European Commission Grants Marketing Authorisation for Lenvima® (lenvatinib) in the Treatment of Advanced Thyroid Cancer Refractory to Radioactive Iodine

HATFIELD, England, May 30, 2015 /PRNewswire/ --

FOR EU MEDIA ONLY: NOT FOR SWISS/AUSTRIAN  MEDIA 

Decision by European Commission provides important new treatment option to people living with advanced thyroid cancer  

The European Commission (EC) today issued marketing authorisation for Lenvima^® (lenvatinib) in the treatment of people with radioactive iodine refractory differentiated thyroid cancer. Differentiated thyroid cancer accounts for 90% of all thyroid cancers and 5-15% of people with differentiated thyroid cancer will develop advanced thyroid cancer that is refractory to radioactive iodine. 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 decision by the European Commission will be welcomed by physicians and patients across Europe. I am proud to have led the SELECT study, and people living with advanced thyroid cancer will now have access to this significantly effective drug," commented Martin Schlumberger, Professor of Oncology, Institut Gustave Roussy, University Paris Sud, Paris, France.

Lenvatinib demonstrates a clinically meaningful and significant median progression free survival of 18.3 months in the lenvatinib group and 3.6 months in the placebo group. The response rate was 64.8% in the lenvatinib group (4 complete responses, 1.5%) and 1.5% in the placebo (p<0.001). 70.4% of patients had a complete or partial response to lenvatinib within 30 days on the 24mg dose. Lenvatinib was associated with a median time to objective response of 2 months (95% CI, 1.9-3.5). Median duration of treatment was 13.8 months with lenvatinib versus 3.9 months for placebo. SELECT is a randomised, double-blind, multicentre trial for people with progressive radioactive iodine refractory differentiated thyroid cancer (n=392).^[1] For lenvatinib, the most common treatment related adverse events were hypertension, diarrhoea, fatigue, decreased appetite, decreased weight, and nausea.

Lenvatinib, discovered and developed by Eisai, is an oral molecular tri-specific targeted therapy that possesses a potent selectivity and a binding mode of action different to other tyrosine kinase inhibitors (TKI). Lenvatinib simultaneously inhibits the activities of several different receptors including vascular endothelial growth factor receptors (VEGFR), fibroblast growth factor receptors (FGFR), RET, KIT and platelet-derived growth factor receptors (PDGFR).^[2] 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.^[3]

"This marketing authorisation underscores Eisai's position as a global leader in oncology and marks an important step forward for people with advanced thyroid cancer. As a company, our first thought is with people in Europe who now have access to a new treatment and the very real benefit it may have for them and their families," said Gary Hendler, President & CEO Eisai EMEA and President, Eisai Global Oncology Business Unit.

Thyroid cancer affects more than 52,000 people in Europe each year.^[4] Thyroid cancer is the most common endocrine malignancy.^[5] Approximately 5-15% of people with differentiated thyroid cancer do not respond to radioactive iodine treatment and is known as radioactive iodine refractory differentiated thyroid cancer.^[6] Approximately 2,000 people in Europe live with this difficult to treat and life threatening illness for which there are few treatment options.^[7]

Lenvatinib has been approved for the treatment of refractory thyroid cancer in the United States and Japan, and has been submitted for regulatory approval in 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.

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)^[4]

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^[2]

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 DTC 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 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])^[8] The median PFS with lenvatinib and placebo were 18.7 months and 3.7 months respectively.  

Two recent subanalyses from the SELECT study have been presented at the Endocrine Society Congress 2015 (ENDO). The first reports the results of the open-label extension phase of SELECT and aims to assess the crossover of patients in the placebo arm to the optional open-label lenvatinib treatment period. The results highlight that patients who crossed over from the placebo arm achieved a median PFS of 12.4 months with open-label lenvatinib treatment. Although toxicities were substantial, these were generally managed with medications, dose interruption, and dose reductions.

The second abstract examines the relationship between thyroid abnormalities and their effect on the safety and efficacy outcomes in SELECT. The analysis shows that although an increase in thyroid-stimulating hormone (TSH) levels was a frequent complication, its direct relationship to lenvatinib therapy has not been established and there is no evidence TSH levels affect tumour responses to lenvatinib treatment.

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.^[9] It is more common in women than in men and most are in their 40s or 50s at time of diagnosis.^[6]

The incidence of thyroid cancer has increased significantly in the last decade by 69% and 65% in men and women, respectively.^[10] 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.^[6]  The remaining cases are classified as either medullary (5-7% of cases) or anaplastic (1-2% of cases).^[11]

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: May 2015

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

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

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

5. Brito J et al. BMJ 2013; 347

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

7. 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

8. 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.  

9. National Cancer Institute at the National Institute of Health. Available at: http://www.cancer.gov/cancertopics/pdq/treatment/thyroid/Patient/page1/AllPages#1  Accessed: May 2015

10. 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: May 2015

11. Thyroid Cancer Basics. 2011. Available at: http://www.thyca.org Accessed: May 2015

Date of preparation: May 2015  
Job code: Lenvima-UK0013