Targeted therapies in advanced differentiated thyroid cancer

Cancer Treatment Reviews xxx (2015) xxx–xxx

Contents lists available at ScienceDirect

Cancer Treatment Reviews journal homepage: www.elsevierhealth.com/journals/ctrv

Anti-Tumour Treatment

Targeted therapies in advanced differentiated thyroid cancer Raquel M. Carneiro a,c,d,⇑,1, Benedito A. Carneiro a,b,d,2, Mark Agulnik b,d,3, Peter A. Kopp c,d,4, Francis J. Giles a,b,d,5 a

Northwestern Medicine Developmental Therapeutics Institute, Northwestern University, United States Division of Hematology and Oncology, Feinberg School of Medicine, Northwestern University, United States c Division of Endocrinology, Metabolism, and Molecular Medicine, Feinberg School of Medicine, Northwestern University, United States d Robert H. Lurie Comprehensive Cancer Center of Northwestern University, United States b

a r t i c l e

i n f o

Article history: Received 10 March 2015 Received in revised form 9 June 2015 Accepted 10 June 2015 Available online xxxx Keywords: Thyroid cancer Tyrosine kinase inhibitors Differentiated thyroid cancer Follicular thyroid carcinoma Targeted therapy

a b s t r a c t Differentiated thyroid cancer is the most common endocrine malignancy, and its incidence has been rising rapidly over the past 10 years. Although most patients with this disease have an excellent prognosis, a subset develops a more aggressive disease phenotype refractory to conventional therapies. Until recently, there was no effective therapy for these patients. With increasing knowledge of the molecular pathogenesis of thyroid cancer, novel targeted therapies are being developed for this group of patients. Sorafenib and lenvatinib, small-molecule multikinase inhibitors, were approved for the treatment of progressive, symptomatic, radioactive iodine refractory, advanced differentiated thyroid cancer in 2013 and 2015, respectively. This represents a major innovation in the therapy of patients with advanced thyroid cancer. However, these therapies still have many limitations and further research needs to be pursued with the ultimate goal of providing safe and effective personalized therapy for patients with advanced thyroid cancer. Ó 2015 Elsevier Ltd. All rights reserved.

Introduction Thyroid cancer is the most common endocrine malignancy with incidence rates increasing rapidly over the past 10 years [1]. According to the Surveillance Epidemiology and End Results (SEER) database, rates for new thyroid cancer cases have risen on average 5% per year [2]. While this rapid increase has been attributed to increased detection of early microcarcinomas (<1 cm in size) in times of more accessible high-resolution imaging techniques, the increase in the incidence of tumor of all sizes suggests other potential causes [3]. Nevertheless, the incidence of advanced ⇑ Corresponding author at: Northwestern Medicine Developmental Therapeutics Institute, 645 N Michigan Ave. Suite 1006, Chicago, IL 60611, United States. Tel.: +1 312 926 3892; fax: +1 312 695 0370. E-mail addresses: [email protected] (R.M. Carneiro), benedito. [email protected] (B.A. Carneiro), [email protected] (M. Agulnik), [email protected] (P.A. Kopp), [email protected] (F.J. Giles). 1 Present address: Rush University Medical Center, Division of Endocrinology and Metabolism, 1725 W. Harrison St. Suite 250, Chicago, IL 60612, United States. 2 Address: 645 N Michigan Ave. Suite 1006, Chicago, IL 60611, United States. Tel.: +1 312 926 3892; fax: +1 312 695 0370. 3 Address: 676 N. Saint Clair St, Suite 850, Chicago, IL 60611, United States. 4 Address: Tarry Building Room 15-709, 300 E Superior, Chicago, IL 60611, United States. 5 Address: 645 N Michigan Ave. Suite 1006, Chicago, IL 60611, United States.

thyroid cancer has also increased, and death rates from thyroid cancer have been rising on average 0.9% each year [2]. Thyroid cancer is a heterogeneous disease arising from two different epithelial cell types. Most thyroid cancers are derived from the follicular cells, including papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC), Hürthle cell carcinoma, and anaplastic thyroid carcinoma (ATC). Medullary thyroid carcinoma (MTC) is derived from the parafollicular calcitonin-producing cells. PTC and FTC are pooled together into the denomination of differentiated thyroid cancer (DTC). Those are by far the most common subtypes of thyroid cancer, accounting for 90–95% of all cases. They are generally slow-growing tumors, and have an excellent overall prognosis with overall 20-year survival rates greater than 90% with conventional therapy [4]. However, a subset of patients with DTC presents a more aggressive disease course and develops recurrent or metastatic disease that is refractory to radioactive iodine therapy. Among these patients, 10-year survival rates decline to approximately 15–20% [5]. Conventional therapies for DTC vary depending on staging of initial diagnosis, but they include surgical resection with or without thyroid remnant ablation with radioactive iodine and thyroid hormone suppression therapy [6]. While this approach has been effective in most patients with DTC, there is a clear unmet need for efficacious therapeutic options for the growing subset of

http://dx.doi.org/10.1016/j.ctrv.2015.06.002 0305-7372/Ó 2015 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Carneiro RM et al. Targeted therapies in advanced differentiated thyroid cancer. Cancer Treat Rev (2015), http:// dx.doi.org/10.1016/j.ctrv.2015.06.002

2

R.M. Carneiro et al. / Cancer Treatment Reviews xxx (2015) xxx–xxx

patients with advanced disease refractory to radioiodine therapy [2]. Exciting new discoveries in the pathogenesis of thyroid cancer, specifically the molecular genetic pathways involved in thyroid tumorigenesis, have led to the development of novel targeted therapies for patients with advanced thyroid cancer. The tyrosine kinase inhibitors (TKIs) vandetanib and cabozantinib were approved for the treatment of medullary thyroid cancer in 2011 and 2012, respectively. More recently, the FDA approved the TKIs sorafenib and lenvatinib for the treatment of advanced iodine-refractory DTC in 2013 and 2015. These advances represent groundbreaking progress in the management of patients with advanced thyroid cancer and have fostered the development of other targeted therapies with the ultimate goal of improving the outcomes for this disease based on a personalized approach to treatment of patients with thyroid cancer. Gaps of knowledge are yet to be filled regarding efficacy, safety, and specific roles of these new therapies. This review will focus on recent molecular discoveries and promising targeted therapies currently being developed. Conventional treatment approach for DTC Thyroid cancer is commonly diagnosed during routine physical examination. Patients are usually asymptomatic at presentation and will have either a palpable thyroid nodule or a nodule incidentally found on imaging exam. Most patients with differentiated thyroid cancer will be cured with surgery alone or a combination of surgery, radioactive iodine therapy, and suppression therapy with thyroid hormone. The goal of surgery is to remove the tumor and any disease extending beyond the thyroid gland, typically through a total thyroidectomy and, if indicated, central and lateral neck dissection. Post-operatively, radioiodine (I-131) may be administered for ablation of normal remnant thyroid tissue, adjuvant therapy of micrometastases, or treatment of apparent residual or metastatic thyroid cancer. Upon uptake by follicular thyroid cells, I-131 induces cell-death by emission of short path-length beta rays. Patients with iodine-avid disease may continue to receive repeated courses of I-131. The ability of the thyroid follicular cell to concentrate iodine may eventually become impaired in advanced dedifferentiated thyroid cancer, which may render radioiodine treatment ineffective. Finally, as part of conventional therapy, thyroid hormone suppression therapy is recommended for patients with intermediate and high-risk thyroid cancer, since thyroid simulating hormone (TSH) may contribute to growth of residual or metastatic thyroid cancer [6]. Until recently, patients with advanced, radioactive iodine refractory progressive disease had limited and ineffective treatment options. The only systemic therapy approved by the FDA for these patients was doxorubicin [7]. However, this therapy alone or in combination with other cytotoxic agents such as cisplatin has very limited efficacy and is associated with serious adverse events including cardiac and hematologic toxicities [8,9]. Therefore, there has been an enormous unmet need for treatment of this disease.

