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Lenvatinib Continues to Demonstrate Significant Improvements in Efficacy Parameters Across Two Tumour Types

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by June 6, 2016 General

HATFIELD, England, June 6, 2016 /PRNewswire/ —

FOR EMEA MEDIA ONLY: NOT FOR AUSTRIAN/SWISS/US MEDIA

Some people live up to four years after initiation of treatment with lenvatinib in differentiated thyroid cancer. Lenvatinib plus everolimus in kidney cancer also shows significantly improved progression free survival (PFS) compared with everolimus or lenvatinib alone according to new data presented at The American Society of Clinical Oncology Annual Meeting

Duration of overall response in people who receive Lenvima® (lenvatinib) is superior to placebo according to new efficacy data[1] from the pivotal SELECT study. Updated results at longer follow-up also show that progression free survival (PFS) continues to improve for people with progressive radioactive iodine refractory differentiated thyroid cancer (RAI refractory DTC).[1]

At the time of the primary analysis median duration of overall response was not reached.[2] Today new efficacy data show that 157 patients (60.2%) respond to lenvatinib and the median duration of response is 30 months (95% CI 18.4-35.2), whereas three patients (2.3%) respond to placebo with a median duration of response of 14.7 months (95% CI 7.5-not evaluable [NE; median not yet reached]).[1]

Median duration of overall response to lenvatinib is similar among all subgroups, except for patients with greater disease burden and patients with liver metastasis. Two patients, both with Hürthle cell variant thyroid cancer, remain on treatment with prolonged responses to lenvatinib. Both patients are alive almost four years after treatment initiation with lenvatinib, including one who has significant multiple metastases.[1]

A statistically significant improvement in PFS continues to be seen at further follow-up for patients receiving lenvatinib compared with placebo (HR=0.24, 99% CI 0.17-0.35, p<0.0001). For lenvatinib PFS is 19.4 months (95% CI 14.8-29.3) versus 3.7 months for placebo (95% CI 3.5-5.4).[1]

Lenvatinib is indicated for the treatment of adult patients with progressive locally advanced or metastatic, differentiated (papillary, follicular, Hürthle cell) thyroid carcinoma refractory to radioactive iodine (RAI refractory DTC).[3]

“These are important results as they provide further data on the long term response of patients to lenvatinib. These patients are very ill and we seldom see such prolonged responses to treatment for differentiated thyroid cancer,” comments Martin Schlumberger, Professor of Oncology, Institut Gustave Roussy, University Paris Sud, Paris, France

In a Phase II lenvatinib study in RAI refractory DTC, medullary thyroid cancer (MTC) and anaplastic thyroid cancer (ATC) tumour shrinkage occurred in most patients,[4] including those with ATC. ATC is a rare and aggressive cancer that is very difficult to treat.[5] This is a single-arm, open-label study conducted in Japan in 51 patients.[4]

Safety is the primary endpoint of this study. Data show lenvatinib has manageable toxicities with dose modifications. All patients in the study had at least one treatment-emergent adverse event (TEAE), and the most common any-grade TEAEs included hypertension, decreased appetite, hand-foot syndrome, fatigue, proteinuria, stomatitis, and diarrhoea. Grade 3 and 4 TEAEs were similar among subgroups and only one patient discontinued treatment due to a TEAE.[4]

For the secondary endpoints, median progression-free survival for RAI refractory DTC is 25.8 months, for MTC 9.2 months, and for ATC 7.4 months. Median overall survival is 31.8 months, 12.1 months, and 10.6 months respectively. Overall response rates for RAI refractory DTC are 68%, for MTC 22%, and for ATC 24%, and Disease Control Rates are 100%, 100% and 94% respectively.[4]

Subgroup analyses from the Phase II trial of lenvatinib, everolimus, and lenvatinib plus everolimus in metastatic renal cell carcinoma[6]

