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Pharmacology Xagena

Differentiated thyroid cancer: Lenvatinib, an orally administered multiple receptor tyrosine kinase inhibitor


Lenvatinib ( Lenvima ) is an orally administered multiple receptor tyrosine kinase ( RTK ) inhibitor with a novel binding mode that selectively inhibits the kinase activities of vascular endothelial growth factor ( VEGF ) receptors ( VEGFR1 ( FLT1 ), VEGFR2 ( KDR ) and VEGFR3 ( FLT4 ) ), in addition to other proangiogenic and oncogenic pathway-related RTKs ( including fibroblast growth factor ( FGF ) receptors FGFR1, 2, 3 and 4; the platelet-derived growth factor ( PDGF ) receptor PDGFRalpha; KIT; and RET ) involved in tumor proliferation.
In particular, the agent simultaneously inhibits VEGFR, FGFR and also RET which are especially involved in tumor angiogenesis and proliferation of thyroid cancer.

Furthermore, Lenvatinib has been confirmed through X-ray crystal structural analysis to be the first compound to demonstrate a new binding mode ( type V ) to VEGFR2, and exhibits rapid and potent inhibition of kinase activity, according to kinetic analysis.

Lenvima has been approved for the treatment of refractory thyroid cancer in the United States.

Eisai is currently conducting clinical studies of Lenvatinib in several types of cancer including hepatocellular carcinoma ( phase III ), renal cell carcinoma ( phase II ), non-small cell lung cancer ( phase II ) and endometrial cancer ( phase II ).
Furthermore, Lenvima was granted Orphan Drug Designation in the United States for treatment of follicular, medullary, anaplastic, and metastatic or locally advanced papillary thyroid cancer and in Europe for follicular and papillary thyroid cancer.

Kinase inhibitors are categorized into several types ( type I to type V ) depending on the binding site and the conformation of the targeted kinase in complex with them. Most of the currently approved tyrosine kinase inhibitors are either type I or type II, however according to X-ray crystal structural analysis, Lenvatinib was found to possess a new type V binding mode of kinase inhibition that is distinct from existing compounds.
In addition, Lenvatinib was confirmed via kinetic analysis to exhibit rapid and potent inhibition of kinase activity, and it is suggested that this may be attributed to its novel binding mode.

The approval was based on the results of the SELECT study (Study of [ E7080 ] LEnvatinib in Differentiated Cancer of the Thyroid ). The SELECT study was a multicenter, randomized, double-blind, placebo-controlled phase III study to compare the progression-free survival ( PFS ) of patients with radioactive iodine-refractory differentiated thyroid cancer and radiographic evidence of disease progression within the prior 13 months, treated with once-daily, oral Lenvatinib ( 24mg ) versus placebo.
Participants were randomized 2:1 to either Lenvatinib or placebo therapy.
The primary endpoint was PFS assessed by independent radiologic review. The secondary endpoints of the study included response rate ( sum of complete and partial responses ), overall survival ( OS ) and safety.
The study enrolled 392 patients in over 100 sites in Europe, North and South America and Asia, including Japan.

Thyroid cancer is more common in women than in men. The most common types of thyroid cancer, papillary and follicular ( including Hürthle cell ), are classified as differentiated thyroid cancer and account for approximately 95% of all cases. The remaining cases are classified as either undifferentiated ( 3-5% of cases ) or medullary carcinoma ( 1-2% of cases ).
While most differentiated thyroid cancer patients are curable with surgery and radioactive iodine treatment, there are a small percentage of patients for which these types of therapies are not suitable. ( Xagena )

Source: Eisai, 2015

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