Vandetanib for the Treatment of Thyroid Cancer

Langmuir, Peter; Yver, Antoine

doi:10.1038/clpt.2011.272

Cited by 42 publications

(33 citation statements)

References 27 publications

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“…Unfortunately, a large proportion of patients was classified as RET mutation status "unknown" (n ¼ 135; 45.3%) due to insufficient tumor DNA to fulfill stringent testing criteria, making subgroup analysis by RET mutation status for PFS and ORR in ZETA inconclusive. Interestingly, patients with sporadic MTC tumors harboring a somatic M198T mutation had a higher response rate to vandetanib (54.5%; 55 of 101) than patients with sporadic MTC tumors without a somatic M918T mutation (32%; 33 of 103).Vandetanib appeared active in all prespecified subgroups (16).…”

Section: Efficacy By Mutation Statusmentioning

confidence: 99%

“…Forty percent had received prior systemic therapy. Calcitonin or carcinoembryonic antigen (CEA) doubling time of 24 months, a marker associated with more aggressive disease, was present in 51% of patients with respect to calcitonin and 31% of patients for CEA (16).…”

Section: Late-stage Developmentmentioning

confidence: 99%

“…Subgroup analyses suggest that there may be a greater chance of benefit in patients with sporadic MTC tumors harboring the aggressive M918T mutation and in patients with CEA doubling times 24 months compared with those with longer doubling times (54% vs. 37%; ref. 16). Judicious evaluation of the treatment risk-to-benefit ratio and close monitoring for toxicities is critical.…”

Section: Integration Of Vandetanib Into the Medullary Thyroid Cancer mentioning

confidence: 99%

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Vandetanib for the Treatment of Medullary Thyroid Cancer

Chau

Haddad

2013

Clinical Cancer Research

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Vandetanib (ZD6474, Caprelsa, AstraZeneca), an oral small-molecule tyrosine kinase inhibitor (TKI) that targets the rearranged during transfection receptor (RET), VEGF receptor (VEGFR2-3), and EGF receptor (EGFR), is the first systemic therapy approved by the U.S. Food and Drug Administration (FDA) for the treatment of symptomatic or progressive advanced medullary thyroid cancer (MTC). In a randomized phase III trial of patients with unresectable, locally advanced, or metastatic MTC, vandetanib improved progression-free survival compared with placebo [HR, 0.46; 95% confidence interval (CI), 0.31-0.69; P < 0.001]. However, the benefits in delaying disease progression need to be balanced against the associated and potentially serious toxicities, including diarrhea, hypertension, and QTc prolongation. Here, we review the clinical development of vandetanib leading to its integration into the current treatment paradigm and highlight the ongoing and future challenges in TKI use in MTC.

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Section: Efficacy By Mutation Statusmentioning

confidence: 99%

Section: Late-stage Developmentmentioning

confidence: 99%

Section: Integration Of Vandetanib Into the Medullary Thyroid Cancer mentioning

confidence: 99%

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Vandetanib for the Treatment of Medullary Thyroid Cancer

Chau

Haddad

2013

Clinical Cancer Research

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“…Vandetanib [N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine], an oral tyrosine kinase inhibitor of vascular endothelial growth factor receptor-, epidermal growth factor receptor-, and rearranged during transfection-dependent signaling, has been approved for the treatment of symptomatic or progressive medullary thyroid cancer (Frampton, 2012;Langmuir and Yver, 2012). Vandetanib is also being developed for the treatment of non-small-cell lung cancer (Stinchcombe and Socinski, 2009;Natale et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Assessment of Vandetanib as an Inhibitor of Various Human Renal Transporters: Inhibition of Multidrug and Toxin Extrusion as a Possible Mechanism Leading to Decreased Cisplatin and Creatinine Clearance

et al. 2013

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Vandetanib was evaluated as an inhibitor of human organic anion transporter 1 (OAT1), OAT3, organic cation transporter 2 (OCT2), and multidrug and toxin extrusion (MATE1 and MATE2K) transfected (individually) into human embryonic kidney 293 cells (HEK293). Although no inhibition of OAT1 and OAT3 was observed, inhibition of OCT2-mediated uptake of 1-methyl-4-phenylpyridinium (MPP + ) and metformin was evident (IC 50 of 73.4 6 14.8 and 8.8 61.9 mM, respectively).

