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Targeted Therapy in Thyroid Cancer: State of the Art
Clinical Oncology 29 (2017) 316e324 Contents lists available at ScienceDirect
Clinical Oncology journal homepage: www.clinicaloncologyonline.net
Overview
Targeted Therapy in Thyroid Cancer: State of the Art L. Valerio, L. Pieruzzi, C. Giani, L. Agate, V. Bottici, L. Lorusso, V. Cappagli, L. Puleo, A. Matrone, D. Viola, C. Romei, R. Ciampi, E. Molinaro, R. Elisei Department of Clinical and Experimental Medicine, Endocrine Unit, University of Pisa, Pisa, Italy Received 6 February 2017; accepted 7 February 2017
Abstract Thyroid cancer typically has a good outcome following standard treatments, which include surgery, radioactive iodine ablation for differentiated tumours and treatment with thyrotropine hormone-suppressive levothyroxine. Thyroid cancers that persist or recur following these therapies have a poorer prognosis. Cytotoxic chemotherapy or external beam radiotherapy has a low efficacy in these patients. ‘Target therapy’ with tyrosine kinase inhibitors (TKIs) represent an important therapeutic option for the treatment of advanced cases of radioiodine refractory (RAI-R) differentiated thyroid cancer (DTC), medullary thyroid cancer (MTC) and possibly for cases of poorly differentiated (PDTC) and anaplastic thyroid cancer (ATC). In the last few years, several TKIs have been tested for the treatment of advanced, progressive and RAI-R thyroid cancers and some of them have been recently approved for use in clinical practice: sorafenib and lenvatinib for DTC and PDTC; vandetanib and cabozantinib for MTC. The objective of this overview is to present the current status of the treatment of advanced DTC, MTC, PDTC and ATC with the use of TKIs by describing the benefits and the limits of their use. A comprehensive analysis and description of the molecular basis of these drugs and the new therapeutic perspectives are also reported. Some practical suggestions are also given for the management to the potential sideeffects of these drugs. Ó 2017 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Key words: Advanced thyroid cancer; adverse events; molecular targets; targeted therapy; tyrosine kinase inhibitors
Statement of Search Strategies Used and Sources of Information A literature search of PubMed was carried out using the following key words: advanced thyroid cancer; advanced medullary thyroid cancer; tyrosine kinase inhibitors in thyroid cancer; vandetanib in thyroid cancer; cabozantinib in thyroid cancer; sorafenib in thyroid cancer; lenvatinib in thyroid cancer; cancer patient communication.
Introduction Differentiated thyroid cancers (DTC), both papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC), are generally associated with an indolent disease course and, as Author for correspondence: R. Elisei, Department of Clinical and Experimental Medicine, Endocrine Unit, University of Pisa, Via Paradisa 2, Pisa, 56124, Italy. Tel: þ39-050-995120; Fax: þ39-050-578772. E-mail address: [email protected] (R. Elisei).
they maintain the typical features of thyroid cells, they are usually curable with surgery and radioactive iodine (131I) therapy [1,2]. In about 10% of cases, patients have a locally advanced or metastatic disease at diagnosis, with local invasion and/or distant metastases in the bone (25%), lungs (50%), lungs and bone (20%) and other sites (5%). In one third of advanced DTC the metastatic lesions have a low avidity for iodine and 131I therapy has no effects [3]. Anaplastic thyroid cancer (ATC) is the undifferentiated form, unable to take up 131I and with no chance of cure [4]. Fortunately it is rare (2% of thyroid cancer) but is associated with rapid progression, especially at the local level, with a high risk of suffocation and a high mortality. Poorly differentiated thyroid cancer (PDTC) has a disease course that is in between those of DTC and ATC. The reason for this poor prognosis is related to the fact that in these cases the tumoural cells become rapidly dedifferentiated and are no longer able to take up iodine and secrete thyroglobulin, if they were in the beginning. Similarly, advanced medullary thyroid cancers (MTCs) are not able to take up 131I, do not produce thyroglobulin
http://dx.doi.org/10.1016/j.clon.2017.02.009 0936-6555/Ó 2017 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
L. Valerio et al. / Clinical Oncology 29 (2017) 316e324
and are not responsive to the thyrotropine hormone . In fact they derive from malignant transformation of parafollicular C-cells that are neuroendocrine cells located peripherally to thyroid follicles. At variance from DTC, they produce several peptides, among which the most important and specific is calcitonin [5]. Until a few years ago, no effective therapeutic options were available for patients with advanced thyroid cancer resistant to radioiodine (RAI-R). Other conventional therapies were used, such as external beam radiotherapy and chemotherapy, but they had important toxicity and played mainly a palliative role as efficacy was low and transient (10e20%) with no prolongation of survival in response to the use of either a single therapeutic agent or a combination [6,7]. In recent years, a variety of molecular-targeted agents have been developed that are able to inhibit tyrosine kinases receptors (TK-R), which are responsible for tumour growth and angiogenesis [8]. In the last 12 years, several of these tyrosine kinase inhibitors (TKIs) have been evaluated in advanced thyroid cancers for their ability to block TK-R and/or other kinases involved in cell proliferation and tumoural transformation of thyroid cells (Table 1). Four of them have now been approved by the Food and Drug Administration (FDA) and the European Medical Agency (EMA) for the treatment of advanced RAI-R (i.e. sorafenib and lenvatinib) and MTC (i.e. vandetanib and cabozantinib).
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The objective of this overview is to present the current status of the treatment of advanced thyroid cancers using these innovative targeted therapies by describing both the benefits and the limits of their use.
The Rationale of Targeted Therapies in Thyroid Cancer: Molecular Alterations Aberrant signalling pathways have been implicated in the onset, progression and invasiveness of DTCs. The most common genetic changes in PTC are point mutations in BRAF and RAS and rearrangement of the RET protooncogene [9]. Several RET/PTC rearrangements have been described, almost exclusively in PTC cells, mainly in radioinduced PTC, but also in a not negligible percentage of sporadic cases [10]. In FTC, point mutations of RAS and rearrangements of PPARg and PAX8 genes, to create the PPFP fusion gene, are the most common oncogenic alterations but, to a lesser extent, also PTEN deletion/mutation, PIK3CA and IDH1 mutations can be found [11]. At variance from PTC and FTC, in which oncogene mutations are almost mutually exclusive, PDTC and even more ATC are characterised by a higher number of mutations in the same tumoural tissue and the overexpression of these proteins is probably responsible for a more aggressive phenotype. The most prevalent oncogene alterations in ATC are p53 point mutations, BRAFV600E, PIK3CA, PTEN, IDH1 and ALK mutations,
Table 1 Tyrosine kinase inhibitors tested in phase II, III or IV clinical trials in thyroid cancer: the multitarget activity and the molecular targets are indicated DRUG
VEGF-R
c-Kit
RET
PDGF-R
FGF-R
EGF-R
Axitinib Bevacizumab Cabozantinib Imatinib Lenvatinib
Yes No Yes No Yes
Yes No Yes Yes Yes
No No Yes No Yes
Yes No No Yes Yes
No No No No Yes
No No No No No
Motesanib Nintedanib Pazopanib Ponatinib Selumetinib Sorafenib Sunitinib Vandetanib Vemurafenib Everolimus Temsirolimus
Yes Yes Yes No No Yes Yes Yes No No Yes
Yes No Yes No No Yes Yes Yes No No No
Yes No No Yes No Yes Yes No No No No
Yes Yes Yes Yes No Yes Yes No No No No
No Yes No Yes No No No No No No No
No No No No No No No Yes No No No
Other targets
dual PI3K/mTOR MET, RET- KIF5B rearrangement Bcr-Abl RET-KIF5B, CCDC6-RET, NcoA4-RET rearrangement
Bcr-Abl, FLT3, KIT MEK Raf, FLT3 FLT3 RET-KIF5B rearrangement BRAFV600E, CRAF mTOR mTOR
Study phase
Approved for thyroid cancer treatment
II II III* II III*
No No Yes No Yes
II II II II III III II III* II II II
No No No No No Yes No Yes No No No
*These drugs have also been tested in phase IV studies devoted to verifying the activity and the adverse events of different daily dosages of the drug. Bcr-Abl, Abelson and breakpoint cluster region fusion gene; CSF-1R, colony stimulating factor 1 receptor; EGF-R, epidermal growth factor receptor; FGF-R, fibroblast growth factor receptor; KIT, v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene; Raf, v-raf murine sarcoma viral oncogene homolog; BRAFV600E, valine to glutamic acid substitution of BRAF gene; CRAF, v-raf murine sarcoma viral oncogene homolog 1; FLT3, Fms-like tyrosine kinase 3; MEK, mitogen activated protein kinase; MET, hepatocyte growth factor [HGF] receptor; PDGF-R, platelet-derived growth factor receptor; RET, REarranged during Transfection receptor; RET gene fusions: KIF5B-RET, CCDC6-RET and NcoA4-RET; VEGF-R, vascular endothelial growth factor receptor.
