Vandetanib: A novel targeted therapy for the treatment of metastatic or locally advanced medullary thyroid cancer

Ton, Giangthy N.; Banaszynski, Megan; Kolesar, Jill

doi:10.2146/ajhp120253

Cited by 25 publications

(10 citation statements)

References 25 publications

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“…Axitinib was associated with a higher risk of hypertension event than sunitinib (Baek et al 2019). And vandetanib's higher cardiac toxicity (Ton et al 2013). Furthermore, this NMA provided the ranking possibility to induce cardiovascular damage (all grades) of nine commonly used VEGFR-TKIs', severe cardiovascular event (Grade 3 or higher), hypertension, serious hypertension (Grade 3 or higher) and cardiac event risk.…”

Section: The Strengths Of Our Network Meta-analysismentioning

confidence: 96%

Comparative evaluation of cardiovascular risks among nine FDA-approved VEGFR-TKIs in patients with solid tumors: a Bayesian network analysis of randomized controlled trials

Hou

Ding

et al. 2021

J Cancer Res Clin Oncol

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Purpose The present meta-analysis study was performed to identify the potential cardiotoxicity risks when using Vascular Endothelial Growth Factor Receptor Tyrosine kinase inhibitors (VEGFR-TKIs) as anticancer drugs in patients with solid tumors. Methods Pubmed, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases were searched for the randomized controlled trials. We have included 45 randomized controlled trials (RCTs) associated with nine VEGFR-TKIs Food and Drug Administration (FDA)-approved drugs used to treat patients with solid tumors. To evaluate the trials’ risk of bias, Cochrane Risk of Bias Tool was assessed. A direct comparison was assessed by RevMan5.3 software, calculating the odds ratio (OR) and 95% confidence interval (CI). Heterogeneity was tested by the I2 statistic and Chi-square test for P value. Bayesian network meta-analysis was performed using Stata 15.0 and GeMTC 0.14.3 software, calculated OR along with corresponding 95% credible interval (CrI). The model’s convergence was evaluated by the potential scale reduced factor (PSRF). Consistency between direct and indirect comparisons was assessed by the “node-splitting” method. Results In this network meta-analysis, a total of 20,027 patients from 45 randomized controlled trials and associated with nine FDA-approved VEGFR-TKIs (axitinib, cabozantinib, lenvatinib, nintedanib, pazopanib, regorafenib, sorafenib, sunitinib, vandetanib), were enrolled. Findings indicated that lenvatinib had the most significant probability of provoking all grades cardiovascular incident and hypertension, followed by vandetanib, cabozantinib, axitinib, pazopanib, sorafenib, sunitinib, regorafenib and nintedanib. The nine agent’s severe cardiovascular and severe hypertension risk was probably similar. The ranking probability of cardiac toxicity shows that vandetanib ranked most likely to have the highest risk for cardiotoxicity among all the VEGFR-TKIs reviewed, followed by pazopanib, axitinib, sorafenib, sunitinib. In contrast, regorafenib and nintedanib did not exhibit an increased risk of cardiac damage. Conclusions The association between the nine VEGFR-TKIs with potential cardiotoxicity occurrence was reviewed. Both the regorafenib and nintedanib did not display detectable signs of cardiotoxic damage. In contrast, lenvatinib and vandetanib are ranked to have the most severe cardiotoxicity side impacts. These results may provide information for clinical practice guidelines, implementing strategies in selecting the adequate VEGFR-TKIs, and understanding the cardiovascular toxicity inflicted by the VEGFR-TKIs. PROSPERO identifier CRD 42,020,167,307.

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Section: The Strengths Of Our Network Meta-analysismentioning

confidence: 96%

Comparative evaluation of cardiovascular risks among nine FDA-approved VEGFR-TKIs in patients with solid tumors: a Bayesian network analysis of randomized controlled trials

Hou

Ding

et al. 2021

J Cancer Res Clin Oncol

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“…Furthermore, dual inhibition of VEGFR and EGFR using vandetanib (ZD6474) resulted in significant tumour growth inhibition in a range of histologically diverse human xenograft models (Wedge et al ., ; Holden et al ., ; Yoshikawa et al ., ). When moved for clinical development, vandetanib demonstrated a high therapeutic efficacy in phases I–III trials against metastatic medullary thyroid cancer, which lead eventually to FDA approval (Leboulleux et al ., ; Wells et al ., ; Ton et al ., ). However, in many other clinical trials, vandetanib showed either acceptable clinical activities along with safety concerns or limited clinical activities that warrant pre‐selection of patients (Blackhall et al ., ; Hsu et al ., ; Kreisl et al ., ; Lee et al ., ; Meyerhardt et al ., ).…”

Section: Mechanisms Of Enhanced Therapeutic Efficacymentioning

confidence: 97%

Angiogenesis inhibitors in cancer therapy: mechanistic perspective on classification and treatment rationales

