HATFIELD, England, October 6, 2016 /PRNewswire/ --

FOR EMEA MEDIA ONLY: NOT FOR AUSTRIAN/SWISS MEDIA   

People with radioiodine-refractory differentiated thyroid cancer treated with lenvatinib had greater tumour shrinkage than with placebo in targeted sites of metastases (lung, liver, lymph nodes and bone), in exploratory subgroup analyses of the pivotal phase III SELECT study, presented at the European Society for Medical Oncology (ESMO) Congress 2016.^[1],[2] Lenvatinib is indicated in the European Union 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).^[3]

In these subanalyses, patients showed greater tumour shrinkage in all targeted sites following treatment with lenvatinib compared with placebo.^[1] The mean maximum change in sum of target lesions from baseline in patients treated with lenvatinib versus placebo in the lungs was -15.1mm vs 1.4mm, in the liver -17.7mm vs 2.5mm, in lymph nodes -17.4mm vs -0.8mm and in bone -6.7mm vs 3.4mm.^[1] Tumours were assessed by independent radiologic review at baseline and at eight week intervals.^[1]

"These data provide insight into the activity of lenvatinib in specific sites of metastases in radioiodine-refractory differentiated thyroid cancer. The study population was shown to have tumour shrinkage in all of the metastatic sites studied when treated with lenvatinib," comments Martin Schlumberger, Primary Author on SELECT and Professor of Oncology, Institut Gustave Roussy, University Paris Sud, Paris, France.

In an investigational phase II study, lenvatinib showed activity in patients with RET fusion positive adenocarcinoma of the lung.^[4] Adenocarcinoma is a type of non-small cell lung carcinoma, one of the most common forms of lung cancer.^[4] RET fusions activate RET kinase and occurs in only 1-2% of patients.^[4] Lenvatinib is a multi-kinase inhibitor whose targets include RET. Twenty five patients with RET-positive lung adenocarcinoma received lenvatinib 24mg/day in 28-day cycles until disease progression or unacceptable toxicity.^[4] The primary endpoint was objective response rate (ORR) and patients treated with lenvatinib had an ORR of 16%.^[4]

Twenty-three patients (92%) had grade ≥3 treatment emergent adverse events (TEAEs).^[4] The most common any grade TEAEs included hypertension (68%), nausea (60%), decreased appetite (52%), diarrhoea (52%), proteinuria (48%), and vomiting (44%).^[4] Of three fatal AEs, one was possibly related to lenvatinib (pneumonia).^[4]

A further study investigated the VEGFR and FGFR signalling pathway participation in tumour growth and angiogenesis in human renal cell carcinoma (RCC) xenografts treated with the combination of lenvatinib plus everolimus.^[5]

The results show that the combined activity of lenvatinib plus everolimus is based on the enhanced inhibition of VEGF and FGF-driven angiogenesis, and the simultaneous impact of the antiangiogenic activity of lenvatinib and the antiproliferative activity of everolimus.^[5] These data also suggest that both VEGFR and FGFR pathways participate in the combined activity observed of lenvatinib plus everolimus in RCC xenograft models.^[5] In August 2016, lenvatinib in combination with everolimus was approved in the European Union for the treatment of adult patients with advanced RCC following one prior vascular endothelial growth factor targeted therapy.^[6]

"These non-clinical data tell us more about the activity of the combination of lenvatinib and everolimus in renal cell carcinoma. These agents were successfully combined in a clinical study, the first time in Europe for treatments inhibiting TKI and mTOR, and led to the recent approval of the combination in renal cell carcinoma following one prior anti-angiogenic therapy," comments Alton Kremer, Chief Clinical Officer and Chief Medical Officer, Oncology Business Group at Eisai.

An ongoing open-label, multicentre phase 1b study investigated the maximum tolerated dose of lenvatinib, when used in combination with pembrolizumab in selected solid tumours.^[7] In the study, patients (≥18 years) with non-small cell lung cancer (n=2), renal cell cancer (n=8), endometrial cancer (n=2) and melanoma (n=1) received either 24mg/day, 20mg/day, or 14mg/day of lenvatinib (oral) plus 200mg of pembrolizumab (intravenous) given once every three weeks.^[7] Lenvatinib had a maximum tolerated dose of 20mg/day when used with pembrolizumab.^[7]

A preclinical study analysed immune response to single agent lenvatinib and combination of lenvatinib plus PD-1 blockade treatment in syngeneic murine (mouse) tumour models.^[8] The study examined activity in lung cancer, liver cancer, and colon cancer models. The combination showed more potent inhibition of tumour growth in all three (syngeneic) mouse tumour models investigated than either single agent.^[8] Complete tumour regressions were detected with the combination treatment in some mice in the liver cancer model.^[8]

The development of lenvatinib reflects 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 Thyroid Cancer 
Thyroid cancer forms in the tissues of the thyroid gland, located at the base of the throat near the trachea.^[9] Thyroid cancer affects more than 52,000 people in Europe each year.^[10]

