Emerging therapeutics for advanced thyroid malignancies: rationale and targeted approaches

INTRODUCTION: Thyroid cancer is an emerging public health concern. In the USA, its incidence has doubled in the past decade, making it the eighth most commonly diagnosed neoplasm in 2010. Despite this alarming increase, most thyroid cancer patients benefit from conventional approaches (surgery, radioiodine, radiotherapy, TSH suppression with levothyroxine) and are often cured. Nevertheless, a minority have aggressive tumors resistant to cytotoxic and other historical therapies; these patients sorely need new treatment options. AREAS COVERED: Herein the biology and molecular characteristics of the common histological types of thyroid cancer are reviewed to provide context for subsequent discussion of recent developments and emerging therapeutics for advanced thyroid cancers. EXPERT OPINION: Several kinase inhibitors, especially those targeting VEGFR and/or RET, have already demonstrated promising activity in differentiated and medullary thyroid cancers (DTC, MTC). Although of minimal benefit in DTC and MTC, cytotoxic chemotherapy with anti-microtubule agents and/or anthracyclines in combination with intensity-modulated radiation therapy appears to extend survival for patients with locoregionally confined anaplastic thyroid cancer (ATC), but to have only modest benefit in metastatic ATC. Further discovery and development of novel agents and combinations of agents will be critical to further progress in treating advanced thyroid cancers of all histotypes.     

Novel therapies for thyroid cancer

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 thyroid-stimulating 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.     

Advances in small molecule therapy for treating metastatic thyroid cancer

Introduction: Multi kinase inhibitors (MKIs) are new drugs, which show activity against receptors of different growth factors leading to the inhibition of tumor cells growth and proliferation. This review summarizes a 10-year experience with the use of MKIs in thyroid cancer (TC). It focuses not only on sorafenib, lenvatinib, vandetanib and cabozantinib, already approved in TC, but also presents an overview of the results of different trials with distinct MKIs so far carried out in TC.

Areas covered: Published results of phase I, II and III studies and other reports evaluated the efficacy of different targeted drugs in TC.

Expert opinion: Despite numerous clinical trials with distinct MKIs, only four of them unequivocally demonstrated a beneficial effect on progression free survival in radioiodine refractory differentiated or medullary TC. In contrast to other solid tumors, we are still lacking in convincing evidences of their impact on overall survival. We still do not have any strong proof fulfilling evidence-based medicine criteria, when to start MKIs and which drug to use. The questions whether we really have to wait for disease progression in patients with a large tumor burden and/or aggressive types TC or when to stop MKIs treatment remain open.     

Drug safety evaluation of lenvatinib for thyroid cancer

Introduction: Lenvatinib is an oral multitargeted tyrosine kinase inhibitor of VEGFR1,2,3,4, FGFR1,2,3,4, PDGFR-α as well as RET and KIT signaling network. Its activity against radioiodine-resistant differentiated thyroid cancer (DTC) has been recently demonstrated. Patients, who were given lenvatinib, showed significantly longer median progression free survival than placebo group, 18.3 vs 3.6 months, respectively. This review is focused on lenvatinib safety profile in patients treated due to DTC and medullary thyroid carcinoma. Among the most frequent lenvatinib-related adverse events (AEs) were hypertension, proteinuria, diarrhea, appetite decrease, weight loss, nausea and stomatitis. Although a lot of them were manageable, in 35–68% of patients dose reduction was required. Nevertheless, only 15% of subjects withdrew the drug due to its toxicity.Areas covered: published results of clinical trials phase II and III investigating both safety and efficacy of lenvatinib in thyroid cancer.Expert opinion: Lenvatinib shows acceptable safety profile in patients with thyroid carcinoma. Treatment-related side effects are usually manageable by dose modifications or by concomitant non-pharmacological and pharmacological treatment. However, the early recognition of any potential drug toxicity is crucial to avoid serious complications as well as to keep a patient on drug as long as the treatment is beneficial.     

The discovery and development of vandetanib for the treatment of thyroid cancer

Introduction: Thyroid cancer represents over 90% of all endocrine malignancies, with medullary thyroid carcinoma (MTC) accounting for 5 – 9% of them. Patients with early-stage disease have a favorable prognosis, but once distant metastasis develops, survival drops to 50% or less. Although surgery remains effective for early-stage disease, patients with advanced disease pose a challenge as traditional therapies have not provided long-term benefits. Vandetanib, initially developed to target other receptors, demonstrated anti-rearranged during transfection (anti-RET) kinase activity. This led to preclinical studies followed by recent human clinical trials, culminating in its FDA approval in April 2011 for application in the treatment of symptomatic or progressive MTC in patients with surgically unresectable, locally advanced or metastatic disease.