cellular proliferation and survival signaling networks. Somatic mutations, including point mutations and chromosomal rearrangements have been described as key determinants of early thyroid cancer development [10,11]. Many of these mutations lead to constitutive activation of two major signaling pathways that regulate cell growth, proliferation, and differentiation: mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase/v-akt murine thymoma viral oncogene homolog 1/mammalian target of rapamycin (PI3K/AKT/mTOR). Thyroid cancer progression appears to result from accumulation of these genetic alterations and corresponding abnormal activation of the signaling pathways. The Cancer Genome Atlas (TCGA) project provided a detailed description of the molecular alterations in 496 cases of papillary thyroid carcinoma with significant impact in the understanding of pathogenesis, and it revealed novel potential therapeutic targets [12]. The study showed that PTC has a lower mutational burden (0.4 mutations/Mb) compared to other epithelial cancers (i.e. melanoma, lung cancer and bladder cancers), but potential driver genetic alterations were identified in approximately 97% of tumors, substantially reducing the previously described ‘‘dark matter’’ from 25% to 3% [13]. The results demonstrated two molecularly driven groups of PTC characterized as BRAF- and RAS-driven tumors with distinct histologic phenotypes and pathway activation patterns. BRAF-driven tumors were frequently undifferentiated with predominant signaling through the MAPK pathway. RAS-driven tumors were well differentiated, associated with follicular histology and displayed activation of both MAPK and PI3K pathways. Additional findings included, among others, novel mutations in the CHEK2, ATM, TERT genes, translocations involving BRAF, ALK and FGFR2, and alterations in DNA repair and chromatin remodeling genes. The landmark nature of these results is reflected by the remarks suggesting a novel classification of thyroid cancers based on the genomic aberrations identified and they provide a solid foundation to advance the treatment of this disease. Angiogenesis Vascular endothelial growth factor (VEGF) stimulates endothelial cell proliferation and is key to tumor angiogenesis and growth [14]. VEGF has shown to have an important role in thyroid cancer development [15,16]. Expression of VEGF is increased in thyroid cancer and its expression level correlates with advanced disease [17–19]. Targeting VEGF or its receptor (VEGFR) may limit tumor induced angiogenesis, vascular supply to the tumor and halt tumor growth. The therapeutic benefits of this strategy have been proven in several solid tumors including non-small cell lung cancer, colon cancer, and renal cell carcinoma [20–23]. The VEGF pathway can be inhibited with monoclonal antibodies against VEGF (e.g. bevacizumab) or the extracellular domain of the VEGFR (e.g. ramucirumab), as well as by several small molecule tyrosine kinase inhibitors targeting VEGFR (e.g. sorafenib, lenvatinib, sunitinib, pazopanib, among others) [24]. The success of VEGF blockage in other diseases combined with the important role of VEGF in thyroid cancer pathogenesis have fostered the investigation of some of these compounds for treatment of advanced thyroid cancer. Ongoing studies and results will be discussed below.

New discoveries in the pathogenesis of thyroid cancer Somatic mutations: BRAF and RAS Over the past 20 years, new discoveries in the pathogenesis of thyroid cancer have given insight into better diagnostic, prognostic and therapeutic procedures for patients with thyroid cancer. Like for other types of cancer, understanding how cancer initiation and progression occur allows for specific interventions for early diagnosis and targeted therapies. Thyroid cancer development occurs when genetic and epigenetic alterations affect the mechanisms controlling cell cycle,

Point mutations are characterized by single nucleotide substitution within the DNA chain. The first and best characterized point mutation in thyroid cancer occurs in the BRAF (v-raf murine sarcoma viral oncogenes homolog B1) gene resulting in a valine to glutamate mutation at residue 600 (V600E) leading to constitutive activation of the BRAF kinase that confers continuous activation of the MAPK signaling pathway with consequent uncontrolled cell

Please cite this article in press as: Carneiro RM et al. Targeted therapies in advanced differentiated thyroid cancer. Cancer Treat Rev (2015), http:// dx.doi.org/10.1016/j.ctrv.2015.06.002

R.M. Carneiro et al. / Cancer Treatment Reviews xxx (2015) xxx–xxx

growth and proliferation [25]. The BRAF V600E mutation occurs in 45–59% of PTC, especially in classic papillary and tall cell variants [12]. In addition, the incidence rates of this mutation increase up to 80% among patients with recurrent or metastatic PTC [26]. It also occurs in 20–40% and 30–40% of poorly differentiated and anaplastic thyroid cancers, respectively [27–30]. The presence of BRAF V600E has been associated with several aggressive tumor features in papillary thyroid carcinoma, including extrathyroidal invasion, lymph node metastasis, advanced TNM stage at presentation, decreased response to radioiodine treatment, tumor persistence, tumor recurrence, and tumor-related mortality [26,31–35]. A recent retrospective analysis of 500 patients with PTC showed tumor recurrence rates of 25% among BRAF V600E mutation positive compared to 9.6% in mutation negative patients [36]. Nevertheless, the utility of BRAF mutations for risk stratification remains controversial. While this mutation occurs in 45% of patients with PTC, only 10–15% of these tumors evolve into a more aggressive phenotype [37]. Also, the TCGA results demonstrate a significant heterogeneity in gene expression pattern among tumors with BRAF V600E mutations pointing out the importance of taking into account other genetic alterations for accurate risk assessment [12]. In agreement with this concept, emerging evidence showing the cooperative nature of BRAF mutations with mutations in the promoter of the gene encoding telomerase reverse transcriptase (TERT 228C > T) offer a more refined strategy to genetic subtyping of thyroid cancers [36,38,39]. PTC harboring both BRAF and TERT mutations has a significantly worse prognosis compared to tumors with either single mutation. For instance, recurrence rates of PTC among patients with isolated BRAF mutation or TERT mutation were 16% and 19% compared to 68% in patients with both mutations [36]. The potential synergistic effect of these mutations remained significant even after adjustment for patient age, multifocality, tumor size, extrathyroidal and vascular invasion, and lymph node metastasis (HR 3.1; 95% CI 1.24–7.75). The prognostic importance of TERT promoter mutations was also demonstrated by the TCGA dataset [12]. These findings not only identified a novel subgroup of high-risk patients, but also exemplify the complexity and effects of co-existing deleterious mutations in thyroid cancer. Considering the interactions of these gene mutations will also be highly relevant for the development of novel treatments. Several BRAF tyrosine kinase inhibitors are either approved or undergoing investigation for treatment of patients with malignancies carrying BRAF mutations. Treatment of patients with BRAF-mutant metastatic melanoma with vemurafenib significantly improved overall survival [40]. Another BRAF inhibitor, dabrafenib, also improved PFS of patients with BRAF V600E-mutated metastatic melanoma in a phase III trial [41]. Both vemurafenib and dabrafenib have been approved for the treatment of BRAF V600E mutation positive metastatic melanoma. The initial excitement with these drugs was tempered by the rapid development of resistance in average 7 months after initiating treatment [40]. The knowledge that resistance was mediated by the reactivation of the MAPK pathway provided the rationale for combining inhibitors of BRAF (dabrafenib) and MEK (trametinib) for metastatic melanoma leading to significant improvements of progression-free survival (PFS) and tumor response rates [42]. In fact, the FDA approved this combination for the treatment of metastatic melanoma in 2014. However, BRAF inhibitors alone have shown limited efficacy in thyroid cancer cell lines [43]. This appears to be secondary to a rebound in ERK and increased HER3 signaling in thyroid cells [43,44]. Nevertheless, three patients with BRAF-mutated PTC treated with vemurafenib in a phase I study obtained clinical benefit (1 patient had a partial response and 2 patients had stable disease lasting 11–13 months) [45]. Based on the proven strategy in melanoma, the combination of BRAF and MEK pathway inhibitors

3

(dabrafenib and trametinib) may lead to better response rates, and is currently being investigated in a phase II trial of patients with recurrent thyroid cancer (NCT01723202). Following mutations in BRAF, the second most frequent driver mutations occur in the RAS genes. There are three isoforms of RAS: HRAS, KRAS and NRAS. The most common mutations in thyroid cancer occur in the NRAS and HRAS genes and lead to constitutive activation of both the MAPK and PI3K/AKT pathways [12,46,47]. RAS mutations are found in 40–50% of follicular carcinomas, 10– 20% of follicular variant-papillary carcinomas, and 20–40% of poorly differentiated and anaplastic carcinomas [48–55]. RAS mutations are also detected in 20–40% of benign follicular adenomas, which may suggest that RAS-positive adenomas represent precursor lesions for follicular or follicular variant-papillary thyroid carcinomas [49,50,52]. Chromosomal rearrangements: RET/PTC and PAX8/PPARc Chromosomal rearrangements are a result of breakage and fusion of segments within a chromosome or amongst different chromosomes. There are several chromosomal rearrangements described in thyroid cancer [12]. The two most common are RET/PTC (papillary thyroid cancer) and PAX8/PPARc (paired box 8-peroxisome proliferator activated receptor-c). In RET/PTC, a segment of the RET gene is fused to a different pair gene, resulting in constitutive activation of the MAPK and PI3K/AKT pathways [56,57]. There are several types of RET/PTC translocations. The two most prevalent are RET/PTC1 and RET/PTC3. Clonal RET/PTC rearrangement occurs in 10–20% of papillary thyroid carcinomas [58,59]. Highly sensitive methods have also detected RET/PTC in 10–45% of thyroid adenomas and other benign nodules [60–66]. RET/PTC rearrangements are commonly found in patients exposed to either accidental or therapeutic radiation of the neck area [67– 69]. In the PAX8/PPARc rearrangement, there is a fusion of a segment of the PAX8 gene with the gene encoding the nuclear hormone receptor PPARc. PAX8/PPARc inhibits the tumor suppressor PPARc and activates genes responsive to PAX8 [70]. This rearrangement occurs in 30–35% of follicular thyroid carcinomas, 1–5% follicular-variant papillary carcinomas, and 2–13% of follicular adenomas [71–75]. There are reports that this rearrangement is present in up to 60% of follicular thyroid cancer and follicular variant-papillary thyroid cancer, and some reports have suggested a potential therapeutic role for PPARc agonists (i.e., thiazolidinediones) in thyroid cancer [73,76–78]. In fact, an ongoing phase 2 trial is investigating the efficacy of pioglitazone in follicular or follicular variant of papillary thyroid cancers harboring the PAX8/PPARc translocation (NCT01655719). Additional rearrangements identified recently by the TCGA project carry potential therapeutic implications. Translocations involving the ALK gene such as EML4/ALK were identified in 4 cases raising the possibility that tyrosine kinase inhibitors of ALK (anaplastic lymphoma kinase) such as crizotinib might be effective. Crizotinib is currently approved for treatment of lung adenocarcinoma carrying this rearrangement. Four novel RET translocations and fusions involving BRAF, FGFR, MET and LTK were also described [12]. Novel therapies for advanced differentiated thyroid cancer The new discoveries elucidating the molecular pathogenesis of thyroid cancer have opened ground for the development of numerous targeted therapies. Inhibition of the abnormally activated pathways in thyroid cancer by specific small-molecule target inhibitors may lead to tumor regression or stabilization. In addition,

