemal, A. Cancer treatment and survivorship statistics, 2016. CA Cancer J. Clin. 2016, 66, 271–289. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  108. Da Cunha Santos, G.; Shepherd, F.A.; Tsao, M.S. EGFR mutations and lung cancer. Annu. Rev. Pathol. 2011, 6, 49–69. [Google Scholar] [CrossRef] [Green Version]
  109. Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2018, 68, 394–424. [Google Scholar] [CrossRef] [Green Version]
  110. Huang, D.; Sun, W.; Zhou, Y.; Li, P.; Chen, F.; Chen, H.; Xia, D.; Xu, E.; Lai, M.; Wu, Y.; et al. Mutations of key driver genes in colorectal cancer progression and metastasis. Cancer Metastasis Rev. 2018, 37, 173–187. [Google Scholar] [CrossRef]
  111. Diaz, L.A., Jr.; Le, D.T. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N. Engl. J. Med. 2015, 373, 1979. [Google Scholar] [CrossRef] [Green Version]
  112. Pardoll, D.M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 2012, 12, 252–264. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  113. Fu, G.; Polyakova, O.; MacMillan, C.; Ralhan, R.; Walfish, P.G. Programmed death-ligand 1 expression distinguishes invasive encapsulated follicular variant of papillary thyroid carcinoma from noninvasive follicular thyroid neoplasm with papillary-like nuclear features. EBioMedicine 2017, 18, 50–55. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  114. Aghajani, M.; Graham, S.; McCafferty, C.; Shaheed, C.A.; Roberts, T.; DeSouza, P.; Yang, T.; Niles, N. Clinicopathologic and prognostic significance of programmed cell death ligand 1 expression in patients with non-medullary thyroid cancer: A systematic review and meta-analysis. Thyroid 2018, 28, 349–361. [Google Scholar] [CrossRef] [PubMed]
  115. Ulisse, S.; Tuccilli, C.; Sorrenti, S.; Antonelli, A.; Fallahi, P.; D’Armiento, E.; Catania, A.; Tartaglia, F.; Amabile, M.I.; Giacomelli, L. PD-1 Ligand Expression in Epithelial Thyroid Cancers: Potential Clinical Implications. Int. J. Mol. Sci. 2019, 20, 1405. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  116. Tahara, M.; Kiyota, N.; Yamazaki, T.; Chayahara, N.; Nakano, K.; Inagaki, L.; Toda, K.; Enokida, T.; Minami, H.; Imamura, Y. Lenvatinib for anaplastic thyroid cancer. Front. Oncol. 2017, 7, 25. [Google Scholar] [CrossRef]
  117. Chowdhury, S.; Veyhl, J.; Jessa, F.; Polyakova, O.; Alenzi, A.; MacMillan, C.; Ralhan, R.; Walfish, P.G. Programmed death-ligand 1 overexpression is a prognostic marker for aggressive papillary thyroid cancer and its variants. Oncotarget 2016, 7, 32318. [Google Scholar] [CrossRef]
  118. Mehnert, J.M.; Varga, A.; Brose, M.S.; Aggarwal, R.R.; Lin, C.-C.; Prawira, A.; DeBraud, F.; Tamura, K.; Doi, T.; Piha-Paul, S.A. Safety and antitumor activity of the anti–PD-1 antibody pembrolizumab in patients with advanced, PD-L1–positive papillary or follicular thyroid cancer. BMC Cancer 2019, 19, 196. [Google Scholar] [CrossRef]
  119. Lawrence, M.S.; Stojanov, P.; Polak, P.; Kryukov, G.V.; Cibulskis, K.; Sivachenko, A.; Carter, S.L.; Stewart, C.; Mermel, C.H.; Roberts, S.A. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 2013, 499, 214–218. [Google Scholar] [CrossRef]
  120. Schlumberger, M.; Tahara, M.; Wirth, L.J.; Robinson, B.; Brose, M.S.; Elisei, R.; Habra, M.A.; Newbold, K.; Shah, M.H.; Hoff, A.O. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N. Engl. J. Med. 2015, 372, 621–630. [Google Scholar] [CrossRef] [Green Version]
  121. Sun, Y.; Du, F.; Gao, M.; Ji, Q.; Li, Z.; Zhang, Y.; Guo, Z.; Wang, J.; Chen, X.; Wang, J. Anlotinib for the treatment of patients with locally advanced or metastatic medullary thyroid cancer. Thyroid 2018, 28, 1455–1461. [Google Scholar] [CrossRef]