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whereas in PDTC, beta-catenin (CTNNB1), p53 and BRAFV600E mutations are the most frequent. Both in ATC and PDTC the prevalence of TERT promoter mutations is high and typically associated with a greater aggressiveness [12]. The most common genetic alterations found in MTC cells are RET-activating point mutations that are present at the germline level in 95% of hereditary forms and 45% of sporadic cases, with a significantly higher prevalence in advanced MTC cases [13]. The only other oncogenic alterations found in sporadic MTC are RAS mutations, mainly Hand K-mutations, which have been reported in about 17% of RET-negative sporadic MTCs [14]. In addition, RAS and RET are mutually exclusive in MTC cases. The increasing knowledge about the molecular alterations underlying thyroid cancer has greatly increased the interest in developing new drugs for targeted treatments. The drugs that have primarily been investigated for the treatment of thyroid cancer are TKIs that are able to bind one or multiple TK-Rs, inhibiting their tyrosine kinase activity [15]. Tyrosine kinases are enzymes responsible for the control of mitogenic signals via the phosphorylation/ dephosphorylation of many intracellular proteins involved in the MAPK signal transduction cascade. The enhanced catalytic activity that is responsible for uncontrolled cell growth is the molecular rationale for the use of TKIs in thyroid cancer treatment. However, considering that the
PI3K/AKT/mTOR pathway is another important pathway for the development of thyroid tumours, other drugs have also been investigated, such as mTOR inhibitors [16] (Table 1). Angiogenesis is also a very important process in tumour progression and a very attractive target for therapy [17]. Angiogenesis is promoted by vascular endothelial growth factor (VEGF), which is overexpressed in response to intratumoural hypoxia via the overactivation of hypoxiainducible factor-1 alpha (HIF1a). This transcriptional factor is upregulated not only by hypoxia but also via growth factor signalling pathways, such as PI3K/AKT and MAPK pathways, and is expressed in thyroid cancer cells, especially in ATC cells, but not in normal thyroid tissue [18,19]. An important target of HIF1a is the MET oncogene, which is upregulated in many thyroid cancers and promotes angiogenesis as well as cellular motility, invasion and metastasis [20e22]. Almost all TKIs target, among all others, the VEGF receptor (VEGF-R), although with different affinities. The multitarget activity of the TKIs makes them able to simultaneously block two or three different pathways, thus ‘fighting’ the cancer from several fronts at the same time. This is also the case for vandetanib and cabozantinib, which have been approved for the treatment of advanced MTC, and sorafenib and lenvatinib, which have been approved for the treatment of advanced RAI-R DTC and PDTC (Table 2).
Table 2 Details of the four phase III studies with the tyrosine kinase inhibitors approved for the treatment of advanced thyroid cancer Drug
Vandetanib
Cabozantinib
Sorafenib
Lenvatinib
Name of the study Tumour Phase Patients (n) Partial response (%) Stable disease 6 months (%) Median progression-free survival (months) Median overall survival (months) Most frequent adverse events (%) Any grade
ZETA MTC III 331 45 87
EXAM MTC III 330 28 NE
DECISION DTC III 417 12.2 42
SELECT DTC III 392 64.8 15.3
30.5*
11.2
10.8
18.3
NE
NE
NE
NE
Diarrhoea (56) Skin rash (45) Nausea (33) Hypertension (32)
Diarrhoea (63) Hand-foot syndrome (50) Weight loss (47) Anorexia (45) Nausea (43) Fatigue (40)
Hypertension (67) Diarrhoea (59) Fatigue or asthenia (59) Anorexia (50) Weight loss (46) Nausea (41) Stomatitis (35)
Molecular targets
VEGF-R, c-Kit, RET, EGF-R, RET-KIF5B rearrangement [23]
VEGF-R, c-Kit, RET, MET, RET-KIF5B rearrangement
Hand-foot syndrome (76) Diarrhoea (68) Alopecia (67) Skin rash (50) Fatigue (49) Weight loss (46) Hypertension (40) Anorexia (31) VEGF-R, c-Kit, RET, PDGF-R, Raf, FLT3
[24]
[25]
Reference
VEGF-R, c-Kit, RET, PDGF-R, FGF-R, RET-KIF5B, CCDC6-RET, NcoA4-RET rearrangement [26]
*Predicted median progression-free survival according to the Weibull model. DTC, differentiated thyroid cancer; MTC, medullary thyroid cancer; NE, not estimated; EGF-R, epidermal growth factor receptor; FGF-R, fibroblast growth factor receptor; KIT, v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene; Raf, v-raf murine sarcoma viral oncogene homolog; FLT3, Fms-like tyrosine kinase 3; MET, hepatocyte growth factor [HGF] receptor; PDGF-R, platelet-derived growth factor receptor; RET, REarranged during Transfection receptor; RET gene fusions: KIF5B-RET, CCDC6-RET and NcoA4-RET; VEGF-R, vascular endothelial growth factor receptor.
