cabozantinib and Thyroid-Neoplasms

This manuscript investigates cabozantinib, vandetanib, pralsetinib, and selpercatinib, four tyrosine kinase inhibitors (TKIs), which are used to treat advanced and/or metastatic medullary thyroid cancer (MTC). Data on efficacy and safety are presented with the main focus on treatment-related hypertension, a well-known adverse effect (AE) of these TKIs. Taken together, TKI-induced hypertension is rarely a dose-limiting side effect. However, with increasing survival times of patients under treatment, hypertension-associated complications can be expected to be on the rise without proper medication.

Topics: Carcinoma, Neuroendocrine; Humans; Hypertension; Piperidines; Protein Kinase Inhibitors; Thyroid Neoplasms

Thyroid cancer (TC) is the most prevalent endocrine malignant tumor. Surgery, chemotherapy, radiotherapy, and radioactive iodine (RAI) therapy are the standard TC treatment modalities. However, recurrence or tumor metastasis remains the main challenge in the management of anaplastic thyroid cancer (ATC) and radioiodine (RAI) radioactive iodine-refractory differentiated thyroid cancer (RR-DTC). Several multi-tyrosine kinase inhibitors (MKIs), or immune checkpoint inhibitors in combination with MKIs, have emerged as novel therapies for controlling the progression of DTC, medullary thyroid cancer (MTC), and ATC. Here, we discuss and summarize the molecular basis of TC, review molecularly targeted therapeutic drugs in clinical research, and explore potentially novel molecular therapeutic targets. We focused on the evaluation of current and recently emerging tyrosine kinase inhibitors approved for systemic therapy for TC, including lenvatinib, sorafenib and cabozantinib in DTC, vandetanib, cabozantinib, and RET-specific inhibitor (selpercatinib and pralsetinib) in MTC, combination dabrafenib with trametinib in ATC. In addition, we also discuss promising treatments that are in clinical trials and may be incorporated into clinical practice in the future, briefly describe the resistance mechanisms of targeted therapies, emphasizing that personalized medicine is critical to the design of second-line therapies.

Topics: Anilides; Humans; Iodine Radioisotopes; Protein Kinase Inhibitors; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms

Many trials have demonstrated prime antitumor activity of novel, small molecule multikinase inhibitors (MKIs) in advanced and/or metastatic thyroid cancer (TC). In this work, the PubMed, EMBASE, Cochrane Central Register of Controlled Trials, Web of Science, SCOPUS, and clinicaltrials.gov databases were searched. Quality/risk of bias were assessed using GRADE criteria. Randomized clinical trials (RCTs) comparing two or more systemic therapies in patients with advanced and/or metastatic thyroid cancer were assessed. A total of 1347 articles and 548 clinical trials in clinicaltrials.gov were screened. We included seven relevant RCTs comprising 1934 unique patients assigned to different MKIs. Two separate network meta-analyses included four RCTs in radioiodine refractory well-differentiated thyroid cancer (RR-WDTC) and three RCTs in medullary thyroid cancer (MTC), respectively; all with a low risk of bias. We identified three therapies for RR-WDTC: sorafenib [disease control rate (DCR) odds ratio (OR): 0.11 (95% CI: 0.03-0.40); progression-free survival (PFS) hazard ratio (HR): 1.99 (95% CI: 1.62-2.46)], vandetanib [DCR_OR:0.26 (95% CI: 0.06-1.24); PFS_HR: 0.99 (95% CI: 0.82-1.20)] and lenvatinib [DCR_OR: 0.26 (95% CI: 0.05-1.33); PFS_HR: 0.99 (95% CI: 0.81-1.22)]; and the following therapies for MTC: vandetanib 300 mg [objective response rate (ORR)_OR: 3.31 (95% CI: 0.68-16.22); vandetanib 150 mg ORR_OR: 0.60 (95% CI: 0.16-2.33)]; and cabozantinib [ORR_OR: 85.32 (95% CI: 5.22-1395.15)]. Serious side effect (SE) analysis per organ/system demonstrated a varying MKI SE profile across both RR-WDTC and MTC diagnoses, more commonly involving metabolic/nutritional disorders [OR: 2.07 [95% CI: 0.82-5.18)] and gastrointestinal SE [OR: 1.63 (95% CI: 1.0-2.66)]. This network meta-analysis on advanced and/or metastatic TC points towards a higher efficacy of lenvatinib in RR-WDTC. The included MKIs exhibit a varying SE profile across different organs/systems favoring a patient-tailored approach with the anticipated toxicities guiding clinicians' decisions.

Topics: Anilides; Antineoplastic Agents; Humans; Network Meta-Analysis; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Quinolines; Randomized Controlled Trials as Topic; Thyroid Neoplasms

Medullary thyroid cancer (MTC) is a rare form of cancer that affects patients' health-related quality of life (HRQoL) and survival. Cabozantinib (Cometriq. (1) To evaluate the clinical effectiveness and safety of cabozantinib and vandetanib. (2) To estimate the incremental cost-effectiveness of cabozantinib and vandetanib versus each other and best supportive care. (3) To identify key areas for primary research. (4) To estimate the overall cost of these treatments in England.. Peer-reviewed publications (searched from inception to November 2016), European Public Assessment Reports and manufacturers' submissions.. A systematic review [including a network meta-analysis (NMA)] was conducted to evaluate the clinical effectiveness and safety of cabozantinib and vandetanib. The economic analysis included a review of existing analyses and the development of a de novo model.. The intention-to-treat populations of the EXAM and ZETA trials are notably different. The analyses of ZETA subgroups may be subject to confounding as a result of differences in baseline characteristics and open-label vandetanib use. Attempts to statistically adjust for treatment switching were unsuccessful. No HRQoL evidence was identified for the MTC population.. The identified trials suggest that cabozantinib and vandetanib improve PFS more than the placebo; however, significant OS benefits were not demonstrated. The economic analyses indicate that within the EU-label population, the ICERs for cabozantinib and vandetanib are > £138,000 per QALY gained. Within the restricted EU-label population, the ICER for vandetanib is expected to be > £66,000 per QALY gained.. (1) Primary research assessing the long-term effectiveness of cabozantinib and vandetanib within relevant subgroups. (2) Reanalyses of the ZETA trial to investigate the impact of adjusting for open-label vandetanib use using appropriate statistical methods. (3) Studies assessing the impact of MTC on HRQoL.. This study is registered as PROSPERO CRD42016050403.. The National Institute for Health Research Health Technology Assessment programme.. Medullary thyroid carcinoma (MTC) is a rare form of cancer that presents as a mass of tumours in the thyroid gland of the neck. MTC affects both patients’ health-related quality of life and survival. Targeted therapies (cabozantinib and vandetanib) are currently used to treat unresectable progressive and symptomatic MTC. The evidence for the use of cabozantinib and vandetanib in patients with unresectable locally advanced or metastatic MTC was reviewed, and two clinical trials were identified. The trials suggest that both drugs improve progression-free survival. Neither trial demonstrated significant survival benefits for cabozantinib or vandetanib. Both drugs produced frequent adverse events, often leading to dose interruption or reduction. Whether or not these therapies represent good value for money for the NHS was also assessed. Analyses indicate that the incremental cost-effectiveness ratios (ICERs) (a measure of cost-effectiveness) for cabozantinib and vandetanib versus best supportive care (BSC) in patients with symptomatic and progressive MTC are > £138,000 per quality-adjusted life-year (QALY) gained. Within a subgroup of patients with symptomatic and progressive MTC and carcinoembryonic antigen and/or calcitonin doubling times of ≤ 24 months, the ICER for vandetanib versus BSC remains > £66,000 per QALY gained.

Topics: Anilides; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Neuroendocrine; Cost-Benefit Analysis; England; Humans; Models, Economic; Piperidines; Pyridines; Quality-Adjusted Life Years; Quinazolines; Technology Assessment, Biomedical; Thyroid Neoplasms

Medullary thyroid cancer (MTC) is a rare malignancy with a poor prognosis. First line therapy is surgery, which is the only curative method of the disease. However, in non-operable cases or with tumor progression and metastases, a systemic treatment is necessary. This form of cancer is often insensitive to conventional chemotherapy, but the use of tyrosine kinase inhibitors (TKIs), such as pazopanib, cabozantinib, and vandetanib, has shown promising results with an increase in progression-free survival and prolonged lifetime. Therefore, we focused on the pharmacological characteristics of TKIs, their mechanism of action, their application as a secondary treatment option for MTC, their efficacy as a cancer drug treatment, and reviewed the ongoing clinical trials. TKIs also act systemically causing various adverse events (AEs). One common AE of this treatment is hypertension, known to be associated with cardiovascular disease and can therefore potentially worsen the well-being of the treated patients. The available treatment strategies of drug-induced hypertension were discussed. The mechanism behind the development of hypertension is still unclear. Therefore, the treatment of this AE remains symptomatic. Thus, future studies are necessary to investigate the link between tumor growth inhibition and hypertension. In addition, optimized, individual treatment strategies should be implemented.

Topics: Anilides; Carcinoma, Neuroendocrine; Cardiotoxicity; Humans; Hypertension; Indazoles; Piperidines; Protein Kinase Inhibitors; Pyridines; Pyrimidines; Quinazolines; Sulfonamides; Thyroid Neoplasms

Medullary thyroid carcinoma (MTC) represents 3-5% of thyroid cancers. 75% is sporadic and 25% is the dominant component of the hereditary multiple endocrine neoplasia (MEN) type 2 syndromes. Three different subtypes of MEN2, such as MEN2A, MEN2B, and Familial MTC (FMTC) have been defined, based on presence or absence of hyperparathyroidism, pheocromocytoma and characteristic clinical features. Mutations of the RET proto-oncogene are implicated in the pathogenesis of MTC, but there are many other mutational patterns involved. In MEN2A, Codon 634 in exon 11 (Cys634Arg), corresponding to a cysteine in the extracellular cysteine-rich domain, is the most commonly altered codon. Many other mutations include codons 611, 618, 620. In the genetical testing of RET mutations in MTCs, Next-Generation Sequencing (NGS) is taking an increasingly important role. One of the most important benefit is the comprehensive analysis of molecular alterations in MTC, which allows rapidly to select patients with different risk levels. There is a difference in miRNA expression pathway between sporadic and hereditary MTCs. Among sporadic cases, expression of miR-127 was significantly lower in those who harbor somatic RET mutations than those with wild-type RET. CDKN1B mutations are associated with many clinical pictures of cancers, such as MEN4. V109G polymorphism is associated with sporadic MTCs negative for RET mutations, and might influence the clinical course of the patients affected by MTC. Although surgery (i.e. total thyroidectomy with neck lymph node dissection) is the elective treatment for MTCs, about 80% of patients have distant metastases at diagnosis and in this cases surgery is not enough and an additional treatment is needed. Interesting results come from two large phase III clinical trials with two targeted tyrosine kinase inhibitors (TKIs), vandetanib and cabozantinib.. New genetical testings and therapeutical approaches open new perspectives in MTC management.

Topics: Anilides; Carcinoma, Medullary; Codon; Exons; Humans; Male; Middle Aged; Multiple Endocrine Neoplasia Type 2a; Mutation; Piperidines; Polymorphism, Genetic; Proto-Oncogene Mas; Proto-Oncogene Proteins c-ret; Pyridines; Quinazolines; Thyroid Neoplasms; Thyroidectomy

Medullary thyroid carcinoma (MTC) is a hyperplasia of thyroid C-cells, accounting for 5-10% of all thyroid cancers. MTCs may appear as sporadic or hereditary forms, and several molecules and signaling pathways have been found to function defectively in MTC cells. Tyrosine kinases are the most well-studied molecules that have abnormal function in these tumor cells. Due to their limited response, chemotherapeutic agents and radiation therapy are not effective in treating patients with advanced metastatic MTC. In the past decade, significant attention has been given to the utilization of multikinase inhibitors as targeted therapeutic agents for treating MTC patients, with the most promising results arising from the study of tyrosine kinase inhibitors, which generally bind to the ATP binding sites of these kinases. Two drugs-vandetanib and cabozantinib-are approved for the treatment of aggressive advanced MTC; however, the potential for toxicities and adverse effects of these agents on patient quality of life need to be considered against any therapeutic gain. According to recent data, it appears that inhibition of only one receptor or molecule in a pathway is not as effective as simultaneous inhibition of different pathways, indicating the need to use combination therapy. The main purpose of this review is to describe the clinical characteristics, molecular mechanisms, and current molecular and targeted therapeutic strategies active in clinical trials for advanced MTC treatment.