Areas covered: The authors provide a review of the discovery strategy and preclinical development of vandetanib. The authors also provide some insight into the clinical development and the drug's post-launch situation.

Expert opinion: Vandetanib has been shown to improve progression-free survival in MTC patients, but its impact on overall survival is still inconclusive. Further data analysis will be needed to answer the question of whether it impacts overall survival in MTC. Despite its advancements, vandetanib still lacks durable efficacy, carries moderate toxicity and has issues with drug resistance over time, not to mention issues of cost. There is a significant need for additional research to discover and develop improved therapeutic strategies for this difficult disease.     

Efficacy of lenvatinib in treating thyroid cancer

Introduction: Radioiodine [RAI]-resistant advanced and progressive differentiated thyroid cancer [DTC], although rare, constitutes a real challenge as its prognosis is poor and available therapeutic options, until now, have been limited. Discovery of a crucial role of distinct tyrosine kinases in DTC pathogenesis opened up new options in systemic treatment. Lenvatinib is an oral potent multi kinase inhibitor [MKI] of different growth factor receptors including VEGFR1/Flt-1, VEGFR2/KDR, VEGFR3, FGFR1,2,3,4, PDGFR-β as well as RET and KIT signaling networks. Its activity against RAI-refractory DTC was demonstrated in clinical studies fulfilling evidence-based medicine [EBM] criteria. The drug showed acceptable tolerance and manageable toxicity.

Areas covered: published results of phase II and III studies and other reports evaluated the efficacy and safety of lenvatinib in DTC and in medullary thyroid carcinoma.

Expert opinion: Currently there are two different MKIs, lenvatinib and sorafenib, which have demonstrated effectiveness against RAI-refractory DTC. However, to date, the question of which drug should be chosen for first line treatment remains open. The other question: when to start the treatment seems to be no less important. Whether disease progression, even by RECIST, is enough to initiate a therapy or tumor burden also plays an important role? EBM study, to resolve these issues, is our task for the nearest future.     

XL184 (cabozantinib) for medullary thyroid carcinoma

Introduction: Intrathyroidal medullary thyroid carcinoma (MTC) can generally be cured by surgery, but distant metastases are often already present at diagnosis. Currently, there is no effective treatment for metastatic MTC. In these cases, consensus treatment guidelines explicitly recommend new experimental drugs. Several kinase inhibitors are now being tested for treatment of MTC in clinical trials and XL184, an oral, small-molecule multi-kinase inhibitor, seems to be one of the most promising of these compounds.

Areas covered: We review preliminary data on the safety and efficacy of XL184 in metastatic MTC based on an extensive search of the literature, which included published articles, abstracts and website information. In particular, the review focuses on the rationale for using XL184 in advanced MTC. The compound has been specifically designed to target multiple signaling pathways, and this is expected to produce synergistic antitumor effects superior to those achieved by single-kinase inhibition. Preliminary results from the Phase I study of XL184 seem to support this hypothesis.

Expert opinion: Multiple receptor tyrosine kinases (RTKs) are concomitantly activated in the same tumor. The blockade of a single RTK may engage compensatory signaling that maintains cell growth. Targeting multiple kinases might overcome both intrinsic and acquired resistance to antitumoral drugs.     

Emerging drugs and therapeutics for systemic sclerosis

Introduction: Treatment of systemic sclerosis (SSc) is challenging despite advances in medical therapeutics for other rheumatologic diseases. Significant disease modifying therapy is lacking for most patients with SSc, due to the heterogeneous multisystem nature of SSc and its complex pathophysiology. The emergence of organ based management strategies has provided guidance in patient care as well as research and drug development.

Areas covered: Design and development of new compounds focused on the underlying fibrotic disease processes have been sparse. Therefore, organ based strategies with targeted approaches have been directed towards the most devastating and life threatening features of systemic sclerosis. These include pulmonary arterial hypertension, interstitial lung disease, peripheral vasculopathy and skin thickening. In this context, new treatment regimens using older drugs as well as discovery of novel compounds based on recent insights of the disease pathophysiology are discussed.