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The Approved Drugs and Their Clinical Use Vandetanib Vandetanib is a once-daily oral multitarget TKI that is very active against RET oncogene, VEGF-R and epidermal growth factor receptor (EGF-R) [27]. Vandetanib is the first drug approved for the treatment of adult patients with symptomatic, unresectable, locally advanced or metastatic MTC in the USA (2011) and Europe (2013) (CaprelsaÒ, Sanofi-Genzyme). The approval of vandetanib was obtained after the encouraging results of the international, multicentric and randomised against placebo, ZETA phase III study [23], which showed a significant prolongation of the progression-free survival (PFS) of treated patients with respect to patients treated with placebo (30.5 versus 19.3 months; P ¼ 0.001). Recently, after the publication of a phase II study specifically dedicated to children affected by the hereditary form of MTC [28], the use of vandetanib has also been approved for children with advanced MTC, usually affected by a hereditary form. The ZETA study also showed that there was a statistically significant difference in the effect of vandetanib with respect to placebo in the objective response rates (ORR) (P < 0.001) and disease control rates (P ¼ 0.001), as well as in the biochemical response (P < 0.001). In other words, the drug was not only able to stop cell growth, as expected and as shown by the prolongation of the PFS, but also induced tumoural shrinkage with a consequent volume reduction of the metastatic lesions [23]. Currently, an international, multicentric phase III clinical trial (VERIFY study) exploring the efficacy of vandetanib in treating progressive RAI-R DTC is ongoing, although no longer enrolling. The study was motivated by the positive results obtained in a phase II study carried out in France in locally advanced or metastatic cases of RAI-R DTC that showed a statistically significant increase in the PFS of patients treated with vandetanib compared with the PFS of those treated with placebo (11.1 months versus 5.9 months) [29]. As previously mentioned, vandetanib has already been approved for the treatment of advanced MTC and this study might allow its use in treating RAI-R DTC, although preliminary data, recently shown at an international meeting, were not so promising [30]. Moreover, a limit of the VERIFY study is that to be enrolled, RAI-R DTC patients had to be ‘naïve’ of any other treatment; thus, the efficacy of vandetanib in DTC as second-line treatment cannot be evaluated. Cabozantinib Cabozantinib is an inhibitor of the hepatocyte growth factor receptor, VEGF-R 2 and RET and this drug has been approved by the FDA (2012) and the EMA (2014) for the treatment of patients with progressive metastatic MTC (CometriqÒ, Exelixis). Cabozantinib has been investigated for the treatment of patients with unresectable, locally advanced or metastatic MTC in a phase III study (EXAM study). A statistically significant longer median PFS has
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been shown in patients treated with the drug with respect to those treated with placebo (11.2 versus 4.0 months) [24]. The longer median PFS durations observed in the ZETA study with respect to those observed in the EXAM study may be explained by the different levels of the severity of disease in the two groups of patients, as shown by the fact that the PFS durations of the two placebo groups were also significantly different (19.3 months in the ZETA study and 4.0 months in the EXAM study). In fact, although symptomatic patients without evidence of progressive disease could be enrolled in the ZETA study, disease progression was a fundamental inclusion criterion in the EXAM study. As for vandetanib, a significant shrinkage of the tumoural lesions could also be shown for cabozantinib, with a 28% ORR [24]. Despite these good results, neither cabozantinib nor vandetanib was able to improve overall survival, although the analysis was invalidated by the crossover design of the ZETA study and by the possibility to treat cases progressing under placebo with other commercial TKIs (used off label) in the EXAM study. However, newly collected data show that overall survival was significantly increased in patients treated with cabozantinib when the analysis was restricted to the subgroup of M918T-RETmutated MTC patients [31]. Sorafenib Sorafenib is a multikinase inhibitor that targets several molecular signals involved in the pathogenesis of thyroid cancer, including those implicated in DTC. These signals include the RAS and BRAF/MEK/ERK signalling pathways; ligand dependent RET/PTC receptor tyrosine kinase activation; and pathways involving VEGF, platelet-derived growth factor (PDGF) and their receptors. The inhibitory effect of sorafenib in the treatment of thyroid tumours was explored in an international, multicentric, phase III study (DECISION study) [25]. Treatment with sorafenib has shown a longer of PFS of treated patients than that of patients treated with placebo (10.8 months versus 5.8 months, respectively, P < 0.0001) (Table 2). There is no evidence of an improvement in overall survival with sorafenib, but the median overall survival has not yet been reached and additional analyses of the overall survival are planned. Moreover, this result is affected by the large proportion of patients in the placebo arm (71%) who crossed over to treatment. Interesting information has been obtained via the exploratory analysis of the outcomes of patients who continued to be open-label treated with sorafenib after the first evidence of progression in the phase III DECISION study [32]. This analysis showed that sorafenib may continue to suppress tumour growth rates after tumour progression because the median PFS of patients receiving this drug was still lower than that of patients treated with placebo (6.7 months versus 5.3 months). This suggests that, despite the evidence of tumour progression, in the absence of an alternative drug, it may be better to continue to treat patients with sorafenib, especially if it is well tolerated. Moreover, this exploratory analysis also showed that those patients in the placebo arm who started
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receiving sorafenib after tumour progression showed a comparable PFS to those who started receiving the drug from the beginning of the trial (9.6 months versus 10.8 months). This indicates, although does not prove, that delaying the initiation of sorafenib treatment should not greatly affect the response to the drug [32]. The positive results in terms of the safety and efficacy of sorafenib allowed the approval of this drug by the FDA (2013) and the EMA (2014) for the treatment of patients with RAI-R DTC (NexavarÒ, Bayer). However, it is worth noting that sorafenib had already been approved by both the FDA and the EMA for the treatment of advanced hepatocellular carcinomas [33] and advanced renal cell carcinomas [34] and for this reason it had been used ‘off label’ before its approval. Lenvatinib Lenvatinib is an oral, multitargeted inhibitor of VEGF-R 1, 2 and 3, fibroblast growth factor receptor 1e4 (FGF-R 1e4), PDGFR a, RET and KIT signalling networks. On the basis of results observed in a phase II study involving patients with RAI-R thyroid cancer, a phase III, multicentre, randomised, placebo-controlled study (SELECT study) was started (Table 2). At the end of the study, patients treated with lenvatinib showed a significantly longer PFS than patients treated with placebo (18.3 months versus 3.6 months, respectively; P < 0.001) [26]. A benefit in terms of PFS was present regardless of the BRAF or RAS mutation status of the patients or previous TKI treatment and was also observed in patients with PDTC. The ORR was more than 50% in all metastatic sites (brain, bone, liver, lungs and lymph nodes) and a PFS benefit associated with lenvatinib was present in all cases, independent of the sites of metastasis, with the exception of patients with brain metastases, in which PFS fell to 8.8 months in patients treated with lenvatinib and to 3.7 months in those receiving the placebo [35]. At the first data cut-off period, overall survival was no different in patients treated with lenvatinib than in those treated with the placebo [26]. When the overall survival analysis was carried out on subgroups of patients, a statistically significant increase in overall survival was observed in patients > 65 years [36] with respect to younger patients and in follicular with respect to papillary histotype [37]. The positive results in terms of the safety and efficacy of lenvatinib allowed for the approval of this drug by the FDA and EMA in 2015 for the treatment of patients with RAI-R DTC (LenvimaÒ, Eisai). Lenvatinib has also been tested in advanced MTC patients in a phase II study and the results are very promising, especially in terms of ORR in most cases, thus suggesting the possibility of using this drug in MTC cases becoming resistant, or not treatable for any reason, to vandetanib and cabozantinib [38].
Tyrosine Kinase Inhibitor Treatment: Who and When? According to expert opinion [39], good candidates for treatment with TKIs are patients with a RAI-R or MTC
metastatic thyroid tumour with lesions radiologically measurable and in progression over the previous 12e14 months, as defined by RECIST [40]. Due to the presence of two specific serum markers in thyroid cancer that could correlate with the tumour burden, calcitonin for MTC and thyroglobulin for DTC, many researchers have investigated their doubling time to assess the progression of the disease [41,42]. Despite the reliability of these markers, progressive diseases must be assessed with standardised imaging, which should be repeated every 6e12 months, and the rate of progression should be calculated using RECIST [40]. Only a few exceptions to this general rule are accepted and include cases with a large tumour burden, the presence of the disease in sites where its progression can be harmful (e.g. trachea, spinal cord, brain) or a high level of 18-FDG uptake [43,44]. Other than the progression of the lesions, before starting TKI therapy we should also consider the size and the site of the lesions [39,45]. If the lesions are centimetric, even multiple, an active surveillance with 6 month controls should be preferred to systemic therapy. Similarly, if the lesion is big but unique the possibility of local treatment should be considered, such as, for example, thermoablation [46]. When the lesions are multiple, distributed in several organs and constantly growing is probably the right time to consider the possibility of using TKIs that are active and also safe in old patients, regardless of other concomitant and relevant diseases.
The Clinical Use of Approved Drugs: How to Choose the Right Drug Despite the approval of both the FDA and the EMA, not all countries have the same access to TKI drugs. In fact, in many cases, local agencies and governments can decide differently and do not allow the prescription or the reimbursement of the cost of the drug, thus the choice of the drug to be used is affected by local availability [47]. This is a big limitation to making suggestions about which drug to use first. Therefore, for the purpose of this discussion we will assume that the four TKIs are available. As far as MTC is concerned, vandetanib and cabozantinib are the two drugs that successfully completed the phase III studies. Both of them showed an improved PFS, although the difference with the placebo arm was more relevant in patients treated with cabozantinib. However, it is important to say that the enrolled patients in the two studies were substantially different. In the vandetanib study, nonprogressive, but symptomatic, patients were also enrolled, whereas in the cabozantinib study, only progressive cases according to RECIST could be enrolled [23,24]. The difference in the PFS of the two groups treated with placebo in the two studies clearly showed that the patients enrolled in the EXAM study were more advanced and severely affected. When comparing adverse events, the severity of the adverse events due to cabozantinib was higher than that of the adverse events observed in the ZETA trial (Table 3). It is also important to say that vandetanib showed a rather high
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percentage (14%) of QT prolongation that was not observed with cabozantinib. At variance, some cases of gastrointestinal perforations were observed in the cabozantinib study that were not reported in the vandetanib study [24]. Although both had cutaneous adverse events [48], vandetanib mainly induces severe erythema due to sun exposure and patients must use highly protective skin cream and wear gloves and a big hat, especially in the summer or if living in sunny countries, whereas cabozantinib mainly induces hand and foot syndrome, which requires local treatment with a urea-based cream and preventive care of hands and feet before starting the drug.
