Novel therapies for thyroid cancer.

Review

Novel therapies for thyroid cancer Jolanta Krajewska & Barbara Jarzab† †

Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Selcuk Universitesi on 01/10/15 For personal use only.

M.Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Nuclear Medicine and Endocrine Oncology Department, Gliwice, Poland

1.

Introduction

2.

Medullary thyroid cancer

3.

Differentiated thyroid cancer

4.

Treatment-related toxicity

5.

Common adverse reactions related to VEGFR inhibitors

6.

Conclusion

7.

Expert opinion

Introduction: New therapeutic options for both differentiated thyroid cancer (DTC) and medullary thyroid cancer (MTC) have opened up during the past few years, as the key role of tyrosine kinases in the pathogenesis of thyroid carcinoma has been proved. Recently, two tyrosine kinase inhibitors (TKIs) targeting VEGFR vandetanib (Caprelsa) and cabozantinib (Cometriq) have been approved for advanced MTC, whereas, sorafenib (Nexavar) has been accepted to treat late-stage of DTC. Their efficacy was demonstrated in Phase III studies, compared to placebo; each of them significantly prolonged the progression-free survival. Areas covered: Common adverse reactions related to VEGFR blockade are hypertension, proteinuria, impaired wound healing, hemorrhage and thrombosis, and congestive heart failure. Fatigue, different gastrointestinal disturbances with diarrhea, appetite decrease and weight loss are observed in the majority of patients. Another frequent TKI side effect is thyroidstimulating hormone increase secondary to inhibition of MCT8-dependent T3 and T4 uptake in pituitary. Expert opinion: So far, no direct comparison of both treatment outcomes and toxicity between particular drugs has been carried out. The evidence-based medicine guidelines are necessary to precisely indicate what drug to use: more effective or less toxic and when to start the treatment. Keywords: cabozantinib, differentiated thyroid cancer, medullary thyroid cancer, sorafenib, tyrosine kinase inhibitors, vandetanib Expert Opin. Pharmacother. (2014) 15(18):2641-2652

1.

Introduction

Thyroid cancer is the most common endocrine malignancy representing about 1% of all cancers. Its incidence rapidly increased during the past few decades [1,2] in the USA from 3.6 per 100,000 in 1973 to 8.7 per 100,000 in 2002 [3]. It constitutes the fifth most common malignancy in women [4]. It is estimated that in 2014, 62,980 new cases of thyroid cancer will be diagnosed in the USA and the disease will count for 1890 deaths [4]. The most common is differentiated thyroid cancer (DTC). Despite a generally good prognosis ~ 3 -- 15% of DTC patients have distant metastases at presentation [5,6], while recurrent disease is diagnosed at a later stage in up to 30% of patients [7], among them distant metastases in 6 -- 23% [5-7]. Approximately twothirds of distant metastases demonstrate the ability to take up radioactive iodine (RAI) [8]. Thus, RAI administration is the treatment of choice [9-11]. The remaining one-third of patients, constituting the RAI refractory group, show much worse prognosis, with overall survival (OS) of ~ 10% at 10 years and 6% at 15 years [8]. The criteria for RAI-resistant DTC, proposed by Schlumberger and Sherman, involved the presence of at least one of the following conditions: at least one lesion without RAI uptake, or disease progression within a year following RAI treatment or persistent disease after the administration of a cumulative activity of > 22 GBq (600 mCi) of RAI [12].

10.1517/14656566.2014.969240 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted

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J. Krajewska & B. Jarzab

Article highlights. . .

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Vandetanib, cabozantinib and sorafenib are VEGFR inhibitors. Vandetanib and cabozantinib have been accepted both by the FDA and EMA to treat advanced, progressive medullary thyroid carcinoma as both comparing with placebo significantly prolong progression free survival. Sorafenib has been approved, both by the FDA and EMA to treat late stage of radioactive iodine-refractory differentiated thyroid cancer in patients, who failed after previous tyrosine kinase inhibitor administration. Serum thyroid-stimulating hormone increase, observed in patients treated with tyrosine kinase inhibitor is related to the disturbances in: -- thyroid integrity and hormone biosynthesis, -- thyroid hormone transport, -- thyroid hormone metabolism and to -- the impact on pituitary gland. VEGFR inhibition may lead to the following side effects: -- hypertension, -- congestive heart failure, -- proteinuria, -- impaired wound healing, -- gastrointestinal perforation, -- hemorrhage and thrombosis.

This box summarizes key points contained in the article.

Medullary thyroid cancer (MTC) constitutes about 4 -- 8% of all thyroid cancers [13,14]. Distant metastases are present in 7 -- 23% of patients at diagnosis or may develop during further follow up [14]. These patients are characterized by much worse prognosis compared to subjects in whom the disease was diagnosed at early stages, 10-year survival for 50 versus 70 -- 80%, respectively [15]. Moreover, 80% of patients with palpable MTC and 50% with nonpalpable, but macroscopic MTC, despite radical surgical approach, show elevated serum calcitonin levels after the operation [16]. More than 50% of them demonstrate cancer relapse during a mean 10-year follow up [16]. So far, the therapeutic options for disseminated MTC and RAI-refractory DTC were limited. Systemic treatment, based on chemotherapy was rather unsuccessful, so it is no longer recommended either in MTC or DTC [11,16-18]. Radiotherapy in advanced MTC and DTC plays a minor role, as a palliative treatment only [11,16-18]. Local treatment modalities, such as radiofrequency ablation, chemoembolization and so on, should also be considered [17]. New treatment opportunities, both for MTC and RAIresistant DTC, have opened up during the past few years, as the key role of different tyrosine kinases in the pathogenesis of thyroid carcinoma has been proved. Several Phase II [19-30] and Phase III [31-34] studies with different tyrosine kinase inhibitors (TKIs) have been carried out, confirming their efficacy in both advanced MTC and DTC. Recently two multikinase inhibitors have been approved in advanced MTC, first by the FDA and then by the European Medicines Agency (EMA). The first one, vandetanib 2642