  122. Li, D.; Tang, P.Z.; Chen, X.; Ge, M.; Zhang, Y.; Guo, Z.; Wang, J.; Shi, F.; Zhang, J.; Cheng, Y.; et al. Anlotinib Treatment in Locally Advanced or Metastatic Medullary Thyroid Carcinoma: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase IIB Trial. J. Clin. Oncol. 2019, 37, 6019. [Google Scholar] [CrossRef]
  123. Cohen, E.E.; Rosen, L.S.; Vokes, E.E.; Kies, M.S.; Forastiere, A.A.; Worden, F.P.; Kane, M.A.; Sherman, E.; Kim, S.; Bycott, P.; et al. Axitinib is an active treatment for all histologic subtypes of advanced thyroid cancer: Results from a phase II study. J. Clin. Oncol. 2008, 26, 4708. [Google Scholar] [CrossRef] [PubMed]
  124. Capdevila, J.; Trigo, J.M.; Aller, J.; Manzano, J.L.; Adrián, S.G.; Llopis, C.Z.; Reig, Ò.; Bohn, U.; Cajal, T.R.; Duran-Poveda, M.; et al. Axitinib treatment in advanced RAI-resistant differentiated thyroid cancer (DTC) and refractory medullary thyroid cancer (MTC). Eur. J. Endocrinol. 2017, 177, 309–317. [Google Scholar] [CrossRef]
  125. Lim, S.M.; Chung, W.Y.; Nam, K.-H.; Kang, S.-W.; Lim, J.Y.; Kim, H.-G.; Shin, S.H.; Sun, J.-M.; Kim, S.-G.; Kim, J.-H.; et al. An open label, multicenter, phase II study of dovitinib in advanced thyroid cancer. Eur. J. Cancer 2015, 51, 1588–1595. [Google Scholar] [CrossRef]
  126. Schlumberger, M.; Jarzab, B.; Cabanillas, M.E.; Robinson, B.; Pacini, F.; Ball, D.W.; McCaffrey, J.; Newbold, K.; Allison, R.; Martins, R.G.; et al. A phase II trial of the multitargeted tyrosine kinase inhibitor lenvatinib (E7080) in advanced medullary thyroid cancer. Clin. Cancer Res. 2016, 22, 44–53. [Google Scholar] [CrossRef] [Green Version]
  127. Bible, K.C.; Suman, V.J.; Molina, J.R.; Smallridge, R.C.; Maples, W.J.; Menefee, M.E.; Rubin, J.; Sideras, K.; Morris, J.C., III; McIver, B.; et al. Efficacy of pazopanib in progressive, radioiodine-refractory, metastatic differentiated thyroid cancers: Results of a phase 2 consortium study. Lancet Oncol. 2010, 11, 962–972. [Google Scholar] [CrossRef] [Green Version]
  128. Bible, K.C.; Suman, V.J.; Molina, J.R.; Smallridge, R.C.; Maples, W.J.; Menefee, M.E.; Rubin, J.; Karlin, N.; Sideras, K.; Morris, J.C., III. A multicenter phase 2 trial of pazopanib in metastatic and progressive medullary thyroid carcinoma: MC057H. J. Clin. Endocrinol. Metab. 2014, 99, 1687–1693. [Google Scholar] [CrossRef]
  129. Bible, K.C.; Suman, V.J.; Menefee, M.E.; Smallridge, R.C.; Molina, J.R.; Maples, W.J.; Karlin, N.J.; Traynor, A.M.; Kumar, P.; Goh, B.C.; et al. A multiinstitutional phase 2 trial of pazopanib monotherapy in advanced anaplastic thyroid cancer. J. Clin. Endocrinol. Metab. 2012, 97, 3179–3184. [Google Scholar] [CrossRef] [Green Version]
  130. Lam, E.T.; Ringel, M.D.; Kloos, R.T.; Prior, T.W.; Knopp, M.V.; Liang, J.; Sammet, S.; Hall, N.C.; Wakely, P.E., Jr.; Vasko, V.V.; et al. Phase II clinical trial of sorafenib in metastatic medullary thyroid cancer. J. Clin. Oncol. 2010, 28, 2323. [Google Scholar] [CrossRef] [Green Version]
  131. Capdevila, J.; Iglesias, L.; Halperin, I.; Segura, A.; Martínez-Trufero, J.; Vaz, M.Á.; Corral, J.; Obiols, G.; Grande, E.; Grau, J.J.; et al. Sorafenib in metastatic thyroid cancer. Endocr. Relat. Cancer 2012, 19, e209. [Google Scholar] [CrossRef] [Green Version]