Topics: Anilides; Antineoplastic Agents; Carcinoma, Neuroendocrine; Clinical Trials as Topic; High-Throughput Nucleotide Sequencing; Humans; Molecular Targeted Therapy; Mutation; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyridines; Quinazolines; Thyroid Neoplasms

Medullary thyroid cancer (MTC) represents 3% of all clinical thyroid cancers and arises from thyroid C cells that produce calcitonin. Locally advanced or metastatic MTC requires a careful work-up including measurement of serum calcitonin and carcinoembryonic antigen, determination of their doubling time and comprehensive imaging to determine the extent of the disease, its aggressiveness, and the need for treatment. Cytotoxic chemotherapy can control tumor burden in some patients with response rates of around 20% in old series. For the last 10 years, systemic therapy for MTC patients with large tumor burden and documented progression of the disease has involved the use of tyrosine kinase inhibitors targeting VEGFR and ret. Progression-free survival benefits have been demonstrated for both vandetanib and cabozantinib, as compared to placebo. Although these molecules are effective, they also have specific toxicity profiles which require a thorough clinical management in specialized centers. In the present review, we describe the work-up and treatment modalities of patients with advanced or metastatic medullary thyroid cancer with a focus on chemotherapy and targeted therapy results.

Topics: Anilides; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Neuroendocrine; Disease-Free Survival; Humans; Molecular Targeted Therapy; Neoplasm Metastasis; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyridines; Quinazolines; Thyroid Neoplasms

Topics: Anilides; Animals; Carcinoma, Renal Cell; Clinical Trials as Topic; Dose-Response Relationship, Drug; Humans; Kidney Neoplasms; Pyridines; Receptor Protein-Tyrosine Kinases; Thyroid Neoplasms

Cabozantinib (XL-184) is a potent inhibitor of MET, VEGFR 2/KDR, RET and other receptor tyrosine kinases, such as KIT, AXL and FLT3. Its efficacy against MTC has been demonstrated in a prospective, randomized, placebo-controlled study (EXAM). Cabozantinib comparing to placebo significantly prolonged progression free survival both in hereditary and sporadic MTC, 11.2 vs 4.0 months, respectively. Final analysis showed no global differences in overall survival (OS) between cabozantinib and placebo. However, in a subgroup with RET M918T mutation the difference in OS was significant: 44.3 vs 18.9 months, respectively. Among the most frequent cabozantinib-related adverse events (AEs), observed in >30% of patients were diarrhea, palmar-plantar erythrodysesthesia, decreased weight, decreased appetite, nausea, fatigue, dysgeusia, hair color changes and hypertension. Expert Commentary: Cabozantinib constitutes an effective treatment option with acceptable toxicity in MTC patients showing either germinal or sporadic tumor RET M918T mutation as the drug prolonged OS in these subjects.

Topics: Anilides; Animals; Antineoplastic Agents; Carcinoma, Neuroendocrine; Disease Progression; Disease-Free Survival; Humans; Mutation; Neoplasm Metastasis; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-ret; Pyridines; Survival Rate; Thyroid Neoplasms

Medullary thyroid cancer arises from calcitonin-producing C-cells and accounts for 3-5% of all thyroid cancers. The discovery of a locally advanced medullary thyroid cancer that is not amenable to surgery or of distant metastases needs careful work-up, including measurement of serum calcitonin and carcinoembryonic antigen (and their doubling times), in addition to comprehensive imaging to determine the extent of the disease, its aggressiveness, and the need for any treatment. In the past, cytotoxic chemotherapy was used for treatment but produced little benefit. For the past 10 years, tyrosine kinase inhibitors targeting vascular endothelial growth factor receptors and RET (rearranged during transfection) have been used when a systemic therapy is indicated for large tumour burden and documented disease progression. Vandetanib and cabozantinib have shown benefits on progression-free survival compared with placebo in this setting, but their toxic effect profiles need thorough clinical management in specialised centres. This Review describes the management and treatment of patients with advanced medullary thyroid cancer with emphasis on current targeted therapies and perspectives to improve patient care. Most treatment responses are transient, emphasising that mechanisms of resistance need to be better understood and that the efficacy of treatment approaches should be improved with combination therapies or other drugs that might be more potent or target other pathways, including immunotherapy.

Topics: Anilides; Antineoplastic Agents; Biomarkers; Calcitonin; Carcinoembryonic Antigen; Carcinoma, Neuroendocrine; Disease Progression; Disease-Free Survival; Humans; Molecular Targeted Therapy; Piperidines; Pyridines; Quinazolines; Receptors, Vascular Endothelial Growth Factor; Thyroid Neoplasms; Treatment Outcome

Although rare, medullary thyroid cancer (MTC) exemplifies the value that ever-expanding knowledge of molecular pathways and mechanisms brings to managing challenging cancers. Although surgery can be curative for MTC in many patients, a substantial proportion of patients present with locoregional or distant metastatic disease. Once distant disease occurs, treatment options are limited, and conventional cancer treatments such as cytotoxic chemotherapy are of minimal benefit. Biomarkers such as calcitonin and carcinoembryonic antigen are important correlates of disease burden as well as predictors of disease progress, including recurrence and survival. MTC is either sporadic (∼75%) or inherited (∼25%) as an autosomal dominant disease. Regardless, germline and somatic mutations, particularly in the rearranged during transfection (RET) proto-oncogene, are key factors in the neoplastic process. Gain-of-function RET mutations result in overactive proteins that lead to abnormal activation of downstream signal transduction pathways, resulting in ligand-independent growth and resistance to apoptotic stimuli. Specific RET mutation variants have been found to correlate with phenotype and natural history of MTC with some defects portending a more aggressive clinical course. Greater understanding of the consequence of the aberrant signaling pathway has fostered the development of targeted therapies. Two small-molecule tyrosine kinase inhibitors, vandetanib and cabozantinib, are currently available as approved agents for the treatment of advanced or progressive MTC and provide significant increases in progression-free survival. Since there have been no head-to-head comparisons, clinicians often select between these agents on the basis of familiarity, patient characteristics, comorbidities, and toxicity profile.

Topics: Anilides; Antineoplastic Agents; Carcinoma, Neuroendocrine; Chemotherapy, Adjuvant; Genotype; Humans; Molecular Targeted Therapy; Phenotype; Piperidines; Proto-Oncogene Mas; Proto-Oncogene Proteins c-ret; Pyridines; Quinazolines; Receptors, Fibroblast Growth Factor; Thyroid Neoplasms; Thyroidectomy; Vascular Endothelial Growth Factor Receptor-2

Most of the genetic events implicated in the pathogenesis of thyroid cancer (TC) involve genes with kinase activity. Thus, kinase inhibitors (KIs) are very relevant in this field. KIs are considered the most suitable treatment for patients with iodine-refractory differentiated TC; these patients comprise the subgroup with the poorer prognosis. To date, only sorafenib has been approved for this indication, but promising results have been reported with several other KIs. In particular, lenvatinib has demonstrated excellent efficacy, with both progression-free survival and objective tumour response being better than with sorafenib. Despite being considered to be well tolerated, both sorafenib and lenvatinib have shown a remarkable toxicity, which has led to dose reductions in the majority of patients and to treatment discontinuation in a significant proportion of cases. The role of KIs in differentiated TC may be revolutionised by the finding that selumetinib may restore a clinical response to radioactive iodine (RAI). Vandetanib and cabozantinib have been approved for the treatment of advanced, progressive medullary TC (MTC). Nevertheless, the toxicity of both compounds suggests their selective use in those patients with strong disease progression. Treatment with the mTOR-inhibitor everolimus, alone or in combination with somatostatin analogues, should be studied in metastatic MTC patients with slow progression of disease, these representing the vast majority of patients. KIs did not significantly impact on the clinical features of anaplastic TC (ATC).

Topics: Angiogenesis Inhibitors; Anilides; Antineoplastic Agents; Humans; Niacinamide; Phenylurea Compounds; Piperidines; Protein Kinase Inhibitors; Pyridines; Quinazolines; Quinolines; Sorafenib; Thyroid Neoplasms

In the last few years, three new drugs for targeted systemic therapies have been approved for advanced and progressive thyroid cancer, namely vandetanib and cabozantinib for medullary and sorafenib for radioiodine refractory differentiated thyroid cancer. Patient selection by an interdisciplinary team and education of patients by the treating physicians play a major role when such a treatment is considered and initiated. Only patients with significant tumor burden and/or symptomatic disease or progression, which cannot be controlled by local therapies, should be treated. In order to preserve quality of life, the management of adverse effects is of utmost importance. Due to the mechanism of action of these tyrosine kinase inhibitors, the reliability of serum tumour markers, calcitonin and thyroglobulin, is limited for the assessment of response and follow-up, therefore morphological and metabolic imaging is of great importance. Minor or localized progression should not automatically trigger the termination of treatment or change of drug. In the near future, it is expected that additional drugs become available.

Topics: Anilides; Antineoplastic Agents; Drug Monitoring; Evidence-Based Medicine; Humans; Piperidines; Protein-Tyrosine Kinases; Pyridines; Quinazolines; Thyroid Neoplasms; Tomography, Emission-Computed; Treatment Outcome

Cabozantinib is an oral once-daily multitarget tyrosine kinase inhibitor of MET, VEGFR2, RET, acting against KIT, AXL, FLT3 and Tie-2. Cabozantinib has shown anti-cancer effects in preclinical and clinical models of cancers derived from both epithelial and mesenchymal origins [prostate cancer, non small lung cancer, medullary thyroid cancer (MTC) and differentiated thyroid cancer (DTC), renal cell carcinoma, etc.]. In a Phase III clinical study, cabozantinib improved PFS (11.2 months versus 4.0 months in the placebo group) of patients with MTC (independently of age, bone metastases, RET status and prior treatment). Cabozantinib was approved in 2012 by FDA for metastatic MTC and in 2013 by EMA. Cabozantinib has been also evaluated in metastatic DTC patients, because they have activation on tyrosine kinases, including MET, VEGFR2 and RET, suggesting the possible use of cabozantinib in metastatic DTC. Actually, two Phase II trials of cabozantinib in DTC patients resistant to RAI are ongoing. To increase the antineoplastic effect of cabozantinib, and to overcome the occurrence of drug resistance, combination studies with other anticancer agents are ongoing. In conclusion, cabozantinib has shown to exert an important therapeutic effect in patients with MTC improving PFS. In DTC patients, cabozantinib has shown promising results.

Topics: Anilides; Animals; Antineoplastic Agents; Clinical Trials as Topic; Humans; Pyridines; Thyroid Neoplasms

Advanced thyroid cancer is not amenable to therapy with conventional cytotoxic chemotherapy. However, newer advances in the understanding of the molecular pathogenesis of different subtypes of thyroid cancer have provided new opportunities for the evaluation of molecularly targeted therapies. This has led to multiple clinical trials using various multi-kinase inhibitors and the subsequent US FDA approval of sorafenib for differentiated thyroid cancer and vandetanib and cabozantinib for medullary thyroid carcinoma. This review provides a summary of the current literature for the treatment of advanced thyroid carcinoma and future directions in this disease.

Topics: Anilides; Antineoplastic Agents; Axitinib; Carcinoma, Neuroendocrine; DNA Mutational Analysis; Drug Approval; Humans; Imidazoles; Indazoles; Indoles; MAP Kinase Signaling System; Molecular Targeted Therapy; Niacinamide; Oligonucleotides; Phenylurea Compounds; Phosphatidylinositol 3-Kinases; Piperidines; Proto-Oncogene Proteins c-ret; Pyridines; Pyrimidines; Pyrroles; Quinazolines; Quinolines; Sorafenib; Sulfonamides; Sunitinib; Thyroid Neoplasms; United States; United States Food and Drug Administration; Vascular Endothelial Growth Factor A

Since chemotherapy has been shown to be unsuccessful in case of advanced thyroid carcinomas, the research for new therapies is fundamental. Clinical trials of many tyrosine kinase inhibitors as well as anti-angiogenic inhibitors suggest that patients with thyroid cancer could have an advantage with new target therapy. Recently, Food and Drug Administration approved two targeted therapies, vandetanib and cabozantinib for the treatment of metastatic thyroid carcinomas with acceptable outcome. We summarized the results and the toxic effects associated with these treatments reported in clinical trials. Future trials should aim at combinations of targeted agents with or without other treatment modalities to obtain a more effective result in thyroid carcinoma treatment.

Topics: Anilides; Antineoplastic Agents; Boronic Acids; Bortezomib; Cell Differentiation; Cell Proliferation; ErbB Receptors; Genetic Therapy; Histone Deacetylase Inhibitors; Humans; Immunotherapy; Lithium; Molecular Targeted Therapy; Piperidines; Protein Kinase Inhibitors; Pyrazines; Pyridines; Quinazolines; Stilbenes; Thalidomide; Thyroid Neoplasms

Cabozantinib (Cometriq(®)) is an orally administered small molecule inhibitor of multiple tyrosine kinase receptors, including those involved in the pathogenesis of medullary thyroid cancer (MTC) [i.e. rearranged during transfection (RET), MET and vascular endothelial growth factor receptor (VEGFR)-2]. Cabozantinib is indicated for the treatment of adults with progressive, unresectable locally advanced (in the EU) or metastatic (in the EU and USA) MTC. Compared with placebo, cabozantinib significantly prolonged progression-free survival, reflecting a 72% reduction in the risk of disease progression or death, in patients with unresectable, locally advanced or metastatic MTC participating in a multinational, phase III study. A significantly higher proportion of patients receiving cabozantinib than those receiving placebo achieved an objective response or disease stabilization (i.e. a complete or partial response, or stable disease). The overall survival benefit with cabozantinib is as yet unclear, with no significant benefit observed in two interim analyses (one prespecified, and one unplanned and conducted at the request of the US FDA). The tolerability profile of oral cabozantinib is typical for a small molecule targeting the VEGFR and other tyrosine kinase-mediated pathways, with adverse events associated with the inhibition of the VEGF pathway (e.g. gastrointestinal perforation, haemorrhage, hypertension and venous thrombosis) reported in the phase III study. Treatment-emergent adverse events were generally managed with supportive therapy, dose reductions and/or dose interruptions. Although final overall survival data are awaited, current evidence suggests cabozantinib to be a valuable treatment option for adults with progressive, unresectable locally advanced or metastatic MTC.