Expert opinion: Systemic sclerosis is a heterogeneous rare disease that carries a high burden of morbidity and mortality. Organ based management strategies have improved the natural history of systemic sclerosis using targeted interventions or strategies, particularly vascular features. However, more research is required to better understand disease mechanisms, including an ultimate unifying pathway that explains the multisystem nature of systemic sclerosis.     

Emerging therapies: angiogenesis inhibitors for ovarian cancer

Introduction: Patients with epithelial ovarian cancer (EOC) have a high rate of recurrence, and overall survival remains at ～ 25%. There is a need for new treatments that can increase progression free survival and quality of life. Recent clinical trials focus on angiogenesis, VEGFs, and tyrosine kinase inhibitors that play a role in recurrence, metastasis, and ascites in EOC.

Areas covered: This review summarizes clinical rationale, mechanisms of action, and clinical data for angiogenesis inhibitors under evaluation in Phase II and III trials for EOC. Anti-angiogenesis agents reviewed in this paper include aflibercept, bevacizumab, cediranib, fosbretabulin, imatinib, nintedanib, pazopanib, saracatinib, sorafenib, sunitinib, and trebananib.

Expert opinion: These agents have particular rationale for potential use in EOC due to the molecular changes associated with EOC tumorigenesis, namely a significant increase in angiogenic activity. Due to the costs and toxicities associated with anti-angiogenics, biomarker or molecular signature selection strategy for patients who will most benefit would be ideal but no such strategy has been validated to date.     

Neovascularization: an attractive but tricky target in thyroid cancer

Introduction: Neovascularization in carcinogenesis and tumor progression is well-established. Molecular mediators implicated in different modes of vascular remodeling and expansion (e.g. sprouting angiogenesis (SA), vasculogenesis, vascular mimicry) are evaluated as prognostic biomarkers and therapeutic targets in different malignant tumors. Significant progress has been made in the understanding of the complex interplay between thyroid cancer (TC) cells and the tumor microenvironment, thus unraveling the role of angiogenic mediators.

Areas covered: This review summarizes current research on neovascularization and TC. Current knowledge on vascular remodeling, in the context of carcinogenesis, is presented. Preclinical and clinical data from TC studies are also discussed.

Expert opinion: There is a remarkable effort to pharmacologically target several key molecules of vessel-forming cascades. Despite encouraging preclinical results, clinical outcomes in TC are not optimal, possibly reflecting knowledge gaps in the pathophysiology of neovascularization in thyroid tissue. Increasing amounts of data support the possibility that redundancy of pathways that regulate vascular network remodeling allows tumors to adapt in different conditions. Hypothesizing that alternative forms of neovascularization upregulate when SA is pharmacologically blocked, targeting two or more different pathways of neovascularization could be a promising future strategy. Further research is required to explore molecular mechanisms of neovascularization in TC.     

Sorafenib for the treatment of thyroid cancer: an updated review

Introduction: Sorafenib (Nexavar) is an oral multi-kinase inhibitor targeting B-type Raf kinase (BRAF) (both wild type and BRAF^V600E), VEGFR1, VEGFR2, VEGFR3, PDGFRβ and RET (also RET/PTC) influencing both differentiated thyroid cancer (DTC) cell proliferation and angiogenesis.

Areas covered: Encouraging results achieved in numerous Phase II trials were confirmed in a Phase III study conducted in radioiodine-refractory DTC. Sorafenib compared to placebo significantly prolongs progression-free survival, 10.8 versus 5.8 months, respectively. However, its administration resulted mainly in disease stabilization. No complete remission was obtained in any study. Beneficial effects were also demonstrated for medullary and anaplastic thyroid cancer; however further studies fulfilling evidence based medicine criteria are necessary. Its toxicity profile is convergent with other VEGFR inhibitors. The most common treatment-related side-effects involve skin toxicity (predominantly hand-foot skin reaction, different rashes and alopecia), gastrointestinal disturbances (diarrhea, abdominal pain), constitutional adverse reactions (anorexia, weight loss, fatigue) and hypertension. Although most adverse reactions are manageable, > 50% of patients required dose reduction.

Expert opinion: Sorafenib constitutes the first line treatment option in advanced, radioiodine-refractory DTC. However, there are still no data on its efficacy in patients progressed after another tyrosine kinase inhibitor. Other applications of the drug, such as use as adjuvant therapy to 131-I treatment, requires further studies.     

Emerging treatment for ALK-positive lung cancer

Introduction: Lung cancer is associated with poor prognosis and limited benefit from chemotherapy. The treatment of non-small cell lung cancer (NSCLC) has been revolutionized by the discovery of targetable genetic alterations, including the ALK fusion oncogene.