About Renal Cell Carcinoma (RCC) 
Kidney cancer is among the ten most frequently occurring cancers in Western (countries) communities. About 270,000 cases of kidney cancer are diagnosed globally each year and 116,000 people die from the disease. Approximately 90% of all kidney cancers are renal cell carcinomas (RCC).^[11]

About Adenocarcinoma of the Lung 
Adenocarcinoma, a type of non-small cell lung carcinoma, is one of the most common forms of lung cancer. RET (rearranged during transfection) fusions activate RET kinase and occur in 1% to 2% of these patients.^[4]  

About Lenvatinib  
Lenvatinib is an oral multikinase inhibitor of vascular endothelial growth factor receptor 1-3, fibroblast growth factor receptor 1-4, platelet-derived growth factor receptor-alpha, and RET and KIT proto-oncogenes.^[12],[13]

Lenvatinib is indicated in the European Union 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).^[3] Lenvatinib is approved for the treatment of refractory thyroid cancer in the United States, Switzerland, the European Union, Canada, Russia, Australia, South Korea, Israel, Singapore, Japan and Brazil.^[3]

In August 2016, the European Commission issued Marketing Authorisation for 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.^[6]

About SELECT^[2]
SELECT (Study of (E7080) LEnvatinib in Differentiated Cancer of the Thyroid) is a multicentre, randomised,
double-blind, placebo-controlled phase III study of patients with radioiodine-refractory differentiated thyroid cancer, treated with once-daily, oral lenvatinib (24mg). The study enrolled 392 patients in over 100 sites in Europe, Americas, Asia, and Australia.

About Study 205^[14] 
Study 205 is a  pivotal randomised phase II study that evaluated 153 people living with unresectable advanced renal cell carcinoma who had progressed after one previous VEGF therapy.^[14]  Patients experienced a median progression-free survival of 14.6 months when treated with lenvatinib in combination with everolimus (n=51), compared with 5.5 months for those who received everolimus alone (n=50) (HR 0.40; 95% CI: 0.24-0.68; p=0.0005).^[14]  Updated median overall survival in the 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).^[14]

For lenvatinib in combination with everolimus, the most common any-grade treatment-emergent adverse events (TEAEs) reported in the lenvatinib plus everolimus group were diarrhoea, decreased appetite and fatigue.^[14] The most common TEAEs of Grade 3 or higher were diarrhoea, fatigue and hypertension.^[14]

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. Robinson B, et al. Responses in Specific Metastases Following Treatment with Lenvatinib (LN): Results from the Phase 3 SELECT Trial. European Society for Medical Oncology 2016; Poster: 962P 
2. Schlumberger M, et al. Lenvatinib versus placebo in radioiodine refractory differentiated thyroid cancer. NEJM 2015; 372: 621-30. Available at http://www.nejm.org/doi/full/10.1056/NEJMoa1406470. Accessed October 2016 
3. SPC lenvatinib (updated June 2015). Available at: http://www.medicines.org.uk/emc/medicine/30412 .
Accessed October 2016 
4. Velcheti V, et al. Phase 2 study of lenvatinib (LN) in patients (Pts) with RET fusion-positive adenocarcinoma of the lung. European Society for Medical Oncology 2016; Poster 1204PD 
5. Kimura T, et al. The Antitumor Activity of Lenvatinib (LEN) in combination with Everolimus (EVE) in Human Renal Cell Carcinoma (RCC) Xenograft Models Is Dependent on VEGFR and FGFR Signaling. European Society for Medical Oncology 2016; Poster: 6P 
6. Kisplyx SMPC, September 2016. Available at: https://www.medicines.org.uk/emc/medicine/32335 . Accessed October 2016  
7. Taylor M, et al. A Phase 1b Trial of Lenvatinib (LEN) plus Pembrolizumab (PEM) in Patients with Selected Solid Tumors. European Society for Medical Oncology 2016; Poster: 776PD 
8. Kato Y, et al. Lenvatinib Mesilate (LEN) Enhanced Antitumor Activity of a PD-1 Blockade Agent by Potentiating Th1 Immune Response. European Society for Medical Oncology 2016; Poster: 2PD 
9. National Cancer Institute at the National Institute of Health. Available at: http://www.cancer.gov/cancertopics/pdq/treatment/thyroid/Patient/page1/AllPages#1 . Accessed October 2016 
10. EUCAN 2015. Available at: http://eu-cancer.iarc.fr/EUCAN/Cancer.aspx?Cancer=35. Accessed October 2016 
11. Ljungberg B, et al. Epidemiology of Renal Cell Carcinoma. European Association of Urology, 2011; 60; 615-21 
12. 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 
13. Okamoto K, et al. Distinct Binding Mode of Multikinase Inhibitor Lenvatinib Revealed by Biochemical Characterization. ACS Medicinal Chemistry Letter 2010 
14. Motzer, R, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncology 2015;16:1473-82

 

October 2016
Lenvatinib-EU0076
 

SOURCE Eisai