  132. Bikas, A.; Kundra, P.; Desale, S.; Mete, M.; O’Keefe, K.; Clark, B.G.; Wray, L.; Gandhi, R.; Barett, C.; Jelinek, J.S.; et al. Phase 2 clinical trial of sunitinib as adjunctive treatment in patients with advanced differentiated thyroid cancer. Eur. J. Endocrinol. 2016, 174, 373–380. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  133. Carr, L.L.; Mankoff, D.A.; Goulart, B.H.; Eaton, K.D.; Capell, P.T.; Kell, E.M.; Bauman, J.E.; Martins, R.G. Phase II study of daily sunitinib in FDG-PET–positive, iodine-refractory differentiated thyroid cancer and metastatic medullary carcinoma of the thyroid with functional imaging correlation. Clin. Cancer Res. 2010, 16, 5260–5268. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  134. Ravaud, A.; de la Fouchardière, C.; Caron, P.; Doussau, A.; Do Cao, C.; Asselineau, J.; Rodien, P.; Pouessel, D.; Nicolli-Sire, P.; Klein, M.; et al. A multicenter phase II study of sunitinib in patients with locally advanced or metastatic differentiated, anaplastic or medullary thyroid carcinomas: Mature data from the THYSU study. Eur. J. Cancer 2017, 76, 110–117. [Google Scholar] [CrossRef] [PubMed]
  135. Leboulleux, S.; Bastholt, L.; Krause, T.; de la Fouchardiere, C.; Tennvall, J.; Awada, A.; Gómez, J.M.; Bonichon, F.; Leenhardt, L.; Soufflet, C.; et al. Vandetanib in locally advanced or metastatic differentiated thyroid cancer: A randomised, double-blind, phase 2 trial. Lancet Oncol. 2012, 13, 897–905. [Google Scholar] [CrossRef]
  136. Falchook, G.S.; Millward, M.; Hong, D.; Naing, A.; Piha-Paul, S.; Waguespack, S.G.; Cabanillas, M.E.; Sherman, S.I.; Ma, B.; Curtis, M.; et al. BRAF inhibitor dabrafenib in patients with metastatic BRAF-mutant thyroid cancer. Thyroid 2015, 25, 71–77. [Google Scholar] [CrossRef] [Green Version]
  137. Brose, M.S.; Cabanillas, M.E.; Cohen, E.E.; Wirth, L.J.; Riehl, T.; Yue, H.; Sherman, S.I.; Sherman, E.J. Vemurafenib in patients with BRAFV600E-positive metastatic or unresectable papillary thyroid cancer refractory to radioactive iodine: A non-randomised, multicentre, open-label, phase 2 trial. Lancet Oncol. 2016, 17, 1272–1282. [Google Scholar] [CrossRef] [Green Version]
  138. Lim, S.; Chang, H.; Yoon, M.; Hong, Y.; Kim, H.; Chung, W.; Park, C.; Nam, K.; Kang, S.; Kim, M.; et al. A multicenter, phase II trial of everolimus in locally advanced or metastatic thyroid cancer of all histologic subtypes. Ann. Oncol. 2013, 24, 3089–3094. [Google Scholar] [CrossRef]
  139. Hanna, G.J.; Busaidy, N.L.; Chau, N.G.; Wirth, L.J.; Barletta, J.A.; Calles, A.; Haddad, R.I.; Kraft, S.; Cabanillas, M.E.; Rabinowits, G.; et al. Genomic correlates of response to everolimus in aggressive radioiodine-refractory thyroid cancer: A phase II study. Clin. Cancer Res. 2018, 24, 1546–1553. [Google Scholar] [CrossRef] [Green Version]
  140. Elisei, R.; Schlumberger, M.J.; Müller, S.P.; Schöffski, P.; Brose, M.S.; Shah, M.H.; Licitra, L.; Jarzab, B.; Medvedev, V.; Kreissl, M.C.; et al. Cabozantinib in progressive medullary thyroid cancer. J. Clin. Oncol. 2013, 31, 3639. [Google Scholar] [CrossRef] [Green Version]
  141. Wells, S.A., Jr.; Robinson, B.G.; Gagel, R.F.; Dralle, H.; Fagin, J.A.; Santoro, M.; Baudin, E.; Elisei, R.; Jarzab, B.; Vasselli, J.R.; et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: A randomized, double-blind phase III trial. J. Clin. Oncol. 2012, 30, 134–141. [Google Scholar] [CrossRef] [Green Version]
  142. Hyman, D.M.; Puzanov, I.; Subbiah, V.; Faris, J.E.; Chau, I.; Blay, J.-Y.; Wolf, J.; Raje, N.S.; Diamond, E.L.; Hollebecque, A.; et al. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N. Engl. J. Med. 2015, 373, 726–736. [Google Scholar] [CrossRef] [PubMed]