El-Kenawi

El-Remessy

2013

British J Pharmacology

212

179

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Angiogenesis, a process of new blood vessel formation, is a prerequisite for tumour growth to supply the proliferating tumour with oxygen and nutrients. The angiogenic process may contribute to tumour progression, invasion and metastasis, and is generally accepted as an indicator of tumour prognosis. Therefore, targeting tumour angiogenesis has become of high clinical relevance. The current review aimed to highlight mechanistic details of anti-angiogenic therapies and how they relate to classification and treatment rationales. Angiogenesis inhibitors are classified into either direct inhibitors that target endothelial cells in the growing vasculature or indirect inhibitors that prevent the expression or block the activity of angiogenesis inducers. The latter class extends to include targeted therapy against oncogenes, conventional chemotherapeutic agents and drugs targeting other cells of the tumour micro-environment. Angiogenesis inhibitors may be used as either monotherapy or in combination with other anticancer drugs. In this context, many preclinical and clinical studies revealed higher therapeutic effectiveness of the combined treatments compared with individual treatments. The proper understanding of synergistic treatment modalities of angiogenesis inhibitors as well as their wide range of cellular targets could provide effective tools for future therapies of many types of cancer.

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“…Vandetanib (VTB) is a MTKi targeting both VEGFR and EGFR, approved for the treatment of advanced medullary thyroid cancer 28 - 31 . It binds covalently to the cysteine residues of the TK domain and prevents binding of ATP, phosphorylation of the TK dimer and initiation of subsequent downstream signalling pathways.…”

Section: Introductionmentioning

confidence: 99%

Vandetanib-eluting Radiopaque Beads: In vivo Pharmacokinetics, Safety and Toxicity Evaluation following Swine Liver Embolization

et al. 2017

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PURPOSE: To evaluate the plasma and tissue pharmacokinetics, safety and toxicity following intra-arterial hepatic artery administration of Vandetanib (VTB)-eluting Radiopaque Beads (VERB) in healthy swine.MATERIALS AND METHODS: In a first phase, healthy swine were treated with hepatic intra-arterial administration of VERB at target dose loading strengths of 36 mg/mL (VERB36), 72 mg/mL (VERB72) and 120 mg/mL (VERB120). Blood and tissue samples were taken and analysed for VTB and metabolites to determine pharmacokinetic parameters for the different dose forms over 30 days. In a second phase, animals were treated with unloaded radiopaque beads or high dose VTB loaded beads (VERB100, 100 mg/mL). Tissue samples from embolized and non-embolized areas of the liver were evaluated at necropsy (30 and 90 days) for determination of VTB and metabolite levels and tissue pathology. Imaging was performed prior to sacrifice using multi-detector computed tomography (MDCT) and imaging findings correlated with pathological changes in the tissue and location of the radiopaque beads.RESULTS: The peak plasma levels of VTB (Cmax) released from the various doses of VERB ranged between 6.19-17.3 ng/mL indicating a low systemic burst release. The plasma profile of VTB was consistent with a distribution phase up to 6 h after administration followed by elimination with a half-life of 20-23 h. The AUC of VTB and its major metabolite N-desmethyl vandetanib (NDM VTB) was approximately linear with the dose strength of VERB. VTB plasma levels were at or below limits of detection two weeks after administration. In liver samples, VTB and NDM VTB were present in treated sections at 30 days after administration at levels above the in vitro IC50 for biological effectiveness. At 90 days both analytes were still present in treated liver but were near or below the limit of quantification in untreated liver sections, demonstrating sustained release from the VERB. Comparison of the reduction of the liver lobe size and associated tissue changes suggested a more effective embolization with VERB compared to the beads without drug.CONCLUSIONS: Hepatic intra-arterial administration of VERB results in a low systemic exposure and enables sustained delivery of VTB to target tissues following embolization. Changes in the liver tissue are consistent with an effective embolization and this study has demonstrated that VERB100 is well tolerated with no obvious systemic toxicity.

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Vandetanib: A novel targeted therapy for the treatment of metastatic or locally advanced medullary thyroid cancer

Cited by 25 publications

References 25 publications

Comparative evaluation of cardiovascular risks among nine FDA-approved VEGFR-TKIs in patients with solid tumors: a Bayesian network analysis of randomized controlled trials

Comparative evaluation of cardiovascular risks among nine FDA-approved VEGFR-TKIs in patients with solid tumors: a Bayesian network analysis of randomized controlled trials

Angiogenesis inhibitors in cancer therapy: mechanistic perspective on classification and treatment rationales

Vandetanib-eluting Radiopaque Beads: In vivo Pharmacokinetics, Safety and Toxicity Evaluation following Swine Liver Embolization

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