cabozantinib and Carcinoma--Neuroendocrine

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

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) 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

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

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

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

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

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

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

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 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

With the advent of potent second-line anti-androgen therapy, we and others have observed an increased incidence of androgen receptor (AR)-null small cell or neuroendocrine prostate cancer (SCNPC) in metastatic castration-resistant prostate cancer (mCRPC). Our study was designed to determine the effect of cabozantinib, a multi-targeted tyrosine kinase inhibitor that inhibits VEGFR2, MET and RET on SCNPC. Transcriptome analysis of the University of Washington rapid autopsy and SU2C mCRPC datasets revealed upregulated MET and RET expression in SCNPCs relative to adenocarcinomas. Additionally, increased MET expression correlated with attenuated AR expression and activity. In vitro treatment of SCNPC patient-derived xenograft (PDX) cells with the MET inhibitor AMG-337 had no impact on cell viability in LuCaP 93 (MET+/RET+) and LuCaP 173.1 (MET-/RET-), whereas cabozantinib decreased cell viability of LuCaP 93, but not LuCaP 173.1. Notably, MET+/RET+ LuCaP 93 and MET-/RET- LuCaP 173.1 tumor volumes were significantly decreased with cabozantinib treatment in vivo, and this activity was independent of MET or RET expression in LuCaP 173.1. Tissue analysis indicated that cabozantinib did not inhibit tumor cell proliferation (Ki67), but significantly decreased microvessel density (CD31) and increased hypoxic stress and glycolysis (HK2) in LuCaP 93 and LuCaP 173.1 tumors. RNA-Seq and gene set enrichment analysis revealed that hypoxia and glycolysis pathways were increased in cabozantinib-treated tumors relative to control tumors. Our data suggest that the most likely mechanism of cabozantinib-mediated tumor growth suppression in SCNPC PDX models is through disruption of the tumor vasculature. Thus, cabozantinib may represent a potential therapy for patients with metastatic disease in tumor phenotypes that have a significant dependence on the tumor vasculature for survival and proliferation.

Topics: Anilides; Animals; Carcinoma, Neuroendocrine; Cell Line, Tumor; Humans; Male; Mice; Mice, SCID; Neovascularization, Pathologic; Prostatic Neoplasms; Proto-Oncogene Proteins c-met; Proto-Oncogene Proteins c-ret; Pyridines; Xenograft Model Antitumor Assays

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

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

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

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

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

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

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