(Caprelsa) was accepted in the USA to treat adult patients with the late-stage MTC and in the EU to treat aggressive and symptomatic MTC in patients with unresectable locally advanced or metastatic disease. The second one, cabozantinib (Cometriq) was registered in the USA to treat MTC that has spread to other parts of the body (metastasized), whereas, in the EU the drug was given ‘conditional approval’ for the use in adult patients with progressive, unresectable locally advanced or metastatic MTC. ‘Conditional approval’ means that the committee opinion was based on data, which, while not yet comprehensive, indicate that the drug’s benefits outweigh its risk. Sorafenib (Nexavar), the first TKI, has been approved by the FDA for the use in late-stage DTC and in May 2014 was approved by the EMA for ‘treatment of patients with progressive, locally advanced or metastatic, differentiated (papillary/follicular/Hu¨rthle cell) thyroid carcinoma, refractory to radioactive iodine’. This review focuses on novel treatment possibilities both in medullary and RAI-refractory DTC. A) The rationale for the use of TKIs in the treatment of thyroid cancer. MTC occurs both in the sporadic (75%) and hereditary (25%) form, which comprises of three distinct syndromes: familiar MTC (FMTC), multiple endocrine neoplasia (MEN) type 2A (MEN2A) and MEN2B. Hereditary type is related to germline single-point mutations in RET protooncogene leading to autophosphorylation of TK residues, which subsequently induces constitutive activation of RET receptor and constant gain-of-function [35,36]. Somatic RET mutations are observed in > 50% of sporadic tumors [37-39]. The most frequent somatic mutation is RET918 mutation that correlates with lymph node metastases and is more aggressive course of the disease [38,40]. In addition to RET, other kinase receptors, involved in MTC pathogenesis, are EGFR, VEGFR, fibroblast growth factor receptor 4 (FGFR4) and finally the MET signaling pathway [41]. Other possible molecular mechanisms involved in MTC pathogenesis include RET interactions with pRB, p53, p18, p27 and the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin and RAS/Raf/MEK/ERK pathways [41]. Several genetic alterations, including B-type Raf kinase (BRAF) point mutations, RAS point mutation and RET/papillary thyroid cancer (PTC) translocations are involved in DTC molecular pathogenesis. The RAF proteins are cytoplasmic serine/threonine protein kinases and represent downstream effector molecules of RAS. The BRAF in the MAPK signaling pathway plays an important role in the development of different neoplasms, among them in thyroid cancer [42]. Point mutations resulting in BRAF activation independent of RAS are observed in up to 70% of PTC [42,43]. The BRAFV600E represents > 90% of BRAF mutations in thyroid cancer [44] and is associated with aggressive pathological features, RAI refractoriness and poor outcomes [45,46], however not in all studies [33]. Its activation,

Expert Opin. Pharmacother. (2014) 15(18)


Novel therapies for thyroid cancer

also found in anaplastic thyroid carcinoma [45], may suggest that some anaplastic cancers arise from PTC. RAS mutations and RET/PTC translocations, found in papillary and follicular thyroid carcinoma also result in aberrant signaling through BRAF [42,47]. Moreover, BRAFV600E is known to be associated with VEGF overexpression leading to tumor invasiveness [48]. RAS point mutations are found in 10 -- 20% of PTC, in 40 -50% of follicular thyroid cancer (FTC) and in 18 -- 27% of poorly DTCs [49]. Other genetic alterations, observed in molecular pathogenesis of thyroid cancer, include, among others mutations of PTEN, PIK3CA, TP53, CTNNB1, ALK and EGFR genes, gene amplifications and copy number gains (genes encoding receptor tyrosine kinases RTKs and genes encoding PI3K-AKT pathway), gene translocations (RETPTC, PAX8-PPARG) and aberrant gene methylation [50]. RET/PTC rearrangements are observed in 20 -- 40% of PTCs. They correlate to radiation exposure [47]. VEGF is one of the most important factors influencing neoangiogenesis, crucial for tumor growth and metastasis. In 1997, Soh et al. demonstrated higher VEGF expression in thyroid cancer cell lines than in normal thyroid [51]. The expression of VEGF was higher in thyroid carcinomas of follicular origin than in those arising from parafollicular cells. Moreover, the VEGF overexpression was similar, both in primary and metastatic thyroid tumors [51]. Various VEGF and their receptors are often overexpressed in thyroid cancer tissues [52-54]. There is a strong association between tumor size and high VEGF level [54], which is also a marker for aggressive PTC and metastatic spread [53]. In PTC, VEGF shows a positive correlation with higher risk of recurrence, shorter disease-free survival in animal xenografts and the presence of activating BRAF mutations [55]. 2.

