Lenvatinib Phase II Results Published in The Lancet Oncology Show Significant Improvement in Progression-Free Survival When Used With Everolimus in Metastatic Renal Cell Carcinoma

HATFIELD, England, October 16, 2015 /PRNewswire/ --

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Potential future role of lenvatinib in combination with everolimus to meet unmet need of people with difficult-to-treat renal cancer   

Phase II results show lenvatinib, when used in combination with everolimus, demonstrates significantly improved progression-free survival (PFS) versus everolimus alone in people with metastatic renal cell carcinoma (mRCC) following prior VEGF-targeted therapy (14.6 months versus 5.5 months respectively (HR=0.40; 95% CI,0.24-0.68; p<0.001)). Further results from the study, published today in The Lancet Oncology, show significant improvements in objective response rates (ORR) for the lenvatinib plus everolimus combination compared to everolimus alone (43% vs. 6%, p<0.0001) and for lenvatinib compared to everolimus alone (27% vs. 6%, p=0.0067). ORR is defined as the proportion of patients to see a tumour size reduction of a predefined amount for a minimum time period.^[1]

"Metastatic renal cell carcinoma remains a difficult-to-treat cancer and people with this tumour type are in desperate need for new treatment options. The publication of these important Phase II results in The Lancet Oncology indicates lenvatinib's potential in treating patients with metastatic renal cell carcinoma," comments Dr James Larkin, Consultant Medical Oncologist at The Royal Marsden, London.

One of the study's secondary endpoints shows that, in an updated analysis, lenvatinib plus everolimus extends overall survival, compared to everolimus alone (median OS 25·5, 95% CI 16·4 to NE and 15·4, 95% CI 11·8 to 19·6 months, respectively; HR 0·51, 95% CI 0·30 to 0·88; P=0·024). For lenvatinib in combination with everolimus, the most common treatment-emergent adverse events (TEAE) reported were diarrhoea, fatigue and decreased appetite. The most common TEAEs of Grade 3 or higher (Common Terminology Criteria for Adverse Events) included diarrhoea, fatigue and hypertension.^[1]

Patients in the study were previously treated with a VEGF-targeted therapy and randomized 1:1:1 to receive lenvatinib (18 mg once a day) and everolimus (5 mg once a day), lenvatinib (24 mg once a day) or everolimus (10 mg once a day). Nearly all patients (99%) had received one prior VEGF-targeted therapy, 1% had received two prior VEGF-targeted therapies, and 18% had received prior immunotherapy treatment.

"Eisai are proud to have these data presented. We look forward to further developing lenvatinib in this indication to help patients with metastatic renal cell cancer that has relapsed after a VEGF-targeted therapy," comments Dr. Alton Kremer, Deputy President, Oncology PCU and Chief Medical Officer, Global Oncology Business Unit, Eisai Inc.

Lenvatinib is currently 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).

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.^[2] Progression-free survival is important as it extends the period of time before which a tumour progresses and improves the overall prognosis for the patient.

Everolimus is a treatment recommended by the National Comprehensive Cancer Network guidelines as a 2nd-line therapy for unresectable advanced or metastatic renal cell carcinoma.^[3] Currently, no combination therapy for this indication has been approved anywhere in the world.

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).^[4],[5] 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.^[6],[7]

Lenvatinib received Marketing Authorisation from the European Commission in May 2015 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).

Eisai is dedicated to discovering, developing and producing innovative oncology therapies that can make a difference and impact the lives of patients and their families. This passion for people is part of Eisai's human health care (hhc) mission, which strives for better understanding of the needs of patients and their families to increase the benefits health care provides.

Notes to Editors   

About Lenvatinib   

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). 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.  

About Lenvatinib's Novel Binding Mode (Type V)^[6],[7]

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, durable and potent inhibition of kinase activity, and it is suggested that this may be attributed to its novel binding mode.

Eisai in Oncology   

Our commitment to meaningful progress in oncology research, built on scientific expertise, is supported by a global capability to conduct discovery and preclinical research, and develop small molecules, therapeutic vaccines, and biologic and supportive care agents for cancer across multiple indications.

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. 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. Available at http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00290-9/abstract

2. National Cancer Institue at the National Institute of Health. Available at: http://www.cancer.gov/types/kidney/patient/kidney-treatment-pdq. Accessed: October 2015

3. Cancer Network. NCCN Updates Kidney Cancer Guidelines to Incorporate FDA Approval of Everolimus. Available at:http://www.cancernetwork.com/kidney-cancer/nccn-updates-kidney-cancer-guidelines-incorporate-fda-approval-everolimus. Assessed: October 2015

4. 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 Sep 1;14(17):5459-65.

5. 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(3):664-71.

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

7. Wu P et al. Small-molecule kinase inhibitors: an analysis of FDA-approved drugs. Drug Discovery Today 2015; 1-6