Sorafenib and lenvatinib are the only two drugs approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the first-line treatment of locally advanced or metastatic radioiodine-refractory differentiated thyroid cancer (DTC).

Sorafenib is a drug able to inhibit the RAS and BRAF/mitogen-activated protein kinase (MEK)/ERK signaling pathways; ligand-dependent REarranged during Transfection receptor (RET)/PTC receptor tyrosine kinase activation and pathways involving vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and their receptors [2]. Lenvatinib is a multitargeted inhibitor of VEGF receptor (VEGFR) 1, 2, and 3, fibroblast growth factor receptor 1-4 (FGFR 1-4), PDGF receptor α (PDGFRα), RET, and v-kit Hardy Zuckerman 4 feline sarcoma viral oncogene (KIT) signaling pathways [2]. Both these drugs demonstrated a potent inhibition of VEGFR and, therefore, have been defined as antiangiogenic drugs. They have been approved according to the results of phase 3 studies in which an improvement in PFS was demonstrated against a placebo [5, 6].

Recently, cabozantinib [7], an MKI that inhibits several tyrosine kinase receptors, including hepatocyte growth factor (HGF) receptor (MET), VEGFR2, and AXL, which are involved in tumor growth, angiogenesis, and metastasis, has also been approved as second-line treatment for radioiodine-refractory advanced/metastatic DTC that has progressed after treatment with other TKIs [8].

By targeting specific molecular alterations in locally advanced or metastatic DTC that carry RET/PTC rearrangement, selpercatinib is another therapeutic option. Selpercatinib is a selective inhibitor of the RET receptor tyrosine kinase, blocking the signaling pathways that promote tumor growth and survival in RET-altered cancers [9].

Among the selective RET drugs, pralsetinib is another selective RET kinase inhibitor authorized by the FDA but not by EMA for treating advanced or metastatic RET fusion-positive DTC [8].

NTRK (neurotrophic tyrosine receptor kinase) fusions are genetic alterations characterized by the fusion of one of the NTRK genes (NTRK1, NTRK2, or NTRK3) with another gene, resulting in the production of a hybrid protein that can drive tumorigenesis via the RAS/RAF/MAPK pathway [10].

NTRK inhibitors can be used in both first-line and subsequent lines of therapy, depending on the specific clinical context and previous treatments [11–13]. Clinical trials have demonstrated the efficacy of these drugs across various tumor types, with durable responses in many cases. By targeting this actionable mutation, entrectinib can be used in advanced DTC patients carrying this fusion [14]. Entrectinib is designed to inhibit several kinases, including NTRK, reactive oxygen species (ROS; ROS1), and anaplastic lymphoma kinase (ALK), which are involved in cancer cell growth and survival. Entrectinib is indicated for patients with advanced or metastatic DTC harboring NTRK gene fusions, especially in cases refractory to standard treatments [8, 15–18].

Also, larotrectinib is a highly selective inhibitor of NTRK fusion proteins [19] involved in cell growth and differentiation and shares the same therapeutic indication as entrectinib.

In locally advanced and metastatic DTC and poorly differentiated thyroid cancer (PDTC) patients who carry the valine to the glutamic acid substitution of BRAF gene (BRAF^V600E) mutation, the therapy with dabrafenib (a BRAF inhibitor) and trametinib (a MEK inhibitor) is a viable option [20–22].

Immunotherapy is an evolving treatment area for DTC, particularly for advanced cases refractory to other therapies. These agents block immune checkpoints (like PD-1, PD-L1, and CTLA-4), enhancing the immune response against cancer cells. Clinical trials are assessing the efficacy of nivolumab (anti-PD-1) and pembrolizumab (anti-PD-1) in DTC, especially in BRAF-mutant and advanced cases [23] (ClinicalTrial.gov—NCT05852223, NCT02973997, NCT03246958, NCT03914300).

Combining immunotherapy with MKIs or other targeted drugs is under investigation to enhance therapeutic effectiveness and overcome resistance.

MKIs and immunotherapy have been combined for advanced metastatic anaplastic thyroid cancer (ATC) [23–29]. A few reports have demonstrated that combining MKIs and pembrolizumab can impact survival [23, 25, 26]. The use of HS-TKIs is based on the presence of specific gene mutations in the ATC. Indeed, molecular biology plays a pivotal role in the treatment options of advanced and metastatic ATC patients.

In almost all published reports, lenvatinib plus pembrolizumab has been used as adjuvant treatment for metastatic ATC after surgical treatment and/or radiotherapy and chemotherapy.