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All of this information must be taken into consideration when it is time to start the systemic therapy and the choice of drug should be tailored according to the patient’s general health conditions, associations with other diseases, the simultaneous use of other drugs that can interfere with the TKIs or potentiate some adverse events such as the prolongation of QT (Table 4), the type of job the patient has, as well as their level of sun exposure. An accurate discussion with the patient [49] regarding not only his/her health conditions but also lifestyle, working commitments and the use of other drugs should always precede the choice of drug. A cardiologist consultation, ECG and a blood pressure measurement
Table 3 Major adverse events reported in the four phase III clinical studies of the tyrosine kinase inhibitors approved for the treatment of advanced thyroid cancer: although similar, a difference in the prevalence of adverse events can be seen by comparing the four drugs Drug
Vandetanib Cabozantinib Sorafenib Lenvatinib
Tumour
MTC MTC DTC DTC
Adverse events (all grades) Hypertension (%)
Diarrhoea (%)
Skin rash (%)
Anorexia (%)
Nausea (%)
Weight loss (%)
Fatigue (%)
QTc prolongation (%)
32 32 40 67
56 63 68 59
45 19 50 15
21 45 32 49
33 43 20 41
10 47 47 45
24 40 50 59
14 NE NE 8
MTC, medullary thyroid cancer; DTC, differentiated thyroid cancer; NE: not estimated.
Similarly, there are differences that must be known and taken into consideration before choosing between sorafenib and lenvatinib (Table 3). The main adverse event of sorafenib is hand and foot syndrome, whereas hypertension is the most frequent adverse event of lenvatinib. In the SELECT study, lenvatinib showed a relevant and rapid shrinkage of tumoural lesions, probably due to its high affinity for VEGFR 2, whereas sorafenib has a slower but still relevant activity. Taking into consideration these differences, lenvatinib is required if there is a need to rapidly reduce the volume of a metastatic lesion in a short period of time, such as a vertebral lesion (Fig 1A and B) compromising the stability of the column and/or compressing the spinal cord. On the contrary, if there is an infiltration (Fig 2A) or a compression (Fig 2B) of a vital organ such as the trachea (Fig 1A and B), it could be better to use a drug with a slower activity to reduce the risk of fistula.
are also part of the medical consultation before starting therapy. An accurate pharmacological correction of high blood pressure should be carried out before starting the TKI or during treatment if it increases after starting the TKI. Once the drug has been chosen and the treatment has been initiated, the patient must be contacted and possibly visited every 15 days in the first 2 months and then less frequently if everything is going well. At the appearance of adverse events the daily dose of the drug can be reduced or the drug can be stopped according to the lower or greater severity of the adverse event. As the biological half-life of the drugs (Table 5) is rather different and is quite long for vandetanib, suspension of the drug must sometimes be long to obtain resolution of the adverse event. As TKIs are cytostatic and not cytotoxic [50] we should be aware that when stopping the drug the cells start to grow rather rapidly and according to the half-life of the drug. For
Figure 1. (A) Axial section and (B) sagittal section of a vertebral lesion in an advanced thyroid cancer that could compromise the stability of the column and the integrity of the spinal cord.
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Figure 2. Tracheal infiltration (A) and compression (B) in advanced thyroid cancer.
Table 4 List of drugs that can prolong QT and should be avoided during treatment with tyrosine kinase inhibitors Drug class
Generic name
Anaesthetics Antihistamine Antibiotic
Propofol, sevoflurane Diphenhydramine, hydroxyzine, terfenadine Trimethoprim-sulfamethoxazole, ciprofloxacin, azithromycin, clarithromycin, metronidazole, ofloxacin, telithromycin, moxifloxacin, levofloxacin Albuterol, arformoterol, ephedrine, formoterol, isoproterenol, metaproterenol, terbutaline, salmeterol Dopamine, dobutamine, norepinephrine, nicardipine, isradipine, indapamide, hydrochlorothiazide, furosemide Sotalol, flecainide, amiodarone, disopyramide, dofetilide, dronedarone, ibutilide, quinidine Amitriptyline, nortriptyline, chlorpromazine, citalopram, clozapine, escitalopram, fluoxetine, iloperidone, imipramine, olanzapine, risperidone, sertraline, ziprasidone, venlafaxine, trimipramine, torsemide, thioridazine, mirtazapine Felbamate Dolasetron, granisetron, metoclopramide, domperidone, ondansetron Chloroquine Amantadine, atazanavir, foscarnet, ritonavir, saquinavir, telaprevir, nelfinavir Fluconazole, itraconazole, ketoconazole, voriconazole, pentamidine Methadone, levomethadyl Cocaine, amphetamine Ritodrine, tolterodine, tizanidine, solifenacin Sibutramine, phenylpropanolamine, phentermine Phenylephrine, midodrine Vardenafil, sildenafil
Bronchodilator Inotrope/anti-hypertensive/ diuretic Anti-arrhythmic Anti-depressant, Anti-psychotic
Anti-convulsant Anti-emetic Anti-malarial Anti-viral Anti-fungal Opiate Narcotics Muscle relaxant Appetite suppressant Vasoconstrictor Phosphodiesterase 5 inhibitor
Table 5 Biological half-life of tyrosine kinase inhibitors approved for the treatment of advanced thyroid cancer Drug
Half-life
Vandetanib Cabozantinib Lenvatinib Sorafenib
19 days 55 h 28 h 25e48 h
this reason, it could be better to avoid suspension by avoiding severe adverse events and just reducing the daily dosage of the drug when the adverse event is present but not yet severe. Patients must be instructed to refer adverse events immediately at onset and not to wait too long for fear of suspension or reduction of the drug. The cytostatic action is a limit of TKIs because, once started, they should be
continued until evidence of tumoural progression or until the appearance of severe adverse events. Moreover, there is some clinical evidence that once TKI treatment is stopped, progression of the disease can become even more rapid.
Conclusions TKIs represent a new and promising approach to the treatment of advanced RAI-R DTC, MTC and probably also for treating PDTC and ATC. At present, sorafenib and lenvatinib have been approved by the FDA and the EMA for the treatment of progressive RAI-DTC and vandetanib and cabozantinib have been approved for treating advanced and progressive MTC. Patients with advanced thyroid cancer, who were without any therapeutic options, finally have
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options for tumour treatment and better control of some cancer-related symptoms. However, many areas of uncertainty in the treatment of thyroid cancer patients with targeted therapies remain to be elucidated. Despite the efficacy of TKIs being shown in many phase III studies in terms of improved PFS and ORR, only a limited amount of data regarding the prolongation of patient overall survival are available at the moment. The escape phenomenon and the restarting growth of some lesions or the appearance of new ones is a common limitation of TKIs. The reasons for this phenomenon are still undefined but this is just a matter of time. Thus, we need second- and third-line drugs as well as new types of drug or drug combinations. The associations between different TKIs and their association with classical cytotoxic chemotherapy and/or external beam radiotherapy should be evaluated in preclinical models as well as in clinical trials. Moreover, new type of drug, like immune checkpoint inhibitors, or drugs used to target cancer stem cells are the new fields to be explored in the future.
[9]
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[11]
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[13]
[14]
Conflict of Interest R. Elisei is a consultant for Bayer, Eisai, Astra Zeneca, Exilixis, Genzyme, but this activity did not influence this work, which has been written independently.
