Federal Joint Committee (G-BA) Publishes Benefit Assessment Report on Lenvima® (Lenvatinib)

HATFIELD, England, October 5, 2015 /PRNewswire/ --

NOT FOR US OR SWISS OR AUSTRIAN MEDIA, PLEASE SEE SPECIFIC PRESS RELEASE IF AVAILABLE 

Report summarises clinical data and results for the advanced thyroid cancer treatment 

Federal Joint Committee (G-BA) today publishes the benefit assessment report for Lenvima^® (lenvatinib) for people with radioactive iodine refractory differentiated thyroid cancer (RAI refractory DTC).

The G-BA will now accept comments from concerned parties, including scientific and medical expert associations, via written statements on the benefit assessment report until 22 October 2015. Eisai will make a formal response to the benefit assessment report in due course.

"Eisai is confident that the G-BA will appreciate the significant therapeutic benefits lenvatinib offers to people in Germany. We will move quickly to provide our comments on a number of important areas in the benefit assessment report and look forward to the discussions in the forthcoming oral hearing with experts," commented Gary Hendler, President and CEO, Eisai EMEA and President, Eisai Oncology Global Business Unit.

"I hope that the G-BA will see the potential that lenvatinib represents for people living with advanced thyroid cancer, a difficult to treat condition with few treatment options. It was crucial that this treatment was made available to people in Germany earlier this year, so that patients living with radioactive iodine refractory differentiated thyroid cancer could begin to experience the benefits it offers," commented Professor Christoph Reuter, Clinic for Haematology, Haemostaseology and Oncology, Hannover Medical School.

Lenvatinib has been approved for the treatment of refractory thyroid cancer in the United States, Europe 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.

While thyroid cancer is relatively rare, over the past few decades the incidence of the disease is rising rapidly across the whole of Europe.^[1],[2] In 2012 there were approximately 5,229 cases in Germany.^[1]  More prevalent in women than men, at a ratio of 2 to 1, thyroid cancer is the most common endocrine malignancy.^[3]

The G-BA report references the National Comprehensive Cancer Network (NCCN), an alliance of the world's leading cancer centres, which recently updated its guidelines to recommended lenvatinib as the preferred treatment for radioactive iodine refractory differentiated thyroid cancer due to its response rate. The NCCN said, "The NCCN Panel feels that lenvatinib is the preferred agent in this setting based on a response rate of 65% for lenvatinib when compared with 12% for sorafenib, although these agents have not been directly compared."^[4]

The G-BA report also provides information on the efficacy of lenvatinib. Lenvatinib demonstrates significantly prolonged progression-free survival (PFS) in RAI refractory DTC versus placebo. Lenvatinib shows a median 18.3 months progression free survival 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. The SELECT study published in the New England Journal of Medicine, is a randomised, double-blind, multicentre trial for people with progressive radioactive iodine refractory differentiated thyroid cancer (n=392).^[5] 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.

An updated analysis from the SELECT study has shown that lenvatinib significantly improves overall survival versus placebo in patients with progressive radioactive iodine refractory differentiated thyroid cancer (RAI Refractory-DTC) (HR=0.53; 95% CI: 0.34, 0.82, nominal p=0.0051). These data was presented at the recent European Cancer Congress (ECC) in Vienna.^[6]

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), rearranged during transfection tyrosine kinase (RET), Tyrosinkinase KIT (KIT) and platelet-derived growth factor receptors (PDGFR). This potentially makes lenvatinib the first TKI that simultaneously inhibits the kinase activities of FGFR 1-4 as well as VEGFR 1-3.^[7],[8] In addition, lenvatinib was found to have a new Type V binding mode of kinase inhibition that is distinct from existing compounds.^[9],[10]

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  

About Lenvatinib  

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).

About Lenvatinib's Novel Binding Mode (Type V)^[9],[10]

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^[11]

The SELECT (Study of (E7080) LEnvatinib in Differentiated Cancer of the Thyroid) study is a multicentre, randomised, double-blind, placebo-controlled Phase III study to compare the 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. 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]).^[12] The median PFS with lenvatinib and placebo were 18.7 months and 3.7 months respectively.^[12]

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.^[13] It is more common in women than in men and most are in their 40s or 50s at time of diagnosis.^[14]

Thyroid cancer affects more than 52,000 people in Europe each year.^[1]  The incidence of thyroid cancer has increased significantly in the last decade by 69% and 65% in men and women, respectively. 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.^[15] The remaining cases are classified as either medullary (5-7% of cases) or anaplastic (1-2% of cases).^[16]

RAI Refractory-DTC is a rare, difficult-to-treat type of cancer, characterised by aggressive growth and spread. While most DTC patients are curable with surgery and radioactive iodine treatment, the prognosis for those patients who do not respond is poor.^[15] There are limited treatment options for this life-threatening and treatment-refractory form of thyroid cancer.^[16]

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 EUCAN 2015. http://eu-cancer.iarc.fr/EUCAN/Cancer.aspx?Cancer=35 Accessed: June 2015

2 Kilfoy BA et al. Cancer Causes Control. 2009 Jul; 20(5):525-31

3 Butterfly Thyroid Cancer Trust. About Thyroid Cancer. Available at: http://www.butterfly.org.uk/about.htm  Accessed: June 2015

4 NCCN Flash Update, page 10. Available at: https://www.sumocancer.org/wp-content/uploads/2015/07/Q2-NCCN-Flash-Update-Report-7.8.2015.pdf  Accessed: September 2015

5 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: June 2015

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

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

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

9 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.  

10 Wirth L et al. 2015; Open-Label Extension Phase Outcomes of the Phase 3 Select Trial of Lenvatinib in Patients with 131I-Refractory Differentiated Thyroid Cancer. Endocrine Reviews; 36;2: Abstract 0R44-6. Available at: http://press.endocrine.org/doi/abs/10.1210/endo-meetings.2015.THPTA.6.OR44-6  Accessed: September 2015

11 Schlumberger M et al. Relationship Between Thyroid-Stimulating Hormone Levels and Outcomes from the Randomized, Double-Blind, Phase 3 Study of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (SELECT).Available at: https://endo.confex.com/endo/2015endo/webprogram/Paper20459.html  Accessed: September 2015

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

13 Brito J et al. BMJ 2013; 347

14 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.

15 Thyroid Cancer Basics. 2011. Available at: http://www.thyca.org  Accessed: June 2015

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

Date of preparation: October 2015
Job code: Lenvima-UK0049