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“…Vandetanib, a tyrosine kinase inhibitor (TKI) targeting the rearranged during transfection proto-oncogene (RET), the vascular endothelial growth factor receptor 2 (VEGFR-2), and the epidermal growth factor receptor (EGFR) (3), was recently demonstrated to be effective in the treatment of locally advanced or metastatic MTC in an international phase III trial (ZETA study) (4). Vandetanib inhibits specific intracellular pathways and induces a reduction of growth and proliferation of MTC tumor and vascular cells (3).…”

mentioning

confidence: 99%

Body Composition Variation and Impact of Low Skeletal Muscle Mass in Patients With Advanced Medullary Thyroid Carcinoma Treated With Vandetanib: Results From a Placebo-Controlled Study

Massicotte

Borget

Broutin

et al. 2013

The Journal of Clinical Endocrinology &Amp; Metabolism

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Objectives:Vandetanib was approved by the U.S. Food and Drug Association for the treatment of advanced medullary thyroid cancer (MTC). Because body weight (BW) loss is observed in MTC and because low skeletal muscle mass (SM) is associated with drug toxicity, this study assessed effects of vandetanib on SM and adipose tissue (AT) and explored the association between SM, toxicity, and serum concentration of vandetanib. Methods:Thirty-three patients with MTC received vandetanib (n ϭ 23) or placebo (n ϭ 10) in the ZETA study. Visceral AT (VAT), sc AT (SAT), and SM were assessed with computed tomography imaging by measuring tissue cross-sectional areas (square centimers per square meter). Doselimiting toxicities (DLTs) were prospectively recorded.Results: Early at 3 months, compared with placebo group who lost BW, muscle, and SAT, patients treated with vandetanib gained 1.5 kg BW (P ϭ 0.02), 1.3 cm 2 /m 2 (ϳ0.7 kg) of SM (P ϭ 0.009), and 4.5 cm 2 /m 2 (ϳ0.5 kg) of SAT (P ϭ 0.004) and gained more VAT, 5.1 cm 2 /m 2 (ϳ0.7 kg) (P ϭ 0.02).Patients with DLT had lower SM index (37.2 vs 44.3 cm 2 /m 2 , P ϭ 0.003) and a higher vandetanib serum concentration (1091 vs 739 ng/mL, P ϭ 0.03). Patients with SM index Ͻ43.1 cm 2 /m 2 had a higher probability of DLT (73% vs 14%, P ϭ 0.004) and a higher vandetanib serum concentration (1037 vs 745 ng/mL, P ϭ 0.04). Patients with the highest compared with the intermediate and lower levels of vandetanib serum concentration experienced more DLT, respectively, 78% vs 40% vs 20% (P ϭ 0.04). M edullary thyroid carcinoma (MTC) accounts for 4% to 8% of thyroid carcinomas, and 10-year overall survival ranges, according to TNM (tumor, node, metastasis) classification, from almost 100% for stage I to 21% for stage IV disease (1, 2). Vandetanib, a tyrosine kinase inhibitor (TKI) targeting the rearranged during Conclusions

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Vandetanib for the Treatment of Thyroid Cancer

Cited by 42 publications

References 27 publications

Vandetanib for the Treatment of Medullary Thyroid Cancer

Vandetanib for the Treatment of Medullary Thyroid Cancer

Assessment of Vandetanib as an Inhibitor of Various Human Renal Transporters: Inhibition of Multidrug and Toxin Extrusion as a Possible Mechanism Leading to Decreased Cisplatin and Creatinine Clearance

Body Composition Variation and Impact of Low Skeletal Muscle Mass in Patients With Advanced Medullary Thyroid Carcinoma Treated With Vandetanib: Results From a Placebo-Controlled Study

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