  143. Drilon, A.; Laetsch, T.W.; Kummar, S.; DuBois, S.G.; Lassen, U.N.; Demetri, G.D.; Nathenson, M.; Doebele, R.C.; Farago, A.F.; Pappo, A.S.; et al. Efficacy of larotrectinib in TRK fusion–positive cancers in adults and children. N. Engl. J. Med. 2018, 378, 731–739. [Google Scholar] [CrossRef] [PubMed]
  144. Doebele, R.C.; Drilon, A.; Paz-Ares, L.; Siena, S.; Shaw, A.T.; Farago, A.F.; Blakely, C.M.; Seto, T.; Cho, B.C.; Tosi, D.; et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: Integrated analysis of three phase 1–2 trials. Lancet Oncol. 2020, 21, 271–282. [Google Scholar] [CrossRef]
  145. Ho, A.L.; Grewal, R.K.; Leboeuf, R.; Sherman, E.J.; Pfister, D.G.; Deandreis, D.; Pentlow, K.S.; Zanzonico, P.B.; Haque, S.; Gavane, S.; et al. Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. N. Engl. J. Med. 2013, 368, 623–632. [Google Scholar] [CrossRef] [Green Version]
  146. Iravani, A.; Solomon, B.; Pattison, D.A.; Jackson, P.; Ravi Kumar, A.; Kong, G.; Hofman, M.S.; Akhurst, T.; Hicks, R.J. Mitogen-Activated Protein Kinase Pathway Inhibition for Redifferentiation of Radioiodine Refractory Differentiated Thyroid Cancer: An Evolving Protocol. Thyroid 2019, 29, 1634–1645. [Google Scholar] [CrossRef]
  147. Budiawan, H.; Salavati, A.; Kulkarni, H.R.; Baum, R.P. Peptide receptor radionuclide therapy of treatment-refractory metastatic thyroid cancer using (90)Yttrium and (177)Lutetium labeled somatostatin analogs: Toxicity, response and survival analysis. Am. J. Nucl. Med. Mol. Imaging 2013, 4, 39–52. [Google Scholar]
  148. Versari, A.; Sollini, M.; Frasoldati, A.; Fraternali, A.; Filice, A.; Froio, A.; Asti, M.; Fioroni, F.; Cremonini, N.; Putzer, D.; et al. Differentiated thyroid cancer: A new perspective with radiolabeled somatostatin analogues for imaging and treatment of patients. Thyroid 2014, 24, 715–726. [Google Scholar] [CrossRef]
  149. Lapa, C.; Werner, R.A.; Schmid, J.S.; Papp, L.; Zsótér, N.; Biko, J.; Reiners, C.; Herrmann, K.; Buck, A.K.; Bundschuh, R.A. Prognostic value of positron emission tomography-assessed tumor heterogeneity in patients with thyroid cancer undergoing treatment with radiopeptide therapy. Nucl. Med. Biol. 2015, 42, 349–354. [Google Scholar] [CrossRef]
  150. Ferrari, S.M.; Elia, G.; Ragusa, F.; Ruffilli, I.; La Motta, C.; Paparo, S.R.; Patrizio, A.; Vita, R.; Benvenga, S.; Materazzi, G.; et al. Novel treatments for anaplastic thyroid carcinoma. Gland. Surg. 2020, 9, S28–S42. [Google Scholar] [CrossRef]
  151. Gunda, V.; Gigliotti, B.; Ndishabandi, D.; Ashry, T.; McCarthy, M.; Zhou, Z.; Amin, S.; Freeman, G.J.; Alessandrini, A.; Parangi, S. Combinations of BRAF inhibitor and anti-PD-1/PD-L1 antibody improve survival and tumour immunity in an immunocompetent model of orthotopic murine anaplastic thyroid cancer. Br. J. Cancer 2018, 119, 1223–1232. [Google Scholar] [CrossRef] [Green Version]
  152. Ganly, I.; Makarov, V.; Deraje, S.; Dong, Y.; Reznik, E.; Seshan, V.; Nanjangud, G.; Eng, S.; Bose, P.; Kuo, F.; et al. Integrated Genomic Analysis of Hurthle Cell Cancer Reveals Oncogenic Drivers, Recurrent Mitochondrial Mutations, and Unique Chromosomal Landscapes. Cancer Cell 2018, 34, 256–270.e5. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  153. Gopal, R.K.; Kubler, K.; Calvo, S.E.; Polak, P.; Livitz, D.; Rosebrock, D.; Sadow, P.M.; Campbell, B.; Donovan, S.E.; Amin, S.; et al. Widespread Chromosomal Losses and Mitochondrial DNA Alterations as Genetic Drivers in Hurthle Cell Carcinoma. Cancer Cell 2018, 34, 242–255.e5. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  154. Iniguez-Ariza, N.M.; Ryder, M.M.; Hilger, C.R.; Bible, K.C. Salvage Lenvatinib therapy in metastatic anaplastic thyroid Cancer. Thyroid 2017, 27, 923–927. [Google Scholar] [CrossRef] [PubMed]
