Lenvima® (Lenvatinib) Receives Positive CHMP Opinion Following Significant Phase III Data in the Treatment of Advanced Thyroid Cancer Refractory to Radioactive Iodine

HATFIELD, England, March 27, 2015 /PRNewswire/ --

FOR EU MEDIA ONLY: NOT FOR SWISS AND AUSTRIAN MEDIA 

Eisai announces today that Lenvima^® (lenvatinib) 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, multicentre 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]

Lenvima 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. Lenvima 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.

The development of lenvatinib underscores Eisai's human health care (hhc) mission, the company's commitment to innovative solutions in disease prevention, cure and care for the health and well-being of people worldwide. Eisai is committed to the therapeutic area of oncology and to address the unmet medical needs of patients and their families.

Notes to Editors  

Lenvatinib (E7080) 

Eisai is currently conducting clinical studies of Lenvima 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).

About Lenvatinib's Novel Binding Mode (Type V)^[5]

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.

About SELECT^[1]

The SELECT (Study of (E7080) LEnvatinib in Differentiated Cancer of the Thyroid) study was a multicentre, randomised, double-blind, placebo-controlled Phase III study to compare the PFS of patients with RR- radioiodine-refractory differentiated thyroid cancer and radiographic evidence of disease progression within the prior 13 months, treated with once-daily, oral lenvatinib (24mg) versus placebo. The study enrolled 392 patients in over 100 sites in Europe, North and South America and Asia and was conducted by Eisai in collaboration with the SFJ Pharmaceuticals Group.

Participants were stratified by age (≤65, >65 years), region and ≤1 prior VEGFR-targeted therapies and randomised 2:1 to either lenvatinib or placebo therapy (24mg/d, 28-d cycle). The primary endpoint was PFS assessed by independent radiologic review. The secondary endpoints of the study included overall response rate (ORR), overall survival (OS) and safety. Rates of complete response were 1.5% (4 patients) for the lenvatinib group and zero in the placebo group. The results for partial response were 63.2% (165 patients) in the lenvatinib group and 1.5% (2 patients) in the placebo arm. The median exposure duration was 13.8 months for lenvatinib and 3.9 months for placebo and the median time to response for lenvatinib was 2.0 months. Median OS has not yet been reached.

The six most common lenvatinib treatment-related adverse events (TRAEs) of any grade were hypertension (67.8%), diarrhea (59.4%), fatigue (59.0%), decreased appetite (50.2%), weight loss (46.4%) and nausea (41.0%). TRAEs of Grade 3 or higher (Common Terminology Criteria for Adverse Events) included hypertension (41.8%), proteinuria (10.0%), weight loss (9.6%), diarrhoea (8.0%), and decreased appetite (5.4%).

Subgroup analyses presented at the European Thyroid Association Annual Meeting in September 2014 showed that lenvatinib maintained a PFS benefit in all pre-defined subgroups of people with progressive radioiodine-refractory differentiated thyroid cancer. In particular, the PFS benefit observed in 195 people with progressive radioiodine-refractory differentiated thyroid cancer in Europe (lenvatinib n=131 and placebo n=64) was similar to the PFS of overall study population (HR=0.24, [95% CI, 0.16-0.35]).^[10] The median PFS with lenvatinib and placebo were 18.7 months and 3.7 months respectively.  

About Thyroid Cancer 

Thyroid cancer refers to cancer that forms in the tissues of the thyroid gland, located at the base of the throat near the trachea.^[11] It is more common in women than in men and most are in their 40s or 50s at time of diagnosis.^[7]

Thyroid cancer affects more than 52,000 people in Europe each year.^[6] The incidence of thyroid cancer has increased significantly in the last decade by 69% and 65% in men and women, respectively.^[12] The most common types of thyroid cancer, papillary and follicular (including Hurthle cell), are classified as differentiated thyroid cancer (DTC) and account for approximately 90% of all cases.^[9] The remaining cases are classified as either medullary (5-7% of cases) or anaplastic (1-2% of cases).^[13]

About Eisai Co., Ltd. 

Eisai Co., Ltd. is a leading global research and development-based pharmaceutical company headquartered in Japan. We define our corporate mission as "giving first thought to patients and their families and to increasing the benefits health care provides," which we call our human health care (hhc) philosophy. With over 10,000 employees working across our global network of R&D facilities, manufacturing sites and marketing subsidiaries, we strive to realise our hhc philosophy by delivering innovative products in multiple therapeutic areas with high unmet medical needs, including Oncology and Neurology. 

As a global pharmaceutical company, our mission extends to patients around the world through our investment and participation in partnership-based initiatives to improve access to medicines in developing and emerging countries.

For more information about Eisai Co., Ltd., please visit http://www.eisai.com.  

References  

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 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: http://www.thyca.org . Accessed: March 2015

Date of preparation: March 2015        

Job code: Lenvatinib-UK0051