Mechanism of Action Magnifier – 2016 Desk Reference
Lenvatinib: a Receptor Tyrosine Kinase Inhibitor
Lenvatinib (Figure) 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) receptors1:
- VEGFR1 (FLT1)
- VEGFR2 (KDR)
- VEGFR3 (FLT4).
Lenvatinib also inhibits other RTKs involved in tumor proliferation, including1:
- Fibroblast growth factor receptors 1, 2, 3, and 4
- The platelet-derived growth factor receptor alpha
In addition to their normal cellular functions, these RTKs have been implicated in1:
- Pathogenic angiogenesis
- Tumor growth
- Cancer progression.
Novel Binding Mode (Type V)
Kinase inhibitors are categorized into several types (type I-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.2 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.
Although treatment is possible for most types of thyroid cancer, there are few treatment options available for patients with radioactive iodine–refractory, locally advanced, or metastatic differentiated thyroid carcinoma.3 Prior to 2015, sorafenib, a multitargeted tyrosine kinase inhibitor, was the only treatment approved by the FDA and was associated with a median progression-free survival (PFS) of 11 months and an overall response rate of 12% in a phase 3 trial.4
In February 2015, the FDA approved lenvatinib for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine–refractory differentiated thyroid cancer.1 The FDA approval was based on the results from a randomized, double-blind, multicenter, phase 3 study (SELECT) in which 392 patients with progressive, radioactive iodine–refractory differentiated thyroid cancer were randomized to receive either lenvatinib (n = 261) or placebo (n = 131).5 The median PFS was 18.3 months in the lenvatinib group and 3.6 months in the placebo group (hazard ratio for progression or death, 0.21; 99% CI, 0.14-0.31; P <.001). The response rate was 64.8% in the lenvatinib group (4 complete responses and 165 partial responses) and 1.5% in the placebo group (P <.001). The most common lenvatinib treatment-related adverse events of any grade, which occurred in more than 40% of patients in the lenvatinib group, were hypertension (67.8%), diarrhea (59.4%), fatigue or asthenia (59.0%), decreased appetite (50.2%), weight loss (46.4%), and nausea (41.0%).
Lenvatinib has been approved for the treatment of refractory thyroid cancer in the United States and is currently undergoing regulatory review for this indication in Japan, the EU, Switzerland, South Korea, Canada, Singapore, Russia, Australia, and Brazil. Meanwhile, clinical studies of lenvatinib are under way in several types of cancer, including hepatocellular carcinoma (phase 3), renal cell carcinoma (phase 2), non–small cell lung cancer (phase 2), and endometrial cancer (phase 2). Furthermore, lenvatinib was granted orphan drug designation in Japan for thyroid cancer, 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.
- Lenvima [package insert]. Woodcliff Lake, NJ: Eisai Inc; 2015.
- Okamoto K, Ikemori-Kawada M, Jestel A, et al. Distinct binding mode of multikinase inhibitor lenvatinib revealed by biochemical characterization. ACS Med Chem Lett. 2015;6:89-94.
- Yeung KT, Cohen EE. Lenvatinib in advanced, radioactive iodine-refractory, differentiated thyroid carcinoma [published online October 20, 2015]. Clin Cancer Res.
- Brose MS, Nutting CM, Jarzab B, et al. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet. 2014;384:319-328.
- Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med. 2015;372:621-630.
Cyclin-dependent kinases (CDKs) 4 and 6 are overactive in many human cancers, resulting in a loss of regulation of the G1 cell cycle restriction point and making malignant cells less responsive to normal growth controls.1,2 CDK4 and CDK6 CDKs are key regulators of cell proliferation.3 In many tumor types, CDK4 [ Read More ]
In the cell nucleus, DNA is maintained in a tightly coiled state around proteins called histones.1 During the process of DNA replication for cell division or during the synthesis of RNA and proteins, histone acetyltransferase adds acetyl groups onto the histones, enabling DNA to uncoil.1 By contrast, histone deacetylases (HDACs) [ Read More ]