Patients treated with lenvatinib plus everolimus following one prior VEGF targeted therapy have significantly improved progression free survival (PFS) compared with everolimus or lenvatinib alone.[7] The PFS advantage of lenvatinib plus everolimus vs everolimus alone remains following one prior VEGF targeted therapy, regardless of Memorial Sloan Kettering Cancer Center (MSKCC) risk group, baseline tumour size, or metastasis site. For the study secondary endpoint, updated median overall survival in the intent-to-treat study population continues to trend towards improvement with lenvatinib plus everolimus (25.5 months (95% CI 16.4-32.1)) compared with lenvatinib alone (19.1 months (95% CI 13.6-26.2)) and everolimus alone (15.4 months (95% CI 11.8-20.6)).[6]

Median PFS, mos
                                                                      
                                                                      HR 95% CI);
                                                                       P-value
                          LEN            LEN+EVE           EVE       (LEN+EVE vs
                  n      n = 52    n      n = 51     n    n = 50         EVE)

                                        MSKCC risk
                                                                       0.25
                                                                       (0.08-0.76);
    Favourable   11       18.4     12       20.1     12       9.8      P = 0.009

                                                                       0.35
                                                                       (0.15-0.80);
    Intermediate 18       7.2      19       14.6     19       5.5      P = 0.0243

                                                                       0.44
                                                                       (0.20-0.98);
    Poor         23       5.6      20       5.6      19       3.5      P = 0.0936

                                Baseline tumour size
                                                                       0.34
                                                                       (0.16-0.71);< Median     27       7.4      24       14.7     25       5.5      P = 0.0035

    greater than                                                       0.39
    or equal to                                                        (0.19-0.80);
    Median       25       7.2      27       11.2     25       5.3      P = 0.0134

                                  Metastasis site
                                                                       0.41
    Bone         23       7.2      16       5.4      17       3.6      (0.18-0.94)

    Visceral                                                           0.44
    organs       49       7.4      41       9.5      44       5.5      (0.26-0.77)

                                                                       0.28
    Lymph nodes  32       8.0      29       14.7     31       5.5      (0.14-0.58)


“These new data confirm those seen in prior reports and show that patients with metastatic renal cell carcinoma regardless of prognosis do benefit from treatment with lenvatinib plus everolimus. Improved progression free survival is very important, and with the trend towards improved survival, these are really impressive results for a disease with a significant unmet need,” comments Dr Hilary Glen, Beatson Institute for Cancer Research, Glasgow, UK.

The full data set, published in the Lancet Oncology and presented at ASCO 2015,[7] show that, for the primary endpoint, progression-free survival is significantly extended in people with mRCC for lenvatinib plus everolimus versus everolimus alone (14.6 versus 5.5 months; HR 0.40; 95% CI: 0.24-0.68; p<0.001).

“Eisai remains committed to the investigation of lenvatinib in advanced thyroid cancer. We are encouraged to see that some people with advanced thyroid cancer experience a long-term benefit with lenvatinib. Lenvatinib also continues to show promise in renal cell cancer,” comments Kenichi Nomoto, Ph.D., Chief Scientific Officer of the Oncology Business Group, Eisai.

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)

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).[8],[9] 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.[10],[11]

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).

Lenvatinib has been approved for the treatment of refractory thyroid cancer in the United States, Switzerland, Europe, Canada, Russia, Australia, South Korea and Japan, and has been submitted for regulatory approval in Singapore 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.[3]

Lenvatinib mesylate in combination with everolimus has received approval from the U.S. Food and Drug Administration (FDA) for the treatment of patients with metastatic renal cell carcinoma following one prior anti-angiogenic therapy. In January 2015, Eisai submitted a Marketing Authorisation Application to the European Medicines Agency (EMA) for the use of lenvatinib in combination with everolimus, to treat people with metastatic renal cell carcinoma who have received one prior vascular endothelial growth factor (VEGF)-targeted therapy.

About Lenvatinibs Novel Binding Mode (Type V)[10],[11]

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 is a multicentre, randomised, double-blind, placebo-controlled Phase III study to compare the PFS of patients with RAI refractory 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.

