Eisai Submits Marketing Authorisation Application to the European Medicines Agency for Lenvatinib in First-Line Hepatocellular Carcinoma

HATFIELD, England, July 26, 2017 /PRNewswire/ --

• Lenvatinib filing based on pivotal Phase III REFLECT study demonstrating non-inferior overall survival compared to sorafenib  
• Simultaneous submissions to EMA and US FDA follow filing with Japan's MHLW in June 2017  

Eisai announced it has submitted a marketing authorisation application to the European Medicines Agency (EMA) for the first-line use of lenvatinib in patients with unresectable hepatocellular carcinoma (uHCC). Patients with hepatocellular carcinoma face a poor prognosis, with a complex disease which accounts for approximately 90% of liver cancer cases worldwide.^[1]

"For a decade there has been no advance in the first-line systemic treatment of unresectable hepatocellular carcinoma in Europe," said Professor Jeff Evans, Professor of Translational Cancer Research, University of Glasgow. "There is a significant unmet need for patients with this advanced form of liver cancer, where treatment options are limited."

The EMA submission is based on results of the pivotal Phase III REFLECT study (Study 304). Lenvatinib was the only first-line agent to demonstrate non-inferior overall survival (OS) versus sorafenib in uHCC, with a significant and clinically meaningful improvement versus sorafenib in all secondary efficacy endpoints of progression-free survival (PFS), time to progression (TTP) and objective response rate (ORR).^[2] The REFLECT study results were presented in an oral session at this year's American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago and will be published soon in the peer-reviewed journal The Lancet.

"This announcement represents another important milestone for lenvatinib in difficult-to-treat cancer types," said Gary Hendler, Chairman & CEO EMEA, Chief Commercial Officer, Oncology Business Group at Eisai. "Based on the results observed in the REFLECT trial we are looking forward to working with the EMA to bring a much-needed first-line new treatment option for liver cancer patients in Europe one step closer."  

Lenvatinib is currently approved in the EU 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 also approved in combination with everolimus for the treatment of adult patients with advanced renal cell carcinoma following one prior vascular endothelial growth factor (VEGF)-targeted therapy.^[4]

Eisai is dedicated to the discovery, development and production of 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 to better understand the needs of patients and their families to increase the benefits health care provides.

About the REFLECT Trial (Study 304)  

REFLECT is an international, multicentre, open-label, randomised, non-inferiority Phase III study to compare the efficacy and safety of lenvatinib versus sorafenib as a first-line systemic treatment in patients with uHCC. Patients (n=954) at 183 trial sites in 21 countries were randomised to receive lenvatinib 12 mg or 8 mg once a day depending on body weight (≥60 kg or <60 kg) (n=478) or sorafenib 400 mg twice a day (n=476). Treatment was continued until disease progression or unacceptable toxicity. The primary endpoint of this study was overall survival. The secondary efficacy endpoints of this study were progression-free survival, time to progression and objective response rate.

The median OS for patients treated with lenvatinib was 13.6 months (95% CI: 12.1 - 14.9 months) compared to 12.3 months (95% CI: 10.4 - 13.9 months) for sorafenib (HR: 0.92; 95% CI: 0.79 - 1.06).^[2] Median PFS was 7.4 months (95% CI: 6.9-8.8 months) with lenvatinib with a median TTP of 8.9 months (95% CI; 7.4-9.2 months) compared to median PFS of 3.7 months (95% CI: 3.6-4.6 months) (HR: 0.66; 95% CI: 0.57 - 0.77; p<0.00001) and median TTP of 3.7 months on sorafenib (95% CI; 3.6-5.4 months) (HR 0.63; 95% CI; 0.53 - 0.73; p<0.00001).^[2] In addition, lenvatinib demonstrated significantly higher ORR (24%) compared to sorafenib (9%) (odds ratio: 3.13; 95% CI: 2.15-4.56; p<0.00001).^[2] ORR was evaluated using mRECIST.^[2]

The most common treatment-emergent adverse events (TEAEs) of any grade among patients who received lenvatinib were hypertension (42.2%), diarrhoea (38.7%), decreased appetite (34.0%), and decreased weight (30.9%).^[2] In the sorafenib arm, the most common TEAEs were palmar-plantar erythrodysesthaesia (hand-foot syndrome) (52.4%), diarrhoea (46.3%), hypertension (30.3%), and decreased appetite (26.3%).^[2] TEAEs occurred in 98.7% of patients in the lenvatinib arm and 99.4% in the sorafenib arm of the study.^[2]

About Hepatocellular Carcinoma (HCC)  

Hepatocellular carcinoma (HCC) is a complex disease associated with a poor prognosis and accounts for approximately 90% of liver cancer cases worldwide.^[1] The incidence of liver cancer in Europe has been rising steadily over the past decade.^[5] uHCC is an advanced hard-to-treat stage of liver cancer that affects >70% of patients.^[6] HCC is the second most common cause of death from cancer worldwide, estimated to be responsible for nearly 746,000 deaths across the globe in 2012.^[7] In Europe an estimated 71,000 people were diagnosed with liver cancer and 69,000 people died from this disease in 2012.^[7]

About Lenvatinib  

Lenvatinib, discovered and developed by Eisai, 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.^[8],[9] Lenvatinib is approved in the EU and the US for specific patient populations:

In the European Union lenvatinib is indicated:

• Under the brand name Lenvima^® 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]
• Under the brand name Kisplyx^® in combination with everolimus in the European Union for the treatment of adult patients with advanced renal cell carcinoma following one prior vascular endothelial growth factor (VEGF)-targeted therapy.^[4]

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 various 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 www.eisai.com.

References  

^[1] Weledj E, et al. (2014) How grim is hepatocellular carcinoma? Annals of Medicine & Surgery. 3(3):71-76.

^[2] Cheng A, et al. (2017) Phase 3 trial of lenvatinib vs sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma (uHCC). J Clin Oncol. 35 (suppl; abstr 4001). Presented at the American Society for Clinical Oncology annual meeting 2017.

^[3] Lenvima^® (lenvatinib) Summary of Product Characteristics. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003727/WC500188674.pdf . Last accessed: 21 July 2017.

^[4] Kisplyx^® (lenvatinib) Summary of Product Characteristics. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/004224/WC500216237.pdf . Last accessed: 21 July 2017.

^[5] McGlynn KA, et al. (2011) The Global Epidemiology of Hepatocellular Carcinoma, Present and Future. Clin Liver Dis. 15(2):223-243.

^[6] Lencioni R, et al. (2010) Treatment of Intermediate/Advanced Hepatocellular Carcinoma in the Clinic: How Can Outcomes Be Improved? The Oncologist. 15:42-52.

^[7] World Health Organization. Estimated Incidence, Mortality and Prevalence Worldwide in 2012. GLOBOCAN Cancer Fact Sheets: Liver Cancer. Available at: http://gco.iarc.fr/today/data/pdf/fact-sheets/cancers/cancer-fact-sheets-7.pdf . Last accessed: 21 July 2017.

^[8] Matsui J, et al. (2008) 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. 122:664-671.

^[9] Okamoto K, et al. (2010) Distinct Binding Mode of Multikinase Inhibitor Lenvatinib Revealed by Biochemical Characterization. ACS Medicinal Chemistry Letter.

Lenvatinib-EU0103
July 2017