The other two drugs used in ATC patients are dabrafenib and trametinib. These drugs act sequentially by blocking the MAP kinase pathway’s RAF/MEK/ERK. Their use on BRAF^V600E-mutated ATC patients has been promising [30–32]. Indeed, combining trametinib with dabrafenib enhances the therapeutic effect, as it addresses resistance mechanisms that may arise with BRAF inhibition alone. Moreover, larotrectinib and entrectinib can also be used in ATC if NTRK fusions are found [33, 34].

Two MKIs were approved for treating advanced metastatic medullary thyroid cancer (MTC) cases according to the phase 3 studies: vandetanib [35] and cabozantinib [36]. In some cases, according to a phase 2 study [37], the salvage therapy with lenvatinib has been used with some success [38]. Developing drugs specifically targeting RET mutations has recently marked a new era in treating advanced MTC cases, both in patients previously treated with MKIs and in naive patients [39–41]. FDA and EMA have approved selpercatinib for treating RET mutant advanced/metastatic MTC patients who require systemic therapy. Also, pralsetinib, another potent, highly selective RET inhibitor, was previously approved by the FDA according to a phase 1/2 study [42, 43]. Still, recently, the manufacturers involved in its development have chosen to withdraw the indication for advanced/metastatic MTC; therefore, it is no longer available.

Figure 1 and Table 1, respectively, report an overview of the tyrosine kinase receptors targeted by the available drugs and each drug’s half-maximal inhibitory concentration (IC₅₀).

ATC is one of the rarest (1–2%) and most aggressive forms of thyroid cancer, characterized by rapidly growing tumors with a poor prognosis (median survival—5 months) [44, 45].

The clinical presentation of ATC is characterized by symptoms like neck swelling, difficulty swallowing, and hoarseness and by fast progression and high mortality rate. If possible, the treatment of ATC is surgery following radiotherapy and/or chemotherapy [29, 46]; however, only in a few cases a complete surgical resection (R0) is possible because of the frequent invasion of critical structures of the neck (i.e., larynx, trachea, pharynx, esophagus, recurrent laryngeal nerve, and carotid artery). In some cases, despite incomplete surgery, the following radiotherapy and/or chemotherapy can improve the prognosis [24, 29, 47]. According to the severity of the disease, supportive care to manage symptoms and improve quality of life is crucial for ATC patients.

Because of the disease’s high aggressiveness, it is crucial to make the correct diagnosis [48] and set up treatment as soon as possible. Molecular biology's role in finding the potential driver mutations of ATC has become a pivotal point in treating this tumor.

Romei et al. [48] evaluated the molecular profile of 21 ATC and 21 PDTC. This analysis showed that ATC had a higher prevalence of TP53 and TERT mutations (47.6% and 42.8%, respectively), while in PDTC, TERT and BRAF mutations were the most prevalent (33.3% and 19%, respectively). Moreover, genetic heterogeneity (> 2 mutations) was more frequent in ATC (28.6%) compared with PDTC (4.7%) (P = 0.03). The authors concluded that ATC and PDTC may be characterized by different clinical, pathological, and genetic profiles; in particular, ATC, but not PDTC, were positive for TP53 and phosphatase and tensin homolog (PTEN) alterations, and genetic heterogeneity was more frequent in ATC than PDTC.

In a larger series, Pozdeyev et al. [49] also evaluated the genetic profiles of 583 advanced DTC and 196 ATC. The two most frequently mutated genes in ATC were TP53 (65%) and TERT (65%). Moreover, 41% of ATC had BRAF gene mutations, and 27% had RAS gene mutations. ATC had more genetic alterations per tumor compared to other thyroid cancer histotypes, and DNA mismatch repair deficit and activity of APOBEC cytidine deaminases were identified as mechanisms associated with a high mutational burden.

Therefore, a specific drug should be started if an actionable mutation is detected. BRAF^V600E is the most common molecular alteration found in ATC [50] with a variable rate according to the different series. Because of this high prevalence of BRAF^V600E in ATC in several tertiary referral centers, the search for this mutation is performed simultaneously with histology by immunohistochemistry [29, 51]. In case of a lack of BRAF^V600E mutation, the American Thyroid Association (ATA) ATC guidelines [29] recommend evaluating other somatic mutations/fusions. This approach offers the potential for surgical treatment in tumors previously defined as unresectable.