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.[12]

Thyroid cancer affects more than 52,000 people in Europe each year.[13] The incidence of thyroid cancer has increased significantly in the last decade by 69% and 65% in men and women, respectively.[14] The most common types of thyroid cancer, papillary and follicular (including Hürthle cell), are classified as differentiated thyroid cancer (DTC) and account for approximately 90% of all cases.[13] The remaining cases are classified as either medullary (5-7% of cases) or anaplastic (1-2% of cases).[15]

About Study 205[7]

Study 205 is a randomised Phase II trial which shows lenvatinib when used in combination with everolimus, significant extends progression-free survival in people with metastatic renal cell carcinoma (mRCC) versus everolimus alone following one prior VEGF targetedtherapy. People treated with the combination regimen experience a median progression-free survival of 14.6 months compared with 5.5 months for those who receive everolimus alone (HR 0.40; 95% CI: 0.24-0.68; p<0.001). These data were presented at the American Society of Clinical Oncology (ASCO) in June 2015 and more recently published in Lancet Oncology.[7]

About Renal Cell Carcinoma

Renal cell carcinoma is the most common form of kidney cancer. The standard treatment for metastatic or advanced renal cell carcinoma is molecular targeted drug therapy, which is designed to interfere with the specific molecules necessary for tumour growth and progression. Despite this, it remains a disease for which patients have very few treatment options. Progression free survival is important as it extends the period of time before a tumour progresses and with it a potential for improved prognosis for the patient.

RCC accounts for approximately 90% of all kidney malignancies and represents an estimated 2-3% of all cancer cases, with the highest incidence occurring in Western countries. During the last two decades, until recently, there has been an annual 2% increase in incidence of the disease worldwide.[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. Gianoukakis A, et al. Duration of response to lenvatinib treatment in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC). American Society for Clinical Oncology annual meeting 2016; Abstract # 6089

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. Lenvima® (lenvatinib) Summary of Product Characteristics. Available at: https://www.medicines.org.uk/emc/medicine/30412 (last updated June 2015). Accessed: May 2016

4. Takahashi S, et al. Phase II study of lenvatinib in patients with differentiated, medullary, and anaplastic thyroid cancer: final analysis results. American Society for Clinical Oncology annual meeting 2016; Abstract # 6088

5. MedlinePlus. Available at: https://www.nlm.nih.gov/medlineplus/ency/article/000352.htm. Accessed: May 2016

6. Hutson T, et al. Subgroup analyses from the phase 2 trial of lenvatinib (LEN), everolimus (EVE), and LEN+EVE in metastatic renal cell carcinoma (mRCC). American Society for Clinical Oncology annual meeting 2016; Abstract # 4553

7. Motzer R, et al. Randomized phase 2 three-arm trial of lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma. The Lancet Oncology 2015;16:1473-82. Available at: http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00290-9/abstract. Last accessed: May 2016

8. Matsui J, et al. Multi-kinase inhibitor E7080 suppresses lymph node and lung metastases of human mammary breast tumor MDA-MB-231 via inhibition of vascular endothelial growth factor receptor (VEGF-R) 2 and VEGF-R3 kinase. Clin Cancer Res 2008;14:5459-65

9. Matsui J, et al. E7080, a novel inhibitor that targets multiple kinases, has potent antitumor activities against stem cell factor producing human small cell lung cancer H146, based on angiogenesis inhibition. Int J Cancer 2008;122:664-671

10.Wu P. Small-molecule kinase inhibitors: an analysis of FDA-approved drugs. Drug Discovery Today, July 2015;1-

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

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: May 2016

13. EUCAN 2015. Available at: http://eu-cancer.iarc.fr/EUCAN/Cancer.aspx?Cancer=35. Accessed: May 2016

14. 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 2016

15. Thyroid Cancer Basics. 2011. Available at: http://www.thyca.org. Accessed: May 2016

16. Ljungberg B, et al. Guidelines on Renal Cell Carcinoma. Available at: http://uroweb.org/wp-content/uploads/10-Renal-Cell-Carcinoma_LR-LV2-2015.pdf. Last accessed May 2016

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