Medullary thyroid cancer

This review starts with new therapies in MTC as these drugs were the first to be introduced into clinical practice. Vandetanib Vandetanib is an oral low molecular weight TKI that selectively blocks VEGFR2, EGFR and RET [56,57]. The activity against RET and VEGFR constitutes the rationale for the use of this drug in MTC. The effect on EGFR enhanced its anti-angiogenic activity, thanks to interference with EGFRinduced production of angiogenic growth factors [57]. Its efficacy in advanced MTC, both familiar and sporadic, was confirmed in clinical trials. Two Phase II studies were devoted to familiar MTC. The first one involved 30 patients with locally advanced or metastatic hereditary MTC (21 with MEN2A syndrome, 5 with FMTC and 4 with MEN2B syndrome), treated with vandetanib 300 mg/day [58]. Partial response (PR) by RECIST criteria was achieved in six (20%) patients. The median duration of response was 10.2 months (range 1.9 -- 16.9). Disease stabilization (stable disease [SD]) for > 24 weeks was observed in 16 patients. To sum up, disease 2.1

control rate was 73%. Six patients had SD for < 24 weeks. Progression as the best response was observed in one patient only and in three patients after initial partial regression [58]. Similar results in locally advanced or metastatic hereditary MTC were also reported by Robinson et al. [59]. Interestingly, 19 subjects (1 MEN2A, 1 MEN2B and 17 FMTC) treated under this study, received vandetanib in lower dose, 100 mg/day. PR and SD ‡ 24 weeks were observed in 3 (16%) and 10 (53%) patients, respectively. Disease control rate was 68%. Two patients (11%) showed SD longer than 8 weeks but shorter than 24 weeks and three patients showed (16%) progressive disease [59]. In 2012, the results of a Phase III trial (ZETA study) involving 331 patients with both sporadic and hereditary locally advanced or metastatic MTC were published [31]. Another key inclusion criterion was serum calcitonin level of at least 500 pg/ml. Important exclusion criteria included the presence of significant cardiac, liver, renal and hematopoietic disorders. The patients were randomly assigned in a 2:1 ratio to receive vandetanib 300 mg/day or placebo. Subjects treated with vandetanib had significantly longer progression-free survival (PFS) than those who were given placebo. The median PFS in the placebo group was 19.3 months, whereas it was 30.5 months in the vandetanib group. However, the median PFS value for the vandetanib group is the predicted one, as it had not been reached at the time of analysis. The efficacy of the drug was observed both in sporadic and hereditary MTC. Interestingly, in the subgroup with somatic M918T mutations, higher response rate was noticed than in the M918T-negative group. Significant advantages of treatment compared to the placebo group were also the secondary end points such as objective response rate, disease control rate as well as calcitonin and CEA biochemical response rate [31]. In 2013, Fox et al. reported the results of a Phase I/II trial evaluating safety and preliminary efficacy of vandetanib in children (6 patients, aged between 5 and 12 years) and adolescents (10 patients, aged between 13 and 16 years) treated due to MTC associated with MEN2B syndrome (15 patients) [60]. In all MEN2B subjects, decrease in tumor size was observed; in 7 patients it achieved PR criteria. However, two patients from this last subgroup demonstrated progressive disease after subsequent 44 and 48 cycles of treatment [60]. Cabozantinib Cabozantinib is a potent inhibitor of MET, VEGFR2 and RET and its mutationally activated forms associated with MTC as well as other receptor tyrosine kinases, such as KIT, AXL and FLT3. It demonstrates strong anti-angiogenic, antitumor and anti-invasive activities in different tumors, among them in MTC [61-63]. The preliminary data regarding the use of cabozantinib in MTC were published by Kurzrock et al. [64]. Advanced MTC was diagnosed in 37 out of 85 patients enrolled to a Phase I, dose-escalation study. Of the 35 MTC patients with measurable disease, 10 (29%) showed confirmed PR, 2.2


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7 additional patients showed unconfirmed response and 15 (41%) of 37 MTC subjects had SD, as the best response for ‡ 6 months. Median time to response was 49.5 days. Median duration of response was not reached at data cutoff; however, it ranged between 3.9 and > 35 months, with minimum 17 months of follow up. Of the 37 MTC patients, 16 (43%) were treated with another TKI before the study entry, among whom 12 received RET inhibitors (vandetanib, motesanib, sorafenib or AEE-788). Three of them, treated earlier with vandetanib or sorafenib, achieved PR. Tumor regression was observed in patients with and without RET mutation. Interestingly, PR or SD occurred in 12 of 15 MTC patients with a somatic M918T RET mutation, which is a negative prognostic factor [64]. The outcomes of the Phase I study stimulated the initiation of a randomized, placebo-controlled, Phase III trial (EXAM study), the results of which were published in 2013 [32]. The key inclusion criteria involved locally advanced or metastatic, measurable, MTC and the evidence of disease progression by RECIST within 14 months prior to study entry, confirmed by an independent reviewer. Main exclusion criteria included significant cardiac, hematopoietic, hepatic or renal disturbances. Earlier exposition to TKI was allowed. A total of 330 patients were randomly assigned in a 2:1 ratio to cabozantinib or placebo group. Patients received 140 mg/day of active drug or placebo in 28-day cycles. Crossover was not permitted. About 86% of patients were diagnosed with sporadic MTC. About 48.2% of tumors were RET-mutation positive (with predominant M918T RET mutation), 12% were RET-mutation negative, whereas in the remaining 39% RET mutation status was unknown. Median time of follow- up was 13.9 months (range 3.6 -- 32.5). PFS was significantly longer in patients treated with cabozantinib than in placebo group, 11.2 versus 4.0 months respectively. The proportions of patients alive and progression-free after 1 year, estimated by Kaplan--Meier, were 47.3% for the cabozantinib arm and 7.2% for placebo group. Prolongation of PFS was also noticed in the following classes: with bone metastases at baseline, with and without prior TKI therapy, both with hereditary and sporadic MTC. The difference between the cabozantinib and the placebo groups in OS was not clinically significant. However, the interim analysis included only 96 (44%) of 271 patient deaths required for the final analysis. The mean baseline calcitonin values were 6370 and 8846 pg/ml in cabozantinib and placebo arm, respectively. After 12 weeks of treatment, the calcitonin values significantly decreased by 45.2% in the cabozantinib group and increased by 57.3% in the placebo group [32]. The requirement of confirmed MTC progression at study entry was the most important difference between the EXAM [32] and ZETA trials [31], where progression was not an inclusion criterion. Thus, the direct comparison of the outcomes of both trials is not possible. Moreover, it is noteworthy, that patients treated under EXAM study had a really aggressive MTC, which was proven by a very short median 2644

