New Preclinical Data Show Combination of Lenvatinib and Everolimus Yield Greater Antitumor Activity Than Either Agent Alone in Kidney Cancer

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Eisai

19 Apr, 2016, 05:01 GMT

HATFIELD, England, April 19, 2016 /PRNewswire/ --

FOR EU MEDIA ONLY: NOT FOR SWISS/AUSTRIAN MEDIA  

Data from the American Association for Cancer Research annual meeting support significant combination effects and possible mechanisms of action of lenvatinib plus everolimus  

A preclinical study of lenvatinib plus everolimus[1] demonstrates enhanced inhibition of vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF)-induced angiogenesis than for either agent alone in human endothelial cell models. The combination also showed synergistic enhancement against bFGF- driven angiogenesis, distinguishing this from other VEGFR2 tyrosine kinase inhibitors (TKIs). These data are one of a number of lenvatinib abstracts presented this week at the American Association for Cancer Research (AACR) Annual Meeting 2016, New Orleans, USA.

"Lenvatinib and everolimus appear to be working together to produce significant combination effects, including synergistic antiangiogenic and additive antiproliferative activities against human umbilical vein endothelial cells (HUVEC). This is because the agents together simultaneously inhibit VEGFR-TK/FGFR-TK and mammalian target of rapamycin (mTOR). In preclinical models, this study examined the inhibition of molecular drivers of cancer associated with development of new blood vessels that tumours need for growth and drivers of rapid growth of cancer cells. The study revealed a possible mechanistic basis of the combination of these two drugs, which could explain the observed magnified clinical benefit," comments Dr Takashi Owa, Chief Medicine Creation Officer Oncology Business Group, Corporate Officer Eisai Co., Ltd.

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).[2] Lenvatinib is an oral multiple receptor tyrosine kinase (RTK) inhibitor that selectively inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors in addition to other proangiogenic and oncogenic pathway-related RTKs including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4; the platelet-derived growth factor (PDGF) receptor PDGFRα; KIT; and rearranged during transfection (RET) proto-oncogene.

A recent Phase II study found lenvatinib in combination with everolimus significantly extends progression-free survival in unresectable advanced renal cell carcinoma (RCC), when compared to either treatment alone.[3] 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).[3]

The enhanced effect of the combination lenvatinib plus everolimus is also demonstrated in a second study presented at AACR[4] in human renal cell carcinoma xenograft models (a graft of tissue or cells from one species to an unlike species). 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. Gene expression analysis also supports the mode of action in this model, i.e., lenvatinib alone upregulates hypoxia-related genes and everolimus decreases proliferation-related genes.

"These preclinical data demonstrate our ongoing search for molecules that go on to be used in clinical practice to help patients living with life-limiting diseases, such as kidney cancer. We are encouraged by these data as they further support our Marketing Authorisation Application to bring this combination to patients with kidney cancer," comments Gary Hendler, Chief Commercial Officer Oncology Business Group, Chairman and CEO EMEA.

In January 2016, Eisai submitted a new Marketing Authorisation Application (MAA) to the European Medicines Agency (EMA) for the use of lenvatinib in combination with everolimus for advanced renal cell carcinoma in people who have received one prior VEGF-targeted therapy. A similar application has already been submitted to the Food and Drug Administration in the US. Lenvatinib was granted an accelerated assessment for advanced RCC in Europe by the EMA in October 2015.

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   

Lenvatinib   

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).[2]

Lenvatinib has been approved for the treatment of refractory thyroid cancer in the United States, Switzerland, Europe, South Korea and Japan, and has been submitted for regulatory approval in 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.[2]

About Lenvatinib's Novel Binding Mode (Type V)[5],[6]  

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.[7],[8]

About Everolimus  

Everolimus is indicated for the treatment of patients with advanced renal cell carcinoma, whose disease has progressed on or after treatment with VEGF-targeted therapy.[7] The treatment is recommended by the National Comprehensive Cancer Network guidelines as a second-line therapy for unresectable advanced or metastatic renal cell carcinoma.

It is a type of treatment called a signal transduction inhibitor. Signal transduction inhibitors stop some of the signals within cells that make them grow and divide. Everolimus stops a particular protein called mTOR from working properly. mTOR controls other proteins that trigger cancer cells to grow. So everolimus helps to stop the cancer growing or may slow it down.[8]

About Advanced Renal Cell Carcinoma  

Renal cell carcinoma originates in the lining of the proximal convoluted tubule, the very small tubes in the kidney that filter the blood and remove waste products. The only tumours of the kidney that are not included in the definition of renal cell carcinoma are tumours of the renal pelvis and ureters.[9]

The standard treatment for metastatic or advanced renal cell carcinoma is molecular targeted drug therapy, which is designed to interfere with the specific cells necessary for tumour growth and progression. Despite this, it remains a disease for which patients have very few treatment options.[9]

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.

