Kisplyx® (lenvatinib) in Combination with everolimus Receives Positive CHMP Opinion in Advanced Renal Cell Carcinoma

HATFIELD, England, July 22, 2016 /PRNewswire/ --


Marketing Authorisation Application (MAA) for the use of lenvatinib in combination with everolimus for the treatment of adult patients with advanced renal cell carcinoma (RCC) following one prior vascular endothelial growth factor (VEGF)-targeted therapy  

The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) today issued a positive opinion for Kisplyx(R) (lenvatinib) in combination with everolimus for the treatment of adult patients with advanced renal cell carcinoma (RCC) following one prior vascular endothelial growth factor (VEGF)-targeted therapy.[1]

The opinion was issued following the evaluation of results from a pivotal Phase II trial, which show lenvatinib plus everolimus significantly extends progression-free survival in patients with unresectable advanced renal cell carcinoma versus everolimus alone.[2] Lenvatinib was granted an accelerated assessment by the European Medicines Agency in October 2015.

Lenvatinib selectively inhibits the kinase 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).[3]

"This is a positive step forward for people with advanced renal cell carcinoma. The phase II trial was the first in which these two types of cancer drugs have been successfully combined in renal cell carcinoma, and the progression free survival results were statistically significant," comments Dr Hilary Glen, Beatson West of Scotland Cancer Centre, Glasgow, UK.

The Phase II study, on which the CHMP opinion is based, shows that people with advanced renal cell carcinoma who progressed on previous VEGF therapy treated with the combination of lenvatinib plus everolimus experienced a median progression-free survival of 14.6 months compared with 5.5 months for those who received everolimus alone (HR 0.40; 95% CI: 0.24-0.68; p=0.0005).[2] In subgroup analyses of the Phase II study presented at the American Society of Clinical Oncology (ASCO) Annual Meeting 2016, progression free survival benefit is maintained across all subgroups regardless of  high risk poor prognosis renal cancer subgroups (MSKCC risk, baseline tumour size, metastasis site).[4]  For the secondary endpoints, updated median overall survival in the intent-to-treat study population was 25.5 months in the lenvatinib plus everolimus group compared with 15.4 months in the everolimus group (HR 0.59; 95% CI 0.36 - 0.97; P=0.065).[4] Adverse events were generally higher for the lenvatinib plus everolimus combination compared with everolimus alone.[4]The most common grade 3 treatment emergent adverse events in the lenvatinib plus everolimus group included constipation (37%), diarrhoea (20%), fatigue or asthenia (14%) and hypertension (14%). The most commons grade 3 TEAEs in the everolimus group included anaemia (12%), dyspnoea (8%), hypertriglyceridaemia (8%) and hyperglycaemia (8%).[4]

Clear cell renal cell carcinoma accounts for approximately 80-90% of all kidney malignancies. Renal cell carcinoma (RCC) represents 2-3% of all cancer cases, with the highest incidence in Western countries. During the last two decades, until recently, there has been about a 2% increase in incidence of RCC worldwide.[5]

"Eisai continues to be committed to the discovery and development of treatments for cancers like advanced renal cell carcinoma. Lenvatinib in combination with everolimus is the first proven combination treatment to treat patients following one prior vascular endothelial growth factor (VEGF)-targeted therapy. The very real treatment benefit of the combination provides patients with an additional treatment option proven to have a beneficial impact on progression free survival," comments Gary Hendler, Chief Commercial Officer Oncology Business Group, Chairman and CEO EMEA.

The effect of the combination of lenvatinib plus everolimus in human renal cell carcinoma xenograft models (a graft of tissue or cells from one species to an unlike species) was also demonstrated in a second study presented at the American Association of Cancer Research in April 2016.[6] Results indicate that lenvatinib in combination with everolimus causes significant antitumour effects through the potent antiangiogenic activity of lenvatinib and direct antitumour activity of everolimus.

Lenvatinib, discovered and developed by Eisai, is an oral molecular targeted therapy that possesses a potent selectivity and a new Type V binding mode of kinase inhibition different to that of other tyrosine kinase inhibitors (TKI).[7]

Lenvatinib has been approved for the treatment of refractory thyroid cancer in the United States, Europe, Russia, Switzerland, Australia, Canada, Singapore, Japan and South Korea and has been submitted for regulatory approval in Brazil. Lenvatinib was granted Orphan Drug Designation in Japan for thyroid cancer, in the United States for treatment of follicular, medullary, anaplastic, and 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  

About Lenvatinib's Novel Binding Mode (Type V)[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 small molecule kinase inhibitors are either Type I or Type II, however lenvatinib was found to possess a new binding mode (Type V) 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.[7]

About Everolimus  

Everolimus is a selective mTOR (mammalian target of rapamycin) inhibitor. mTOR is a key serine-threonine kinase, the activity of which is known to be upregulated in a number of human cancers.[8]

About Advanced Renal Cell Carcinoma  

Renal cell carcinoma originates in the lining of the tubules,[9] the very small tubes in the kidney along with other parts of the nephron are involved in the blood filtration process to remove waste products.[10]

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


1. European Medicines Agency. Summary of Opinion (post authorisation) Lenvatinib, July 2016.

2. 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 . Last accessed: June 2016

3. 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

4 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; Poster # 175

5. Ljungberg et al. Guidelines on Renal Cell Carcinoma. Available at: . Accessed: June 2016

6. Adachi Y, et al. Lenvatinib in Combination with Everolimus Demonstrated Enhanced Antiangiogenesis and Antitumor Activity in Human RCC Xenograft Models. AACR 2016; #3264

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

8. SPC Afinitor. Available at:  Accessed: June 2016

9. National Cancer Institute at the National Institute of Health. Available at:    

10. National Cancer Institute at the National Institute of Health. Available at: accessed: June 2016

Date of preparation: July 2016 
Job code: Lenvatinib-UK0068




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