PFS in placebo group -- 4.0 months only, whereas, the median PFS in placebo arm under ZETA trial was 19.3 months. 3.

Differentiated thyroid cancer

Sorafenib Sorafenib is an oral multi-TKI targeting BRAF (both wildtype and BRAFV600E), VEGFR1, VEGFR2, VEGFR3, platelet-derived growth factor receptor-b (PDGFR-b) and RET (also RET/PTC) [65,66]. Sorafenib affects both DTC cell proliferation and angiogenesis, which justifies its use in DTC treatment. In 2008, the results of the first Phase II study assessing the efficacy of sorafenib in advanced thyroid cancer were published [20]. The study involved 30 patients with metastatic, RAI-refractory thyroid carcinoma receiving sorafenib at a dose 400 mg twice a day (b.i.d.), including 18 patients with PTC, 9 with FTC, 1 with MTC and 2 with poorly differentiated/anaplastic thyroid cancer (ATC). All patients had measurable disease and demonstrated disease progression within a year before treatment. Prior systemic therapy including TKI was allowed, however not RAF, MEK, EGFR inhibitors. Median treatment duration was 27 weeks. PR by RECIST was achieved in 11 (23%) patients, whereas SD was achieved in 16 (53%) patients. However, patients with poorly differentiated and ATC had progressive disease as the best response. Median PFS was 84 weeks and no significant differences between PTC and FTC were noticed. Serum thyroglobulin level, evaluated in 17 of 19 DTC subjects, showed a marked decrease of 70% within 4 months from the beginning of therapy [20]. Another Phase II study was published by Kloos et al. in 2009 [22]. A total of 52 DTC and 4 ATC patients with measurable disease were enrolled. Disease progression was not listed among the inclusion criteria. PR as the best treatment response was observed in 5 of 28 chemotherapy-naı¨ve PTC patients and in 1 of 8 PTC patients with previous chemotherapy. Durable SD > 6 months was demonstrated in 19 of 28 chemotherapy-naı¨ve PTC patients and in 6 of 8 PTC patients with previous chemotherapy. In total, SD was seen in 25 of 32 PTC patients, in 9 of 10 FTC patients and in 1 of 4 ATC subjects. Median PFS in PTC subjects with and without previous chemotherapy and in FTC patients were, respectively, 16, 10 and 4.5 months [22]. In 2009, the results of a single-arm, 26-week, prospective Phase II study, were reported [67]. A total of 31 patients with progressive, RAI-refractory DTC were treated with sorafenib, 400 mg bid. The primary end point was reinduction of RAI uptake at metastatic sites. The rationale for the use of sorafenib was based on the relationship between genetic alterations in RET, RAS, RAF cascade and loss of NIS expression. After 26 weeks of sorafenib administration, no changes in RAI uptake were observed; however, 19 (59%) patients demonstrated clinical benefit (8 PR and 11 SD). It is noteworthy that in the case of bone metastases the treatment response 3.1