Topics: Anilides; Antineoplastic Agents; Carcinoma, Neuroendocrine; Humans; Pyridines; Thyroid Neoplasms; Vascular Endothelial Growth Factors

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.. 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.. 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.

Topics: Anilides; Antineoplastic Agents; Clinical Trials as Topic; Diarrhea; Humans; Phenylurea Compounds; Piperidines; Protein Kinase Inhibitors; Pyridines; Quinazolines; Quinolines; Receptors, Vascular Endothelial Growth Factor; Thyroid Neoplasms

Conventional treatment modalities for thyroid cancer lead to complete remission in only one-third of patients with distant metastases. On the other hand, medullary thyroid cancer (MTC) and anaplastic thyroid cancer (ATC), although rare, are responsible for a significant percentage of thyroid cancer-related deaths. New treatments are needed to treat such patients.. The aim of this review is to provide the latest information on cabozantinib (CBZ), a new tyrosine kinase inhibitor (TKI) that is currently used mainly as a treatment of MTC. The authors collated data that were retrieved from a PubMed literature search.. CBZ targets multiple cell-signaling pathways involved in the molecular pathogenesis of thyroid cancer. These are namely VEGF receptor-2, hepatocyte growth factor receptor and rearranged during transfection receptor. Furthermore, it is a drug which may be used in cases where conventional therapies (mainly for MTC) are proved ineffective or have shown poor results with a good outcome. CBZ may also be administered alone or in combination with other drugs of the same family.

Topics: Anilides; Carcinoma, Neuroendocrine; Clinical Trials as Topic; Drug Evaluation, Preclinical; Humans; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyridines; Signal Transduction; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Vascular Endothelial Growth Factor Receptor-2

The incidence of thyroid cancer continues to increase and this neoplasia remains the most common endocrine malignancy. No effective systemic treatment currently exists for iodine-refractory differentiated or medullary thyroid carcinoma, but recent advances in the pathogenesis of these diseases have revealed key targets that are now being evaluated in the clinical setting. RET (rearranged during transfection)/PTC (papillary thyroid carcinoma) gene rearrangements, B-Raf gene mutations, and vascular endothelial growth factor receptor 2 (VEGFR-2) angiogenesis pathways are some of the known genetic alterations playing a crucial role in the development of thyroid cancer. Several novel agents have demonstrated promising responses. Of the treatments studied, multi-kinase inhibitors such as axitinib, sorafenib, motesanib, and XL-184 have shown to be the most effective by inducing clinical responses and stabilizing the disease process. Randomized clinical trials are currently evaluating these agents, results that may soon change the management of thyroid cancer.

Topics: Angiogenesis Inhibitors; Anilides; Antineoplastic Agents; Axitinib; Benzamides; Benzenesulfonates; Benzoquinones; Bibenzyls; Boronic Acids; Bortezomib; Depsipeptides; ErbB Receptors; Gefitinib; Histone Deacetylase Inhibitors; HSP90 Heat-Shock Proteins; Humans; Hydroxamic Acids; Imatinib Mesylate; Imidazoles; Indazoles; Indoles; Lactams, Macrocyclic; Lenalidomide; Niacinamide; Oligonucleotides; Phenylurea Compounds; Piperazines; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-kit; Pyrazines; Pyridines; Pyrimidines; Pyrroles; Quinazolines; Quinolines; Receptor Protein-Tyrosine Kinases; Receptors, Vascular Endothelial Growth Factor; Sorafenib; Sulfonamides; Sunitinib; Thalidomide; Thyroid Neoplasms; Valproic Acid; Vorinostat

Patients with advanced medullary thyroid cancer (MTC) have poor prognoses and limited treatment options. Improved knowledge about molecular aberrations associated with MTC and the availability of novel targeted tyrosine kinase inhibitors (TKIs) have led to new potential treatment modalities. Cabozantinib is an oral multitargeted TKI with activity against multiple receptors including RET, vascular endothelial growth factor receptor type 2 (VEGFR2), and MET that has been evaluated in MTC in the preclinical and clinical arenas.. This article reviews unmet clinical needs in advanced MTC. The authors consider novel agents that have been studied in MTC, with a focus on the investigational agent cabozantinib. Up-to-date clinical data of cabozantinib in MTC are discussed.. Recent clinical evaluation suggests that cabozantinib is the first agent to prolong progression-free survival in patients with progressive MTC. These findings indicate that cabozantinib may be an effective therapy in advanced MTC. No improvement in overall survival has been demonstrated but data are not mature.. Cabozantinib may be an effective treatment option for patients with advanced MTC and is worthy of further evaluation.

Topics: Administration, Oral; Adult; Aged; Anilides; Biopsy, Needle; Carcinoma, Neuroendocrine; Clinical Trials, Phase I as Topic; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Immunohistochemistry; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Patient Selection; Prognosis; Protein-Tyrosine Kinases; Pyridines; Survival Analysis; Thyroid Neoplasms; Treatment Outcome

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.. 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.. 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.

Topics: Anilides; Animals; Carcinoma, Medullary; Carcinoma, Neuroendocrine; Clinical Trials as Topic; Humans; Neoplasm Metastasis; Protein Kinase Inhibitors; Pyridines; Signal Transduction; Thyroid Neoplasms

The prognosis of almost all thyroid cancers is good, but some patients have indications for these molecularly targeted drugs. Some of these drugs, i.e., vandetanib, XL-184, sorafenib, motesanib, axitinib, and pazopanib, are clearly useful clinically.

Topics: Anilides; Benzenesulfonates; Disease Progression; Humans; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Piperidines; Protein Kinase Inhibitors; Pyridines; Quinazolines; Sorafenib; Thyroid Neoplasms

Metastatic medullary thyroid cancer (MTC) is an incurable disease once metastasis becomes unresectable. Many therapeutic drugs and methods have been tried to circumvent this difficulty. We review currently published treatments and hope for future developments of more effective treatment methods.. Motesanib, vandetanib, axitinib (tyrosine kinase inhibitors), and XL184 (multikinase inhibitor) have been shown to achieve partial response or stable disease state of metastatic MTC. Sunitinib and sorafenib, currently available tyrosine kinase inhibitors, can also be tried for patients with MTC. However, these medications are not curative and do not improve survival rate. Only carcinoembryonic antigen-I-iodine-based radioimmunotherapy improved survival of a subset of patients with a very aggressive type of MTC. Drugs currently available for possible use of MTC treatment include bortezomib (proteasome inhibitor), valproic acid (histone deacetylase inhibitor), capecitabine (5-fluorouracil prodrug), and indomethacin (NSAID), although clinical studies have yet to be done. Cardiac natriuretic hormones and an extract of the plant Cautleya gracilis are new agents to be studied for MTC.. Kinase inhibitors are the first drugs showing some efficacy in MTC. To improve survival, unconventional drugs or other therapies with or without kinase inhibitors need to be considered.

Topics: Anilides; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Medullary; Humans; Neoplasm Metastasis; Pyridines; Therapies, Investigational; Thyroid Neoplasms

Selpercatinib, a highly selective, potent RET inhibitor, has shown efficacy in advanced. We conducted a phase 3, randomized trial comparing selpercatinib as first-line therapy with the physician's choice of cabozantinib or vandetanib (control group). Eligible patients had progressive disease documented within 14 months before enrollment. The primary end point in the protocol-specified interim efficacy analysis was progression-free survival, assessed by blinded independent central review. Crossover to selpercatinib was permitted among patients in the control group after disease progression. Treatment failure-free survival, assessed by blinded independent central review, was a secondary, alpha-controlled end point that was to be tested only if progression-free survival was significant. Among the other secondary end points were overall response and safety.. A total of 291 patients underwent randomization. At a median follow-up of 12 months, median progression-free survival as assessed by blinded independent central review was not reached in the selpercatinib group and was 16.8 months (95% confidence interval [CI], 12.2 to 25.1) in the control group (hazard ratio for disease progression or death, 0.28; 95% CI, 0.16 to 0.48; P<0.001). Progression-free survival at 12 months was 86.8% (95% CI, 79.8 to 91.6) in the selpercatinib group and 65.7% (95% CI, 51.9 to 76.4) in the control group. Median treatment failure-free survival as assessed by blinded independent central review was not reached in the selpercatinib group and was 13.9 months in the control group (hazard ratio for disease progression, discontinuation due to treatment-related adverse events, or death, 0.25; 95% CI, 0.15 to 0.42; P<0.001). Treatment failure-free survival at 12 months was 86.2% (95% CI, 79.1 to 91.0) in the selpercatinib group and 62.1% (95% CI, 48.9 to 72.8) in the control group. The overall response was 69.4% (95% CI, 62.4 to 75.8) in the selpercatinib group and 38.8% (95% CI, 29.1 to 49.2) in the control group. Adverse events led to a dose reduction in 38.9% of the patients in the selpercatinib group, as compared with 77.3% in the control group, and to treatment discontinuation in 4.7% and 26.8%, respectively.. Selpercatinib treatment resulted in superior progression-free survival and treatment failure-free survival as compared with cabozantinib or vandetanib in patients with

Topics: Antineoplastic Agents; Disease Progression; Humans; Piperidines; Proto-Oncogene Proteins c-ret; Pyridines; Quinazolines; Thyroid Neoplasms

On September 17, 2021, the FDA approved cabozantinib (Cabometyx; Exelixis, Inc.) for the treatment of adult and pediatric patients 12 years of age and older with locally advanced or metastatic differentiated thyroid cancer (DTC) that has progressed following prior VEGFR-targeted therapy and who are radioactive iodine (RAI)-refractory or ineligible. This is the first approval for patients with RAI-refractory locally advanced or metastatic DTC who have progressed following prior therapy and the first approval in pediatric patients with DTC. The approval was based on data from COSMIC-311 (Study XL184-311, NCT03690388), an international, randomized, double-blind trial in which patients with locally advanced or metastatic RAI-refractory DTC that progressed during or following treatment with at least one VEGFR-targeting tyrosine kinase inhibitor were treated with either cabozantinib 60 mg orally once daily (N = 170) or placebo with best supportive care (N = 88). The primary efficacy outcome measures were progression-free survival (PFS) and overall response rate (ORR) by blinded independent central review per RECIST 1.1. The median PFS was 11.0 months [95% confidence interval (CI), 7.4-13.8] in the cabozantinib arm compared with 1.9 months (95% CI, 1.9-3.7) in the control arm, with an HR of 0.22 (95% CI, 0.15-0.31). The endpoint of ORR was not met. No new safety signals were identified with the exception of hypocalcemia, which was added as a warning in the product labeling.

Topics: Adenocarcinoma; Adult; Angiogenesis Inhibitors; Anilides; Child; Humans; Iodine Radioisotopes; Protein Kinase Inhibitors; Pyridines; Thyroid Neoplasms

At an interim analysis (median follow-up, 6.2 months; n = 187), the phase 3 COSMIC-311 trial met the primary end point of progression-free survival (PFS): cabozantinib improved PFS versus a placebo (median, not reached vs. 1.9 months; p < .0001) in patients with previously treated radioiodine-refractory differentiated thyroid cancer (RAIR-DTC). The results from an exploratory analysis using an extended datacut are presented.. Patients 16 years old or older with RAIR-DTC who progressed on prior lenvatinib and/or sorafenib were randomized 2:1 to oral cabozantinib tablets (60 mg/day) or a placebo. Placebo patients could cross over to open-label cabozantinib upon radiographic disease progression. The objective response rate (ORR) in the first 100 randomized patients and the PFS in the intent-to-treat population, both according to Response Evaluation Criteria in Solid Tumors version 1.1 by blinded, independent review, were the primary end points.. At the data cutoff (February 8, 2021), 258 patients had been randomized (cabozantinib, n = 170; placebo, n = 88); the median follow-up was 10.1 months. The median PFS was 11.0 months (96% confidence interval [CI], 7.4-13.8 months) for cabozantinib and 1.9 months (96% CI, 1.9-3.7 months) for the placebo (hazard ratio, 0.22; 96% CI, 0.15-0.32; p < .0001). The ORR was 11.0% (95% CI, 6.9%-16.9%) versus 0% (95% CI, 0.0%-4.1%) (p = .0003) with one complete response with cabozantinib. Forty placebo patients crossed over to open-label cabozantinib. Grade 3/4 treatment-emergent adverse events occurred in 62% and 28% of the cabozantinib- and placebo-treated patients, respectively; the most common were hypertension (12% vs. 2%), palmar-plantar erythrodysesthesia (10% vs. 0%), and fatigue (9% vs. 0%). There were no grade 5 treatment-related events.. At extended follow-up, cabozantinib maintained superior efficacy over a placebo in patients with previously treated RAIR-DTC with no new safety signals.