Please cite this article in press as: Carneiro RM et al. Targeted therapies in advanced differentiated thyroid cancer. Cancer Treat Rev (2015), http:// dx.doi.org/10.1016/j.ctrv.2015.06.002

4

R.M. Carneiro et al. / Cancer Treatment Reviews xxx (2015) xxx–xxx

inhibition of tumor angiogenesis alone has been shown to have anti-tumor effects in this setting. Among the new therapeutic approaches for these patients, the most promising compounds are the multikinase inhibitors, selective BRAF inhibitors, and mTOR inhibitors. Multikinase inhibitors Sorafenib is an oral serine-threonine TKI with multiple targets including BRAF, RET/PTC, VEGFR 1-3, PDGFR, and c-KIT. After numerous phase II trials revealed promising results for the use of sorafenib in advanced thyroid cancer, a multicenter, randomized, placebo-controlled, phase III trial was conducted [79–81]. In this study, 417 adult patients with progressive radioactive iodine-refractory locally advanced or metastatic differentiated thyroid cancer were assigned to sorafenib 400 mg twice daily or placebo. Progression determined by RECIST was required to have occurred within 14 months prior to enrollment. Radioactive iodine refractory was defined by the presence of at least one target lesion without iodine uptake; patients whose tumors progressed after radioiodine treatment; or received a cumulative radioiodine activity of 22.3 GBq (600 mCi) or greater. The results showed a significant improvement in median PFS of patients treated with sorafenib compared to placebo (10.8 vs 5.8 months; P < 0.0001). There was no difference in overall survival, but 71% of patients in the placebo group crossed over to the sorafenib arm upon disease progression. Disease control including partial responses and stable disease occurred in 54% of patients treated with sorafenib. Adverse events (AEs) occurred in almost all patients, but most were tolerable, grade 1 or 2. The most frequent AEs were dermatological – hand-foot syndrome (76%), alopecia (67%), and rash or desquamation (50%); gastrointestinal – diarrhea (68%); constitutional – fatigue (49%), weight loss (46%); and hypertension (40%). Serious AEs occurred in more than one third of patients, the most frequent being secondary malignancy (4.3%), dyspnea (3.4%), and pleural effusion (2.9%). Dose reduction or suspension were necessary in 66% and 18% of patients receiving sorafenib. This landmark trial led to approval of sorafenib by the FDA in November 2013 for the treatment of advanced, radioactive iodine-refractory thyroid cancer and represented an important advance for the treatment of this disease. However, it is notable that 33% of patients in the placebo group had stable disease for P6 months compared to 41% in the sorafenib group, which highlights that the rate of progression is variable among these patients and the critical need for stringent criteria to initiate treatment that carry significant toxicity risk. Lenvatinib is another TKI targeting VEGFR1-3, FGFR1-4, PDGFR-b, RET, and c-KIT. Phase II trials in advanced thyroid cancer documented response rates of up to 50% and provided the rationale for a subsequent randomized, placebo-controlled phase III trial [82–84]. A total of 392 patients with radioactive iodine resistant progressive DTC (i.e., documentation of progression within the previous 13 months according to RECIST) were randomized to lenvatinib (n = 261) or placebo (n = 131). A significant improvement in the median PFS was documented among patients treated with lenvatinib compared to placebo (18.3 months vs. 3.6 months; hazard ration 0.21; 99% CI, 0.14–0.31; P < 0.001). The PFS benefit was evident among all prespecified subgroups including patients previously treated with another TKI (20–25% of patients), distinct histologic subtypes (i.e. papillary, poorly differentiated, follicular, and Hürthle cell), and it was independent of BRAF and RAS mutational status of the tumor. In addition, a significant response rate of 64.8% was documented among patients taking lenvatinib compared to 1.5% in the placebo group, and it included complete responses in 4 patients and prolonged stable disease (longer than 23 weeks) in 39 patients (29.8%). Grade 3 or higher adverse events

related to lenvatinib occurred in 75% of patients and led to dose reductions in 67%, dose interruption in 82%, and discontinuation of treatment in 14% of patients receiving lenvatinib. Most frequent grade 3 or higher treatment-related AEs were hypertension (42%), proteinuria (10%), arterial and venous thromboembolic effects (2.7% and 3.8%, respectively), acute renal failure (1.9%), QT prolongation (1.5%) and hepatic failure (0.4%). Clinically significant diarrhea and decreased appetite required dose modifications in 22% and 18% of patients. Of note, six deaths in the lenvatinib group were considered treatment-related: 3 cases resulted from unspecified causes and 3 were associated with pulmonary embolism, hemorrhagic stroke, and health deterioration. The median overall survival was not reached and no significant overall survival benefit was demonstrated with lenvatinib thus far (hazard ratio 0.73; 95% CI 0.5–1.0; P = 0.10). As of November 2013, 130 patients were still receiving blinded treatment. Despite the considerable adverse event profile, the clinically meaningful benefit in PFS and tumor response rate in this disease setting supported the FDA approval of lenvatinib in February 2015. Sunitinib is a multitargeted TKI of VEGFR, PDGFR, c-KIT, FLT3, and RET/PTC. In a phase II trial, sunitinib was given to 33 patients with radioiodine-refractory advanced differentiated or medullary thyroid cancer. Partial response to therapy was seen in 28% of patients and stable disease in 46% of patients with DTC. The most common adverse events included fatigue, neutropenia, hand-foot syndrome, diarrhea, and leukopenia [85] (See Table 1). Axitinib is an oral multitargeted TKI that modulates VEGFR1-3, and PDGFR, and c-KIT. A phase II clinical trial evaluated the efficacy and safety of axitinib (5 mg twice daily) among 60 patients with advanced radioiodine-refractory thyroid cancer [86]. Objective responses and stable disease were documented in 30% and 38% of the patients, respectively. Median PFS was 18.1 months. Adverse events occurred in most patients and included fatigue (50%), diarrhea (48%), nausea (33%), anorexia (30%), hypertension (28%), stomatitis (25%), weight loss (25%), and headache (22%). Dose reduction or discontinuation was necessary in 38% and 13% respectively due to adverse events. Grade 3 adverse events occurred in 32% of patients, the most common being hypertension. Four patients experienced grade 4 adverse events including stroke, reversible posterior leukoencephalopathy, and proteinuria. Axitinib is FDA approved for the treatment of renal cell carcinoma. Pazopanib is also a TKI with multiple targets such as VEGFR1-3, PDGFR-a and -b, and c-KIT. The efficacy of pazopanib was investigated among 39 patients with previously treated advanced radioiodine-refractory thyroid cancer in a phase II trial [87]. A partial response occurred in 49% of patients. The PFS at one year was 47%. A dose reduction was needed in 43% patients to control adverse events, which included fatigue, hair and skin hypopigmentation, alopecia, diarrhea, nausea, vomiting, anorexia, weight loss, hypertension, elevated liver function tests, proteinuria, and hematologic cytopenias. Serious adverse events were uncommon and included lower gastrointestinal hemorrhage (grade 3), and intracranial hemorrhage (grade 4). Two deaths were potentially related to the study drug. One patient with pre-existing coronary artery disease had a massive myocardial infarction. The second patient had acute cholecystitis requiring surgery, which was complicated by bowel perforation. Pazopanib is currently FDA approved for treatment of renal cell carcinoma and soft tissue sarcomas. Motesanib (a multitargeted TKI of VEGFR1-3, PDGFR, RET, and c-KIT) has been investigated in a multicenter, phase II trial where 93 patients with advanced, radioiodine-resistant differentiated thyroid cancer were treated [88]. Stable disease was documented in 67% of patients and a partial response was observed in 14%. The median PFS was 40 weeks. Adverse events were common

Please cite this article in press as: Carneiro RM et al. Targeted therapies in advanced differentiated thyroid cancer. Cancer Treat Rev (2015), http:// dx.doi.org/10.1016/j.ctrv.2015.06.002