Unlike ATC, which is a rare tumor, DTC is the most frequently diagnosed thyroid cancer. According to histologic features, it can be divided into two main subtypes: PTC and FTC. PTC is the most common, accounting for about 80% of thyroid cancers. It typically grows slowly and is often diagnosed at an early stage with a good prognosis, so much so that active surveillance strategies are currently the standard of care in selected low-risk cases [65–67].

FTC accounts for 10–15% of thyroid cancers and is more aggressive than PTC because it can spread through blood vessels to distant sites like the lungs and bones. It is often found in older adults. Treatment of DTC usually starts with surgery according to the clinical presentation of the tumor: hemi or total thyroidectomy with or without prophylactic or therapeutic lymph node dissection [68]. Radioactive iodine therapy after surgery is now allowed for adjuvant or therapeutic purposes [69] and is usually performed in cases at intermediate-high or high risk of recurrence [68]. These cancers are usually treatable with surgery, achieving complete removal (R0) in most cases. MKIs or HS-TKIs are used only for patients with advanced or metastatic disease when standard treatments are no longer effective. In these cases, several drugs are tested [2], but only sorafenib and lenvatinib are approved as first-line treatments. Little evidence is available regarding the MKIs and HS-TKIs used as neoadjuvant treatments for DTC to improve surgical outcomes in those unresectable cases. Lenvatinib, as a neoadjuvant treatment, may be considered in selected patients with aggressive or advanced DTC or PDTC before surgery. In these cases, this drug can help to reduce tumor burden and improve subsequent surgical treatment [70, 71]. Infiltration of vital neck structures like the trachea or esophagus can increase the risk of fistulas or organ perforation but is not a strict contraindication for treatment. While EBRT isn’t strongly linked to these complications, it may still contribute to the risk of perforation. The anti-angiogenic effect of lenvatinib can lead to fistulas by necrosis of the tumoral lesions [72].

A Latin American study reported using lenvatinib or sorafenib as a neoadjuvant treatment in DTC and PDTC. Patients received sorafenib (n = 6) or lenvatinib (n = 12) with a median reduction in the diameter of the primary tumor of 25% after a median of 6 months of treatment. Surgical treatment was performed in 10 patients (55%) of whom 6 cases achieved R0/R1 resection status [73].

In 2017, Tsuboi et al. [74] reported the use of lenvatinib as a neoadjuvant therapy in a 73-year-old case of advanced DTC with multiple lymph node metastases invading the right internal jugular vein, the esophagus, and trachea. Due to the complex surgical nature of the lymphadenopathy, lenvatinib at 14 mg daily was administered for 22 weeks, resulting in an 84.3% reduction in one lymph node and a 56% reduction in the other, enabling resection while preserving the esophagus. After 11 months, radioiodine treatment was performed, and no distant metastases were observed. Another case report described a DTC patient with a tumor invasion of the trachea, making it initially unresectable. Lenvatinib was administered as neoadjuvant treatment at 24 mg daily for 14 months, resulting in tumor shrinkage, which allowed for complete surgical resection of the tumor and following radioiodine treatment [75]. In 2020, Iwasaki et al. [76] reported a case of DTC localized to the mediastinum with pulmonary metastases. The mediastinal mass obstructed the brachiocephalic trunk and the superior vena cava. This patient was treated with lenvatinib as a neoadjuvant treatment at 14 mg daily for 16 weeks with relevant tumor shrinkage and subsequent total thyroidectomy and resection of the mediastinal mass. Three months after surgery, the metastatic lesions disappeared, and the mediastinal mass was completely resected. Sorafenib was used as a neoadjuvant treatment, too. Danilovic et al. [77] reported a case of 20-year-old DTC patients with an unresectable large cervical mass with severe tracheal stenosis and suspicious lung and lymph node metastases. In this patient, neoadjuvant treatment with sorafenib at 400 mg daily was started. After 13 months of treatment, there was a relevant tumor shrinkage, which allowed for near-total thyroidectomy and lymphadenectomy without achieving R0, followed by radiotherapy and radioiodine treatment that showed uptake in the cervical area and lung metastases. A total body CT scan performed 16 months after radioiodine therapy showed a persistent but stable disease in the thyroid bed, neck lymph nodes, and lung metastases. The patient performed a second treatment with radioiodine and a post-treatment whole-body scan confirming persistent radioiodine avid lesions. At the last available evaluation, 52 months after the initial diagnosis, the patient had stable metastatic disease but without relevant symptoms.