was significantly worse than in patients without bone involvement (p = 0.004). Estimated median PFS was 58 weeks [67]. Similar efficacy of sorafenib in advanced thyroid cancer was observed in a British Phase II study [19]. A total of 34 subjects, 19 with DTC and 14 with MTC were given sorafenib at a dose of 400 mg b.i.d. A total of 28 patients had progressive disease by RECIST, whereas the 6 remaining subjects demonstrated biochemical progression (> 25% increase in serum markers within 12 months prior study entry). After a 6-month treatment period, 15% of patients experienced PR, whereas in 73% of patients SD was observed. The response rates for MTC and DTC patients at 6 months were 13 and 16% and at 12 months it were 25 and 18%, respectively, whereas biochemical response rates for all patients were 63, 57, 50 and 48% at 3, 6, 9 and 12 months, respectively [19]. The next was a retrospective analysis carried out in Spanish population [68]. A total of 34 patients (7 PTC, 9 FTC, 15 MTC and 3 ATC), with confirmed cancer progression within 12 months prior to study, were given sorafenib offlabel at a dose of 400 mg b.i.d. The response rate was 47% for MTC, 19% for DTC and 33% (one of three) for ATC, whereas median PFS were 13.5, 10.5 and 4.4 months, respectively [68]. In 2010 and 2012, two cases of DTC patients with brain metastases, successfully and safely treated with sorafenib, were reported [69,70]. In the first case, SD was achieved after 16 weeks on sorafenib. However, 2 months after drug withdrawal, due to administrative reasons, rapid disease progression was noticed [69]. In the second case, sorafenib administration led to PR in the brain and SD in lungs, despite the use of a lower dose, 200 mg b.i.d. This effect remained stable after 14 months from the start of treatment [70]. There were also a few attempts of the use of sorafenib in a pediatric DTC [71,72]. In the first case report [71], a 14-year-old girl with progressive, RAI-refractory DTC lung metastases was given sorafenib at starting dose of 200 mg b.i.d. that was decreased after 3 weeks to 200 mg/day due to treatment side effects. Significant improvement was achieved after about a 3-month treatment period. Nevertheless, the drug had to be withdrawn due to treatment-related toxicities, neutropenia G3 and G2 pruritic skin rash. Minimal regrowth was observed after drug withdrawal. Another sorafenib administration was also described as successful and led to clinical response [71]. In the second case, the drug was given to an 8-year-old boy with serious respiratory failure, secondary to multiple lung micrometastases, requiring mechanical ventilation. Initial dose of 200 mg/day was subsequently increased up to 400 mg/day. CT scan performed after 52-day treatment, compared to initial study, showed reduction in size of lung nodules. While taking sorafenib the patient underwent total thyroidectomy followed by neck lymphadenectomy and, after sorafenib withdrawal, RAI treatment was given. Post-therapeutic whole body scan revealed diffuse tracer uptake in lungs confirming lung metastases. The authors concluded that sorafenib could be considered for gap therapy

when RAI could not be administered in a timely manner [72]. In our opinion this statement is not justified. There is no evidence that short pretreatment with sorafenib, before RAI administration, may be beneficial for patient with RAI-avid pulmonary micrometastases. Moreover, there is also no evidence that recovering from respiratory failure was a consequence of sorafenib administration. A multicenter, double-blind, placebo-controlled, Phase III study (DECISION trial) [33] involving 417 adult patients with locally advanced or metastatic, RAI-refractory DTC, were randomly assigned on a 1:1 basis to sorafenib (n = 207) or placebo (n = 210). More than 75% showed positive tracer uptake at FDG-PET/CT. The other key inclusion criteria included confirmed progression of the disease by RECIST within 14 months before the study. Patients with cardiological, renal, thrombotic, liver disorders, uncontrolled hypertension and serious risk of bleeding were excluded from the study. Previous TKI therapy, thalidomide and chemotherapy were prohibited. The primary end point was PFS. Patients from the placebo arm were allowed to crossover to the open-label sorafenib arm at disease progression. Significant improvement in PFS was observed in the sorafenib arm compared to the placebo group; median PFS were 10.8 versus 5.8 months, respectively, with a 41% reduction in the risk of progression or death within double-blind phase. OS did not differ significantly between the groups. However, at the time of primary analysis, median OS had not been reached yet. Objective response rate (all PR) in the sorafenib group was 12.2%, whereas in the placebo arm it was 0.5%. The median duration of response in subjects with PR was 10.2 months. SD > 6 months was observed in 41.8% subjects treated with sorafenib and in 33.2% receiving placebo. Either BRAF or RAS mutation status was not predictive of sorafenib benefit for PFS. Moreover, they were also not independent factors influencing PFS in multivariate analysis both in the whole group and in only the PTC subgroup [33].

Lenvatinib Although not approved by medical agencies yet, lenvatinib should be mentioned in this paper, as the promising results of the Phase III, double-blind, placebo-controlled study, SELECT trial (NCT01321554), have been presented during the annual 2014 ASCO meeting in Chicago [34]. Lenvatinib (E7080) is an oral potent inhibitor of VEGFR2/KDR and VEGFR3. It also potently blocks VEGFR1/Flt-1, FGFR1, 2, 3, 4, PDGFR-b as well as the RET and KIT signaling network [73]. The study, published by Glen et al., demonstrated direct effect of lenvatinib on tumor cells that correlated with inhibition of FGFR-1 and PDGFR-b. Lenvatinib inhibited tumor cell migration and invasion. However, it did not significantly affect tumor cell proliferation [74]. Lenvatinib showed activity against RET gene fusion kinases by inhibiting RET gene fusion signaling in papillary thyroid carcinoma TPC-1 cell lines [75]. 3.2