R.M. Carneiro et al. / Cancer Treatment Reviews xxx (2015) xxx–xxx

5

Table 1 Targeted therapies of differentiated thyroid cancer in clinical development. Stage of clinical development

Histology types

PFS (months)

Partial response rate (%)

Adverse events

Phase III

PTC, FTC, poorly differentiated

10.8

12.2

Lenvatinib

Phase III

PTC, FTC, poorly-differentiated

18.3

64.8

Axitinib

Phase II

PTC, FTC, MTC, anaplastic, other

18.1

30

Pazopanib

Phase II

PTC, FTC

11.7

49

Motesanib Vandetanib## Sunitinib

Phase II Phase II Phase II

PTC, FTC, other differentiated PTC, FTC, poorly differentiated PTC, FTC, MTC

14 8 28

Selumetinib Vemurafenib

Phase II Phase II

PTC PTC

10 11 Not reported 8 16.6

Hand-foot syndrome, alopecia, rash, desquamation, diarrhea, fatigue, weight loss, hypertension Hypertension, diarrhea, fatigue, decreased appetite, nausea, vomiting, weight loss Fatigue, diarrhea, nausea, anorexia, hypertension, stomatitis, weight loss, headache Fatigue, hair and skin hypopigmentation, alopecia, diarrhea, nausea, vomiting, anorexia, weight loss, hypertension Diarrhea, hypertension, fatigue, weight loss QTc prolongation, diarrhea, asthenia, fatigue Fatigue, neutropenia, hand-foot syndrome, diarrhea, leukopenia

Cabozantinib

Phase I

PTC, FTC

53

Everolimus

Phase II

PTC, FTC, MTC, anaplastic, poorly differentiated

Not reached 16

Rash, fatigue, diarrhea, peripheral edema Rash, fatigue, weight loss, dysgeusia, anemia, increased creatinine, liver function test abnormalities Diarrhea, hypertension, decreased appetite, weight loss, fatigue

5

Mucositis, anorexia, ALT/AST elevation

Therapy

Sorafenib# #

3 26–35*

PTC: papillary thyroid cancer; FTC: follicular thyroid cancer; MTC: medullary thyroid cancer. # FDA approved for metastatic differentiates thyroid cancer. ## FDA approved for medullary thyroid cancer. * 35% in TKI treatment-naïve patients and 26% in pts previously treated with TKI.

(94%) and included diarrhea (59%), hypertension (56%), fatigue (46%), and weight loss (40%). Grade 3 adverse events were seen in 55% of patients. Five patients had grade 4 adverse events that included hypocalcemia, hyperuricemia, hypokalemia, cerebral hemorrhage, confusion, agitation, and oliguria. There were two treatment-related deaths, both due to pulmonary hemorrhage. Vandetanib is a TKI with multiple targets including RET, VEGFR, and EGFR. The FDA approved it for the treatment of advanced medullary thyroid cancer based on the significant results of a phase III trial [89]. Vandetanib has also been evaluated in a phase II clinical trial for patients with advanced radioiodine-resistance differentiated thyroid cancer [90]. In this trial, median PFS was 11.1 vs. 5.9 months in the vandetanib group compared to placebo. The most common grade 3 adverse events were QTc prolongation (14%), diarrhea (10%), asthenia (7%), and fatigue (5%). There were three treatment-related deaths due to pneumonia and hemorrhage from skin metastasis. Cabozantinib, another TKI targeting MET, VEGFR2 and RET kinases and currently approved for treatment of advanced medullary thyroid cancer, has also shown preliminary efficacy among 15 patients with radioiodine-refractory DTC in a phase I trial [91]. The patient population included papillary (7 patients), follicular (5), and Hürthle cell thyroid carcinomas with 10 patients previously treated with sorafenib. Partial response and stable disease were observed in 8 (53%) and 6 patients (40%), respectively. While 5 out 11 patients with prior VEGF inhibitor therapies achieved a partial response, all 3 patients without prior anti-VEGF treatment had a partial response. In agreement with prior results in prostate cancer, cabozantinib showed meaningful activity in osteoblastic bone lesions supporting the preclinical relevance of MET and VEGF in regulating osteoblast function [92]. Adverse events profile was consistent with prior studies with cabozantinib and included grade 3 diarrhea (20%), hypertension (13%), decreased appetite (13%), and fatigue (7%). One patient developed aspiration pneumonia and ultimately died from complications related to tracheoesophageal fistula that was considered a treatment-related death. The efficacy of cabozantinib is being further investigated in ongoing phase II trials involving both first line and second line treatment of radioiodine-refractory DTC (NCT02041260; NCT01811212).

Selective BRAF-inhibitors Most of the therapies listed above are inhibitors of angiogenesis. Sorafenib is an inhibitor of both angiogenesis (VEGFR) and BRAF. However, sorafenib has been described as a weak in vivo inhibitor of the BRAF kinase, and its effect is mostly attributed to inhibition of angiogenesis, as seen with other VEGFR tyrosine kinase inhibitors [93]. The role of targeting specific mutant oncogenes in advanced thyroid cancer continues to be investigated in studies with more selective BRAF inhibitors such as vemurafenib and dabrafenib. Vemurafenib, a selective RAF inhibitor, was tested in 3 patients in a phase I clinical trial [45]. One patient had partial response and the other two, stable disease. One common adverse event was cutaneous squamous cell carcinoma (SCC), which occurred in 2 patients. The development of cutaneous keratinocytic lesions, including SCC has been well described in patients taking BRAF inhibitors [94]. Vemurafenib has also been evaluated in a multicenter, phase 2 study in 51 patients with advanced, radioiodine-refractory, BRAF-mutated papillary thyroid cancer [95]. Patients who underwent previous TKI therapy were included in the study. The best overall response rate was 35% in the TKI treatment-naïve patients and 26% in the patients previously treated with TKIs. The median PFS was 16.6 months in TKI treatment-naïve patients and 6.8 months in patients previously treated with TKIs. Adverse events were common and included weight loss, dysgeusia, anemia, increased creatinine, liver function test abnormalities, rash, and fatigue [95]. A retrospective analysis of 17 patients with advanced, BRAF-mutated papillary thyroid cancer treated with vemurafenib documented overall response rate of 47% and median time to treatment failure of 13 months [96]. The selective BRAF inhibitor dabrafenib has also shown activity among 14 patients with advanced BRAF-mutated thyroid cancer [97]. Four patients had partial responses (29%), six patients had stable disease, and four of these patients achieved durable benefit and received dabrafenib for more than 2.5 years. The most frequent grade 1 adverse events included skin papillomas (57%), hyperkeratosis (36%), and alopecia (29%). Grade 3 or 4 treatment-related adverse events were increased lipase or amylase, fatigue, febrile neutropenia and cutaneous squamous cell carcinoma. These

Please cite this article in press as: Carneiro RM et al. Targeted therapies in advanced differentiated thyroid cancer. Cancer Treat Rev (2015), http:// dx.doi.org/10.1016/j.ctrv.2015.06.002

6

R.M. Carneiro et al. / Cancer Treatment Reviews xxx (2015) xxx–xxx

encouraging results are limited by the small number of patients. An ongoing phase II study randomizing patients with BRAF-mutated DTC to dabrafenib alone or dabrafenib plus trametinib (MEK inhibitor) will help elucidating the clinical efficacy of dabrafenib in this setting (NCT01723202). Mammalian target of rapamycin (mTOR) inhibitors Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, was evaluated in 31 patients with aggressive radioactive iodine refractory thyroid cancer in a phase 2 trial. The median PFS was 16 months. Stable disease was seen in 58% of patients at 6 months [98]. Another phase II study investigated the efficacy of everolimus among 40 patients with advanced thyroid cancer including various histologies (i.e. PTC, medullary, follicular, anaplastic, and poorly differentiated) and documented partial response in two patients (5%) and stable disease in 29 patients [99]. Activation of both mTORC1 and mTORC2 complexes have been documented in PTC and preclinical results suggest that dual mTORC inhibitors might be more effective in this disease compared to mTORC1 inhibitor such as everolimus and temsirolimus [100]. Redifferentiation agents Mortality in DTC sharply increases once a tumor becomes radioiodine-refractory [5]. Several trials have explored agents that may promote tumor redifferentiation, rendering them radioiodine-avid, and allowing additional I-131 therapy. These agents include retinoids, lithium, and rosiglitazone, all with non-clinically significant benefits [101–103]. In a recent pilot trial, the MAPK kinase (MEK) inhibitor selumetinib (75 mg twice daily orally) was given to 20 patients with advanced radioiodine-refractory DTC which resulted in very promising results [104]. Eight patients (40%) treated with selumetinib achieved significant redifferentiation as measured by dosimetry thresholds, and were given a therapeutic dose of I-131. All patients who received I-131 therapy had a decrease in tumor size, three had partial response and five stable disease. All patients were able to tolerate selumetinib. Adverse events were mild and included fatigue (80%), maculopapular rash (70%), grade 1 elevation of liver enzymes (70%), and acneiform rash (25%). In this trial, patients with NRAS-mutant tumors appeared to be particularly responsive to this therapy. Selumetinib 100 mg twice daily was also investigated for the treatment of 32 patients with radioiodine-refractory PTC in a multicenter phase II trial. One patient achieved partial response, 54% achieved stable disease and 28% had progressive disease [105]. The median PFS was 32 weeks. Most common adverse events included rash, fatigue, diarrhea, and peripheral edema. These results provided the proof-of-principle necessary to support the development of additional treatments aimed to reverse radioiodine refractoriness with concomitant anti-tumor effect. The presence of the BRAF V600E mutation is associated with a decreased expression of the sodium-iodide symporter (NIS) in thyroid cancer cell lines and BRAF inhibitors increased NIS expression in vivo [106–108]. These results provided the rationale to investigate whether dabrafenib could induce radioiodine uptake in BRAF-mutant papillary thyroid cancer refractory to radioiodine [109]. Ten patients with metastatic or unresectable BRAF-mutant papillary thyroid cancer without iodine-131 uptake on whole-body scan, and not previously treated with tyrosine kinase inhibitors or chemotherapy, received dabrafenib for 25 days before repeating a whole-body radioiodine scan [109]. Patients only continued dabrafenib until day 42 if radioiodine uptake was demonstrated. New radioiodine uptake was documented in 6 patients (60%) and 2 of these patients had a partial response on CT scan