Areas covered: Three drugs have been approved for clinical use in ALK-positive patients – crizotinib, ceritinib and alectinib. Unfortunately, treatment resistance inevitably develops. Several mechanisms of acquired resistance are reported. In this review, we will discuss emerging treatment options in ALK-positive advanced NSCLC and strategies to overcome resistance mechanisms, including newer generation of ALK inhibitors, Hsp90 inhibitors and immunotherapy.

Expert opinion: Tremendous advances have been made in the treatment of ALK-positive lung cancers, but management hurdles still exist, including universal development of resistance to ALK inhibitors and limited CNS activity. Given that specific treatment strategies target distinct patterns of resistance, re-biopsy at the time of progression appears necessary to optimize management. However, there remain many issues in routine clinical application including the burden placed on the patients by serial biopsies and the risks of repeat invasive procedures. Future studies are needed to validate the usage of non- or minimally invasive tests and to determine the optimal orders of utilizing different ALK inhibitors.     

Emerging antiangiogenics for renal cancer

Introduction: Antiangiogenic therapy is considered to be the backbone of treatment strategy in metastatic renal cell carcinoma (mRCC). New, more focused, targeted drugs are emerging, while other targeted drugs oriented toward resistance or alternative mechanisms are under development.

Areas covered: Antiangiogenic agents include two types of agents: the monoclonal antibody, targeting vascular endothelial growth factor (VEGF), bevacizumab and the tyrosine kinase inhibitors (TKIs). Data regarding efficacy and safety of these agents are reported. Differences between the first generation of TKIs, sunitinib, sorafenib, and the new generation, pazopanib, axitinib and tivozanib are also detailed. Most of these agents have been approved in the treatment of kidney cancer in specific settings of the disease.

Expert opinion: The class of antiangiogenic drugs for treatment of mRCC is already relatively full. After ‘me-too' drugs, more targeted drugs against VEGFR have been developed but have to demonstrate a benefit in first-line treatment. Another option for the development is to combine a known drug with an antiangiogenic inhibition profile and at least one additional target involved in resistance to an antiangiogenic or in an alternative pathway. The cost of approach with targeted drugs, including antiangiogenics, has led to a tremendous increase in the cost of care in mRCC.     

Targeting non-receptor tyrosine kinases using small molecule inhibitors: an overview of recent advances

Protein tyrosine kinases are enzymes that catalyze the transfer of phosphate groups from ATP to tyrosine residues on other proteins as substrate. Phosphorylation at tyrosine residues regulates several functions, including enzyme activity, cellular localization, signal transduction and interactions between proteins. Non-receptor tyrosine kinases (nRTKs) are one of the main players in intracellular signaling pathways. Dysregulation of nRTKs leads to their constitutive activation, which might contribute to initiation or progression of cancer. Therefore, targeting dysregulated nRTKs may prevent the process of tumorigenesis. Targeted-based cancer therapy (TBCT) methods and agents or personalized medicine have emerged as the main tools for cancer treatment. Currently, several TBCT agents, including monoclonal antibodies (mAbs) and small molecules inhibitors of tyrosine kinases (TKIs) have been developed. TKIs of cytoplasmic kinases inhibit intracellular signaling pathways and interfere with tumor cell functions. In this article, the recent progresses in development of TKIs of nRTKs approved by the US Food and Drug Administration (FDA) and current promising TKIs in pre-clinical and clinical settings have been reviewed.     

Emerging drugs for malignant glioma

Background: Malignant gliomas are amongst the most devastating and intractable of all cancers. The most common malignant glioma, glioblastoma multiforme (GBM), is associated with a median survival in the range of 12 – 15 months. Survival for patients with GBM has improved with the addition of temozolomide chemotherapy to post-operative radiotherapy. Further advances in the treatment of malignant glioma will hinge on the discovery of novel and likely targeted therapies with activity against these diseases. Objective: Review recent published experience using targeted therapeutics for malignant glioma. Methods: Key studies from a Medline review of targeted therapies for malignant glioma performed between 2000 and the present are summarised in this review. Conclusions: Experience with targeted therapeutics for malignant glioma has been to date disappointing. These agents are generally well tolerated, but activity is limited. Novel therapeutics with activity against malignant gliomas must be identified to improve prognosis for patients with these diseases.     