  155. Iyer, P.C.; Dadu, R.; Gule-Monroe, M.; Busaidy, N.L.; Ferrarotto, R.; Habra, M.A.; Zafereo, M.; Williams, M.D.; Gunn, G.B.; Grosu, H.; et al. Salvage pembrolizumab added to kinase inhibitor therapy for the treatment of anaplastic thyroid carcinoma. J. Immunother. Cancer 2018, 6, 68. [Google Scholar] [CrossRef] [Green Version]
  156. Cabanillas, M.E.; Ferrarotto, R.; Garden, A.S.; Ahmed, S.; Busaidy, N.L.; Dadu, R.; Williams, M.D.; Skinner, H.; Gunn, G.B.; Grosu, H.; et al. Neoadjuvant BRAF- and immune-directed therapy for anaplastic thyroid carcinoma. Thyroid 2018, 28, 945–951. [Google Scholar] [CrossRef]
  157. Wang, J.R.; Zafereo, M.E.; Dadu, R.; Ferrarotto, R.; Busaidy, N.L.; Lu, C.; Ahmed, S.; Gule-Monroe, M.K.; Williams, M.D.; Sturgis, E.M.; et al. Complete surgical resection following neoadjuvant dabrafenib plus trametinib in BRAFV600E-mutated anaplastic thyroid carcinoma. Thyroid 2019, 29, 1036–1043. [Google Scholar] [CrossRef] [Green Version]
  158. Wirth, L.; Eigendorff, E.; Capdevila, J.; Paz-Ares, L.G.; Lin, C.; Taylor, M.H.; Ramlau, R.; Butler, M.; Delord, J.-P.; Gelderblom, H.; et al. Phase I/II study of spartalizumab (PDR001), an anti-PD1 mAb, in patients with anaplastic thyroid cancer. J. Clin. Oncol. 2018, 36, 6024. [Google Scholar] [CrossRef]
  159. Sukari, A.; Kukreja, G.; Nagasaka, M.; Shukairy, M.K.; Yoo, G.; Lin, H.S.; Hotaling, J.; Kim, H. The role of immune checkpoint inhibitors in anaplastic thyroid cancer (Case Series). Oral Oncol. 2020, 109, 104744. [Google Scholar] [CrossRef]
  160. Kulkarni, P.; Hall, J.; Wang, L.; Henderson, S. Papillary Thyroid Cancer Differentiating into Anaplastic Carcinoma with Near-Complete Response to Targeted Dabrafenib/Trametinib Combination Therapy. Cureus 2021, 13, e20693. [Google Scholar] [CrossRef]
  161. Khoja, L.; Butler, M.O.; Kang, S.P.; Ebbinghaus, S.; Joshua, A.M. Pembrolizumab. J. Immunother. Cancer 2015, 3, 36. [Google Scholar] [CrossRef] [Green Version]
  162. Brahmer, J.R.; Hammers, H.; Lipson, E.J. Nivolumab: Targeting PD-1 to bolster antitumor immunity. Future Oncol. 2015, 11, 1307–1326. [Google Scholar] [CrossRef] [PubMed]
  163. Khunger, M.; Hernandez, A.V.; Pasupuleti, V.; Rakshit, S.; Pennell, N.A.; Stevenson, J.; Mukhopadhyay, S.; Schalper, K.; Velcheti, V. Programmed cell death 1 (PD-1) ligand (PD-L1) expression in solid tumors as a predictive biomarker of benefit from PD-1/PD-L1 axis inhibitors: A systematic review and meta-analysis. JCO Precis. Oncol. 2017, 1, 1–15. [Google Scholar] [CrossRef] [PubMed]
  164. Capdevila, J.; Wirth, L.J.; Ernst, T.; Ponce Aix, S.; Lin, C.C.; Ramlau, R.; Butler, M.O.; Delord, J.P.; Gelderblom, H.; Ascierto, P.A. PD-1 Blockade in Anaplastic Thyroid Carcinoma. J. Clin. Oncol. 2020, 38, 2620–2627. [Google Scholar] [CrossRef] [PubMed]
  165. Crespo-Rodriguez, E.; Bergerhoff, K.; Bozhanova, G.; Foo, S.; Patin, E.C.; Whittock, H.; Buus, R.; Haider, S.; Muirhead, G.; Thway, K.; et al. Combining BRAF inhibition with oncolytic herpes simplex virus enhances the immune-mediated antitumor therapy of BRAF-mutant thyroid cancer. J. Immunother. Cancer. 2020, 8, e000698. [Google Scholar] [CrossRef]
Table
Table 1. In vivo studies on TC treated with different KIs.
Table 1. In vivo studies on TC treated with different KIs.
StudyIndicationMain ResultsReference