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The key inclusion criteria involved subjects with advanced, histologically confirmed, RAI-refractory, measurable DTC and objective disease progression by RECIST within 12 months prior to the study entry. Previous one type of VEGF/VEGFR targeted treatment was accepted. More than one VEGF/VEGFR-targeted therapies, urine protein excretion > 1 g/24 h, significant cardiovascular impairment, bleeding or thrombotic disorders constituted the key exclusion criteria. The patients were randomized 2:1 to lenvatinib or placebo arm and were treated with a starting dose of 24 mg/day in 28-day cycles. The drug was continued until cancer progression, fulfilled RECIST criteria or unmanageable toxicity. On progression, patients receiving placebo were allowed to crossover to open-label lenvatinib. The primary end point was PFS, whereas the secondary end points were: overall response rate (complete response [CR] + PR), OS and safety. A total of 392 patients were randomized. Median treatment duration was 13.8 months in the active group and 3.9 months in placebo group. The group treated with lenvatinib demonstrated significantly longer PFS than placebo group, 18.3 versus 3.6 months, respectively. Median time to response in the lenvatinib group was 2.0 months. Median PFS in the lenvatinib group with prior TKI-targeted therapy and no prior TKI-targeted therapy was 15.1 versus 18.7 months, respectively. There were 4 (1,5%) CRs observed in lenvatinib arm only. A total of 71 (27.2%) patients treated with lenvatinib died compared to 47 (35.9%) from the placebo group [34]. The assumptions of the lenvatinib SELECT trial [34] are contrary to the sorafenib DECISION trial, where previous targeted therapy was prohibited [33]. It is probably the most important difference between these two trials involving similar patient populations. However, the direct comparison of both studies is rather difficult, also because of other minor differences -- progressive disease before the study entry required central confirmation within the SELECT trial, whereas in the DECISION study this assessment was based only on investigator’s opinion. The outcomes of the SELECT trial, demonstrate that lenvatinib may be effective not only as the first-line but also as the second-line targeted therapy in patients who failed after previous TKI administration. Dadu et al. assessed the role of salvage targeted therapy in DTC patients who failed firstline sorafenib [76]. Among 25 patients after unsuccessful sorafenib treatment, lenvatinib was given as second-line therapy in three subjects. In one patient, dramatic response was achieved (> 53% tumor reduction), whereas in two other patients lenvatinib led to SD [76]. Undoubtedly, these scarce data, although encouraging, require further confirmation. 4.

Treatment-related toxicity

Vandetanib Vandetanib-related adverse reactions reported by patients treated during Phase II and Phase III studies involve diarrhea 4.1

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56 -- 74%; nausea 25 -- 33%; skin toxicities: rash 25 -- 67%, acne 20 -- 27%; hypertension 25 -- 33%; headache 26 -47%; fatigue 23 -- 63% and appetite loss 21 -- 26% [30,31,58,59]. The most common side effects that fulfilled G3 or higher criteria according to Common Terminology Criteria for Adverse Events (CTCAE) and that were observed in patients receiving vandetanib during the ZETA trial were diarrhea in 11% of subjects, hypertension in 9%, QTc prolongation in 8%, fatigue in 6 %, decreased appetite in 4% and rash in 3%. A total of 12% of patients from the vandetanib arm and 3% from the placebo group discontinued treatment due to its poor tolerance. The adverse events (AEs) causing vandetanib withdrawal, observed in > 1% of patients, were asthenia (1.7%) and rash (1.3%). Nineteen patients (8%) demonstrated protocol-defined QTc prolongation. However, no episodes of ventricular tachycardia (torsade de pointes) were reported [31]. Vandetanib may constitute a safe treatment modality for children and adolescents with advanced MTC. The vast majority of AEs reported by children and adolescents treated under PhaseI/II study fulfilled G1 and G2 criteria. Common AEs, not requiring dose reduction were QTc prolongation, hypertension, diarrhea, rash and thyroid-stimulating hormone (TSH) increase [60]. QTc prolongation seems to be one of the most dangerous vandetanib-related side effects as it increases the risk of serious, life-threatening ventricular arrhythmias. In meta-analysis by Zang et al., the risk of all grade and high grade (‡ G3) QTc prolongation, in patients receiving vandetanib at a dose of 300 mg/day due to thyroid cancer, were 18.0 and 12.0%. These values are higher than noticed in non-thyroid cancer subjects, 16.4 and 3.7%, respectively [77]. There is also an abstract in PubMed showing that so far three cases of torsade de pointes and nine sudden deaths have been reported on vandetanib therapy [78]. No authors were listed, no affiliations given, so we have to be cautious reading it. However, we should be aware that such signals exist. Moreover, it is not clear, whether QTc prolongation occurs mainly at the beginning of therapy or increases with time of treatment. Cabozantinib The most frequent (> 20% of patients), treatment related side effects noticed in a Phase I study were: diarrhea, fatigue, appetite decrease, nausea, palmar-plantar erythrodysesthesia (PPE -- hand-foot skin reaction), rash, increased AST level, vomiting and mucosal inflammation. One event of pulmonary embolism, fulfilling G4 criteria, according to CTCAE, was observed [64]. Among the most common, all grades of cabozantinibrelated adverse reactions in the EXAM trial [32] that occurred in > 30% of patients were: diarrhea 63%, PPE 50%, weight loss 47.7%, decreased appetite 45.8%, nausea 43.0%, fatigue 40.7%, dysgeusia 34.1%, hair color changes 33.6%, hypertension 32.7%. Grade 3 or 4 AEs occurred in 69% of subjects from the cabozantinib group and in 33% from the placebo 4.2




group. Laboratory abnormalities included increased ASP, ALT, alkaline phosphate, hyperbilirubinemia, hypocalcemia, hypokalemia, hypomagnesemia, lymphopenia, neutropenia and thrombocytopenia. Dose reduction and dose interruptions were necessary in 79 and 65% of patients from the cabozantinib arm, whereas in the placebo group, these were necessary in 9 and 17% of subjects, respectively. The drug was withdrawn in 16% of patients treated with cabozantinib and in 8% receiving placebo [32]. Similar cabozantinib toxicity profile was observed in other clinical trials conducted in different malignancies [63].