About the studies presented at AACR  

Mitsuhashi et al - abstract # 3262   

  • Effects of lenvatinib, everolimus, and its combination on VEGF or bFGF activated intracellular signalling were analysed in human umbilical vein endothelial cells (HUVEC) by western blotting. Combination effects of lenvatinib and everolimus on VEGF and bFGF-induced proliferation or tube formation of HUVEC were examined using combination indexes (CI).
  • Antitumor activities were tested in the KP-1/VEGF or KP-1/FGF models, where VEGF or FGF-induced tumour angiogenesis and tumour growth were enhanced in nude mice due to overexpressed VEGF or FGF in human pancreatic cancer KP-1cells.
  • Lenvatinib inhibited the VEGF or bFGF-driven phosphorylation of Erk1/2 (Thr202/Tyr204), S6K (Thr389), and S6K (Thr421/Ser424), and S6 (Ser235/Ser236), indicating the inhibition of both the MAPK pathway and the mTOR-S6K-S6 pathway.
  • Everolimus inhibited the phosphorylation of S6K (Thr389), S6K (Thr421/Ser424), and S6 (Ser235/Ser236), but not Erk1/2.
  • The combination showed greater inhibition for the phosphorylation of S6K (Thr421/Ser424) and S6 (Ser235/Ser236) than each single agent.
  • Inhibitory activity of the combination at several molar ratios was mostly additive for VEGF-driven proliferation (CI: 0.799-1.167) and mostly synergistic for bFGF-driven tube formation (CI: 0.469-0.741). In the KP-1/VEGF or KP-1/FGF xenograft models, lenvatinib, everolimus, and the combination (p.o., qd x 14) significantly inhibited tumor growth compared to vehicle.
  • In addition the combination of lenvatinib (7.5 mg/kg) and everolimus (15 mg/kg) showed significantly greater antitumor activity than higher dose of either lenvatinib (10 mg/kg) or everolimus (30 mg/kg) monotherapy.
  • The vertical inhibition of angiogenic signalling pathways with lenvatinib (RTK) and everolimus (mTOR) may contribute to enhanced antiangiogenic activity by dual targeting of the mTOR-S6K-S6 pathway.

Adachi Y et al - abstract # 3264  

  • Antitumor activity in two human RCC (A-498 and Caki-1) xenograft models was examined for orally treated with lenvatinib (10 mg/kg), everolimus (30 mg/kg), and the combination of lenvatinib and everolimus for 1 or 2 weeks. The antitumor proliferation and antiangiogenic effects were evaluated by immunohistochemistry using anti Ki67 antibody and anti CD31 antibody, respectively. The induction of apoptosis was detected by TUNEL assay (Terminal deoxynucleotidyl transferase dUTP nick end labelling), a method for detecting DNA fragmentation by labelling the terminal end of nucleic acids. Gene expression profile of tumour samples by microarray analysis were also conducted.
  • The antitumor activity of the combination of lenvatinib and everolimus was greater than that of either agent administered alone in A-498 and Caki-1 xenograft models. The combination caused tumour regression and had no remarkable body weight loss. IHC analysis revealed decrease of microvessel density in lenvatinib and combination groups, and also decrease in the proportion of proliferative cells in everolimus treated and combination-treated group in A-498 model. In TUNEL assay, significant induction of apoptosis was observed only in the combination-treatment group. The analysis of gene expression profile in A-498 xenograft tumours also supported these results: lenvatinib alone upregulated hypoxia-related genes and everolimus decreased proliferation-related genes. The combination of these 2 drugs induced blends of the gene expression changes caused by each single treatment.

References   

1. Mitsuhashi K, et al. Effects of lenvatinib mesilate in combination with everolimus on VEGF and FGF-driven angiogenesis and tumor growth. AACR 2016; #3262

2. SPC Lenvima. Available at: http://www.medicines.org.uk/emc/medicine/30412 . Accessed: April 2016

3. 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: April 2016

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

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

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

7. SPC Afinitor. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/001038/WC500022814.pdf Accessed: April 2016

8. Cancer Research UK. Available at: http://www.cancerresearchuk.org/about-cancer/cancers-in-general/treatment/cancer-drugs/everolimus . Accessed: April 2016

9. National Cancer Institute at the National Institute of Health. Available at: http://www.cancer.gov/types/kidney/patient/kidney-treatment-pdq. Accessed: April 2016