An open-label phase II study enrolled 55 metastatic RAI-refractory TC patients (47% with PTC, 36% with FTC/Hürthle Cell, 9% with PDTC/ATC, and 8% with MTC) treated with sorafenib (400 mg orally bid).Metastatic RAI-refractory TCPFS was better in PTC/FTC patients with V600EBRAF mutation than in wild type (84 weeks vs. 54).[49]
A phase II trial investigated sorafenib (400 mg twice daily) to reinduce RAI uptake in 31 patients treated for 26 weeks.RAI-refractory DTCThe study reported partial response (PR) (25%), stable disease (SD) (34%), clinical response (59%), and progression-free survival (PFS) (58 weeks). No reinduction of RAI uptake was reported.[50]
In a study, 13 patients with RAI-refractory PTC or FTC received sorafenib.RAI-refractory PTC or FTCThe remission rate was 20%, with a durable response rate in 66% and a clinical benefit rate of 80%. Overall survival (OS) was 67% at 2 years with a PFS of 19 months.[51]
In a UPCC 03305 phase II study, 55 patients with advanced TC (85% with DTC/PDTC, 9% with ATC, and 6% with MTC) were enrolled and treated with sorafenib (400 mg bid). Advanced TC (85% with DTC/PDTC, 9% with ATC, and 6% with MTC)DTC/PDTC patients had a higher PFS with respect to the other TCs (96 vs. 93.6 weeks); in addition, 38% of them had a PR, and 47% a SD.[52]
In a phase II trial, 15 patients with aggressive MTC and 19 with RAI-refractory DTC were administered with sorafenib (400 mg twice daily).Aggressive MTC and RAI-refractory DTCThe radiological response rate was 18%. A patient with a mutated BRAF exon 15 had an important response after 3 months.[53]
In a phase II study, 31 RAI-refractory DTC patients received sorafenib (400 mg bid).RAI-refractory DTCThe 31% of patients achieved a PR and 42% had a SD, after a median follow-up of 25 months. V600EBRAF did not correlate with the progression of the disease.[54]
In a phase II trial, 20 ATC patients were treated with sorafenib (400 mg bid).ATCPatients reached a PR in 10% and SD in 25%. Only 20% of patients reached a survival of 1-year, suggesting the ineffectiveness of sorafenib in ATC patients.[55]
In a double-blinded randomized phase III (DECISION) trial, 417 patients with RAI-refractory, locally advanced or metastatic DTC were enrolled, of which 207 received sorafenib and 210 received a placebo.RAI-refractory, locally advanced or metastatic DTCPFS was higher in patients treated with the drug than in those treated with placebo (10.8 vs. 5.8 months). PFS improved in all subgroups, with or without mutations. AEs occurred in 98.6% of sorafenib-treated patients.[56]
Outside of clinical trials, 62 patients were treated with sorafenib (62%), sunitinib (22%), and vandetanib (16%).PTC, FTC, Hürthle cell, PDTC, MTCAmong the 39 sorafenib and 12 sunitinib treatments in DTC patients, partial response rate was 15 and 8% respectively. In the 11 MTC patients treated with vandetanib, 36% had PR. Median PFS was similar in second-line therapy compared with first-line sorafenib or sunitinib therapy (6.7 vs. 7.0 months) in DTC patients, but there was no PR with second- and third-line treatments. Bone and pleural lesions were the most refractory sites to treatment.[57]
Off-label observational study. Sorafenib 400 mg twice daily was evaluated. Therapy duration was 12 ± 3 months (range 6–16 months).Progressive radioiodine resistant metastatic TCOne patient showed a PR with tumor regression of −35% six months after the beginning of the treatment; five patients exhibited SD, and two patients had progressive disease (PD) and died.[58]