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Clinical Oncology journal homepage: www.clinicaloncologyonline.net
Overview
Targeted Therapy in Thyroid Cancer: State of the Art L. Valerio, L. Pieruzzi, C. Giani, L. Agate, V. Bottici, L. Lorusso, V. Cappagli, L. Puleo, A. Matrone, D. Viola, C. Romei, R. Ciampi, E. Molinaro, R. Elisei Department of Clinical and Experimental Medicine, Endocrine Unit, University of Pisa, Pisa, Italy Received 6 February 2017; accepted 7 February 2017
Abstract Thyroid cancer typically has a good outcome following standard treatments, which include surgery, radioactive iodine ablation for differentiated tumours and treatment with thyrotropine hormone-suppressive levothyroxine. Thyroid cancers that persist or recur following these therapies have a poorer prognosis. Cytotoxic chemotherapy or external beam radiotherapy has a low efficacy in these patients. ‘Target therapy’ with tyrosine kinase inhibitors (TKIs) represent an important therapeutic option for the treatment of advanced cases of radioiodine refractory (RAI-R) differentiated thyroid cancer (DTC), medullary thyroid cancer (MTC) and possibly for cases of poorly differentiated (PDTC) and anaplastic thyroid cancer (ATC). In the last few years, several TKIs have been tested for the treatment of advanced, progressive and RAI-R thyroid cancers and some of them have been recently approved for use in clinical practice: sorafenib and lenvatinib for DTC and PDTC; vandetanib and cabozantinib for MTC. The objective of this overview is to present the current status of the treatment of advanced DTC, MTC, PDTC and ATC with the use of TKIs by describing the benefits and the limits of their use. A comprehensive analysis and description of the molecular basis of these drugs and the new therapeutic perspectives are also reported. Some practical suggestions are also given for the management to the potential sideeffects of these drugs. Ó 2017 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Key words: Advanced thyroid cancer; adverse events; molecular targets; targeted therapy; tyrosine kinase inhibitors
Statement of Search Strategies Used and Sources of Information A literature search of PubMed was carried out using the following key words: advanced thyroid cancer; advanced medullary thyroid cancer; tyrosine kinase inhibitors in thyroid cancer; vandetanib in thyroid cancer; cabozantinib in thyroid cancer; sorafenib in thyroid cancer; lenvatinib in thyroid cancer; cancer patient communication.
Introduction Differentiated thyroid cancers (DTC), both papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC), are generally associated with an indolent disease course and, as Author for correspondence: R. Elisei, Department of Clinical and Experimental Medicine, Endocrine Unit, University of Pisa, Via Paradisa 2, Pisa, 56124, Italy. Tel: þ39-050-995120; Fax: þ39-050-578772. E-mail address: [email protected] (R. Elisei).
they maintain the typical features of thyroid cells, they are usually curable with surgery and radioactive iodine (131I) therapy [1,2]. In about 10% of cases, patients have a locally advanced or metastatic disease at diagnosis, with local invasion and/or distant metastases in the bone (25%), lungs (50%), lungs and bone (20%) and other sites (5%). In one third of advanced DTC the metastatic lesions have a low avidity for iodine and 131I therapy has no effects [3]. Anaplastic thyroid cancer (ATC) is the undifferentiated form, unable to take up 131I and with no chance of cure [4]. Fortunately it is rare (2% of thyroid cancer) but is associated with rapid progression, especially at the local level, with a high risk of suffocation and a high mortality. Poorly differentiated thyroid cancer (PDTC) has a disease course that is in between those of DTC and ATC. The reason for this poor prognosis is related to the fact that in these cases the tumoural cells become rapidly dedifferentiated and are no longer able to take up iodine and secrete thyroglobulin, if they were in the beginning. Similarly, advanced medullary thyroid cancers (MTCs) are not able to take up 131I, do not produce thyroglobulin
http://dx.doi.org/10.1016/j.clon.2017.02.009 0936-6555/Ó 2017 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
L. Valerio et al. / Clinical Oncology 29 (2017) 316e324
and are not responsive to the thyrotropine hormone . In fact they derive from malignant transformation of parafollicular C-cells that are neuroendocrine cells located peripherally to thyroid follicles. At variance from DTC, they produce several peptides, among which the most important and specific is calcitonin [5]. Until a few years ago, no effective therapeutic options were available for patients with advanced thyroid cancer resistant to radioiodine (RAI-R). Other conventional therapies were used, such as external beam radiotherapy and chemotherapy, but they had important toxicity and played mainly a palliative role as efficacy was low and transient (10e20%) with no prolongation of survival in response to the use of either a single therapeutic agent or a combination [6,7]. In recent years, a variety of molecular-targeted agents have been developed that are able to inhibit tyrosine kinases receptors (TK-R), which are responsible for tumour growth and angiogenesis [8]. In the last 12 years, several of these tyrosine kinase inhibitors (TKIs) have been evaluated in advanced thyroid cancers for their ability to block TK-R and/or other kinases involved in cell proliferation and tumoural transformation of thyroid cells (Table 1). Four of them have now been approved by the Food and Drug Administration (FDA) and the European Medical Agency (EMA) for the treatment of advanced RAI-R (i.e. sorafenib and lenvatinib) and MTC (i.e. vandetanib and cabozantinib).
317
The objective of this overview is to present the current status of the treatment of advanced thyroid cancers using these innovative targeted therapies by describing both the benefits and the limits of their use.
The Rationale of Targeted Therapies in Thyroid Cancer: Molecular Alterations Aberrant signalling pathways have been implicated in the onset, progression and invasiveness of DTCs. The most common genetic changes in PTC are point mutations in BRAF and RAS and rearrangement of the RET protooncogene [9]. Several RET/PTC rearrangements have been described, almost exclusively in PTC cells, mainly in radioinduced PTC, but also in a not negligible percentage of sporadic cases [10]. In FTC, point mutations of RAS and rearrangements of PPARg and PAX8 genes, to create the PPFP fusion gene, are the most common oncogenic alterations but, to a lesser extent, also PTEN deletion/mutation, PIK3CA and IDH1 mutations can be found [11]. At variance from PTC and FTC, in which oncogene mutations are almost mutually exclusive, PDTC and even more ATC are characterised by a higher number of mutations in the same tumoural tissue and the overexpression of these proteins is probably responsible for a more aggressive phenotype. The most prevalent oncogene alterations in ATC are p53 point mutations, BRAFV600E, PIK3CA, PTEN, IDH1 and ALK mutations,
Table 1 Tyrosine kinase inhibitors tested in phase II, III or IV clinical trials in thyroid cancer: the multitarget activity and the molecular targets are indicated DRUG
VEGF-R
c-Kit
RET
PDGF-R
FGF-R
EGF-R
Axitinib Bevacizumab Cabozantinib Imatinib Lenvatinib
Yes No Yes No Yes
Yes No Yes Yes Yes
No No Yes No Yes
Yes No No Yes Yes
No No No No Yes
No No No No No
Motesanib Nintedanib Pazopanib Ponatinib Selumetinib Sorafenib Sunitinib Vandetanib Vemurafenib Everolimus Temsirolimus
Yes Yes Yes No No Yes Yes Yes No No Yes
Yes No Yes No No Yes Yes Yes No No No
Yes No No Yes No Yes Yes No No No No
Yes Yes Yes Yes No Yes Yes No No No No
No Yes No Yes No No No No No No No
No No No No No No No Yes No No No
Other targets
dual PI3K/mTOR MET, RET- KIF5B rearrangement Bcr-Abl RET-KIF5B, CCDC6-RET, NcoA4-RET rearrangement
Bcr-Abl, FLT3, KIT MEK Raf, FLT3 FLT3 RET-KIF5B rearrangement BRAFV600E, CRAF mTOR mTOR
Study phase
Approved for thyroid cancer treatment
II II III* II III*
No No Yes No Yes
II II II II III III II III* II II II
No No No No No Yes No Yes No No No
*These drugs have also been tested in phase IV studies devoted to verifying the activity and the adverse events of different daily dosages of the drug. Bcr-Abl, Abelson and breakpoint cluster region fusion gene; CSF-1R, colony stimulating factor 1 receptor; EGF-R, epidermal growth factor receptor; FGF-R, fibroblast growth factor receptor; KIT, v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene; Raf, v-raf murine sarcoma viral oncogene homolog; BRAFV600E, valine to glutamic acid substitution of BRAF gene; CRAF, v-raf murine sarcoma viral oncogene homolog 1; FLT3, Fms-like tyrosine kinase 3; MEK, mitogen activated protein kinase; MET, hepatocyte growth factor [HGF] receptor; PDGF-R, platelet-derived growth factor receptor; RET, REarranged during Transfection receptor; RET gene fusions: KIF5B-RET, CCDC6-RET and NcoA4-RET; VEGF-R, vascular endothelial growth factor receptor.