Sorafenib In the Phase III study [33], AEs were observed in 98.6% of patients from the sorafenib arm and in 87.6% from the placebo group. Most of them were G1 and G2. The most common sorafenib-related side effects, affecting > 30% of subjects, were PPE (76.3%), diarrhea (68.8%), alopecia (67.1%), rash (50.2%), fatigue (49.8%), weight loss (46.9%), hypertension (40.6%) and anorexia (31.9%). Among G3 events, mainly PPE and hypertension were observed, 20.3 and 9.7%, respectively. Serious AEs occurred in 37.2% of subjects from the sorafenib group and in 26.3% from the placebo arm. In the sorafenib arm, 4.3% of them were secondary malignancy, 3.4% dyspnea and 2.9% pleural effusion. The initial dose of sorafenib was 800 mg/day, whereas the mean daily dose was 651 mg. Dose interruptions, reductions and withdrawals in the sorafenib arm were necessary in 66.2, 64.3 and 18.8%, respectively. The most common sorafenib-related side effects reported across the studies were skin toxicities: PPE in 56 -- 87% of patients, rash in 44 -- 74% and alopecia in 43 -- 100%, gastrointestinal toxicities: diarrhea 44 -- 79%, nausea 26 -- 53%, stomatitis 11 -- 47%, abdominal pain 35 -- 89%, constitutional: fatigue 33 -- 74%, weight loss 44 -- 89%, anorexia 17 -- 38%, musculoskeletal pain 22 -- 58%, hypertension 30 -- 43% and infection 6 -- 44%. Dose reductions occurred 0 -- 79%. Sorafenib had to be withdrawn due to treatment-related toxicities in 0 -- 20% [19-22,67,68,79,80]. Sorafenib may constitute a safe therapeutic option for patients with brain metastases as no neurological deterioration was reported in published case reports [69,70]. The use of sorafenib might also be considered in pediatric patients. However, available data are scarce. Anyway, strict monitoring is necessary and lower doses due to its toxicity may be considered. The most frequent AE related to sorafenib, reported in numerous studies is PPE (hand-foot skin reaction), its intensity varies from mild erythema to severe hyperesthesia accompanied by skin desquamation. The exact pathomechanism of this reaction remains still unclear; however, there are some possible explanations. First, direct toxicity related to high drug concentration in eccrine glands is considered. Second, the inhibition of VEGF and PDGFR is believed to play an important role as it leads to impairment in cell growth and 4.3

repair in these areas particularly exposed to pressure and friction [81]. Lenvatinib The most common AEs related to lenvatinib reported in Phase II and Phase III studies were hypertension, diarrhea, weight loss, appetite decrease, fatigue and proteinuria [34,82,83]. Among DTC patients treated with lenvatinib under the SELECT trial [34], 68% of subjects developed treatmentrelated hypertension, 59% demonstrated elevated protein urinary excretion (proteinuria), 50% had decreased appetite, 46% experienced weight loss and 41% demonstrated nausea. The dose was reduced in 78.5% of patients and 14.2% discontinued treatment because of poor drug tolerance [34]. 4.4

Common adverse reactions related to VEGFR inhibitors

5.

Many of the abovementioned TKI-related side effects are caused by VEGF inhibition. VEGF is crucial for tumor angiogenesis, essential for tumor growth and metastases development [84]. Simultaneously, VEGF exerts physiological effects in embryonic development as well as in adults in survival in blood pressure regulation and function of normal blood vessels, liver, kidney and nervous system. [85]. Therefore, VEGF inhibition, besides its benefits in anticancer therapy, must result in disturbances related to blocking of physiological VEGF action such as hypertension, proteinuria, impaired wound healing, gastrointestinal perforation, hemorrhage and thrombosis, congestive heart failure (CHF) and thyroid dysfunction [86-92]. However, two recently meta-analyses did not confirm the impact of VEGFR-inhibitors on gastrointestinal perforation and venous thrombotic events [87,89]. Proteinuria represents dose-related TKI toxicity. The inhibition of the VEGF signaling pathway results in downexpression or suppression of nephrin, important for the maintenance of glomerular split diaphragm. Thus, it may result in serious glomerular damage up to nephritic syndrome and/or glomerular thrombotic microangiopathy [90]. The intensity of proteinuria varies between different TKIs. According to a meta-analysis, published by Zhang et al., total risk of all-grade proteinuria was 11.6%, 20.2% for sorafenib, 10% for pazopanib and 7% for vandetanib [86], whereas, in case of lenvatinib, elevated urine protein excretion (all-grade) was present in 39 -- 58% in treated subjects [34,82,83]. Increasing incidence of CHF was reported with reference to different TKIs [88]. In a meta-analysis, involving 10,553 patients from 36 clinical trials, overall incidence of all-grade and high-grade CHF was 3.2 and 1.4%, respectively, regardless of tumor type and drug administered [88]. In 2013, a case of fatal toxic cardiomyopathy that developed after 14 months of vandetanib therapy was reported [93]. Its relationship to vandetanib was confirmed by an autopsy demonstrating pathological changes similar to those observed in TKI-treated rats [93]. Another case of fatal heart failure was observed in a