Topics: Adenocarcinoma; Adolescent; Anilides; Antineoplastic Agents; Humans; Iodine Radioisotopes; Pyridines; Thyroid Neoplasms

Patients with radioiodine-refractory differentiated thyroid cancer (DTC) previously treated with vascular endothelial growth factor receptor (VEGFR)-targeted therapy have aggressive disease and no available standard of care. The aim of this study was to evaluate the tyrosine kinase inhibitor cabozantinib in this patient population.. In this global, randomised, double-blind, placebo-controlled, phase 3 trial, patients aged 16 years and older with radioiodine-refractory DTC (papillary or follicular and their variants) and an Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned (2:1) to oral cabozantinib (60 mg once daily) or matching placebo, stratified by previous lenvatinib treatment and age. The randomisation scheme used stratified permuted blocks of block size six and an interactive voice-web response system; both patients and investigators were masked to study treatment. Patients must have received previous lenvatinib or sorafenib and progressed during or after treatment with up to two VEGFR tyrosine kinase inhibitors. Patients receiving placebo could cross over to open-label cabozantinib on disease progression confirmed by blinded independent radiology committee (BIRC). The primary endpoints were objective response rate (confirmed response per Response Evaluation Criteria in Solid Tumours [RECIST] version 1.1) in the first 100 randomly assigned patients (objective response rate intention-to-treat [OITT] population) and progression-free survival (time to earlier of disease progression per RECIST version 1.1 or death) in all patients (intention-to-treat [ITT] population), both assessed by BIRC. This report presents the primary objective response rate analysis and a concurrent preplanned interim progression-free survival analysis. The study is registered with ClinicalTrials.gov, NCT03690388, and is no longer enrolling patients.. Between Feb 27, 2019, and Aug 18, 2020, 227 patients were assessed for eligibility, of whom 187 were enrolled from 164 clinics in 25 countries and randomly assigned to cabozantinib (n=125) or placebo (n=62). At data cutoff (Aug 19, 2020) for the primary objective response rate and interim progression-free survival analyses, median follow-up was 6·2 months (IQR 3·4-9·2) for the ITT population and 8·9 months (7·1-10·5) for the OITT population. An objective response in the OITT population was achieved in ten (15%; 99% CI 5·8-29·3) of 67 patients in the cabozantinib group versus 0 (0%; 0-14·8) of 33 in the placebo (p=0·028) but did not meet the prespecified significance level (α=0·01). At interim analysis, the primary endpoint of progression-free survival was met in the ITT population; cabozantinib showed significant improvement in progression-free survival over placebo: median not reached (96% CI 5·7-not estimable [NE]) versus 1·9 months (1·8-3·6); hazard ratio 0·22 (96% CI 0·13-0·36; p<0·0001). Grade 3 or 4 adverse events occurred in 71 (57%) of 125 patients receiving cabozantinib and 16 (26%) of 62 receiving placebo, the most frequent of which were palmar-plantar erythrodysaesthesia (13 [10%] vs 0), hypertension (11 [9%] vs 2 [3%]), and fatigue (ten [8%] vs 0). Serious treatment-related adverse events occurred in 20 (16%) of 125 patients in the cabozantinib group and one (2%) of 62 in the placebo group. There were no treatment-related deaths.. Our results show that cabozantinib significantly prolongs progression-free survival and might provide a new treatment option for patients with radioiodine-refractory DTC who have no available standard of care.. Exelixis.

Topics: Aged; Anilides; Double-Blind Method; Drug Resistance, Neoplasm; Female; Humans; Male; Middle Aged; Progression-Free Survival; Pyridines; Thyroid Neoplasms

An integrated population pharmacokinetic (PPK) model was used to evaluate the effects of liver dysfunction on the pharmacokinetics (PK) of cabozantinib in patients with hepatocellular carcinoma and to determine whether clinical dosage adjustment may be necessary in this population. An integrated PPK model previously developed in healthy volunteers and patients with various cancer types was updated with cabozantinib concentration data from hepatocellular carcinoma patients in phase 2 and 3 studies (total 2023; hepatocellular carcinoma 489 patients). Covariate effects of cancer type including hepatocellular carcinoma population and liver dysfunction per the National Cancer Institute Organ Dysfunction Working Group criteria were evaluated (normal 1425; mild liver dysfunction 558; moderate/severe liver dysfunction 15/1 patients). With hepatocellular carcinoma patients, PK parameter estimates and covariate effects were similar to the previous PPK model (2 compartments with first- and zero-order absorption and first-order elimination). Only medullary thyroid cancer had appreciable PK differences from healthy volunteers. PK parameter estimates were similar with and without addition of liver dysfunction covariates. Patients with mild liver dysfunction were predicted to have minimal differences in apparent clearance of cabozantinib relative to patients with normal liver function. Therefore, no initial cabozantinib dosage adjustment is recommended for cancer patients with mild liver dysfunction. The small sample size for patients with moderate and severe liver dysfunction limited dosing recommendations in these subpopulations. The results from this PPK analysis were different from those of the single-dose hepatic impairment study in healthy volunteers and more reflective of exposure in cancer patients following daily cabozantinib dosing.

Topics: Adult; Aged; Aged, 80 and over; Anilides; Antineoplastic Agents; Carcinoma, Hepatocellular; Carcinoma, Neuroendocrine; Female; Humans; Liver; Male; Middle Aged; Pyridines; Thyroid Neoplasms

This study evaluated factors impacting QTc interval in a phase 3 trial of cabozantinib in progressive, metastatic, medullary thyroid cancer (MTC).. Electrocardiogram (12-lead ECG) measurements were obtained at screening, and at pre-dose, and 2, 4, and 6 h post-dose on Days 1 and 29 in a phase 3 study in patients with MTC treated with cabozantinib (140 mg/day). Central tendency analyses were conducted on baseline-corrected QTc values. Linear and nonlinear mixed-effects models were used to evaluate potential factors affecting the QTc interval, including serum electrolytes, patient demographics, and cabozantinib concentration.. Central tendency analysis showed that oral cabozantinib (140 mg/day) produced a 10-15 ms increase in delta-delta Fridericia corrected QT (∆∆QTcF) and delta-delta study-specific corrected QT (∆∆QTcS) on Day 29, but not on Day 1. Further analysis showed that QTcS provided a slightly more accurate QT correction than QTcF. Mixed-effects models evaluating serum electrolytes, age, sex, and cabozantinib concentration showed that decreased serum calcium and potassium could explain the majority of cabozantinib treatment-associated QTcS prolongation observed in this study.. Cabozantinib treatment prolongs the ∆∆QTcF interval by 10-15 ms. There was the absence of a strong relationship between cabozantinib concentration and QTcS prolongation. Cabozantinib treatment effects on serum calcium and potassium best explain the QTcS prolongation observed in this study.

Topics: Anilides; Antineoplastic Agents; Calcium; Carcinoma, Neuroendocrine; Double-Blind Method; Electrocardiography; Electrolytes; Female; Humans; Linear Models; Long QT Syndrome; Male; Neoplasm Metastasis; Nonlinear Dynamics; Potassium; Pyridines; Thyroid Neoplasms; Time Factors

Purpose Sorafenib and lenvatinib are oral multikinase inhibitors targeting vascular endothelial growth factor receptor (VEGFR) and approved for radioiodine (RAI)-refractory differentiated thyroid cancer (DTC). However, there are no approved second- or third-line therapies. MET is implicated in resistance to VEGFR inhibitors. Cabozantinib is an oral multikinase inhibitor targeting MET in addition to VEGFR and is approved for medullary thyroid cancer. In a phase I study of cabozantinib, five of eight patients with DTC previously treated with a VEGFR-targeted therapy had an objective response to cabozantinib. Patients and Methods Patients with RAI-refractory disease with Response Evaluation Criteria in Solid Tumor (RECIST) measurable disease and evidence of progression on prior VEGFR-targeted therapy were enrolled in this single-arm phase II study. The cabozantinib starting dose was 60 mg/day orally but could be escalated to 80 mg if the patient did not experience a response. Patients underwent tumor assessment according to RECIST v1.1 every 8 weeks. In this study, if at least five of 25 response-evaluable patients had an objective response, cabozantinib would be considered a promising agent in this patient population. Results Twenty-five patients were enrolled. The median age was 64 years, and 64% of patients were men. Twenty-one patients had received only one prior VEGFR-targeted therapy (sorafenib, pazopanib, or cediranib), and four patients had received two such therapies. The most common treatment-related adverse events were fatigue, weight loss, diarrhea, palmar-plantar erythrodysesthesia, and hypertension. One drug-related death was noted. Of the 25 patients, 10 (40%) had a partial response, 13 (52%) had stable disease, and two (8%) had nonevaluable disease. The median progression-free survival and overall survival were 12.7 months and 34.7 months, respectively. Conclusion Cabozantinib demonstrated clinically significant, durable objective response activity in patients with RAI-refractory DTC who experienced disease progression while taking prior VEGFR-targeted therapy.

Topics: Adult; Aged; Aged, 80 and over; Anilides; Cell Differentiation; Disease Progression; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Molecular Targeted Therapy; Prospective Studies; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyridines; Receptors, Vascular Endothelial Growth Factor; Salvage Therapy; Signal Transduction; Therapeutics; Thyroid Neoplasms; Time Factors; United States

Primary analysis of the double-blind, phase III Efficacy of XL184 (Cabozantinib) in Advanced Medullary Thyroid Cancer (EXAM) trial demonstrated significant improvement in progression-free survival with cabozantinib versus placebo in patients with progressive medullary thyroid cancer (MTC). Final analysis of overall survival (OS), a key secondary endpoint, was carried out after long-term follow-up.. EXAM compared cabozantinib with placebo in 330 patients with documented radiographic progression of metastatic MTC. Patients were randomized (2:1) to cabozantinib (140 mg/day) or placebo. Final OS and updated safety data are reported.. Minimum follow-up was 42 months. Kaplan-Meier analysis showed a 5.5-month increase in median OS with cabozantinib versus placebo (26.6 versus 21.1 months) although the difference did not reach statistical significance [stratified hazard ratio (HR), 0.85; 95% confidence interval (CI), 0.64-1.12; P = 0.24]. In an exploratory assessment of OS, progression-free survival, and objective response rate, cabozantinib appeared to have a larger treatment effect in patients with RET M918T mutation-positive tumors compared with patients not harboring this mutation. For patients with RET M918T-positive disease, median OS was 44.3 months for cabozantinib versus 18.9 months for placebo [HR, 0.60; 95% CI, 0.38-0.94; P = 0.03 (not adjusted for multiple subgroup analyses)], with corresponding values of 20.2 versus 21.5 months (HR, 1.12; 95% CI, 0.70-1.82; P = 0.63) in the RET M918T-negative subgroup. Median treatment duration was 10.8 months with cabozantinib and 3.4 months with placebo. The safety profile for cabozantinib remained consistent with that of the primary analysis.. The secondary end point was not met in this final OS analysis from the trial of cabozantinib in patients with metastatic, radiographically progressive MTC. A statistically nonsignificant increase in OS was observed for cabozantinib compared with placebo. Exploratory analyses suggest that patients with RET M918T-positive tumors may experience a greater treatment benefit with cabozantinib.. NCT00704730.

Topics: Aged; Anilides; Carcinoma, Medullary; Diagnostic Imaging; Double-Blind Method; Female; Follow-Up Studies; Humans; International Agencies; Male; Prognosis; Pyridines; Survival Rate; Thyroid Neoplasms

Cabozantinib significantly prolonged progression-free survival (PFS) versus a placebo in patients with progressive, metastatic medullary thyroid cancer (MTC; P < .001). An exploratory analysis of phase 3 trial data evaluated the influence of rearranged during transfection (RET) and RAS (HRAS, KRAS, and NRAS) mutations on cabozantinib clinical activity.. Patients (n = 330) were randomized to cabozantinib (140 mg/day) or a placebo. The primary endpoint was PFS. Additional outcome measures included PFS, objective response rates (ORRs), and adverse events in RET and RAS mutation subgroups.. Among all study patients, 51.2% were RET mutation-positive (38.2% with RET M918T), 34.8% were RET mutation-unknown, and 13.9% were RET mutation-negative. Sixteen patients were RAS mutation-positive. Cabozantinib appeared to prolong PFS versus the placebo in the RET mutation-positive subgroup (hazard ratio [HR], 0.23; 95% confidence interval [CI], 0.14-0.38; P < .0001), the RET mutation-unknown subgroup (HR, 0.30; 95% CI, 0.16-0.57; P = .0001), and the RAS mutation-positive subgroup (HR, 0.15; 95% CI, 0.02-1.10; P = .0317). The RET M918T subgroup achieved the greatest observed PFS benefit from cabozantinib versus the placebo (HR, 0.15; 95% CI, 0.08-0.28; P < .0001). The ORRs for RET mutation-positive, RET mutation-negative, and RAS mutation-positive patients were 32%, 22%, and 31%, respectively. No PFS benefit was observed in patients lacking both RET and RAS mutations, although the ORR was 21%. The safety profile for all subgroups was similar to that for the overall cabozantinib arm.. These data suggest that cabozantinib provides the greatest clinical benefit to patients with MTC who have RET M918T or RAS mutations. However, a prospective trial is needed to confirm the relation between genetic variation and the response to cabozantinib. Cancer 2016;122:3856-3864. © 2016 American Cancer Society.