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whereas in PDTC, beta-catenin (CTNNB1), p53 and BRAFV600E mutations are the most frequent. Both in ATC and PDTC the prevalence of TERT promoter mutations is high and typically associated with a greater aggressiveness [12]. The most common genetic alterations found in MTC cells are RET-activating point mutations that are present at the germline level in 95% of hereditary forms and 45% of sporadic cases, with a significantly higher prevalence in advanced MTC cases [13]. The only other oncogenic alterations found in sporadic MTC are RAS mutations, mainly Hand K-mutations, which have been reported in about 17% of RET-negative sporadic MTCs [14]. In addition, RAS and RET are mutually exclusive in MTC cases. The increasing knowledge about the molecular alterations underlying thyroid cancer has greatly increased the interest in developing new drugs for targeted treatments. The drugs that have primarily been investigated for the treatment of thyroid cancer are TKIs that are able to bind one or multiple TK-Rs, inhibiting their tyrosine kinase activity [15]. Tyrosine kinases are enzymes responsible for the control of mitogenic signals via the phosphorylation/ dephosphorylation of many intracellular proteins involved in the MAPK signal transduction cascade. The enhanced catalytic activity that is responsible for uncontrolled cell growth is the molecular rationale for the use of TKIs in thyroid cancer treatment. However, considering that the
PI3K/AKT/mTOR pathway is another important pathway for the development of thyroid tumours, other drugs have also been investigated, such as mTOR inhibitors [16] (Table 1). Angiogenesis is also a very important process in tumour progression and a very attractive target for therapy [17]. Angiogenesis is promoted by vascular endothelial growth factor (VEGF), which is overexpressed in response to intratumoural hypoxia via the overactivation of hypoxiainducible factor-1 alpha (HIF1a). This transcriptional factor is upregulated not only by hypoxia but also via growth factor signalling pathways, such as PI3K/AKT and MAPK pathways, and is expressed in thyroid cancer cells, especially in ATC cells, but not in normal thyroid tissue [18,19]. An important target of HIF1a is the MET oncogene, which is upregulated in many thyroid cancers and promotes angiogenesis as well as cellular motility, invasion and metastasis [20e22]. Almost all TKIs target, among all others, the VEGF receptor (VEGF-R), although with different affinities. The multitarget activity of the TKIs makes them able to simultaneously block two or three different pathways, thus ‘fighting’ the cancer from several fronts at the same time. This is also the case for vandetanib and cabozantinib, which have been approved for the treatment of advanced MTC, and sorafenib and lenvatinib, which have been approved for the treatment of advanced RAI-R DTC and PDTC (Table 2).
Table 2 Details of the four phase III studies with the tyrosine kinase inhibitors approved for the treatment of advanced thyroid cancer Drug
Vandetanib
Cabozantinib
Sorafenib
Lenvatinib
Name of the study Tumour Phase Patients (n) Partial response (%) Stable disease 6 months (%) Median progression-free survival (months) Median overall survival (months) Most frequent adverse events (%) Any grade
ZETA MTC III 331 45 87
EXAM MTC III 330 28 NE
DECISION DTC III 417 12.2 42
SELECT DTC III 392 64.8 15.3
30.5*
11.2
10.8
18.3
NE
NE
NE
NE
Diarrhoea (56) Skin rash (45) Nausea (33) Hypertension (32)
Diarrhoea (63) Hand-foot syndrome (50) Weight loss (47) Anorexia (45) Nausea (43) Fatigue (40)
Hypertension (67) Diarrhoea (59) Fatigue or asthenia (59) Anorexia (50) Weight loss (46) Nausea (41) Stomatitis (35)
Molecular targets
VEGF-R, c-Kit, RET, EGF-R, RET-KIF5B rearrangement [23]
VEGF-R, c-Kit, RET, MET, RET-KIF5B rearrangement
Hand-foot syndrome (76) Diarrhoea (68) Alopecia (67) Skin rash (50) Fatigue (49) Weight loss (46) Hypertension (40) Anorexia (31) VEGF-R, c-Kit, RET, PDGF-R, Raf, FLT3
[24]
[25]
Reference
VEGF-R, c-Kit, RET, PDGF-R, FGF-R, RET-KIF5B, CCDC6-RET, NcoA4-RET rearrangement [26]
*Predicted median progression-free survival according to the Weibull model. DTC, differentiated thyroid cancer; MTC, medullary thyroid cancer; NE, not estimated; EGF-R, epidermal growth factor receptor; FGF-R, fibroblast growth factor receptor; KIT, v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene; Raf, v-raf murine sarcoma viral oncogene homolog; FLT3, Fms-like tyrosine kinase 3; MET, hepatocyte growth factor [HGF] receptor; PDGF-R, platelet-derived growth factor receptor; RET, REarranged during Transfection receptor; RET gene fusions: KIF5B-RET, CCDC6-RET and NcoA4-RET; VEGF-R, vascular endothelial growth factor receptor.
