News | October 20, 2014

Late Breaking Results Suggest Angiopoietin-2 Protein Levels May Be Predictive Indicator for Lenvatinib Efficacy in Radioiodine-refractory Differentiated Thyroid Cancer

Additional new subgroup analyses for Phase III SELECT trial at the European Society for Medical Oncology (ESMO) 2014 Congress

October 20, 2014 — A new analysis from the Phase III SELECT (Study of (E7080) LEnvatinib in Differentiated Cancer of the Thyroid) trial of lenvatinib (E7080) in the treatment of radioiodine-refractory differentiated thyroid cancer shows that the level of baseline angiopoietin-2 may be a predictive factor for lenvatinib response and therefore tumor shrinkage and prolonged progression free survival (PFS).[1] Angiopoietin-2 is a protein which regulates the formation of new blood vessels in tumors.

A second analysis from SELECT shows a statistically significant correlation between hypertension and PFS in people with radioiodine-refractory differentiated thyroid cancer. Hypertension is a known adverse event of vascular endothelial growth factor receptor (VEGFR) inhibition and a biomarker for tyrosine kinase inhibitor efficacy in renal cell carcinoma treatment.[2],[3] In the SELECT study, 73 percent of lenvatinib treated patients experienced hypertension.[3]

"To date, there are no established prognostic or predictive biomarkers for radioiodine-refractory differentiated thyroid cancer or its treatment, so these studies are crucial in helping to understand further this disease and the best approach to treatment. Although hypertension is a significant adverse event that must be carefully monitored and managed, it may be an important indicator of the efficacy of treatments such as lenvatinib. Further studies are needed to investigate hypertension as a predictive indicator of lenvatinib response so that people with radioiodine-refractory differentiated thyroid cancer can be managed appropriately to ensure they get the most out of their treatment," commented Lori Wirth, M.D., assistant professor of Medicine, Harvard Medical School and medical director, Center for Head and Neck Cancers, Massachusetts General Hospital.

A third analysis characterises the change in tumour size in people with radioiodine-refractory differentiated thyroid cancer and provides important clinical insight for lenvatinib use in this difficult-to-treat cancer type. Patients who received lenvatinib treatment for one year or more saw a rapid tumour shrinkage in the first eight weeks of treatment, followed by a slower, continuous shrinkage.[4]

Other data being presented at ESMO 2014 show that the PFS benefit with lenvatinib vs placebo observed in the overall study population was maintained in all subgroups examined, including patients with papillary and follicular thyroid cancer.[5]

Data from a Phase II study of lenvatinib in patients with all subtypes of advanced thyroid cancer (differentiated, medullary and anaplastic) demonstrate promising activity across all types of advanced thyroid cancer. Adverse event profiles were generally similar to data from previous clinical studies.[6]

"The data being presented at this year's ESMO showcases the wealth of evidence to support lenvatinib in the treatment of radioiodine-refractory differentiated thyroid cancer. We remain committed to understanding more about the potential role of lenvatinib in thyroid cancer and we are dedicated to the discovery, development and production of innovative oncology therapies that can make a difference to the lives of patients and their families," commented Gary Hendler, President & CEO Eisai EMEA and president, Eisai Oncology Global Business Unit.

Lenvatinib is an oral multiple receptor tyrosine kinase (TKI) inhibitor with a novel binding mode that selectively inhibits the kinase activities of all vascular endothelial growth factor receptors (VEGFR), in addition to other proangiogenic and oncogenic pathway-related TKIs including all fibroblast growth factor receptors (FGFR), the platelet-derived growth factor (PDGF) receptor PDGFR?, KIT and RET that are involved in tumor proliferation. This potentially makes lenvatinib the first TKI that simultaneously inhibits the kinase activities of FGFR 1-4 as well as VEGFR 1-3.[7],[8],[9]

Lenvatinib, discovered and developed by Eisai, received accelerated European Medicines Agency (EMA) review on the 31 July and was filed in Europe and the U.S. on 18 August 2014. Lenvatinib was filed in Japan in June 2014. Lenvatinib was granted orphan drug designation (ODD) for the treatment of follicular and papillary thyroid cancer by the European Commission in April 2013. It also has ODD for follicular, medullary, anaplastic and metastatic or locally advanced papillary thyroid cancer in the United States and thyroid cancer in Japan.

The development of lenvatinib underscores Eisai's human health care 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 addressing the unmet medical needs of patients and their families.

Lenvatinib, discovered and developed by Eisai, is an oral multiple receptor tyrosine kinase (TKI) inhibitor with a novel binding mode that selectively inhibits the kinase activities of all vascular endothelial growth factor receptors (VEGFR), in addition to other proangiogenic and oncogenic pathway-related TKIs including all fibroblast growth factor receptors (FGFR), the platelet-derived growth factor (PDGF) receptor PDGFR?, KIT and RET that are involved in tumour proliferation.[10],[11] This potentially makes lenvatinib the first TKI that simultaneously inhibits the kinase activities of FGFR 1-4 as well as VEGFR 1-3. It is currently under investigation as a treatment for thyroid, hepatocellular carcinoma (Phase III), non-small cell lung cancer (Phase II) and other solid tumour types.