Topics: Anilides; Disease-Free Survival; Double-Blind Method; Humans; Mutation; Proto-Oncogene Proteins c-ret; Pyridines; ras Proteins; Thyroid Neoplasms

Cabozantinib targets tyrosine kinases including MET, vascular endothelial growth factor (VEGF) receptor 2, and rearranged during transfection (RET). Differentiated thyroid cancer (DTC) is a tumor type that may be sensitive to cabozantinib. Therefore, we evaluated cabozantinib in a cohort of heavily pretreated patients with metastatic DTC.. This single-arm open-label phase I trial assessed the safety, tolerability, and antitumor activity of cabozantinib in DTC patients taking part in a drug-drug interaction study. Adult patients with histologically confirmed metastatic or surgically unresectable DTC (including papillary, follicular, or Hürthle cell) were enrolled. Patients received daily oral dosing of 140 mg cabozantinib. Safety was assessed by evaluation of adverse events (AEs), vital signs, electrocardiograms, laboratory tests, and concomitant medications. Tumor response by magnetic resonance imaging or computed tomography scan was investigator assessed using Response Evaluation Criteria In Solid Tumors (RECIST) v1.0.. The study enrolled 15 patients who had failed standard radioactive iodine therapy. Patients had received a median of two prior systemic agents, and 11 patients (73%) had previously received at least one VEGF pathway inhibiting therapy. Common AEs included diarrhea, nausea, fatigue, and decreased appetite. Partial response was reported in eight patients (53%). Median progression-free survival and median overall survival were not reached.. Cabozantinib demonstrates a safety profile similar to other multitargeted VEGFR inhibitors in advanced DTC patients. The antitumor activity observed in this study warrants further investigation of cabozantinib in patients with advanced DTC.

Topics: Administration, Oral; Adult; Aged; Anilides; Antineoplastic Agents; Carcinoma; Cell Differentiation; Disease-Free Survival; Drug Administration Schedule; Humans; Kaplan-Meier Estimate; Magnetic Resonance Imaging; Male; Middle Aged; Protein Kinase Inhibitors; Pyridines; Thyroid Neoplasms; Time Factors; Tomography, X-Ray Computed; Treatment Outcome; United States

RET kinase inhibitors have significant activity in patients with medullary thyroid carcinoma (MTC).. We retrospectively reviewed the electronic medical record for patterns of calcitonin, carcinoembryonic antigen (CEA) and tumor measurement responses in consecutive patients with MTC who received treatment with a RET inhibitor for at least 6 months.. Twenty-six patients who received RET kinase inhibitors for at least 6 months were included. All patients experienced an initial decline in calcitonin; 20 (77%) demonstrated later fluctuations in calcitonin, which spiked above baseline levels in 9 individuals (35%). Twenty of the 22 patients (91%) with elevated CEA experienced a decline with treatment, with 11 individuals (50%) later demonstrating transient fluctuations in CEA, including spikes above baseline in 7 patients (32%). Ten of the 26 patients (38%) also demonstrated short-lived fluctuations in RECIST measurements, including changes of over 20% from nadir values. Vacillations in calcitonin, CEA and measurements often occurred repeatedly in individual patients and did not regularly correlate with each other.. Repeated transient fluctuations in tumor markers and measurements are a characteristic of patients with MTC receiving treatment with RET inhibitors, and such short-term vacillations may not reflect responsiveness over the long term.. NCT00215605; NCT00244972; NCT00121680; NCT00495872.

Topics: Adult; Aged; Aged, 80 and over; Anilides; Antineoplastic Agents; Biomarkers, Tumor; Calcitonin; Carcinoembryonic Antigen; Carcinoma, Neuroendocrine; Disease Progression; Female; Humans; Indoles; Male; Middle Aged; Niacinamide; Phenylurea Compounds; Proto-Oncogene Proteins c-ret; Pyridines; Pyrroles; Quinolines; Quinolones; Retrospective Studies; Sorafenib; Sunitinib; Thyroid Neoplasms; Treatment Outcome; Valproic Acid

Cabozantinib, a tyrosine kinase inhibitor (TKI) of hepatocyte growth factor receptor (MET), vascular endothelial growth factor receptor 2, and rearranged during transfection (RET), demonstrated clinical activity in patients with medullary thyroid cancer (MTC) in phase I.. We conducted a double-blind, phase III trial comparing cabozantinib with placebo in 330 patients with documented radiographic progression of metastatic MTC. Patients were randomly assigned (2:1) to cabozantinib (140 mg per day) or placebo. The primary end point was progression-free survival (PFS). Additional outcome measures included tumor response rate, overall survival, and safety.. The estimated median PFS was 11.2 months for cabozantinib versus 4.0 months for placebo (hazard ratio, 0.28; 95% CI, 0.19 to 0.40; P < .001). Prolonged PFS with cabozantinib was observed across all subgroups including by age, prior TKI treatment, and RET mutation status (hereditary or sporadic). Response rate was 28% for cabozantinib and 0% for placebo; responses were seen regardless of RET mutation status. Kaplan-Meier estimates of patients alive and progression-free at 1 year are 47.3% for cabozantinib and 7.2% for placebo. Common cabozantinib-associated adverse events included diarrhea, palmar-plantar erythrodysesthesia, decreased weight and appetite, nausea, and fatigue and resulted in dose reductions in 79% and holds in 65% of patients. Adverse events led to treatment discontinuation in 16% of cabozantinib-treated patients and in 8% of placebo-treated patients.. Cabozantinib (140 mg per day) achieved a statistically significant improvement of PFS in patients with progressive metastatic MTC and represents an important new treatment option for patients with this rare disease. This dose of cabozantinib was associated with significant but manageable toxicity.

Topics: Adult; Aged; Aged, 80 and over; Anilides; Calcitonin; Carcinoembryonic Antigen; Carcinoma, Neuroendocrine; Disease-Free Survival; Double-Blind Method; Female; Humans; Male; Middle Aged; Protein Kinase Inhibitors; Pyridines; Thyroid Neoplasms

XL184 (cabozantinib) is a potent inhibitor of MET, vascular endothelial growth factor receptor 2 (VEGFR2), and RET, with robust antiangiogenic, antitumor, and anti-invasive effects in preclinical models. Early observations of clinical benefit in a phase I study of cabozantinib, which included patients with medullary thyroid cancer (MTC), led to expansion of an MTC-enriched cohort, which is the focus of this article.. A phase I dose-escalation study of oral cabozantinib was conducted in patients with advanced solid tumors. Primary end points included evaluation of safety, pharmacokinetics, and maximum-tolerated dose (MTD) determination. Additional end points included RECIST (Response Evaluation Criteria in Solid Tumors) response, pharmacodynamics, RET mutational status, and biomarker analyses.. Eighty-five patients were enrolled, including 37 with MTC. The MTD was 175 mg daily. Dose-limiting toxicities were grade 3 palmar plantar erythrodysesthesia (PPE), mucositis, and AST, ALT, and lipase elevations and grade 2 mucositis that resulted in dose interruption and reduction. Ten (29%) of 35 patients with MTC with measurable disease had a confirmed partial response. Overall, 18 patients experienced tumor shrinkage of 30% or more, including 17 (49%) of 35 patients with MTC with measurable disease. Additionally, 15 (41%) of 37 patients with MTC had stable disease (SD) for at least 6 months, resulting in SD for 6 months or longer or confirmed partial response in 68% of patients with MTC.. Cabozantinib has an acceptable safety profile and is active in MTC. Cabozantinib may provide clinical benefit by simultaneously targeting multiple pathways of importance in MTC, including MET, VEGFR2, and RET. A global phase III pivotal study in MTC is ongoing (ClinicalTrials.gov number NCT00215605).

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anilides; Antineoplastic Agents; Carcinoma, Neuroendocrine; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-ret; Pyridines; Thyroid Neoplasms

Medullary thyroid cancer (MTC) is a rare type of neuroendocrine tumor that produces a hormone called calcitonin (CT). Thyroidectomy is the preferred treatment for MTC, as chemotherapy has been shown to have limited effectiveness. Targeted therapy approaches are currently being used for patients with advanced, metastatic MTC. Several studies have identified microRNAs, including miR-21, as playing a role in the development of MTC. Programmed cell death 4 (PDCD4) is a tumor suppressor gene that is an important target of miR-21. Our previous research has shown that high levels of miR-21 are associated with low PDCD4 nuclear scores and high CT levels. The aim of this study was to investigate the potential of this pathway as a novel therapeutic target for MTC.. We used a specific process to silence miR-21 in two human MTC cell lines. We studied the effect of this anti-miRNA process alone and in combination with cabozantinib and vandetanib, two drugs used in targeted therapy for MTC. We analyzed the effect of miR-21 silencing on cell viability, PDCD4 and CT expression, phosphorylation pathways, cell migration, cell cycle, and apoptosis.. Silencing miR-21 alone resulted in a reduction of cell viability and an increase in PDCD4 levels at both mRNA and protein levels. It also led to a reduction in CT expression at both mRNA and secretion levels. When combined with cabozantinib and vandetanib, miR-21 silencing did not affect cell cycle or migration but was able to enhance apoptosis.. Silencing miR-21, although not showing synergistic activity with TKIs (tyrosine kinase inhibitors), represents a potential alternative worth exploring as a therapeutic target for MTC.

Topics: Apoptosis Regulatory Proteins; Biomarkers; Humans; MicroRNAs; Piperidines; Prognosis; RNA-Binding Proteins; RNA, Messenger; Thyroid Neoplasms

Cabozantinib (Cabometyx) is now approved to treat locally advanced or metastatic differentiated thyroid cancer that has progressed following prior vascular endothelial growth factor receptor-targeted therapy.

Topics: Anilides; Cell Differentiation; Humans; Protein Kinase Inhibitors; Pyridines; Thyroid Neoplasms; Vascular Endothelial Growth Factor A

Topics: Anilides; Antineoplastic Agents; Drug Approval; Humans; Iodine Radioisotopes; Protein Kinase Inhibitors; Thyroid Neoplasms

Topics: Anilides; Antineoplastic Agents; Carcinoma, Medullary; Drug Approval; Humans; Mutation; Phenylurea Compounds; Piperidines; Precision Medicine; Proto-Oncogene Proteins c-ret; Pyrazoles; Pyridines; Pyrimidines; Quinazolines; Quinolines; Thyroid Cancer, Papillary; Thyroid Neoplasms

Medullary thyroid cancer (MTC) is infrequently found among all thyroid nodules in previously iodine deficient regions. Measurement of serum calcitonin is an important tool for early identification of MTC among the large number of thyroid nodules. With the use of modern laboratory assays and sex-specific reference intervals, clinical diagnostic specificity has considerably improved. While the prognosis of MTC confined to the thyroid (stage I/II tumors) is favorable with a disease specific survival similar to the general population, biochemical cure rates by surgery decreases in extensive disease. Few patients present with aggressive tumours that show rapid progression or advanced disease at diagnosis. Oncogenic mutations in the RET protooncogene occur in ~25 % of patients as part of the multiple endocrine neoplasia type 2 syndromes and are present as somatic mutations in 60 % of all MTC and up to 90 % of metastatic cases.The multi-tyrosine kinase inhibitors vandetanib and cabozantinib have been approved for progressive advanced disease but have low specificity for the RET tyrosine kinase. With the advent of highly selective RET inhibitors selpercatinib and pralsetinib, the treatment landscape has profoundly changed. Selpercatinib is approved in the EU for treatment in the second and later lines of treatment. They have demonstrated a favorable safety profile and high objective response rates also in previously treated MTC patients. The use of selective RET inhibitors in the first line setting is currently the subject of clinical trials.. Calcitonin ist ein sensitiver und spezifischer Tumormarker zur Früherkennung und Verlaufskontrolle des MTC. Daneben kommt dem Ultraschall der Schilddrüse eine entscheidende Rolle zu.. Das medulläre Schilddrüsenkarzinom (MTC) nimmt seinen Ursprung aus den parafollikulären Calcitonin-produzierenden C-Zellen. Es macht nur ca. 3–8 % aller Schilddrüsenkarzinome aus. Aktivierende Mutationen im RET (rearranged during transfection)-Gen liegen bei etwa 25 % der Patienten in der Keimbahn vor, werden aber auch beim sporadischen MTC als somatische Mutationen in ca. 60 % der Fälle beobachtet. Bei metastasierter Erkrankung findet sich in 90 % eine RET-Mutation. RET-Mutationen gelten als Treibermutationen und schließen weitere Treibermutationen weitestgehend aus. Seltener sind somatische Mutationen der RAS-Gene.. Die chirurgische Resektion ist bis heute der einzige kurative Therapieansatz. Entscheidend für eine frühzeitige Diagnosestellung ist die Bestimmung des Serum-Calcitonins bei Nachweis von Schilddrüsenknoten. Die chirurgische Therapie steht auch bei der Behandlung lokoregionärer Rezidive oder lokal angehbarer Metastasen im Zentrum.. Bei irresektabel fortgeschrittener und progredienter Erkrankung mit signifikanter Tumorlast kann eine systemische Therapie erforderlich werden. Neuerdings ist die Kenntnis einer RET-Mutation im Tumorgewebe therapeutisch relevant, da mit den selektiven RET-Inhibitoren Selpercatinib und zukünftig Pralsetinib neue, effektive und gut verträgliche Systemtherapien zur Verfügung stehen. Ihr Einsatz ist nach Vortherapie mit einem der Multityrosinkinase-Inhibitoren Vandetanib oder Cabozantinib zugelassen und wird derzeit in der Erstlinientherapie in klinischen Studien untersucht.