L. Valerio et al. / Clinical Oncology 29 (2017) 316e324
The Approved Drugs and Their Clinical Use Vandetanib Vandetanib is a once-daily oral multitarget TKI that is very active against RET oncogene, VEGF-R and epidermal growth factor receptor (EGF-R) [27]. Vandetanib is the first drug approved for the treatment of adult patients with symptomatic, unresectable, locally advanced or metastatic MTC in the USA (2011) and Europe (2013) (CaprelsaÒ, Sanofi-Genzyme). The approval of vandetanib was obtained after the encouraging results of the international, multicentric and randomised against placebo, ZETA phase III study [23], which showed a significant prolongation of the progression-free survival (PFS) of treated patients with respect to patients treated with placebo (30.5 versus 19.3 months; P ¼ 0.001). Recently, after the publication of a phase II study specifically dedicated to children affected by the hereditary form of MTC [28], the use of vandetanib has also been approved for children with advanced MTC, usually affected by a hereditary form. The ZETA study also showed that there was a statistically significant difference in the effect of vandetanib with respect to placebo in the objective response rates (ORR) (P < 0.001) and disease control rates (P ¼ 0.001), as well as in the biochemical response (P < 0.001). In other words, the drug was not only able to stop cell growth, as expected and as shown by the prolongation of the PFS, but also induced tumoural shrinkage with a consequent volume reduction of the metastatic lesions [23]. Currently, an international, multicentric phase III clinical trial (VERIFY study) exploring the efficacy of vandetanib in treating progressive RAI-R DTC is ongoing, although no longer enrolling. The study was motivated by the positive results obtained in a phase II study carried out in France in locally advanced or metastatic cases of RAI-R DTC that showed a statistically significant increase in the PFS of patients treated with vandetanib compared with the PFS of those treated with placebo (11.1 months versus 5.9 months) [29]. As previously mentioned, vandetanib has already been approved for the treatment of advanced MTC and this study might allow its use in treating RAI-R DTC, although preliminary data, recently shown at an international meeting, were not so promising [30]. Moreover, a limit of the VERIFY study is that to be enrolled, RAI-R DTC patients had to be ‘naïve’ of any other treatment; thus, the efficacy of vandetanib in DTC as second-line treatment cannot be evaluated. Cabozantinib Cabozantinib is an inhibitor of the hepatocyte growth factor receptor, VEGF-R 2 and RET and this drug has been approved by the FDA (2012) and the EMA (2014) for the treatment of patients with progressive metastatic MTC (CometriqÒ, Exelixis). Cabozantinib has been investigated for the treatment of patients with unresectable, locally advanced or metastatic MTC in a phase III study (EXAM study). A statistically significant longer median PFS has
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been shown in patients treated with the drug with respect to those treated with placebo (11.2 versus 4.0 months) [24]. The longer median PFS durations observed in the ZETA study with respect to those observed in the EXAM study may be explained by the different levels of the severity of disease in the two groups of patients, as shown by the fact that the PFS durations of the two placebo groups were also significantly different (19.3 months in the ZETA study and 4.0 months in the EXAM study). In fact, although symptomatic patients without evidence of progressive disease could be enrolled in the ZETA study, disease progression was a fundamental inclusion criterion in the EXAM study. As for vandetanib, a significant shrinkage of the tumoural lesions could also be shown for cabozantinib, with a 28% ORR [24]. Despite these good results, neither cabozantinib nor vandetanib was able to improve overall survival, although the analysis was invalidated by the crossover design of the ZETA study and by the possibility to treat cases progressing under placebo with other commercial TKIs (used off label) in the EXAM study. However, newly collected data show that overall survival was significantly increased in patients treated with cabozantinib when the analysis was restricted to the subgroup of M918T-RETmutated MTC patients [31]. Sorafenib Sorafenib is a multikinase inhibitor that targets several molecular signals involved in the pathogenesis of thyroid cancer, including those implicated in DTC. These signals include the RAS and BRAF/MEK/ERK signalling pathways; ligand dependent RET/PTC receptor tyrosine kinase activation; and pathways involving VEGF, platelet-derived growth factor (PDGF) and their receptors. The inhibitory effect of sorafenib in the treatment of thyroid tumours was explored in an international, multicentric, phase III study (DECISION study) [25]. Treatment with sorafenib has shown a longer of PFS of treated patients than that of patients treated with placebo (10.8 months versus 5.8 months, respectively, P < 0.0001) (Table 2). There is no evidence of an improvement in overall survival with sorafenib, but the median overall survival has not yet been reached and additional analyses of the overall survival are planned. Moreover, this result is affected by the large proportion of patients in the placebo arm (71%) who crossed over to treatment. Interesting information has been obtained via the exploratory analysis of the outcomes of patients who continued to be open-label treated with sorafenib after the first evidence of progression in the phase III DECISION study [32]. This analysis showed that sorafenib may continue to suppress tumour growth rates after tumour progression because the median PFS of patients receiving this drug was still lower than that of patients treated with placebo (6.7 months versus 5.3 months). This suggests that, despite the evidence of tumour progression, in the absence of an alternative drug, it may be better to continue to treat patients with sorafenib, especially if it is well tolerated. Moreover, this exploratory analysis also showed that those patients in the placebo arm who started
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receiving sorafenib after tumour progression showed a comparable PFS to those who started receiving the drug from the beginning of the trial (9.6 months versus 10.8 months). This indicates, although does not prove, that delaying the initiation of sorafenib treatment should not greatly affect the response to the drug [32]. The positive results in terms of the safety and efficacy of sorafenib allowed the approval of this drug by the FDA (2013) and the EMA (2014) for the treatment of patients with RAI-R DTC (NexavarÒ, Bayer). However, it is worth noting that sorafenib had already been approved by both the FDA and the EMA for the treatment of advanced hepatocellular carcinomas [33] and advanced renal cell carcinomas [34] and for this reason it had been used ‘off label’ before its approval. Lenvatinib Lenvatinib is an oral, multitargeted inhibitor of VEGF-R 1, 2 and 3, fibroblast growth factor receptor 1e4 (FGF-R 1e4), PDGFR a, RET and KIT signalling networks. On the basis of results observed in a phase II study involving patients with RAI-R thyroid cancer, a phase III, multicentre, randomised, placebo-controlled study (SELECT study) was started (Table 2). At the end of the study, patients treated with lenvatinib showed a significantly longer PFS than patients treated with placebo (18.3 months versus 3.6 months, respectively; P < 0.001) [26]. A benefit in terms of PFS was present regardless of the BRAF or RAS mutation status of the patients or previous TKI treatment and was also observed in patients with PDTC. The ORR was more than 50% in all metastatic sites (brain, bone, liver, lungs and lymph nodes) and a PFS benefit associated with lenvatinib was present in all cases, independent of the sites of metastasis, with the exception of patients with brain metastases, in which PFS fell to 8.8 months in patients treated with lenvatinib and to 3.7 months in those receiving the placebo [35]. At the first data cut-off period, overall survival was no different in patients treated with lenvatinib than in those treated with the placebo [26]. When the overall survival analysis was carried out on subgroups of patients, a statistically significant increase in overall survival was observed in patients > 65 years [36] with respect to younger patients and in follicular with respect to papillary histotype [37]. The positive results in terms of the safety and efficacy of lenvatinib allowed for the approval of this drug by the FDA and EMA in 2015 for the treatment of patients with RAI-R DTC (LenvimaÒ, Eisai). Lenvatinib has also been tested in advanced MTC patients in a phase II study and the results are very promising, especially in terms of ORR in most cases, thus suggesting the possibility of using this drug in MTC cases becoming resistant, or not treatable for any reason, to vandetanib and cabozantinib [38].
Tyrosine Kinase Inhibitor Treatment: Who and When? According to expert opinion [39], good candidates for treatment with TKIs are patients with a RAI-R or MTC
metastatic thyroid tumour with lesions radiologically measurable and in progression over the previous 12e14 months, as defined by RECIST [40]. Due to the presence of two specific serum markers in thyroid cancer that could correlate with the tumour burden, calcitonin for MTC and thyroglobulin for DTC, many researchers have investigated their doubling time to assess the progression of the disease [41,42]. Despite the reliability of these markers, progressive diseases must be assessed with standardised imaging, which should be repeated every 6e12 months, and the rate of progression should be calculated using RECIST [40]. Only a few exceptions to this general rule are accepted and include cases with a large tumour burden, the presence of the disease in sites where its progression can be harmful (e.g. trachea, spinal cord, brain) or a high level of 18-FDG uptake [43,44]. Other than the progression of the lesions, before starting TKI therapy we should also consider the size and the site of the lesions [39,45]. If the lesions are centimetric, even multiple, an active surveillance with 6 month controls should be preferred to systemic therapy. Similarly, if the lesion is big but unique the possibility of local treatment should be considered, such as, for example, thermoablation [46]. When the lesions are multiple, distributed in several organs and constantly growing is probably the right time to consider the possibility of using TKIs that are active and also safe in old patients, regardless of other concomitant and relevant diseases.
The Clinical Use of Approved Drugs: How to Choose the Right Drug Despite the approval of both the FDA and the EMA, not all countries have the same access to TKI drugs. In fact, in many cases, local agencies and governments can decide differently and do not allow the prescription or the reimbursement of the cost of the drug, thus the choice of the drug to be used is affected by local availability [47]. This is a big limitation to making suggestions about which drug to use first. Therefore, for the purpose of this discussion we will assume that the four TKIs are available. As far as MTC is concerned, vandetanib and cabozantinib are the two drugs that successfully completed the phase III studies. Both of them showed an improved PFS, although the difference with the placebo arm was more relevant in patients treated with cabozantinib. However, it is important to say that the enrolled patients in the two studies were substantially different. In the vandetanib study, nonprogressive, but symptomatic, patients were also enrolled, whereas in the cabozantinib study, only progressive cases according to RECIST could be enrolled [23,24]. The difference in the PFS of the two groups treated with placebo in the two studies clearly showed that the patients enrolled in the EXAM study were more advanced and severely affected. When comparing adverse events, the severity of the adverse events due to cabozantinib was higher than that of the adverse events observed in the ZETA trial (Table 3). It is also important to say that vandetanib showed a rather high
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percentage (14%) of QT prolongation that was not observed with cabozantinib. At variance, some cases of gastrointestinal perforations were observed in the cabozantinib study that were not reported in the vandetanib study [24]. Although both had cutaneous adverse events [48], vandetanib mainly induces severe erythema due to sun exposure and patients must use highly protective skin cream and wear gloves and a big hat, especially in the summer or if living in sunny countries, whereas cabozantinib mainly induces hand and foot syndrome, which requires local treatment with a urea-based cream and preventive care of hands and feet before starting the drug.