In 2019, Nava et al. [78] reported a case of unresectable DTC (7.8 cm in the largest dimension) invading the trachea and esophagus. Sorafenib was administered for 6 months, resulting in a 70% reduction in tumor size and detachment from adjacent structures. Total thyroidectomy and radioiodine treatment were performed, and after one year of follow-up, the patient is asymptomatic with a status of disease defined as an incomplete biochemical response. Although neoadjuvant therapy is not standard for most DTC cases, several clinical trials are exploring its safety and efficacy (Table 2).

Regarding lenvatinib, an ongoing clinical trial is recruiting DTC patients with invasive extrathyroidal cancer (ClinicalTrial.gov—NCT04321954). This multicenter, phase 2, open-label study examines the effect of neoadjuvant lenvatinib given to patients with extrathyroidal DTC before thyroidectomy. Lenvatinib is administered orally daily at a predetermined dose for 2, 4, or 6 cycles (1 cycle = 28 days), dependent on response. Total thyroidectomy or near-total thyroidectomy is the objective to reach after lenvatinib treatment. The main aim of this study is to evaluate the overall R0/R1 resection rate, as defined by the proportion of patients who undergo successful thyroidectomy with clear (R0) or microscopically positive surgical margins (R1). The secondary objectives are evaluating change in surgical complexity and morbidity score, the RR before surgery based on Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST), the adverse events, and the conversion rate of the tumor from unresectable to resectable.

Another ongoing clinical trial is recruiting RET-mutant DTC patients with locally advanced primary tumors to use selpercatinib as a neoadjuvant treatment before surgery (ClinicalTrial.gov—NCT04759911). This phase 2 trial mainly aims to evaluate the ORR after 7 months of treatment and the rate of patients who can be successfully treated with thyroidectomy with clear (R0) or microscopically positive (R1) surgical margin. The secondary endpoints are to evaluate PFS, locoregional PFS, surgical morbidity/complexity score, OS, the incidence of adverse events, and quality of life. Patients receive selpercatinib orally twice daily on days 1–28 (1 cycle). Without disease progression or unacceptable toxicity, treatment is performed for 7 cycles. Then, patients perform surgery. After completing the study treatment, patients will be followed up to evaluate potential disease progression status every 3–4 months for the first 2 years (ClinicalTrial.gov—NCT04759911).

A phase 2 trial has been performed with anlotinib (VEGFR2 and VEGFR3 inhibitor) as neoadjuvant treatment in locally advanced DTC patients. The primary endpoint was to evaluate the ORR, while the secondary outcomes were the R0/R1 resection rate, disease control rate, OS, and incidence of adverse events. A total of 13 patients were enrolled and received anlotinib treatment (3.5 cycles) with an ORR of 76.9%, a median time to response of 61.5 days, and most patients achieved R0/R1 resection [79].

Another phase 2 study evaluated the combination therapy of surufatinib (FGFR1 inhibitor) and toripalimab (anti-PD-1 antibody) in locally advanced DTC. The surufatinib dose was 300 mg/daily once daily for a 28-day cycle. After treatment, the patients received surgical treatment if the tumor is considered resectable by clinical examination. Patients with a high risk of postoperative recurrence received radioiodine treatment. After radioiodine treatment, maintenance treatment with surufatinib was determined according to the recurrence risk stratification. The main aim of this study was to evaluate the ORR. The secondary endpoints were to evaluate R0/R1 resection rate, disease control rate, PFS and incidence of adverse events. Ten patients were enrolled in the study and received at least 4 treatment cycles. The ORR was 60%, and 9 patients showed R0/R1 resections after neoadjuvant treatment [80].

Another study is ongoing to determine the efficacy and safety of the anti-PD-1 antibody camrelizumab combined with apatinib (VEGFR2 inhibitor) for neoadjuvant therapy in locally advanced thyroid cancer. Patients received apatinib 250 mg/daily and camrelizumab 200 mg/daily, intravenous once every 2 weeks as neoadjuvant treatment for at least two cycles (1 cycle = 28 days). The primary objective of this phase 2 trial is to evaluate ORR after 24 weeks of treatment, and the secondary endpoints are to evaluate the rate of R0/R1 resection and to assess disease control rate after 6 weeks, OS up to 3 years and the incidence of adverse events (Clinicaltrial.gov—NCT04612894).