Topics: Anilides; Antineoplastic Agents; Carcinoma, Neuroendocrine; Humans; Piperidines; Pyridines; Quinazolines; Thyroid Neoplasms

The use of tyrosine kinase inhibitors (TKIs) in thyroid cancer patients is often limited by toxicities. Some have a long-term onset and potentially could impact patients' survival. Among them, there is the nephrotoxicity, mainly represented by proteinuria. The aim of the study was to evaluate the prevalence of proteinuria in medullary thyroid cancer patients treated with cabozantinib, to examine whether it could be a marker for treatment monitoring and to evaluate histological kidney alterations.. We collected data of 31 medullary thyroid cancer patients enrolled in the EXAM trial. Proteinuria was defined and evaluated using the National Cancer Institute's Common Terminology Criteria for Adverse Events. In two symptomatic cases with high-grade proteinuria, a kidney biopsy was performed.. Proteinuria was observed in 4/18 patients (22.2%) and occurred after a mean period of 38 months (median: 35.5 months). It was significantly associated with previous chemotherapy (p = 0.005) and/or treatment with other TKIs (p = 0.04), a prolonged use of cabozantinib (p = 0.0004), and a better radiological response at the end of follow-up (p = 0.002). The kidney biopsy showed pathognomonic features of thrombotic microangiopathy in both cases and a focal amyloid deposit in one.. Proteinuria is a quite frequent adverse event during cabozantinib treatment. It is relatively well manageable with the early detection and correction of risk factors, the temporary discontinuation of cabozantinib and/or its dose reduction, and the use of anti-proteinuric and renoprotective drugs in patient with hypertension. The histological findings confirmed some typical features of the anti-VEGF inhibition injury, already described for other TKIs.

Topics: Age of Onset; Anilides; Carcinoma, Neuroendocrine; Female; Follow-Up Studies; Humans; Male; Middle Aged; Prognosis; Protein Kinase Inhibitors; Proteinuria; Pyridines; Retrospective Studies; Thyroid Neoplasms

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anilides; Antineoplastic Agents; Carcinoma, Neuroendocrine; Female; Germany; Humans; Male; Middle Aged; Piperidines; Progression-Free Survival; Protein Kinase Inhibitors; Pyridines; Quinazolines; Registries; Retrospective Studies; Thyroid Neoplasms; Time Factors; Young Adult

Medullary thyroid carcinoma (MTC) is a tumor deriving from the thyroid C cells. Vandetanib (VAN) and cabozantinib (CAB) are two tyrosine kinase inhibitors targeting REarranged during Transfection (RET) and other kinase receptors and are approved for the treatment of advanced MTC. We aim to compare the in vitro and in vivo anti-tumor activity of VAN and CAB in MTC. The effects of VAN and CAB on viability, cell cycle, and apoptosis of TT and MZ-CRC-1 cells are evaluated in vitro using an MTT assay, DNA flow cytometry with propidium iodide, and Annexin V-FITC/propidium iodide staining, respectively. In vivo, the anti-angiogenic potential of VAN and CAB is evaluated in

Topics: Angiogenesis Inhibitors; Anilides; Animals; Apoptosis; Carcinoma, Neuroendocrine; Cell Cycle; Cell Line, Tumor; Cell Survival; Disease Models, Animal; Embryo, Nonmammalian; Humans; Neovascularization, Pathologic; Neovascularization, Physiologic; Piperidines; Pyridines; Quinazolines; Thyroid Neoplasms; Zebrafish

Topics: Adult; Anilides; Benzamides; Drug Resistance, Neoplasm; ETS Translocation Variant 6 Protein; Gene Fusion; Humans; Indazoles; Male; Mutation; Proto-Oncogene Proteins c-ets; Pyridines; Receptor, trkC; Repressor Proteins; Thyroid Neoplasms; Treatment Outcome

Medullary thyroid carcinoma (MTC) accounts for 1% to 2% of thyroid cancers in the United States. When identified early, total thyroidectomy is most often curative. However, in advanced disease, more aggressive treatment such as laryngectomy and esophagectomy may be indicated. Postsurgical fistula formation and leak is a potential complication in such cases. These fistulas are most likely to occur at the anastomotic site in cases of laryngectomy or esophagectomy. Concomitant chemotherapy and radiation increase this risk. Tyrosine kinase inhibitors (TKI) such as Cabozantinib are used as therapy for metastatic MTC. These drugs have previously been associated with dehiscence of anastomotic sites in the gastrointestinal tract. While previously identified in the bowel, this report represents the first documented case of gastropharyngeal anastomosis leak described in the context of TKI use for head and neck cancer.. We present the case of a 72-year-old male previously diagnosed with MTC. His gastropharyngeal anastomosis status-post laryngopharyngectomy and gastric pull up had been stable for 23 years. Over the past year, he developed back pain and was found to have spinal metastases of MTC. He was subsequently started on Cabozantinib to slow the progression of the disease. Within months of starting this TKI, a bleeding pharyngocutaneous fistula developed at the anastomosis site of the gastric pull up and pharynx. Upon discontinuation of Cabozantinib, the fistula healed with no further complications.. To our knowledge, this is the first documented case of gastropharyngeal anastomotic leak related to TKI use. A causal relationship is highly plausible given the previously stable anastomosis and the suspicious advent of complications within months of initiation of this new drug. While previously limited to cases of intraabdominal bowel dehiscence, this report now suggests that wound dehiscence must be considered a known side effect of TKIs throughout the gastrointestinal tract, including the gastropharynx. As such, the risk of anastomotic dehiscence should be discussed with the patient prior to starting a TKI.

Topics: Aged; Anastomosis, Surgical; Anastomotic Leak; Anilides; Carcinoma, Neuroendocrine; Esophagectomy; Humans; Laryngectomy; Male; Pharynx; Protein Kinase Inhibitors; Pyridines; Spinal Neoplasms; Stomach; Thyroid Neoplasms; Thyroidectomy

Since patients with medullary thyroid cancer (MTC) often have metastatic disease at the time of diagnosis, the development of efficient systemic treatment options for MTC is important. Vandetanib and cabozantinib are two tyrosine kinase inhibitors (TKIs) that were recently approved by FDA and EMA for systemic treatment of metastatic MTC. Additionally, since MTC is of a neuroendocrine tumour type, treatment with radiolabelled somatostatin analogues (e.g. 177Lu-octreotate) is a valid option for patients with MTC. The aim of this study was to investigate the potentially increased therapeutic effect of combining radiation therapy with these TKIs for treatment of MTC in a mouse model. Nude mice carrying patient-derived MTC tumours (GOT2) were treated with external beam radiotherapy (EBRT) and/or one of the two TKIs vandetanib or cabozantinib. The tumour volume was determined and compared with that of mock-treated controls. The treatment doses were chosen to give a moderate effect as monotherapy to be able to detect any increased therapeutic effect from the combination therapy. At the end of follow-up, tumours were processed for immunohistochemical (IHC) analyses. The animals in the combination therapy groups showed the largest reduction in tumour volume and the longest time to tumour progression. Two weeks after start of treatment, the tumour volume for these mice was reduced by about 70-75% compared with controls. Furthermore, also EBRT and TKI monotherapy resulted in a clear anti-tumour effect with a reduced tumour growth compared with controls. The results show that an increased therapeutic effect could be achieved when irradiation is combined with TKIs for treatment of MTC. Future studies should evaluate the potential of using 177Lu-octreotate therapy in combination with TKIs in patients.

Topics: Anilides; Animals; Carcinoma, Neuroendocrine; Chemoradiotherapy; Female; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Proteins; Piperidines; Protein-Tyrosine Kinases; Pyridines; Quinazolines; Thyroid Neoplasms; Xenograft Model Antitumor Assays

Topics: Anilides; Antineoplastic Agents; Carcinoma, Hepatocellular; Carcinoma, Neuroendocrine; Carcinoma, Renal Cell; Drug Approval; Humans; Kidney Neoplasms; Liver Neoplasms; Pyridines; Thyroid Neoplasms; United States; United States Food and Drug Administration

Topics: Anilides; Animals; Apoptosis; Carcinoma, Medullary; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Humans; Mice; MicroRNAs; Proto-Oncogene Mas; Proto-Oncogene Proteins c-ret; Pyridines; Receptor Protein-Tyrosine Kinases; Thyroid Neoplasms

Topics: Anilides; Humans; Mitochondria; Piperidines; Pyridines; Quinazolines; Thyroid Neoplasms

XL184 is a small-molecule kinase inhibitor recently included in first-line systemic therapy for patients with advanced, progressive medullary thyroid cancer (MTC). EF24 is a curcumin analog with a high bioavailability, and ZSTK474 is an inhibitor of the phosphatidylinositol 3-kinase signaling pathway. We investigated the effect of these compounds, alone and in combination, in two rearranged during transfection (RET)-mutated TT and MZ-CRC-1 MTC cell lines and in six mostly RET wild-type human MTC primary cultures. Low IC50 values demonstrated the efficacy of the drugs, whereas the combination index revealed an important synergistic effect of combinations of XL184 + ZSTK474 and XL184 + EF24. Cell-cycle changes and the induction of apoptosis or necrosis were modulated by single compounds or combinations thereof. Both XL184 and EF24, alone or combined, were effective in reducing calcitonin secretion. Western blot and in-cell Western analysis showed that the compounds prompted a decrease in general reactivity to phosphorylated antibodies. Our data confirm XL184 alone as the reference drug for RET-mutated MTC, but we also demonstrated that EF24 alone is effective in inhibiting MTC cell viability. We tested the combinations XL184 + ZSTK474 and XL184 + EF24 too, finding that they act synergistically, irrespective of RET mutation status.

Topics: Aged; Anilides; Antineoplastic Agents; Benzylidene Compounds; Carcinoma, Neuroendocrine; Cell Proliferation; Drug Synergism; Female; Humans; Male; Middle Aged; Piperidones; Pyridines; Thyroid Neoplasms; Triazines; Tumor Cells, Cultured

Topics: Anilides; Animals; Carcinoma, Neuroendocrine; Cell Cycle; Cell Line, Tumor; Cell Survival; Disease Models, Animal; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Membrane Potential, Mitochondrial; Mice; Mitochondria; Mitochondrial Dynamics; Piperidines; Protein Kinase Inhibitors; Pyridines; Quinazolines; Thyroid Neoplasms; Xenograft Model Antitumor Assays

Cabozantinib is an oral multiple tyrosine kinase receptor inhibitor (ITK): VEGFR2, c-MET and RET. Inhibition of VEGFR and c-MET decrease resistance of VEGFR inhibitor via c-MET axis. Cabozantinib improve progression-free survival (PFS) in progressive metastatic medullary thyroid cancer (MTC): 4 months in the placebo group and 11.2 months in the cabozantinib group (P<0.001) in all patient subgroups including those with or without prior ITK and RET mutation status. Cabozantinib increased overall survival (OS) compared with everolimus in patients with advanced renal cell carcinoma who progressed after previous VEGFR ITK treatment: 21.4 months in cabozantinib group and 16.5 months in everolimus group (P<0.0003). Cabozantinib obtained the AMM for the treatment of progressive metastatic MTC and advanced renal cell carcinoma. Cabozantinib is a new option in the treatment of MTC by inclusion in therapeutic trials (no payment in this indication) and advanced renal cell carcinoma (hospital delivery). Its tolerance is similar to anti-angiogenic therapies and justifies an optimal management of the secondary effect.