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patient treated with combination of two TKIs for 26 months -- imatinib due to chronic myeloid leukemia and sorafenib due to RAI-refractory DTC [94]. Therefore, a strict monitoring of cardiac function in patients given TKI is necessary, as the increased risk of long-term cardiovascular mortality in DTC patients has been recently demonstrated [95]. Serum TSH increase belongs to common AEs related to TKI [92,96,97]. It was previously believed to be related with VEGFR inhibition and the atrophy of the thyroid gland. However, recently four proposed pathomechanisms are considered: disturbances in thyroid integrity and hormone biosynthesis, thyroid hormone transport, thyroid hormone metabolism and impact on pituitary gland [98]. Abdulrahman et al. demonstrated that sorafenib-induced hypothyroidism was related to increased type 3 deiodination [99]. Braun et al. showed that TKI inhibited MCT8-dependent T3 and T4 uptake leading to partial inhibition of pituitary and hypothalamic thyroid hormone feedback [100]. Diarrhea is an AE noticed in most patients treated with TKI due to thyroid cancer. The precise reason remains unclear. One probable pathomechanism is poor bioavailability leading to potentially toxic drug intestinal concentration responsible for local irritation of intestinal mucosa and transient lactose intolerance. The other reason may be related to a direct effect on gut receptors expressed on interstitial cells of Cajal, adjacent to nerve fibers of the myenteric plexus which regulate smooth muscle contractions [101]. 6.

Conclusion

TKIs are now widely expanding in oncology and new drugs have started to be investigated in the therapy for DTC and MTC. Vandetanib and cabozantinib have been approved both by the FDA and EMA to treat advanced MTC and sorafenib has been approved by the FDA and EMA to treat advanced, RAI-refractory DTC. Lenvatinib and vandetanib are under Phase III studies in DTC. The time for the comparison of the efficacy of particular drugs and their toxicity is coming. The evidence-based medicine (EBM) guidelines are necessary to indicate what drug to use: more effective or less toxic and when to start the treatment. 7.

Expert opinion

This review is devoted to targeted therapies in thyroid cancer. The term ‘targeted therapy’ is doubly confusing. First, because it suggests untruthfully that these drugs are highly

2648

specific in action, whereas they are directed against multiple targets in normal cells. Thus, they demonstrate numerous side effects, which may sometimes be much more serious that those related to chemotherapy and disease itself. Therefore, the safety of treatment comes ahead, particularly in thyroid cancer, which may be an indolent disease not resulting in fatal outcome within the short time period, while, treatmentrelated adverse reactions might quickly lead to lethal consequences. On the other hand, the term ‘targeted therapy’ also suggests that molecular targets are crucial for the use of a particular drug in thyroid cancer. However, the proofs fulfilling EBM criteria are equivocal. The results published by Brose et al. are surprising [33]; they demonstrated, contrary to expectations, that the presence of BRAF mutation had no impact on effectiveness of BRAF-targeted therapy in thyroid cancer. This observation is in contrast to the previous experiences in oncology. Another important issue is the increase of serum TSH level observed in patients treated with TKI, also in thyroid cancer. Initially, a possible pathomechanism was explained by antiVEGFR effect and thyroid atrophy. However, is seemed unlikely that patients with thyroid cancer routinely underwent total thyroidectomy and usually took a more or less fixed L-thyroxin dose. Only in 2012 this phenomenon was explained by Braun et al. [100] who demonstrated that abnormality observed in thyroid function tests were secondary to inhibition of MCT8-dependent T3 and T4 uptake in pituitary. So far, no direct comparison of both treatment outcomes and treatment-related toxicity between particular drugs has been carried out. So, the new guidelines, meeting EBM criteria are necessary to precisely indicate which drug should be recommended: more effective or less toxic and when to start the treatment. That is the aim for the near future.

Declaration of interest J Krajewska has participated on the advisory board for Bayer, B Jarzab has participated on their advisory board for AstraZeneca and Sobi and has received honoraria from Sanofi, Novartis, Ipsen, Pfizer, Bayer, Roche, Eisai, Oxigene and Exelixis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.



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Affiliation

Jolanta Krajewska1 & Barbara Jarzab†2 MD PhD † Author for correspondence 1 M.Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Nuclear Medicine and Endocrine Oncology Department, Gliwice, Poland 2 Professor, M.Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Nuclear Medicine and Endocrine Oncology Department, Wybrzeze AK 15 44-101 Gliwice, Poland Tel: + 48 32 2789301; Fax: +48 32 2789310; E-mail: [email protected]

Stem cell biology in thyroid cancer: Insights for novel therapies.

New therapies for dedifferentiated papillary thyroid cancer.

Molecular Targeted Therapies of Aggressive Thyroid Cancer.

Targeted therapies in advanced differentiated thyroid cancer.

Novel Therapies in Development for Metastatic Colorectal Cancer.

Exploiting DNA repair defects for novel cancer therapies.

Novel targeted therapies for the treatment of penile cancer.

Novel therapies in small cell lung cancer.

MicroRNAs: emerging novel targets of cancer therapies.

Novel CD9-targeted therapies in gastric cancer.

Personalizing therapies for gastric cancer: molecular mechanisms and novel targeted therapies.

Novel Therapies for Heart Failure.

Novel therapies for multiple myeloma.

Epigenetic Modifications: Novel Therapeutic Approach for Thyroid Cancer.

Autophagy, a novel target for chemotherapeutic intervention of thyroid cancer.

Overview and management of dermatologic events associated with targeted therapies for medullary thyroid cancer.

Novel therapies for diabetic kidney disease.

A review of novel therapies for melanoma.

Novel therapies for treating familial hypercholesterolemia.

Emerging Novel Therapies for Heart Failure.

Novel adjuvant therapies for pancreatic adenocarcinoma.

Novel therapies for T1D on the horizon.

Novel biologic therapies for thymic epithelial tumors.

Novel investigational therapies for atopic dermatitis.