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All of this information must be taken into consideration when it is time to start the systemic therapy and the choice of drug should be tailored according to the patient’s general health conditions, associations with other diseases, the simultaneous use of other drugs that can interfere with the TKIs or potentiate some adverse events such as the prolongation of QT (Table 4), the type of job the patient has, as well as their level of sun exposure. An accurate discussion with the patient [49] regarding not only his/her health conditions but also lifestyle, working commitments and the use of other drugs should always precede the choice of drug. A cardiologist consultation, ECG and a blood pressure measurement
Table 3 Major adverse events reported in the four phase III clinical studies of the tyrosine kinase inhibitors approved for the treatment of advanced thyroid cancer: although similar, a difference in the prevalence of adverse events can be seen by comparing the four drugs Drug
Vandetanib Cabozantinib Sorafenib Lenvatinib
Tumour
MTC MTC DTC DTC
Adverse events (all grades) Hypertension (%)
Diarrhoea (%)
Skin rash (%)
Anorexia (%)
Nausea (%)
Weight loss (%)
Fatigue (%)
QTc prolongation (%)
32 32 40 67
56 63 68 59
45 19 50 15
21 45 32 49
33 43 20 41
10 47 47 45
24 40 50 59
14 NE NE 8
MTC, medullary thyroid cancer; DTC, differentiated thyroid cancer; NE: not estimated.
Similarly, there are differences that must be known and taken into consideration before choosing between sorafenib and lenvatinib (Table 3). The main adverse event of sorafenib is hand and foot syndrome, whereas hypertension is the most frequent adverse event of lenvatinib. In the SELECT study, lenvatinib showed a relevant and rapid shrinkage of tumoural lesions, probably due to its high affinity for VEGFR 2, whereas sorafenib has a slower but still relevant activity. Taking into consideration these differences, lenvatinib is required if there is a need to rapidly reduce the volume of a metastatic lesion in a short period of time, such as a vertebral lesion (Fig 1A and B) compromising the stability of the column and/or compressing the spinal cord. On the contrary, if there is an infiltration (Fig 2A) or a compression (Fig 2B) of a vital organ such as the trachea (Fig 1A and B), it could be better to use a drug with a slower activity to reduce the risk of fistula.
are also part of the medical consultation before starting therapy. An accurate pharmacological correction of high blood pressure should be carried out before starting the TKI or during treatment if it increases after starting the TKI. Once the drug has been chosen and the treatment has been initiated, the patient must be contacted and possibly visited every 15 days in the first 2 months and then less frequently if everything is going well. At the appearance of adverse events the daily dose of the drug can be reduced or the drug can be stopped according to the lower or greater severity of the adverse event. As the biological half-life of the drugs (Table 5) is rather different and is quite long for vandetanib, suspension of the drug must sometimes be long to obtain resolution of the adverse event. As TKIs are cytostatic and not cytotoxic [50] we should be aware that when stopping the drug the cells start to grow rather rapidly and according to the half-life of the drug. For
Figure 1. (A) Axial section and (B) sagittal section of a vertebral lesion in an advanced thyroid cancer that could compromise the stability of the column and the integrity of the spinal cord.
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Figure 2. Tracheal infiltration (A) and compression (B) in advanced thyroid cancer.
Table 4 List of drugs that can prolong QT and should be avoided during treatment with tyrosine kinase inhibitors Drug class
Generic name
Anaesthetics Antihistamine Antibiotic
Propofol, sevoflurane Diphenhydramine, hydroxyzine, terfenadine Trimethoprim-sulfamethoxazole, ciprofloxacin, azithromycin, clarithromycin, metronidazole, ofloxacin, telithromycin, moxifloxacin, levofloxacin Albuterol, arformoterol, ephedrine, formoterol, isoproterenol, metaproterenol, terbutaline, salmeterol Dopamine, dobutamine, norepinephrine, nicardipine, isradipine, indapamide, hydrochlorothiazide, furosemide Sotalol, flecainide, amiodarone, disopyramide, dofetilide, dronedarone, ibutilide, quinidine Amitriptyline, nortriptyline, chlorpromazine, citalopram, clozapine, escitalopram, fluoxetine, iloperidone, imipramine, olanzapine, risperidone, sertraline, ziprasidone, venlafaxine, trimipramine, torsemide, thioridazine, mirtazapine Felbamate Dolasetron, granisetron, metoclopramide, domperidone, ondansetron Chloroquine Amantadine, atazanavir, foscarnet, ritonavir, saquinavir, telaprevir, nelfinavir Fluconazole, itraconazole, ketoconazole, voriconazole, pentamidine Methadone, levomethadyl Cocaine, amphetamine Ritodrine, tolterodine, tizanidine, solifenacin Sibutramine, phenylpropanolamine, phentermine Phenylephrine, midodrine Vardenafil, sildenafil
Bronchodilator Inotrope/anti-hypertensive/ diuretic Anti-arrhythmic Anti-depressant, Anti-psychotic
Anti-convulsant Anti-emetic Anti-malarial Anti-viral Anti-fungal Opiate Narcotics Muscle relaxant Appetite suppressant Vasoconstrictor Phosphodiesterase 5 inhibitor
Table 5 Biological half-life of tyrosine kinase inhibitors approved for the treatment of advanced thyroid cancer Drug
Half-life
Vandetanib Cabozantinib Lenvatinib Sorafenib
19 days 55 h 28 h 25e48 h
this reason, it could be better to avoid suspension by avoiding severe adverse events and just reducing the daily dosage of the drug when the adverse event is present but not yet severe. Patients must be instructed to refer adverse events immediately at onset and not to wait too long for fear of suspension or reduction of the drug. The cytostatic action is a limit of TKIs because, once started, they should be
continued until evidence of tumoural progression or until the appearance of severe adverse events. Moreover, there is some clinical evidence that once TKI treatment is stopped, progression of the disease can become even more rapid.
Conclusions TKIs represent a new and promising approach to the treatment of advanced RAI-R DTC, MTC and probably also for treating PDTC and ATC. At present, sorafenib and lenvatinib have been approved by the FDA and the EMA for the treatment of progressive RAI-DTC and vandetanib and cabozantinib have been approved for treating advanced and progressive MTC. Patients with advanced thyroid cancer, who were without any therapeutic options, finally have
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options for tumour treatment and better control of some cancer-related symptoms. However, many areas of uncertainty in the treatment of thyroid cancer patients with targeted therapies remain to be elucidated. Despite the efficacy of TKIs being shown in many phase III studies in terms of improved PFS and ORR, only a limited amount of data regarding the prolongation of patient overall survival are available at the moment. The escape phenomenon and the restarting growth of some lesions or the appearance of new ones is a common limitation of TKIs. The reasons for this phenomenon are still undefined but this is just a matter of time. Thus, we need second- and third-line drugs as well as new types of drug or drug combinations. The associations between different TKIs and their association with classical cytotoxic chemotherapy and/or external beam radiotherapy should be evaluated in preclinical models as well as in clinical trials. Moreover, new type of drug, like immune checkpoint inhibitors, or drugs used to target cancer stem cells are the new fields to be explored in the future.
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Conflict of Interest R. Elisei is a consultant for Bayer, Eisai, Astra Zeneca, Exilixis, Genzyme, but this activity did not influence this work, which has been written independently.
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