Topics: Anilides; Antineoplastic Agents; Bone Neoplasms; Carcinoma, Neuroendocrine; Carcinoma, Non-Small-Cell Lung; Carcinoma, Renal Cell; Clinical Trials as Topic; Disease-Free Survival; Everolimus; Humans; Kidney Neoplasms; Lung Neoplasms; Male; Piperidines; Prostatic Neoplasms; Proto-Oncogene Proteins c-ret; Pyridines; Quinazolines; Receptor Protein-Tyrosine Kinases; Thyroid Neoplasms; Vascular Endothelial Growth Factor Receptor-2

Medullary thyroid cancer (MTC) is an aggressive tumor that harbors activating mutations of the RET proto-oncogene. We previously reported that RET inhibits transcriptional activity of ATF4, the master regulator of the stress response pathway, to prevent cell death.. We hypothesized that loss of function of ATF4 plays a role in initiation of MTC.. Targeted deletion of Atf4 in mice was used to assess ATF4 function in the thyroid gland. ATF4 overexpression was achieved by adenoviral and lentiviral vectors. We used immunohistochemical analysis and western blotting of MTC tumors to determine protein levels of RET and ATF4 and the Kaplan-Meier method to determine their association with clinical outcome.. Targeted deletion of Atf4 in mice causes C-cell hyperplasia, a precancerous lesion for MTC. Forced ATF4 expression decreased survival of MTC cells and blocked the activation of RET downstream signaling pathways (phosphorylated ERK, phosphorylated AKT, and p70S6K). ATF4 knockdown decreased sensitivity to tyrosine kinase inhibitor-induced apoptosis. Moreover, ATF4 expression decreased RET protein levels by promoting RET ubiquitination. We found decreased or loss of ATF4 in 52% of MTC tumors (n = 39) compared with normal thyroid follicle cells. A negative correlation was observed between RET and ATF4 protein levels in MTC tumors, and low ATF4 expression was associated with poor overall survival in patients with MTC.. ATF4 was identified as a negative regulator of RET, a candidate tumor suppressor gene, and may be a molecular marker that distinguishes patients at high risk of MTC from those with a longer survival prognosis.

Topics: Activating Transcription Factor 4; Adolescent; Adult; Aged; Aged, 80 and over; Anilides; Animals; Apoptosis; Blotting, Western; Carcinoma, Neuroendocrine; Cell Proliferation; Cell Survival; Female; Genes, Tumor Suppressor; HEK293 Cells; Humans; Immunohistochemistry; Indoles; Kaplan-Meier Estimate; Male; Mice; Mice, Knockout; Middle Aged; Protein Kinase Inhibitors; Proto-Oncogene Mas; Proto-Oncogene Proteins c-ret; Pyridines; Pyrroles; Real-Time Polymerase Chain Reaction; Sunitinib; Thyroid Gland; Thyroid Neoplasms; Ubiquitination; Young Adult

Aberrant RET kinase signaling plays critical roles in several human cancers such as thyroid carcinoma. The gatekeeper mutants (V804L or V804M) of RET are resistant to currently approved RET inhibitors such as cabozantinib and vandetanib. We, for the first time, report a highly selective and extremely potent RET inhibitor, 6i rationally designed. Compound 6i inhibits strongly RET gatekeeper mutants and other clinically relevant RET mutants as well as wt-RET. This substance also significantly suppresses growth of thyroid cancer-derived TT cell lines and Ba/F3 cells transformed with various RET mutants. Docking studies reveal that the isoxazole moiety in 6i is responsible for binding affinity improvement by providing additional site for H-bonding with Lys758. Also, 6i not only substantially blocks cellular RET autophosphorylation and its downstream pathway, it markedly induces apoptosis and anchorage-independent growth inhibition in TT cell lines while having no effect on normal thyroid Nthy ori-3-1 cells.

Topics: Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Survival; Drug Design; Drug Resistance, Neoplasm; Humans; Models, Molecular; Molecular Docking Simulation; Mutation; Phosphorylation; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-ret; Quinazolines; Structure-Activity Relationship; Substrate Specificity; Thyroid Neoplasms

Cabozantinib is a tyrosine kinase inhibitor approved in the USA and EU for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC). The indicated cabozantinib dose is 140 mg/day, with dose modifications allowed for patients who develop adverse events (AEs). The analysis objective was to develop a population pharmacokinetic (PopPK) model in MTC patients and to use the model for exposure-response (ER) analysis of dose modifications.. A PopPK model for cabozantinib was developed using data from three clinical trials (2079 evaluations from 289 patients), including a randomized, double-blind, placebo-controlled phase III study of patients with progressive, metastatic MTC. The PopPK model predictions [model-predicted steady-state area under the plasma concentration-time curve (AUCss,pred)] were used for an ER analysis of the time to first dose modification.. The final PopPK model was a one-compartment model with first-order absorption and first-order elimination. Estimated cabozantinib apparent oral clearance (CL/F) and apparent volume of distribution (V c/F) were 106 L/day [±2.98 % relative standard error (RSE)] (males) and 349 L (±2.73 % RSE), respectively. CL/F was reduced by 22 % (to 83 L/day) in females. Sex and body mass index (BMI) were significant covariates that combined contributed 15 % to the variability in cabozantinib CL/F, but did not warrant dose adjustment. Higher cabozantinib AUCss,pred was correlated to an increased risk of early dose modification and a lower average dose through to Day 85. Early cabozantinib dose modification was not associated with a reduction in progression-free survival (PFS).. A PopPK model was developed for cabozantinib pharmacokinetics in MTC patients. Higher cabozantinib exposure was associated with earlier first dose modification and a lower average administered dose through to Day 85. Early first dose modification did not appear to impact PFS.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anilides; Carcinoma, Neuroendocrine; Clinical Trials as Topic; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Models, Biological; Protein Kinase Inhibitors; Pyridines; Randomized Controlled Trials as Topic; Thyroid Neoplasms; Treatment Outcome; Young Adult

Cabozantinib is a multi-targeted tyrosine kinase inhibitor targeting vascular endothelial growth factor (VEGF) receptor (VEGFR)-2, MET (c-Met, also called hepatocyte growth factor (HGF) receptor), and other receptor tyrosine kinases. Cabozantinib has recently been approved for treating advanced medullary thyroid carcinoma (MTC), but its long-term benefit remains uncertain and dose-dependent adverse events are very common. The present study has demonstrated that 2-methoxyestradiol (2ME2), an inhibitor of hypoxia-inducible factors (HIFs) and a promising anticancer agent under investigation in clinical trials, strengthens anticancer activities of cabozantinib against MTC cells in vitro and in vivo. The activated hypoxia-inducible pathways, which are mainly regulated by HIF-1, contribute to the resistance of hypoxic MTC cells to cabozantinib. Cabozantinib upregulated HIF-1α expression at translational levels and increased the expression of the downstream factors including VEGF, lactate dehydrogenase A (LDHA), HGF, and MET. 2ME2 corrected the activated pathways by cabozantinib through downregulating HIF-1α expression and inhibiting its nuclear translocation in hypoxic MTC cells. Administration of 2ME2 enhanced the efficacy of cabozantinib in suppressing the growth of MTC cell line xenografts and patient-derived xenografts established in mice. Given that 2ME2 targets insensitive hypoxic cancer cells to cabozantinib and can inhibit the activated pathways by cabozantinib, the present results warrant further investigation of 2ME2, particularly in combination with cabozantinib, for the treatment of MTC.

Topics: 2-Methoxyestradiol; Active Transport, Cell Nucleus; Adult; Anilides; Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Neuroendocrine; Cell Proliferation; Cell Survival; Estradiol; Female; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Isoenzymes; Ki-67 Antigen; L-Lactate Dehydrogenase; Lactate Dehydrogenase 5; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Pyridines; Signal Transduction; Thyroid Neoplasms; Xenograft Model Antitumor Assays

Nonlinear mixed effects models were developed to describe the relationship between cabozantinib exposure and target lesion tumor size in a phase III study of patients with progressive metastatic medullary thyroid cancer. These models used cabozantinib exposure estimates from a previously published population pharmacokinetic model for cabozantinib in cancer patients that was updated with data from healthy-volunteer studies. Semi-mechanistic models predict well for tumors with static, increasing, or decreasing growth over time, but they were not considered adequate for predicting tumor sizes in medullary thyroid cancer patients, among whom an early reduction in tumor size was followed by a late stabilization phase in those receiving cabozantinib. A semi-empirical tumor model adequately predicted tumor profiles that were assumed to have a net growth rate constant that was piecewise continuous in the regions of 0-110 and 110-280 days. Emax models relating average concentration to average change in tumor size predicted that an average concentration of 79 and 58 ng/ml, respectively, would yield 50% of the maximum possible tumor reduction during the first 110 days of dosing and during the subsequent 110-280 days of dosing. Simulations of tumor responses showed that daily doses of 60 mg or greater are expected to provide a similar tumor reduction. Both model evaluation of observed data and simulation results suggested that the two protocol-defined cabozantinib dose reductions from 140 to 100 mg/day and from 100 to 60 mg/day are not projected to result in a marked reduction in target lesion regrowth.

Topics: Anilides; Antineoplastic Agents; Carcinoma, Neuroendocrine; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Dose-Response Relationship, Drug; Humans; Models, Biological; Pyridines; Randomized Controlled Trials as Topic; Thyroid Neoplasms; Tumor Burden

Surgery is the mainstay of treatment for medullary thyroid cancer. Cytotoxic chemotherapy is generally ineffective in patients with progressive, inoperable, advanced-stage or metastatic tumours. Vandetanib is also authorised in this setting, but it has more harms than benefits. Cabozantinib, like vandetanib, inhibits several tyrosine kinases involved in angiogenesis. Cabozantinib has been authorised in the European Union for use in this setting. In a randomised, placebo-controlled trial in 330 patients, adding cabozantinib to tailored symptomatic treatment did not prolong survival or improve symptoms, despite a favourable effect on tumour imaging and certain laboratory parameters. On the contrary, cabozantinib appeared to undermine quality of life and aggravate diarrhoea. The known adverse effects of cabozantinib are numerous and often severe: diarrhoea, hand-foot syndrome, hypertension, venous and arterial thrombosis, bleeding and fistulae. Deaths unrelated to tumour progression were more frequent with cabozantinib than with placebo. Cabozantinib carries a risk of multiple pharmacokinetic interactions by interfering with cytochrome P450 isoenzyme CYP3A4 and P-glycoprotein. In animals, cabozantinib is teratogenic and also impairs male and female fertility. Contraception is required for women, and also for the partners of treated men, who must use condoms. These precautions must be maintained for at least 4 months after the end of treatment. In practice, in mid-2015, cabozantinib, like vandetanib, has an unfavourable harm-benefit balance in medullary thyroid cancer. The focus should remain on tailored symptomatic care.

Topics: Anilides; Antineoplastic Agents; Carcinoma, Neuroendocrine; Female; Humans; Male; Piperidines; Protein Kinase Inhibitors; Pyridines; Quality of Life; Quinazolines; Thyroid Neoplasms

The aim of this study was to determine the genomic alterations of cancer-related genes in advanced medullary thyroid carcinoma during the course of clinical care.. Hybrid-capture-based comprehensive genomic profiling was performed on 34 consecutive medullary thyroid carcinoma cases to identify all four classes of genomic alterations, and outcome for an index patient was collected.. RET was mutated in 88% (30/34) of cases, with RET M918T being responsible for 70% (21/30) of the RET alterations. The other RET alterations were RET E632_L633del, C634R, C620R, C618G/R/S, V804M, and RET amplification. Two of the four RET wild-type patients harbored mutations in KRAS or HRAS (1/34 each). The next most frequent genomic alterations were amplifications of CCND1, FGF3, and FGF19 and alterations in CDKN2A (3/34 each). One case with a RET M918T mutation developed acquired resistance to progressively dose-escalated vandetanib. When the mTOR inhibitor everolimus was added to continued vandetanib treatment, the patient achieved a second 25% reduction of tumor volume (RECIST 1.1) for 8 months.. Comprehensive genomic profiling identified the full breadth of RET alterations in metastatic medullary thyroid carcinoma and possible cooperating oncogenic driver alterations. This approach may refine the use of targeted therapy for these patients.

Topics: Aged; Anilides; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Neuroendocrine; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p16; Drug Resistance, Neoplasm; Everolimus; Female; Fibroblast Growth Factor 3; Fibroblast Growth Factors; Gene Amplification; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Male; Methionine; Middle Aged; Molecular Targeted Therapy; Mutation; Piperidines; Proto-Oncogene Proteins c-ret; Proto-Oncogene Proteins p21(ras); Pyridines; Quinazolines; Threonine; Thyroid Neoplasms

Since the discovery of bisphosphonate-related osteonecrosis of the jaw, there has been increasing evidence in recent years of osteonecrosis induced by drugs other than bisphosphonates, mainly agents with antiangiogenic and antiosteoclastic activity. Mandibular osteonecrosis was observed in a 51-year-old female with medullary thyroid cancer receiving cabozantinib, a new tyrosine kinase inhibitor having antiangiogenic activity. The bone necrosis appeared after a dental extraction. The clinical, radiographic and histologic picture of a chronic non-healing extraction socket was consistent with drug-induced osteonecrosis of the jaw. Healing was achieved by segmental ostectomy. The osteonecrosis was likely associated with a vascular endothelial growth factor (VEGF) pathway inhibition, implying inhibition of angiogenesis and hampering of the local host defence mechanisms.