The SELECT (Study of (E7080) LEnvatinib in Differentiated Cancer of the Thyroid)[12] study was a multicentre, randomised, double-blind, placebo-controlled Phase III study to compare the PFS of patients with RR- radioiodine-refractory differentiated thyroid cancer and radiographic evidence of disease progression within the prior 13 months, treated with once-daily, oral lenvatinib (24mg) versus placebo. The study enrolled 392 patients in over 100 sites in Europe, North and South America and Asia and was conducted by Eisai in collaboration with the SFJ Pharmaceuticals Group.

Participants were stratified by age (?65, >65 years), region and ?1 prior VEGFR-targeted therapies and randomised 2:1 to either lenvatinib or placebo therapy (24mg/d, 28-d cycle). The primary endpoint was PFS assessed by independent radiologic review. The secondary endpoints of the study included overall response rate (ORR), overall survival (OS) and safety. Rates of complete response were 1.5% (4 patients) for the lenvatinib group and zero in the placebo group. The results for partial response were 63.2% (165 patients) in the lenvatinib group and 1.5% (2 patients) in the placebo arm. The median exposure duration was 13.8 months for lenvatinib and 3.9 months for placebo and the median time to response for lenvatinib was 2.0 months. Median OS has not yet been reached.

The five most common lenvatinib treatment-related adverse events (TRAEs) of any grade were hypertension (67.8%), diarrhea (59.4%), decreased appetite (50.2%), weight loss (46.4%) and nausea (41.0%). TRAEs of Grade 3 or higher (Common Terminology Criteria for Adverse Events) included hypertension (41.8%), proteinuria (10.0%), weight loss (9.6%), diarrhoea (8.0%), and decreased appetite (5.4%).

New subgroup analyses presented at the European Thyroid Association Annual Meeting in September 2014 showed that lenvatinib maintained a PFS benefit in all pre-defined subgroups of people with progressive radioiodine-refractory differentiated thyroid cancer. In particular, the PFS benefit observed in 195 people with progressive radioiodine-refractory differentiated thyroid cancer in Europe (lenvatinib n=131 and placebo n=64) was similar to the PFS of overall study population (HR=0.24, [95% CI, 0.16-0.35]). [13] The median PFS with lenvatinib and placebo were 18.7 months and 3.7 months respectively.

For more information: www.eisai.com

References:

1.Tahara et al. Comprehensive Analysis of Serum Biomarker and Tumor Gene Mutation associated with clinical outcomes in the Phase 3 Study of (E7080) LEnvatinib in Differentiated Cancer of the Thyroid (SELECT). ESMO 2014 abstract #LBA30

2.Hayman S, et al. Current Oncology Reports 2012; 14(4):285-294

3.Wirth L, et al. Treatment-emergent hypertension and efficacy in the Phase 3 study of (E7080) lenvatinib in differentiated cancer of the thyroid (SELECT). ESMO 2014 abstract #1030P

4.Robinson B et al. Characterization of tumour size change over time from the Phase 3 study of (E7080) lenvatinib in differentiated cancer of the thyroid (SELECT). ESMO 2014 abstract #1031P

5.Elisei R et al. Subgroup analyses of a Phase 3, multicentre, double-blind, placebo-controlled trial of lenvatinib (E7080) in patients with 131I-refractory differentiated thyroid cancer. ESMO 2014 abstract #1033P

6.Takahashi S et al. Phase II study of lenvatinib (LEN), a multi-targeted tyrosine kinase inhibitor, in patients with all histologic subtypes of advanced thyroid cancer (differentiated, medullary and anaplastic). ESMO 2014 abstract #995PD

7.Data on file, Eisai.Co.Ltd

8.Zuccotto F et al. J. Med. Chem. 2010, 53, 2681-2694.

9.Liao et al. Journal of Medicinal Chemistry, 2007, 50;3:409-422

10.Matsui J, et al. Clin Cancer Res 2008;14:5459-65

11.Matsui J, et al. Int J Cancer 2008;122:664-71

12.Schlumberger M et al. A phase 3, multicenter, double-blind, placebo-controlled trial of lenvatinib (E7080) in patients with 131I-refractory differentiated thyroid cancer (SELECT). ASCO 2014 abstract #E450

13.Newbold K et al. Phase 3 study of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (SELECT): Results and subgroup analysis of patients from Europe. Presented as a digital poster at ETA 2014.

14.National Cancer Institute at the National Institute of Health. Available at: http://www.cancer.gov/cancertopics/pdq/treatment/thyroid/Patient/page1/A... Accessed: September 2014

15.Brito J et al. BMJ 2013; 347

16.Cooper DS et al. Thyroid. 2009;19(11):1167-1214

17.Thyroid Cancer Basics. 2011. Available at: http://www.thyca.org Accessed: September 2014

18.Gild M et al. Multikinase inhibitors: a new option for the treatment of thyroid cancer. Nature Reviews Endocrinology. 2011; 7: 617-624

19.Bible K, et al. Lancet Oncology 2010;11(10):962-972

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