A phase II trial investigated the effect of sorafenib in patients with aggressive ATC or MTC.Aggressive ATC or MTCThe study reported, (a) in ATC, a median OS of 5.0 months and PFS of 2.8 months; and (b) in MTC, an objective response rate of 25% and disease control rate in 75%. It was concluded that sorafenib was effective in MTC, but not in ATC.[59]
In a phase II study, sorafenib was administered to 36 patients with metastatic TC (i.e., PTC, Hürthle cell, FTC, or ATC) (200 mg twice daily per os., combined with intravenous temsirolimus (25 mg weekly)).Metastatic TC (i.e., PTC, Hürthle cell, FTC, or ATC)The study reported: 22% PR, 58% SD, and 3% PD.[60]
A meta-analysis investigated the safety and efficacy of sorafenib in RAI-refractory DTC patients.RAI-refractory DTCSorafenib improved PFS in comparison to placebo. [61]
A study compared sorafenib or sunitinib in 28 RAI-refractory metastatic DTC patients (26 treated with sorafenib as first-line therapy (8 patients switched successively to sunitinib), and 2 with sunitinib).RAI-refractory metastatic DTCPR rate and mean PFS were 30.7% and 10.8 months, respectively, for sorafenib, and 37.5% and 6 months for sunitinib, as a second-line therapy.[62]
In a phase I study, 184 terminal patients with inoperable solid tumors (carrying the V600EBRAF mutation) received dabrafenib (300 mg daily orally).PTCA total of 14/184 patients had PTC, and nine of these survived for all the duration of the study, showing PR in 33% of cases. However, as reported by many other clinical studies, BRAF-positive tumors exhibited resistance to dabrafenib in 6 to 7 months.[63]
In a case report, two patients with V600EBRAF-positive ATC were administered with dabrafenib.V600EBRAF ATCBRAF inhibitor monotherapy appears to obtain only temporary clinical improvement in ATC.[64]
A woman with an ATC with V600EBRAF mutation (treated with EBRT, and then with pazopanib when the metastatic disease progressed to the neck and lung, with no benefits) was treated with dabrafenib (150 mg bid) and trametinib (2 mg/day).V600EBRAF ATCThe treatment led to a PR in 2 weeks. Then the disease progressed, and the patient died upon 6 months.[65]
In a phase II open-label trial, patients with BRAF V600E-mutated ATC received dabrafenib 150 mg twice daily and trametinib 2 mg once daily until unacceptable toxicity, disease progression, or death. V600EBRAF ATCGood clinical effect and a good tolerance; overall response rate of 69% (95% CI, 41–89%), with 7 ongoing responses.[66]
Real-World Experience: ten patients (eight BRAF wild type and two V600EBRAF mutant tumors) were started on lenvatinib, and six with V600EBRAF-mutated tumors received a combination of dabrafenib plus trametinib.ATCIn the entire cohort, 6/16 (38%) had a PR, 6/16 (38%) had SD, and 2/16 (12%) had PD. Median follow-up time was 11.8 months. Median progression-free survival was 3.7 months (CI 1.8–7.6) in the entire cohort, 2.7 months for lenvatinib, and 5.2 months for dabrafenib plus trametinib. Median OS was 6.3 months (CI 1.8–7.6) for the entire cohort, 3.9 months for lenvatinib, and 9.3 months for dabrafenib plus trametinib.[67]
In a phase II Rare Oncology Agnostic Research (ROAR) basket study, thirty-six patients with ATC received dabrafenib (150 mg twice daily + trametinib 2 mg once) until disease progression, unacceptable toxicity, or death. V600EBRAF ATCThe overall RR was 56%, including 3 complete responses; the 12-month duration of response rate was 50%. OS was 14.5 months, while PFS was 6.7. The OS at 12 months was 43.2%, and at 24 months, it was 31.5%.[68]
Table
Table 2. Clinical trials conducted in patients with melanoma, NSCLC, and CRC.