Topics: Anilides; Bone Density Conservation Agents; Female; Humans; Mandible; Mandibular Diseases; Middle Aged; Osteonecrosis; Protein Kinase Inhibitors; Pyridines; Thyroid Neoplasms; Tooth Extraction

In Spain medullary thyroid carcinoma (MTC) would not exceed 80 new cases per year and less than half of them would be good candidates for systemic treatment with novel agents.. Relevant literature was reviewed, including PubMed searches supplemented with additional articles.. The consensus summarizes the clinical outcomes in terms of activity and toxicity of each of the available drugs. A brief summary of the minimum requirements in terms of follow up and genetic counseling around MTC is also included.. Only those patients with objective imaging progression in the last 12-14 months with large volume of disease are clear candidates to start systemic treatment. However, those patients with low disease volume should be considered for 'wait and see' strategy until symptoms of the disease appear. Multidisciplinary approach for the management of MTC patient is mandatory nowadays.

Topics: Anilides; Antineoplastic Agents; Biomarkers, Tumor; Calcitonin; Carcinoembryonic Antigen; Carcinoma, Medullary; Combined Modality Therapy; Diagnostic Imaging; Disease Management; Doxorubicin; Genetic Association Studies; Humans; Neoplasm Metastasis; Prognosis; Proto-Oncogene Proteins c-ret; Pyridines; Radiotherapy; Thyroid Neoplasms

The aberrant silencing of iodide-handling genes accompanied by up-regulation of glucose metabolism presents a major challenge for radioiodine treatment of papillary thyroid cancer (PTC).. This study aimed to evaluate the effect of tyrosine kinase inhibitors on iodide-handling and glucose-handling gene expression in BHP 2-7 cells harboring RET/PTC1 rearrangement.. In this in vitro study, the effects of sorafenib or cabozantinib on cell growth, cycles, and apoptosis were investigated by cell proliferation assay, cell cycle analysis, and Annexin V-FITC apoptosis assay, respectively. The effect of both agents on signal transduction pathways was evaluated using the Western blot. Quantitative real-time PCR, Western blot, immunofluorescence, and radioisotope uptake assays were used to assess iodide-handling and glucose-handling gene expression.. Both compounds inhibited cell proliferation in a time-dependent and dose-dependent manner and caused cell cycle arrest in the G0/G1 phase. Sorafenib blocked RET, AKT, and ERK1/2 phosphorylation, whereas cabozantinib blocked RET and AKT phosphorylation. The restoration of iodide-handling gene expression and inhibition of glucose transporter 1 and 3 expression could be induced by either drug. The robust expression of sodium/iodide symporter induced by either agent was confirmed, and (125)I uptake was correspondingly enhanced. (18)F-fluorodeoxyglucose accumulation was significantly decreased after treatment by either sorafenib or cabozantinib.. Sorafenib and cabozantinib had marked effects on cell proliferation, cell cycle arrest, and signal transduction pathways in PTC cells harboring RET/PTC1 rearrangement. Both agents could be potentially used to enhance the expression of iodide-handling genes and inhibit the expression of glucose transporter genes.

Topics: Anilides; Antineoplastic Agents; Apoptosis; Autoantigens; Carcinoma, Papillary; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Glucose Transporter Type 1; Glucose Transporter Type 3; Humans; Iodide Peroxidase; Iron-Binding Proteins; Microfilament Proteins; Muscle Proteins; Niacinamide; Phenylurea Compounds; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-ret; Pyridines; Receptors, Thyrotropin; Signal Transduction; Sorafenib; Symporters; Thyroid Neoplasms

Clinical evidence shows that dual inhibition of kinases as well angiogenesis provides ideal therapeutic option in the treatment of medullary thyroid carcinoma (MTC) than inhibiting either of these with the events separately. Although treatment with dual inhibitors has shown good clinical responses in patients with MTC, it has been associated with serious side effects. Some inhibitors are active agents for both angiogenesis or kinase activity. Owing to narrow therapeutic window of established inhibitors, the present study aims to identify high affinity dual inhibitors targeting RET and VEGFR2 respectively for kinase and angiogenesis activity. Established inhibitors like Vandetanib, Cabozantinib, Motesanib, PP121, RAF265 and Sunitinib served as query parent compounds for identification of structurally similar compounds by Tanimoto-based similarity searching with a threshold of 95% against the PubChem database. All the parent inhibitors and respective similar compounds were docked against RET and VEGFR2 in order to retrieve high affinity compounds with these two proteins. AGN-PC-0CUK9P PubCID: 59320403 a compound related to PPI21 showed almost equal affinity for RET and VEGFR2 and unlike other screened compounds with no apparent bias for either of the receptors. Further, AGN- PC-0CUK9P demonstrated appreciable interaction with both RET and VEGFR2 and superior kinase activity in addition to showed optimal ADMET properties and pharmacophore features. From our in silico investigation we suggest AGN-PC-0CUK9P as a superior dual inhibitor targeting RET and VEGFR2 with high efficacy which should be proposed for pharmacodynamic and pharmacokinetic studies for improved treatment of MTC.

Topics: Angiogenesis Inhibitors; Anilides; Carcinoma, Neuroendocrine; Databases, Chemical; Drug Discovery; Humans; Imidazoles; Indoles; Molecular Docking Simulation; Molecular Structure; Niacinamide; Oligonucleotides; Piperidines; Protein Binding; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-ret; Pyrazoles; Pyridines; Pyrimidines; Pyrroles; Quinazolines; Sunitinib; Thyroid Neoplasms; Vascular Endothelial Growth Factor Receptor-2

In the past decade, targeted therapy with antiangiogenic drugs has become standard of care for most types of metastatic, progressive thyroid cancer. While these drugs were thought initially to be less toxic than traditional chemotherapy, they can have rare but serious and fatal toxicities. Once such toxicity that has been reported in other tumor types is upper airway fistula formation, which can be life-threatening.. Here, we describe three patients treated with antiangiogenic tyrosine kinase inhibitors at two academic institutions who developed aerodigestive fistula. All three patients had risk factors for fistula formation, which included external beam radiation and/or large tumor with invasion of the tracheal wall.. Fistula formation is a known but rare side effect of antiangiogenic tyrosine kinase inhibitors. Knowledge of the risk factors that may predispose thyroid cancer patients to this serious adverse event is vital prior to prescribing antiangiogenics. Particular caution should be observed when using these drugs in patients undergoing radiation therapy or surgery, or in patients whose tumor is invading vital structures of the neck, as they may be at higher risk of developing this rare complication. In these patients, antiangiogenic tyrosine kinase inhibitors should be used cautiously, patients should be aware of the risk, and physicians should monitor patients for symptoms of fistula.

Topics: Academic Medical Centers; Angiogenesis Inhibitors; Anilides; Combined Modality Therapy; Drugs, Investigational; Esophageal Fistula; Fatal Outcome; Humans; Indoles; Male; Middle Aged; Neck Dissection; Phenylurea Compounds; Postoperative Complications; Protein Kinase Inhibitors; Pyridines; Pyrroles; Quinolines; Receptor Protein-Tyrosine Kinases; Respiratory Tract Fistula; Risk Factors; Sunitinib; Texas; Thyroid Neoplasms; Thyroidectomy; Tracheoesophageal Fistula

Medullary thyroid cancer (MTC) is a rare form of thyroid cancer comprising approximately 4% of all thyroid cancers. The majority of patients have a relatively good prognosis; however, a subgroup of patients will require systemic therapy. Large phase III randomized trials led to the approval of two drugs--vandetanib and cabozantinib--for progressive or symptomatic MTC. The decision regarding which drug to initiate first is not entirely clear and is a common concern amongst treating physicians.. A review of the literature in English was conducted, and data were summarized and integrated into a decision matrix.. The decision regarding which drug to initiate first for progressive MTC should be based on a careful review of the medical history, physical examination findings, medication list, electrocardiogram, laboratory results, and tumor characteristics. It is necessary to consider the relative contraindications when choosing which drug to initiate first.

Topics: Anilides; Carcinoma, Neuroendocrine; DNA Mutational Analysis; Humans; Male; Middle Aged; Piperidines; Precision Medicine; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyridines; Quinazolines; Thyroid Neoplasms; Thyroidectomy

These NCCN Guidelines Insights focus on some of the major updates to the 2014 NCCN Guidelines for Thyroid Carcinoma. Kinase inhibitor therapy may be used to treat thyroid carcinoma that is symptomatic and/or progressive and not amenable to treatment with radioactive iodine. Sorafenib may be considered for select patients with metastatic differentiated thyroid carcinoma, whereas vandetanib or cabozantinib may be recommended for select patients with metastatic medullary thyroid carcinoma. Other kinase inhibitors may be considered for select patients with either type of thyroid carcinoma. A new section on "Principles of Kinase Inhibitor Therapy in Advanced Thyroid Cancer" was added to the NCCN Guidelines to assist with using these novel targeted agents.

Topics: Adenocarcinoma; Anilides; Carcinoma, Neuroendocrine; Guidelines as Topic; Humans; Neoplasm Metastasis; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Sorafenib; Thyroid Neoplasms

A limited number of approved therapeutic options are available to metastatic medullary thyroid cancer (MTC) patients, and the response to conventional chemotherapy and/or radiotherapy strategies is inadequate. Sporadic and inherited mutations in the tyrosine kinase RET result in oncogenic activation that is associated with the pathogenesis of MTC. Cabozantinib is a potent inhibitor of MET, RET, and vascular endothelial factor receptor 2 (VEGFR2), as well as other tyrosine kinases that have been implicated in tumor development and progression. The object of this study was to determine the in vitro biochemical and cellular inhibitory profile of cabozantinib against RET, and in vivo antitumor efficacy using a xenograft model of MTC.. Cabozantinib was evaluated in biochemical and cell-based assays that determined the potency of the compound against wild type and activating mutant forms of RET. Additionally, the pharmacodynamic modulation of RET and MET and in vivo antitumor activity of cabozantinib was examined in a MTC tumor model following subchronic oral administration.. In biochemical assays, cabozantinib inhibited multiple forms of oncogenic RET kinase activity, including M918T and Y791F mutants. Additionally, it inhibited proliferation of TT tumor cells that harbor a C634W activating mutation of RET that is most often associated with MEN2A and familial MTC. In these same cells grown as xenograft tumors in nude mice, oral administration of cabozantinib resulted in dose-dependent tumor growth inhibition that correlated with a reduction in circulating plasma calcitonin levels. Moreover, immunohistochemical analyses of tumors revealed that cabozantinib reduced levels of phosphorylated MET and RET, and decreased tumor cellularity, proliferation, and vascularization.. Cabozantinib is a potent inhibitor of RET and prevalent mutationally activated forms of RET known to be associated with MTC, and effectively inhibits the growth of a MTC tumor cell model in vitro and in vivo.

Topics: Anilides; Animals; Carcinoma, Medullary; Cell Line, Tumor; Cell Proliferation; Mice; Mice, Nude; Phosphorylation; Proto-Oncogene Proteins c-met; Proto-Oncogene Proteins c-ret; Pyridines; Receptor Protein-Tyrosine Kinases; Thyroid Neoplasms; Treatment Outcome; Vascular Endothelial Growth Factor Receptor-2

Cabozantinib (XL184) is an oral multiple receptor tyrosine kinase inhibitor manufactured by Exelixis Inc., CA, USA. It mainly inhibits three tyrosine kinase receptors: MET, VEGFR2 and RET. In both preclinical and clinical studies it has been shown to inhibit tumor angiogenesis, invasiveness and metastases. The most frequent side effects are fatigue, diarrhea, decreased appetite, nausea, weight loss and palmar-plantar erythrodysesthesia. A Phase III clinical trial (EXAM study) of XL184 versus placebo in advanced and progressive medullary thyroid cancer showed a 28 versus 0% overall response rate and a progression-free survival of 11.2 versus 4.0 months (hazard ratio: 0.28; 95% CI: 0.19-0.40; p < 0.0001) in patients treated with cabozantinib and placebo, respectively. The drug has been approved by the US FDA for the treatment of advanced/progressive metastatic medullary thyroid cancer in the USA. The EMA is now evaluating its approval in Europe.

Topics: Anilides; Carcinoma, Neuroendocrine; Clinical Trials, Phase III as Topic; Drug Approval; Drug-Related Side Effects and Adverse Reactions; Humans; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neovascularization, Pathologic; Protein Kinase Inhibitors; Pyridines; Thyroid Neoplasms

Topics: Anilides; Biomarkers, Tumor; Calcitonin; Carcinoembryonic Antigen; Carcinoma, Neuroendocrine; Disease Progression; Humans; Piperidines; Proto-Oncogene Proteins c-ret; Pyridines; Quinazolines; Thyroid Neoplasms

Topics: Anilides; Carcinoma, Neuroendocrine; Female; Humans; Male; Protein Kinase Inhibitors; Pyridines; Thyroid Neoplasms

Topics: Administration, Oral; Anilides; Antineoplastic Agents; Carcinoma, Neuroendocrine; Dose-Response Relationship, Drug; Humans; Neoplasm Staging; Pyridines; Randomized Controlled Trials as Topic; Risk Factors; Thyroid Neoplasms; Treatment Outcome

Topics: Anilides; Antineoplastic Agents; Carcinoma; Carcinoma, Neuroendocrine; Clinical Trials as Topic; Cohort Studies; Genotype; Humans; Medical Oncology; Mutation; Phenotype; Pyridines; Thyroid Neoplasms; Treatment Outcome