MTC originates from parafollicular, or C cells derived from the neural crest. The peculiarity of MTC is that can be inherited in about 25% of the cases [81, 82] in an autosomal dominant way. Although it could carry several types of mutations [83–85], like DTC, in almost all familial cases of multiple endocrine neoplasia type 2A (MEN 2A) and 2B (MEN 2B) and about half of sporadic cases [85–87] mutations in RET gene are detected. This prevalence in sporadic cases can increase to 80% if advanced metastatic cases are considered [88]. The high prevalence of RET gene mutation in MTC makes this gene an ideal diagnostic and therapeutic target for MTC treatment [81, 89, 90]. Total thyroidectomy, central compartment lymph node dissection (prophylactic or therapeutic), and oriented lateral-cervical lymph node compartment dissection are the gold standard of the initial treatment of MTC [91]. The impossibility of surgical resection is an uncommon event in managing MTC; however, it can happen in some locally advanced cases. Because of the high prevalence of RET gene mutation in advanced MTC, the low prevalence of grades 3 and 4 adverse events [39, 41] according to CTCAE [60], and the good preservation of the quality of life, highly selective RET inhibitor drugs have been more frequently tested in a neoadjuvant setting.

In 2021, the first case of neoadjuvant salvage therapy for a locally advanced, inoperable MTC patient with selpercatinib was reported [92]. The use of selpercatinib in a neoadjuvant setting in 4 MTC cases was subsequently reported by the same group [93]. In all cases, neoadjuvant treatment was followed by surgery, and patients were followed up for a median of 2 years after selpercatinib initiation. Locoregional disease control with a reduction in surgical morbidity was obtained. Based on these results, a clinical trial was built to evaluate the efficacy of neoadjuvant selpercatinib treatment in RET mutant MTC cases (ClincalTrial.gov—NCT04759911). Very recently, a Latin American real-life experience reported a 25% tumor reduction and an R2 resection after surgery in a single patient treated with selpercatinib as first-line therapy. However, complete resection was hindered by tumor extension [73]. Differently from DTC, in whom the tracheal and/or esophageal invasion is more frequent and the risk of fistula is high, in a patient with MTC, the tumor lysis syndrome has been reported as an adverse event of neoadjuvant treatment with selpercatinib [94].

In the absence of RET mutation, therapy with MKIs has been used in a neoadjuvant setting. In the Latin American experience, Pitoia et al. [73] treated 27 patients with thyroid cancer in a neoadjuvant setting. Of these, 6 cases had MTC: 5 treated with vandetanib and 1 with selpercatinib. In this study, none had germline RET mutations, although two were positive for somatic Met918Thr RET mutation. The authors reported a median tumor diameter reduction of 24.5% after 9.5 months of treatment in the 5 patients treated with vandetanib, with a median follow-up of 50 months. The best overall response included one partial response and three cases of stable disease. However, despite this shrinkage, only one patient achieved a complete (R0/R1) resection. Grasic Kuhar et al. [95] reported their experience with MKIs used as neoadjuvant therapies in patients with advanced unresectable MTC. They treated 8 patients, 7 with sunitinib and 1 with vandetanib. The median duration of MKI treatment was 7.8 months, and the median OS of these patients was 20 months. In 4 (50%) patients, the neoadjuvant therapies led to a partial response, while 2 (25%) patients had stable disease, and the other 2 (25%) showed progressive disease in distant metastases but not in the neck. Overall, in 5/8 (62.5%) cases, the tumor became treatable by surgery after MKI treatment, but surgery was performed only in 2 cases. Sunitinib was also used for treating an unresectable MTC [96] with an initial misleading diagnosis of ATC, who failed to respond to two lines of chemotherapy plus radiotherapy. After 19 months from the beginning of sunitinib, the tumor became resectable, sunitinib was stopped 6 weeks before, and surgical treatment was performed. Histological examination revealed the tumor to be MTC rather than ATC, with no RET mutations but a homozygous Leu769Leu (2307T > G) polymorphism detected. Because of its greater potency of inhibition on VEGFR, lenvatinib was used as a single agent in treating an advanced unresectable MTC suspected of tracheal and esophageal infiltration [97]. The tumor measured 8.3 cm, and several ipsilateral left lateral cervical metastatic lymph nodes, the larger of 6.9 cm, were detected. Calcitonin levels were 32,926 pg/mL. Then, lenvatinib was initiated at a dosage of 10 mg twice daily. After about 22 weeks of therapy, a left lobectomy with ipsilateral laryngeal nerve and lateral cervical lymph node removal was performed. Notably, during surgical inspection, the esophagus, trachea, and great vessels were free of gross tumor invasion. The patient showed a significant drop in the calcitonin values and was followed up over time without any other systemic treatment.