Table 2. Clinical trials conducted in patients with melanoma, NSCLC, and CRC.
National Clinical Trial (NCT) NumberIndicationDrugsPhaseReference
NCT01400451MelanomaVemurafenib and ipilimumabIThe study is terminated [83,85,86,87]
NCT01673854MelanomaVemurafenib, followed by ipilimumabIIThe study is completed [83,88]
NCT03235245MelanomaIpilimumab and nivolumab preceded or not by a targeted therapy with encorafenib and binimetinibIIThe study is in recruiting phase [83]
NCT02967692MelanomaSpartalizumab/trametinib/dabrafenibIIIThe study is active, not recruiting [83,89,90]
NCT02902042MelanomaEncorafenib/binimetinib/pembrolizumabI/IIThe study is completed [83,91]
NCT02858921MelanomaTrametinib, dabrafenib and/or pembrolizumab, administered before surgeryIIThe study is active, not recruiting [83]
NCT03991819NSCLCBinimetinib and pembrolizumabI/IbThe study is in recruiting phase [83]
NCT03600701NSCLCAtezolizumab and cobimetinibIIThe study is in recruiting phase [83]
NCT03581487NSCLCSelumetinib, durvalumab, and tremelimumabI/IIThe study is in recruiting phase [83]
NCT03299088NSCLCPembrolizumab and trametinibIbThe study is active, not recruiting [83]
NCT03225664NSCLCTrametinib and pembrolizumabIb/IIThe study is active, not recruiting [83]
NCT04044430CRCBinimetinib, encorafenib, and nivolumabI/IIThe study is active, not recruiting [83]
NCT03428126CRCDurvalumab and trametinibIIThe study is active, not recruiting [83]
NCT03374254CRCPembrolizumab and binimetinib, with respect to the combination of chemotherapy and pembrolizumab, with/without binimetinibIbThe study is active, not recruiting [83]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Ragusa, F.; Ferrari, S.M.; Elia, G.; Paparo, S.R.; Balestri, E.; Botrini, C.; Patrizio, A.; Mazzi, V.; Guglielmi, G.; Foddis, R.; et al. Combination Strategies Involving Immune Checkpoint Inhibitors and Tyrosine Kinase or BRAF Inhibitors in Aggressive Thyroid Cancer. Int. J. Mol. Sci. 2022, 23, 5731. https://doi.org/10.3390/ijms23105731

AMA Style

Ragusa F, Ferrari SM, Elia G, Paparo SR, Balestri E, Botrini C, Patrizio A, Mazzi V, Guglielmi G, Foddis R, et al. Combination Strategies Involving Immune Checkpoint Inhibitors and Tyrosine Kinase or BRAF Inhibitors in Aggressive Thyroid Cancer. International Journal of Molecular Sciences. 2022; 23(10):5731. https://doi.org/10.3390/ijms23105731

Chicago/Turabian Style

Ragusa, Francesca, Silvia Martina Ferrari, Giusy Elia, Sabrina Rosaria Paparo, Eugenia Balestri, Chiara Botrini, Armando Patrizio, Valeria Mazzi, Giovanni Guglielmi, Rudy Foddis, and et al. 2022. "Combination Strategies Involving Immune Checkpoint Inhibitors and Tyrosine Kinase or BRAF Inhibitors in Aggressive Thyroid Cancer" International Journal of Molecular Sciences 23, no. 10: 5731. https://doi.org/10.3390/ijms23105731

APA Style

Ragusa, F., Ferrari, S. M., Elia, G., Paparo, S. R., Balestri, E., Botrini, C., Patrizio, A., Mazzi, V., Guglielmi, G., Foddis, R., Spinelli, C., Ulisse, S., Antonelli, A., & Fallahi, P. (2022). Combination Strategies Involving Immune Checkpoint Inhibitors and Tyrosine Kinase or BRAF Inhibitors in Aggressive Thyroid Cancer. International Journal of Molecular Sciences, 23(10), 5731. https://doi.org/10.3390/ijms23105731

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop