Lenvatinib (Lenvima) has received a positive opinion for the treatment of people with radioactive iodine refractory differentiated thyroid cancer (RAI refractory DTC) from the Committee for Medicinal Products for Human Use (CHMP).

Lenvatinib is indicated for the treatment of adult patients with progressive locally advanced or metastatic, differentiated (papillary, follicular, Hürthle cell) thyroid carcinoma (DTC) refractory to radioactive iodine (RAI).

The CHMP opinion is based on evidence from the lenvatinib SELECT study which demonstrates significantly prolonged progression-free survival (PFS) in RAI refractory DTC versus placebo.

Lenvatinib shows a median 18.3 months PFS versus 3.6 months for placebo (hazard ratio [HR] 0.21; 99% confidence interval 0.14–0.31, p<0.0001).

In addition, the study underlines the rapid response of lenvatinib, with a median time to first objective response of two months.

SELECT is a randomised, double-blind, multi-centre trial for people with progressive radioiodine-refractory differentiated thyroid cancer (n=392).^{1, 2}

Lenvatinib significantly improves objective response rate versus placebo (64.8% versus 1.5%; p<0.0001).

For lenvatinib, the most common treatment related adverse events were hypertension, diarrhoea, fatigue, decreased appetite, decreased weight, and nausea.

“Lenvatinib represents a paradigm shift in the treatment of advanced thyroid cancer, and will bring new options to patients and clinicians. Clinicians will be excited to prescribe a treatment with significant benefits in progression-free survival” commented Martin Schlumberger, Primary Investigator and Professor of Oncology, Institut Gustave Roussy, University Paris Sud, Paris, France.

Lenvatinib, discovered and developed by Eisai, is an oral molecular tri-specific targeted therapy that possesses a potent selectivity and a binding mode different to other tyrosine kinase inhibitors (TKI).

Lenvatinib simultaneously inhibits the activities of several different molecules including vascular endothelial growth factor receptors (VEGFR), fibroblast growth factor receptors (FGFR), RET, KIT and platelet-derived growth factor receptors (PDGFR).^{3, 4}

This potentially makes lenvatinib the first TKI that simultaneously inhibits the kinase activities of FGFR 1-4 as well as VEGFR 1-3.

In addition, lenvatinib was found to have a new Type V binding mode of kinase inhibition that is distinct from existing compounds.⁵

Thyroid cancer affects more than 52,000 people in Europe each year.⁶

Thyroid cancer is the most common endocrine malignancy.⁷

Approximately 10% of patients with differentiated thyroid cancer do not respond to radioiodine treatment and is known as radioiodine-refractory differentiated thyroid cancer.⁸

Approximately 2,000 people in Europe live with this difficult to treat and life threatening illness for which there are few treatment options.⁹

Lenvatinib has been approved for the treatment of refractory thyroid cancer in the United States and Japan, and is currently undergoing regulatory review for this indication in the EU, Switzerland, South Korea, Canada, Singapore, Russia, Australia and Brazil.

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.

Reference

1. Schlumberger M et al. 'Lenvatinib versus placebo in radioiodine refractory differentiated thyroid cancer'. NEJM 2015; 372: 621-630. Available at http://www.nejm.org/doi/full/10.1056/NEJMoa1406470 Accessed: March 2015

2. Schlumberger M et al.  'A phase 3, multicenter, double-blind, placebo-controlled trial of lenvatinib (E7080) in patients with 131I-refractory differentiated thyroid cancer (SELECT)'. ASCO 2014 abstract #E450

3. Matsui J, et al. Clin Cancer Res 2008;14:5459-65

4. Matsui J, et al. Int J Cancer 2008;122:664-671

5. Okamoto K, et al. 'Distinct Binding Mode of Multikinase Inhibitor Lenvatinib Revealed by Biochemical Characterization'. ACS Med. Chem. Lett 2015;6:89-94

6. Eucan. Thyroid Cancer Factsheet. Available at: http://eu-cancer.iarc.fr/EUCAN/Cancer.aspx?Cancer=35.
  Accessed: March 2015

7.Brito J et al. BMJ 2013; 347

8. Pacini F et al. 'ESMO Guidelines Working Group'. Ann Oncol. 2012;23(suppl 7):vii110-vii119.

9. Cabanillas ME., Dadu R. 'Optimizing therapy for radioactive iodine-refractory differentiated thyroid cancer: Current state of the art and future directions'. Minerva Endocrinol 2012 Dec; 37(4): 335-356.

10. Newbold K et al. 'Phase 3 study of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (SELECT): Results and subgroup analysis of patients from Europe'. Presented as a digital poster at ETA 2014.

11. National Cancer Institute at the National Institute of Health. Available at: http://www.cancer.gov/cancertopics/pdq/treatment/thyroid/Patient/page1/AllPages#1. Accessed: March 2014

12. Cancer Research UK. Thyroid cancer incidence statistics. Available at:
http://www.cancerresearchuk.org/cancer-info/cancerstats/types/thyroid/incidence/uk-thyroid-cancer-incidence-statistics Accessed: March 2015

13. Thyroid Cancer Basics. 2011. Available at: www.thyca.org. Accessed: March 2015

Source: Eisai