6 months following radioiodine treatment. Only 5 of the study participants had evidence of disease progression within 14 months from enrollment. Reduction in lesions size was also seen in 3 of 4 patients who enrolled in the study while having stable disease. These results highlight the potential clinical relevance of redifferentiation agents for patients with both stable or progressive thyroid cancer and confirm the important role of the MAPK pathway in regulating iodine uptake.

Discussion Exciting new discoveries have been made in understanding the biology of differentiated thyroid cancer, and significant progress has occurred in developing novel and efficacious therapies for advanced radioactive iodine refractory disease. Sorafenib is the first therapy approved for advanced radioactive-refractory differentiated thyroid cancer since doxorubicin was approved in the mid-seventies. Many other small molecule TKIs are currently under investigation and have generated early promising efficacy and safety outcomes. One clear challenge is the presence of frequent and numerous adverse events associated with TKIs. Although most are mild to moderate and resolve with dose adjustment or discontinuation of therapy, some are more severe and potentially lethal. In addition, even milder adverse events may negatively impact quality of life of these patients, who otherwise may have relatively indolent and asymptomatic disease. In the phase III sorafenib trial, quality-of-life scores were slightly lower in the sorafenib arm compared to placebo. It is very important that careful selection of patients be done to assure that benefits will outweigh risks of therapy. Clear discussions with patients exploring their understanding of the natural history of their disease, potential toxicities in the context of their own preferences and performance status can be instrumental in the decision to initiate therapy. In addition, patients and physicians need to be carefully educated about the possible adverse events and their management. The experience from expert centers brings a positive balance to this equation through development of standardized approaches to using TKIs in patients with thyroid cancer and developing validated instruments to promptly recognize and treat adverse events. In fact, structured protocols for adverse event recognition and treatment have showed excellent outcomes [110,111]. The impact of targeted therapy in quality-of-life would be very helpful in guiding the decision to start therapy and needs to be carefully evaluated in future clinical trials [112]. Limited tumor responses documented with these novel therapies represent another shortcoming. Complete responses are rarely seen. Moreover, although PFS is clearly increased, overall survival benefit has not been demonstrated, perhaps due to cross over effects in placebo controlled trials. Targeting multiple pathways simultaneously may improve response rates as it has been shown in thyroid cancer cells. For example, simultaneous targeting of MAPK and PI3K/AKT pathways has shown synergistic response in cells harboring genetic abnormalities in both pathways [113]. Redifferentiation therapy is also very attractive in improving outcomes, since the combination of short-term TKI treatment followed by radioiodine therapy may induce radioiodine uptake while minimizing TKI-related adverse events. In this strategy, it is important to consider the adverse event profile of radioactive iodine therapy, and it may not be feasible in patients who have already received high cumulative doses of radioiodine. Another promising strategy to improve efficacy of therapy is to pursue a mutational profile-guided targeted therapy for each patient. Considering that aggressive thyroid cancer develops when multiple signaling pathways are involved, and new mutations are acquired as tumors progress, characterizing exactly which genetic

Please cite this article in press as: Carneiro RM et al. Targeted therapies in advanced differentiated thyroid cancer. Cancer Treat Rev (2015), http:// dx.doi.org/10.1016/j.ctrv.2015.06.002

R.M. Carneiro et al. / Cancer Treatment Reviews xxx (2015) xxx–xxx

alterations and pathways are involved in a specific patient may reveal additional therapeutic options [10,11]. For this purpose, individual testing of the mutational profile in patients would be necessary. Financial cost is of consideration, but this strategy is greatly limited by unknown relevance of some genetic alterations to disease pathogenesis and the lack of rigorous clinical validation of combinatorial and single agent targeted therapy strategies, a significant challenge given the relatively small number of patients with advanced thyroid cancer participating in clinical trials [114,115]. Finally, development of resistance has been consistently reported with targeted therapies. The BRAF-mutated metastatic melanomas treated with BRAF inhibitors would be a prototypical example. After excellent initial response in the majority of patients, resistance develops through various mechanisms including reactivation of the MAPK pathway and activation of the PI3K pathway [116,117]. Understanding the mechanisms of resistance has led to the further development of drugs that block these mechanisms and prolong effectiveness of the BRAF-inhibitors. Both vemurafenib and dabrafenib are currently being evaluated in clinical trials for patients with BRAF-mutated advanced thyroid cancer. Preliminary data with vemurafenib and dabrafenib in patients with BRAF-mutated advanced thyroid cancer show encouraging response rates of 35–47% and 29% that need to be confirmed in larger ongoing clinical trials [95–97]. Several pre-clinical and clinical trials are testing the combination of MEK and BRAF inhibitors as well as MEK or BRAF with PI3K, mTOR or AKT inhibitors with promising results [113,118–120]. The question on how to overcome resistance needs to be further explored. In conclusion, targeted therapies are now an option for a group of patients who previously had no clinically meaningful therapies available. Sorafenib and lenvatinib have been approved by the FDA, and many other small molecule TKIs are under investigation for treatment of advanced thyroid cancer. Recent American Thyroid Association (ATA) and National Comprehensive Cancer Network (NCCN) guidelines recommend that patients with progressive or symptomatic disease with radioiodine-refractory tumors pursue clinical trials or consider systemic therapy with small-molecule kinase inhibitors if a trial is not available [6]. Further research is necessary to provide a more personalized approach to each of these patients, with the ultimate goal of improving efficacy, while minimizing adverse events. Declaration of interest The authors state no conflict of interest. References [1] Pellegriti G, Frasca F, Regalbuto C, Squatrito S, Vigneri R. Worldwide increasing incidence of thyroid cancer: update on epidemiology and risk factors. J Cancer Epidemiol 2013;2013:965212. [2] Howlader NN, Noone AM, Krapcho M, Garshell J, Miller D, Altekruse SF, et al., editors. SEER Cancer Statistics Review, 1975–2011. Bethesda, MD: National Cancer Institute; 2014. , based on November 2013 SEER data submission, posted to the SEER web site, April 2014. [3] Chen AY, Jemal A, Ward EM. Increasing incidence of differentiated thyroid cancer in the United States, 1988–2005. Cancer 2009;115:3801–7. [4] Brenner H. Long-term survival rates of cancer patients achieved by the end of the 20th century: a period analysis. Lancet 2002;360:1131–5. [5] Durante C, Haddy N, Baudin E, Leboulleux S, Hartl D, Travagli JP, et al. Longterm outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy. J Clin Endocrinol Metab 2006;91:2892–9. [6] Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2009;19: 1167–214. [7] Gottlieb JA, Hill Jr CS. Chemotherapy of thyroid cancer with adriamycin. Experience with 30 patients. N Engl J Med 1974;290:193–7.

7

[8] Sarlis NJ. Metastatic thyroid cancer unresponsive to conventional therapies: novel management approaches through translational clinical research. Curr Drug Targets Immune Endocr Metabol Disord 2001;1:103–15. [9] Shimaoka K, Schoenfeld DA, DeWys WD, Creech RH, DeConti R. A randomized trial of doxorubicin versus doxorubicin plus cisplatin in patients with advanced thyroid carcinoma. Cancer 1985;56:2155–60. [10] Nikiforov YE, Nikiforova MN. Molecular genetics and diagnosis of thyroid cancer. Nat Rev Endocrinol 2011;7:569–80. [11] Xing M. Molecular pathogenesis and mechanisms of thyroid cancer. Nat Rev Cancer 2013;13:184–99. [12] The Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary thyroid carcinoma. Cell 2014;159:676–90. [13] Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A, et al. Mutational heterogeneity in cancer and the search for new cancerassociated genes. Nature 2013;499:214–8. [14] Kerbel RS. Tumor angiogenesis. N Engl J Med 2008;358:2039–49. [15] Klein M, Picard E, Vignaud JM, Marie B, Bresler L, Toussaint B, et al. Vascular endothelial growth factor gene and protein: strong expression in thyroiditis and thyroid carcinoma. J Endocrinol 1999;161:41–9. [16] Bunone G, Vigneri P, Mariani L, Buto S, Collini P, Pilotti S, et al. Expression of angiogenesis stimulators and inhibitors in human thyroid tumors and correlation with clinical pathological features. Am J Pathol 1999;155: 1967–76. [17] Yu XM, Lo CY, Chan WF, Lam KY, Leung P, Luk JM. Increased expression of vascular endothelial growth factor C in papillary thyroid carcinoma correlates with cervical lymph node metastases. Clin Cancer Res 2005;11: 8063–9. [18] Lennard CM, Patel A, Wilson J, Reinhardt B, Tuman C, Fenton C, et al. Intensity of vascular endothelial growth factor expression is associated with increased risk of recurrence and decreased disease-free survival in papillary thyroid cancer. Surgery 2001;129:552–8. [19] Klein M, Vignaud JM, Hennequin V, Toussaint B, Bresler L, Plenat F, et al. Increased expression of the vascular endothelial growth factor is a pejorative prognosis marker in papillary thyroid carcinoma. J Clin Endocrinol Metab 2001;86:656–8. [20] Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335–42. [21] Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. Paclitaxelcarboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006;355:2542–50. [22] Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007;356:125–34. [23] Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007;356:115–24. [24] Grothey A, Galanis E. Targeting angiogenesis: progress with anti-VEGF treatment with large molecules. Nat Rev Clin Oncol 2009;6:507–18. [25] Hou P, Liu D, Xing M. Functional characterization of the T1799–1801del and A1799–1816ins BRAF mutations in papillary thyroid cancer. Cell Cycle 2007;6:377–9. [26] Elisei R, Ugolini C, Viola D, Lupi C, Biagini A, Giannini R, et al. BRAF(V600E) mutation and outcome of patients with papillary thyroid carcinoma: a 15year median follow-up study. J Clin Endocrinol Metab 2008;93:3943–9. [27] Namba H, Nakashima M, Hayashi T, Hayashida N, Maeda S, Rogounovitch TI, et al. Clinical implication of hot spot BRAF mutation, V599E, in papillary thyroid cancers. J Clin Endocrinol Metab 2003;88:4393–7. [28] Nikiforova MN, Kimura ET, Gandhi M, Biddinger PW, Knauf JA, Basolo F, et al. BRAF mutations in thyroid tumors are restricted to papillary carcinomas and anaplastic or poorly differentiated carcinomas arising from papillary carcinomas. J Clin Endocrinol Metab 2003;88:5399–404. [29] Begum S, Rosenbaum E, Henrique R, Cohen Y, Sidransky D, Westra WH. BRAF mutations in anaplastic thyroid carcinoma: implications for tumor origin, diagnosis and treatment. Mod Pathol 2004;17:1359–63. [30] Ricarte-Filho JC, Ryder M, Chitale DA, Rivera M, Heguy A, Ladanyi M, et al. Mutational profile of advanced primary and metastatic radioactive iodinerefractory thyroid cancers reveals distinct pathogenetic roles for BRAF, PIK3CA, and AKT1. Cancer Res 2009;69:4885–93. [31] Xing M. BRAF mutation in papillary thyroid cancer: pathogenic role, molecular bases, and clinical implications. Endocr Rev 2007;28:742–62. [32] Kebebew E, Weng J, Bauer J, Ranvier G, Clark OH, Duh QY, et al. The prevalence and prognostic value of BRAF mutation in thyroid cancer. Ann Surg 2007;246:466–70. discussion 70–1. [33] O’Neill CJ, Bullock M, Chou A, Sidhu SB, Delbridge LW, Robinson BG, et al. BRAF(V600E) mutation is associated with an increased risk of nodal recurrence requiring reoperative surgery in patients with papillary thyroid cancer. Surgery 2010;148:1139–45. discussion 45–6. [34] Riesco-Eizaguirre G, Gutierrez-Martinez P, Garcia-Cabezas MA, Nistal M, Santisteban P. The oncogene BRAF V600E is associated with a high risk of recurrence and less differentiated papillary thyroid carcinoma due to the impairment of Na+/I- targeting to the membrane. Endocr Relat Cancer 2006;13:257–69. [35] Durante C, Puxeddu E, Ferretti E, Morisi R, Moretti S, Bruno R, et al. BRAF mutations in papillary thyroid carcinomas inhibit genes involved in iodine metabolism. J Clin Endocrinol Metab 2007;92:2840–3.

Please cite this article in press as: Carneiro RM et al. Targeted therapies in advanced differentiated thyroid cancer. Cancer Treat Rev (2015), http:// dx.doi.org/10.1016/j.ctrv.2015.06.002

8

R.M. Carneiro et al. / Cancer Treatment Reviews xxx (2015) xxx–xxx

[36] Xing M, Liu R, Liu X, Murugan AK, Zhu G, Zeiger MA, et al. BRAF V600E and TERT promoter mutations cooperatively identify the most aggressive papillary thyroid cancer with highest recurrence. J Clin Oncol 2014;32:2718–26. [37] Soares P, Sobrinho-Simoes M. Cancer: small papillary thyroid cancers–is BRAF of prognostic value? Nat Rev Endocrinol 2011;7:9–10. [38] Liu X, Qu S, Liu R, Sheng C, Shi X, Zhu G, et al. TERT promoter mutations and their association with BRAF V600E mutation and aggressive clinicopathological characteristics of thyroid cancer. J Clin Endocrinol Metab 2014;99. E1130-6. [39] Melo M, da Rocha AG, Vinagre J, Batista R, Peixoto J, Tavares C, et al. TERT promoter mutations are a major indicator of poor outcome in differentiated thyroid carcinomas. J Clin Endocrinol Metab 2014;99. E754-65. [40] McArthur GA, Chapman PB, Robert C, Larkin J, Haanen JB, Dummer R, et al. Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol 2014;15:323–32. [41] Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, openlabel, phase 3 randomised controlled trial. Lancet 2012;380:358–65. [42] Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 2012;367:1694–703. [43] Montero-Conde C, Ruiz-Llorente S, Dominguez JM, Knauf JA, Viale A, Sherman EJ, et al. Relief of feedback inhibition of HER3 transcription by RAF and MEK inhibitors attenuates their antitumor effects in BRAF-mutant thyroid carcinomas. Cancer Discov 2013;3:520–33. [44] Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364:2507–16. [45] Kim KB, Cabanillas ME, Lazar AJ, Williams MD, Sanders DL, Ilagan JL, et al. Clinical responses to vemurafenib in patients with metastatic papillary thyroid cancer harboring BRAF(V600E) mutation. Thyroid 2013;23:1277–83. [46] Abubaker J, Jehan Z, Bavi P, Sultana M, Al-Harbi S, Ibrahim M, et al. Clinicopathological analysis of papillary thyroid cancer with PIK3CA alterations in a Middle Eastern population. J Clin Endocrinol Metab 2008;93:611–8. [47] Liu Z, Hou P, Ji M, Guan H, Studeman K, Jensen K, et al. Highly prevalent genetic alterations in receptor tyrosine kinases and phosphatidylinositol 3kinase/akt and mitogen-activated protein kinase pathways in anaplastic and follicular thyroid cancers. J Clin Endocrinol Metab 2008;93:3106–16. [48] Suarez HG, du Villard JA, Severino M, Caillou B, Schlumberger M, Tubiana M, et al. Presence of mutations in all three ras genes in human thyroid tumors. Oncogene 1990;5:565–70. [49] Esapa CT, Johnson SJ, Kendall-Taylor P, Lennard TW, Harris PE. Prevalence of Ras mutations in thyroid neoplasia. Clin Endocrinol (Oxf) 1999;50:529–35. [50] Motoi N, Sakamoto A, Yamochi T, Horiuchi H, Motoi T, Machinami R. Role of ras mutation in the progression of thyroid carcinoma of follicular epithelial origin. Pathol Res Pract 2000;196:1–7. [51] Manenti G, Pilotti S, Re FC, Della Porta G, Pierotti MA. Selective activation of ras oncogenes in follicular and undifferentiated thyroid carcinomas. Eur J Cancer 1994;30A:987–93. [52] Namba H, Rubin SA, Fagin JA. Point mutations of ras oncogenes are an early event in thyroid tumorigenesis. Mol Endocrinol 1990;4:1474–9. [53] Karga H, Lee JK, Vickery Jr AL, Thor A, Gaz RD, Jameson JL. Ras oncogene mutations in benign and malignant thyroid neoplasms. J Clin Endocrinol Metab 1991;73:832–6. [54] Ezzat S, Zheng L, Kolenda J, Safarian A, Freeman JL, Asa SL. Prevalence of activating ras mutations in morphologically characterized thyroid nodules. Thyroid 1996;6:409–16. [55] Zhu Z, Gandhi M, Nikiforova MN, Fischer AH, Nikiforov YE. Molecular profile and clinical-pathologic features of the follicular variant of papillary thyroid carcinoma. An unusually high prevalence of ras mutations. Am J Clin Pathol 2003;120:71–7. [56] Castellone MD, De Falco V, Rao DM, Bellelli R, Muthu M, Basolo F, et al. The beta-catenin axis integrates multiple signals downstream from RET/papillary thyroid carcinoma leading to cell proliferation. Cancer Res 2009;69:1867–76. [57] Miyagi E, Braga-Basaria M, Hardy E, Vasko V, Burman KD, Jhiang S, et al. Chronic expression of RET/PTC 3 enhances basal and insulin-stimulated PI3 kinase/AKT signaling and increases IRS-2 expression in FRTL-5 thyroid cells. Mol Carcinog 2004;41:98–107. [58] Santoro M, Carlomagno F, Hay ID, Herrmann MA, Grieco M, Melillo R, et al. Ret oncogene activation in human thyroid neoplasms is restricted to the papillary cancer subtype. J Clin Invest 1992;89:1517–22. [59] Zhu Z, Ciampi R, Nikiforova MN, Gandhi M, Nikiforov YE. Prevalence of RET/ PTC rearrangements in thyroid papillary carcinomas: effects of the detection methods and genetic heterogeneity. J Clin Endocrinol Metab 2006;91:3603–10. [60] Ishizaka Y, Kobayashi S, Ushijima T, Hirohashi S, Sugimura T, Nagao M. Detection of retTPC/PTC transcripts in thyroid adenomas and adenomatous goiter by an RT-PCR method. Oncogene 1991;6:1667–72. [61] Wirtschafter A, Schmidt R, Rosen D, Kundu N, Santoro M, Fusco A, et al. Expression of the RET/PTC fusion gene as a marker for papillary carcinoma in Hashimoto’s thyroiditis. Laryngoscope 1997;107:95–100. [62] Sheils OM, O’Eary JJ, Uhlmann V, Lattich K, Sweeney EC. Ret/PTC-1 activation in Hashimoto Thyroiditis. Int J Surg Pathol 2000;8:185–9.

[63] Elisei R, Romei C, Vorontsova T, Cosci B, Veremeychik V, Kuchinskaya E, et al. RET/PTC rearrangements in thyroid nodules: studies in irradiated and not irradiated, malignant and benign thyroid lesions in children and adults. J Clin Endocrinol Metab 2001;86:3211–6. [64] Chiappetta G, Toti P, Cetta F, Giuliano A, Pentimalli F, Amendola I, et al. The RET/PTC oncogene is frequently activated in oncocytic thyroid tumors (Hurthle cell adenomas and carcinomas), but not in oncocytic hyperplastic lesions. J Clin Endocrinol Metab 2002;87:364–9. [65] Sapio MR, Guerra A, Marotta V, Campanile E, Formisano R, Deandrea M, et al. High growth rate of benign thyroid nodules bearing RET/PTC rearrangements. J Clin Endocrinol Metab 2011;96. E916-9. [66] Guerra A, Sapio MR, Marotta V, Campanile E, Moretti MI, Deandrea M, et al. Prevalence of RET/PTC rearrangement in benign and malignant thyroid nodules and its clinical application. Endocr J 2011;58:31–8. [67] Rabes HM, Demidchik EP, Sidorow JD, Lengfelder E, Beimfohr C, Hoelzel D, et al. Pattern of radiation-induced RET and NTRK1 rearrangements in 191 post-chernobyl papillary thyroid carcinomas: biological, phenotypic, and clinical implications. Clin Cancer Res 2000;6:1093–103. [68] Nikiforov YE, Rowland JM, Bove KE, Monforte-Munoz H, Fagin JA. Distinct pattern of ret oncogene rearrangements in morphological variants of radiation-induced and sporadic thyroid papillary carcinomas in children. Cancer Res 1997;57:1690–4. [69] Bounacer A, Wicker R, Caillou B, Cailleux AF, Sarasin A, Schlumberger M, et al. High prevalence of activating ret proto-oncogene rearrangements, in thyroid tumors from patients who had received external radiation. Oncogene 1997;15:1263–73. [70] Placzkowski KA, Reddi HV, Grebe SK, Eberhardt NL, McIver B. The role of the PAX8/PPARgamma fusion oncogene in thyroid cancer. PPAR Res 2008;2008:672829. [71] French CA, Alexander EK, Cibas ES, Nose V, Laguette J, Faquin W, et al. Genetic and biological subgroups of low-stage follicular thyroid cancer. Am J Pathol 2003;162:1053–60. [72] Nikiforova MN, Lynch RA, Biddinger PW, Alexander EK, Dorn 2nd GW, Tallini G, et al. RAS point mutations and PAX8-PPAR gamma rearrangement in thyroid tumors: evidence for distinct molecular pathways in thyroid follicular carcinoma. J Clin Endocrinol Metab 2003;88:2318–26. [73] Dwight T, Thoppe SR, Foukakis T, Lui WO, Wallin G, Hoog A, et al. Involvement of the PAX8/peroxisome proliferator-activated receptor gamma rearrangement in follicular thyroid tumors. J Clin Endocrinol Metab 2003;88:4440–5. [74] Nikiforova MN, Biddinger PW, Caudill CM, Kroll TG, Nikiforov YE. PAX8PPARgamma rearrangement in thyroid tumors: RT-PCR and immunohistochemical analyses. Am J Surg Pathol 2002;26:1016–23. [75] Marques AR, Espadinha C, Catarino AL, Moniz S, Pereira T, Sobrinho LG, et al. Expression of PAX8-PPAR gamma 1 rearrangements in both follicular thyroid carcinomas and adenomas. J Clin Endocrinol Metab 2002;87:3947–52. [76] Kroll TG, Sarraf P, Pecciarini L, Chen CJ, Mueller E, Spiegelman BM, et al. PAX8PPARgamma1 fusion oncogene in human thyroid carcinoma [Corrected]. Science 2000;289:1357–60. [77] Eberhardt NL, Grebe SK, McIver B, Reddi HV. The role of the PAX8/ PPARgamma fusion oncogene in the pathogenesis of follicular thyroid cancer. Mol Cell Endocrinol 2010;321:50–6. [78] Klopper JP, Hays WR, Sharma V, Baumbusch MA, Hershman JM, Haugen BR. Retinoid X receptor-gamma and peroxisome proliferator-activated receptorgamma expression predicts thyroid carcinoma cell response to retinoid and thiazolidinedione treatment. Mol Cancer Ther 2004;3:1011–20. [79] Schneider TC, Abdulrahman RM, Corssmit EP, Morreau H, Smit JW, Kapiteijn E. Long-term analysis of the efficacy and tolerability of sorafenib in advanced radio-iodine refractory differentiated thyroid carcinoma: final results of a phase II trial. Eur J Endocrinol 2012;167:643–50. [80] Ahmed M, Barbachano Y, Riddell A, Hickey J, Newbold KL, Viros A, et al. Analysis of the efficacy and toxicity of sorafenib in thyroid cancer: a phase II study in a UK based population. Eur J Endocrinol 2011;165:315–22. [81] Brose MS, Nutting CM, Jarzab B, Elisei R, Siena S, Bastholt L, et al. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet 2014;384:319–28. [82] Sherman SI, Jarzab B, Cabanillas ME, Licitra LF, Pacini F, Martins R, et al. A phase II trial of the multitargeted kinase inhibitor E7080 in advanced radioiodine (RAI)-refractory differentiated thyroid cancer (DTC). J Clin Oncol 2011;29. abstract 5503. [83] Schlumberger M, Jarzab B, Cabanillas ME, Robinson B, Pacini F, Ball DW, et al. A phase II trial of the multitargeted kinase inhibitor lenvatinib (E7080) in advanced medullary thyroid cancer (MTC). J Clin Oncol 2012;30. abstract 5591. [84] Schlumberger M, Tahara M, Wirth LJ, Robinson B, Brose MS, Elisei R, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med 2015;372:621–30. [85] Carr LL, Mankoff DA, Goulart BH, Eaton KD, Capell PT, Kell EM, et al. Phase II study of daily sunitinib in FDG-PET-positive, iodine-refractory differentiated thyroid cancer and metastatic medullary carcinoma of the thyroid with functional imaging correlation. Clin Cancer Res 2010;16:5260–8. [86] Cohen EE, Rosen LS, Vokes EE, Kies MS, Forastiere AA, Worden FP, et al. Axitinib is an active treatment for all histologic subtypes of advanced thyroid cancer: results from a phase II study. J Clin Oncol 2008;26:4708–13.

Please cite this article in press as: Carneiro RM et al. Targeted therapies in advanced differentiated thyroid cancer. Cancer Treat Rev (2015), http:// dx.doi.org/10.1016/j.ctrv.2015.06.002

R.M. Carneiro et al. / Cancer Treatment Reviews xxx (2015) xxx–xxx [87] Bible KC, Suman VJ, Molina JR, Smallridge RC, Maples WJ, Menefee ME, et al. Efficacy of pazopanib in progressive, radioiodine-refractory, metastatic differentiated thyroid cancers: results of a phase 2 consortium study. Lancet Oncol 2010;11:962–72. [88] Sherman SI, Wirth LJ, Droz JP, Hofmann M, Bastholt L, Martins RG, et al. Motesanib diphosphate in progressive differentiated thyroid cancer. N Engl J Med 2008;359:31–42. [89] Wells Jr SA, Robinson BG, Gagel RF, Dralle H, Fagin JA, Santoro M, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol 2012;30:134–41. [90] Leboulleux S, Bastholt L, Krause T, de la Fouchardiere C, Tennvall J, Awada A, et al. Vandetanib in locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 2 trial. Lancet Oncol 2012;13:897–905. [91] Cabanillas ME, Brose MS, Holland J, Ferguson KC, Sherman SI. A phase I study of cabozantinib (XL184) in patients with differentiated thyroid cancer. Thyroid 2014;24:1508–14. [92] Dai J, Zhang H, Karatsinides A, Keller JM, Kozloff KM, Aftab DT, et al. Cabozantinib inhibits prostate cancer growth and prevents tumor-induced bone lesions. Clin Cancer Res 2014;20:617–30. [93] Sherman SI. Advances in chemotherapy of differentiated epithelial and medullary thyroid cancers. J Clin Endocrinol Metab 2009;94:1493–9. [94] Robert C, Arnault JP, Mateus C. RAF inhibition and induction of cutaneous squamous cell carcinoma. Curr Opin Oncol 2011;23:177–82. [95] Brose MS, Cabanillas ME, Cohen EEW, Wirth L, Sherman SI, Riehl T, et al. An open-label, multi-center phase 2 study of the BRAF inhibitor vemurafenib in patients with metastatic or unresectable papillary thyroid cancer positive for the BRAF V600 mutation and resistant to radioactive iodine. Eur J Cancer 2013;49. abstract 28. [96] Dadu R, Shah K, Busaidy NL, Waguespack SG, Habra MA, Ying AK, et al. Efficacy and tolerability of vemurafenib in patients with BRAF(V600E)positive papillary thyroid cancer: M.D. Anderson Cancer Center off label experience. J Clin Endocrinol Metab 2015;100. E77-81. [97] Falchook GS, Millward M, Hong D, Naing A, Piha-Paul S, Waguespack SG, et al. BRAF inhibitor dabrafenib in patients with metastatic BRAF-mutant thyroid cancer. Thyroid 2015;25:71–7. [98] Lorch JH, Busaidy N, Ruan DT, Janne PA, Limaye SA, Wirth LJ, et al. A phase II study of everolimus in patients with aggressive RAI refractory (RAIR) thyroid cancer (TC). J Clin Oncol 2013;31. abstract 6023. [99] Lim SM, Chang H, Yoon MJ, Hong YK, Kim H, Chung WY, et al. A multicenter, phase II trial of everolimus in locally advanced or metastatic thyroid cancer of all histologic subtypes. Ann Oncol 2013;24:3089–94. [100] Ahmed M, Hussain AR, Bavi P, Ahmed SO, Al Sobhi SS, Al-Dayel F, et al. High prevalence of mTOR complex activity can be targeted using Torin2 in papillary thyroid carcinoma. Carcinogenesis 2014;35:1564–72. [101] Liu YY, van der Pluijm G, Karperien M, Stokkel MP, Pereira AM, Morreau J, et al. Lithium as adjuvant to radioiodine therapy in differentiated thyroid carcinoma: clinical and in vitro studies. Clin Endocrinol (Oxf) 2006;64:617–24. [102] Handkiewicz-Junak D, Roskosz J, Hasse-Lazar K, Szpak-Ulczok S, Puch Z, Kukulska A, et al. 13-cis-retinoic acid re-differentiation therapy and recombinant human thyrotropin-aided radioiodine treatment of nonFunctional metastatic thyroid cancer: a single-center, 53-patient phase 2 study. Thyroid Res 2009;2:8. [103] Kebebew E, Lindsay S, Clark OH, Woeber KA, Hawkins R, Greenspan FS. Results of rosiglitazone therapy in patients with thyroglobulin-positive and radioiodine-negative advanced differentiated thyroid cancer. Thyroid 2009;19:953–6. [104] Ho AL, Grewal RK, Leboeuf R, Sherman EJ, Pfister DG, Deandreis D, et al. Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. N Engl J Med 2013;368:623–32.

9

[105] Hayes DN, Lucas AS, Tanvetyanon T, Krzyzanowska MK, Chung CH, Murphy BA, et al. Phase II efficacy and pharmacogenomic study of Selumetinib (AZD6244; ARRY-142886) in iodine-131 refractory papillary thyroid carcinoma with or without follicular elements. Clin Cancer Res 2012;18:2056–65. [106] Knauf JA, Ma X, Smith EP, Zhang L, Mitsutake N, Liao XH, et al. Targeted expression of BRAFV600E in thyroid cells of transgenic mice results in papillary thyroid cancers that undergo dedifferentiation. Cancer Res 2005;65:4238–45. [107] Riesco-Eizaguirre G, Rodriguez I, De la Vieja A, Costamagna E, Carrasco N, Nistal M, et al. The BRAFV600E oncogene induces transforming growth factor beta secretion leading to sodium iodide symporter repression and increased malignancy in thyroid cancer. Cancer Res 2009;69:8317–25. [108] Chakravarty D, Santos E, Ryder M, Knauf JA, Liao XH, West BL, et al. Small-molecule MAPK inhibitors restore radioiodine incorporation in mouse thyroid cancers with conditional BRAF activation. J Clin Invest 2011;121: 4700–11. [109] Rothenberg SM, McFadden DG, Palmer EL, Daniels GH, Wirth LJ. Redifferentiation of iodine-refractory BRAF V600E-mutant metastatic papillary thyroid cancer with dabrafenib. Clin Cancer Res 2015;21:1028–35. [110] Carhill AA, Cabanillas ME, Jimenez C, Waguespack SG, Habra MA, Hu M, et al. The noninvestigational use of tyrosine kinase inhibitors in thyroid cancer: establishing a standard for patient safety and monitoring. J Clin Endocrinol Metab 2013;98:31–42. [111] Brose MS, Frenette CT, Keefe SM, Stein SM. Management of sorafenib-related adverse events: a clinician’s perspective. Semin Oncol 2014;41(Suppl 2). S1S16. [112] Schlumberger M, Jarzab B, Elisei R, Siena S, Bastholt L, de la Fouchardiere C, et al. Phase III randomized, double-blinded, placebo-controlled trial of sorafenib in locally advanced or metastatic patients with radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC) – exploratory analyses of patient-reported outcomes. Thyroid 2013;23. abstract 100. [113] Liu D, Xing J, Trink B, Xing M. BRAF mutation-selective inhibition of thyroid cancer cells by the novel MEK inhibitor RDEA119 and genetic-potentiated synergism with the mTOR inhibitor temsirolimus. Int J Cancer 2010;127:2965–73. [114] Von Hoff DD, Stephenson Jr JJ, Rosen P, Loesch DM, Borad MJ, Anthony S, et al. Pilot study using molecular profiling of patients’ tumors to find potential targets and select treatments for their refractory cancers. J Clin Oncol 2010;28:4877–83. [115] Roychowdhury S, Iyer MK, Robinson DR, Lonigro RJ, Wu YM, Cao X, et al. Personalized oncology through integrative high-throughput sequencing: a pilot study. Sci Transl Med 2011;3:111ra21. [116] Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 2010;363:809–19. [117] Van Allen EM, Wagle N, Sucker A, Treacy DJ, Johannessen CM, Goetz EM, et al. The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma. Cancer Discov 2014;4:94–109. [118] Liu D, Xing M. Potent inhibition of thyroid cancer cells by the MEK inhibitor PD0325901 and its potentiation by suppression of the PI3K and NF-kappaB pathways. Thyroid 2008;18:853–64. [119] Jin N, Jiang T, Rosen DM, Nelkin BD, Ball DW. Synergistic action of a RAF inhibitor and a dual PI3K/mTOR inhibitor in thyroid cancer. Clin Cancer Res 2011;17:6482–9. [120] Liu R, Liu D, Xing M. The Akt inhibitor MK2206 synergizes, but perifosine antagonizes, the BRAF(V600E) inhibitor PLX4032 and the MEK1/2 inhibitor AZD6244 in the inhibition of thyroid cancer cells. J Clin Endocrinol Metab 2012;97. E173-82.

Please cite this article in press as: Carneiro RM et al. Targeted therapies in advanced differentiated thyroid cancer. Cancer Treat Rev (2015), http:// dx.doi.org/10.1016/j.ctrv.2015.06.002