Emerging drugs for EGFR-mutated non-small cell lung cancer

Introduction: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) represent the standard of care for patients with metastatic non-small-cell lung cancer (NSCLC) harboring sensitizing EGFR mutations. However, these agents are associated with inevitable treatment resistance. Newer generations of TKIs are under development that may prevent or overcome resistance and enhance intracranial activity.

Areas covered: In this review, we will discuss newer generations of EGFR TKIs for EGFR-mutated NSCLC. We will also address resistance mutations and escape pathways associated with these agents such as secondary mutations, downstream signaling, bypass pathways, phenotypic transformation, anti-apoptotic signaling, immune evasion, and angiogenesis. Furthermore, this article encompasses emerging data from combination trials with next-generation TKIs that are being pursued to delay or prevent the occurrence of resistance.

Expert opinion: The promise and challenge of precision oncology is encapsulated in the treatment of EGFR-mutated NSCLC with TKIs. Third generation TKIs have shown superior efficacy in the front-line setting and have become standard of care. A better understanding of mechanisms of treatment failure and disease relapse will be required to develop novel therapeutic strategies to further improve patient outcomes in the future.     

Sunitinib for the treatment of thyroid cancer

Introduction: Sunitinib is an oral oxindol derivative and a potent inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor and a multitargeted tyrosine-kinase inhibitor, which has antitumor and antiangiogenic activity due to the selective inhibition that can stabilize progressive metastatic disease. The aim of this review is to expose whether the drug could be considered as a new promising therapy compared with other tyrosine-kinase inhibitors.

Areas covered: In seven open-label studies carried out with sunitinb, the drug showed its anti-tumoral activity in advanced differentiated thyroid carcinoma and in medullary thyroid carcinoma. The reported objectives in advanced differentiated thyroid carcinoma, partial response ranges 13% to 55.5%, stable disease ranges 44.4% to 68%, progressive disease ranges 10% to 21% of patients, progression free survival ranges 3 to 13.3% months. In medullary thyroid carcinoma, PR ranges 0% to 55%, SD ranges 44.4% to 87.5%, PD ranges 7% to 18.8% and progression free survivalranges seven to 21 months.

Expert opinion: Sunitinib has demonstrated a potent anti-tumoral activity in differentiated thyroid carcinoma and in medullary thyroid carcinoma, but the results of the open-label trials single arm are limited. Further investigations with this agent with randomized trials are warranted.     

The safety of vandetanib for the treatment of thyroid cancer

ABSTRACT

Introduction: The tyrosine kinase inhibitor vandetanib was approved for use in 2012 for aggressive and symptomatic medullary thyroid cancer (MTC) in patients with unresectable locally advanced or metastatic disease. As the first effective systemic therapy for MTC, vandetanib is a major step forward and the phase III study suggests an important role for this agent. Trials have also been performed for its use in differentiated thyroid cancer (DTC) though it is not yet approved for use for this indication.

Areas covered: The efficacy and safety of vandetanib is discussed. Studies suggest improvement in progression-free survival (PFS) without clear overall survival benefit but with manageable low grade toxicities and improved quality of life on therapy.

Expert opinion: Vandetanib has an important role in the management of patients with progressive metastatic MTC. The use in patients with stable or asymptomatic disease has no proven benefit. The side effects can usually be managed with dose reduction, interruption, and/or specific symptomatic therapy.     

不同剂量131I对分化型甲状腺癌患者血清中TH水平及生活质量的影响

目的：探讨不同剂量131I对分化型甲状腺癌患者血清中甲状腺激素水平及生活质量的影响。方法：回顾性分析2012年1月—2015年3月我院收治的85例分化型甲状腺癌患者,所有患者均进行甲状腺癌切除手术,术后给予131I治疗,根据剂量不同分为3组,A组为1次应用131I治疗的患者,共27例,累计剂量为2.96～3.70 GBq,B组为2次应用131I治疗的患者,共23例,累计剂量为8.14～10.36 GBq,C组3次应用131I治疗的患者,共20例,累计剂量为12.95～17.02 GBq,比较3组患者治疗前后的临床疗效,生活质量评分,另15例同期未接受131I治疗的患者作为对照。结果：131I治疗组的有效率均显著高于对照组,B、C组有效率最高,A组次之（P<0.05）;3组患者治疗后躯体功能、角色功能、认知功能、情绪功能以及社会功能等方面的评分均显著高于治疗前, B组治疗后的生存质量评分最高,C组次之,A组最低,组间差异有统计学意义。结论：131I治疗分化型甲状腺癌疗效显著,可提高患者的生活质量,其中以B组的治疗方案效果最佳。