New Subgroup Analyses Shows Lenvatinib to Significantly Improve Progression-free Survival in Radioiodine-Refractory Differentiated Thyroid Cancer

In people with progressive radioiodine-refractory differentiated thyroid cancer progression free survival is significantly extended by lenvatinib (E7080; Eisai), an oral multiple receptor tyrosine kinase (RTK) inhibitor, compared to placebo 18.3 months vs 3.6 months. (RR-DTC) (Hazard Ratio (HR)=0.21, [95% CI, 0.14-0.31]; p<0.0001). This is the conclusion based on data from the SELECT-study, a phase III Study of LEnvatinib in Differentiated Cancer of the Thyroid, presented at the 38th Annual Meeting of the European Thyroid Association being held September 6 - 10, 2014 in Santiago de Compostela, Spain.

Thyroid cancer refers to cancer that forms in the tissues of the thyroid gland, located at the base of the throat near the trachea.[11] It is more common in women than in men and most patients are in their 40s or 50s at time of diagnosis.[3] Thyroid cancer is the most common endocrine malignancy. [3] In Europe alone, over 50,000 cases of thyroid cancer were diagnosed in 2012.[4] Global figures show that its incidence has increased significantly over the last 50 years.[3] Although treatment is possible for most types of thyroid cancer, there remains an unmet need for treatment options for thyroid cancer once the disease has progressed.

...patients...across Europe are in urgent need of options to treat this aggressive form of thyroid cancer...

The most common types of thyroid cancer, papillary and follicular, which including Hurthle cell, are classified as differentiated thyroid cancer (DTC) and account for approximately 90% of all cases.[12] The remaining cases are classified as either medullary (5-7% of cases) or anaplastic (1-2% of cases).[13]While most DTC patients are curable with surgery and radioactive iodine treatment, the prognosis for those patients who do not respond is poor.[14] There are limited treatment options for this difficult-to-treat, life-threatening and treatment-refractory form of thyroid cancer.[15]

One possible new treatment options is lenvatinib. The trial drug, lenvatinib, has 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 RTKs including all fibroblast growth factor receptors (FGFR), the platelet-derived growth factor (PDGF) receptor PDGFRα, KIT and RET that are involved in tumor proliferation.[9],[10] This potentially makes lenvatinib the first tyrosine kinase inhibitor, that simultaneously inhibits the kinase activities of FGFR-4 as well as VEGFR1-3. The drug is currently under investigation as a treatment for thyroid, hepatocellular carcinoma (Phase III), non-small cell lung cancer (Phase II) and other solid tumor types.[5][6][7]

Subgroup analyses
An exploratory subgroup analyses from the SELECT-trial suggest that lenvatinib maintains PFS benefit in people with progressive RR-DTC including people with lung metastasis, median PFS: lenvatinib, 18.7 months; placebo, 3.6 months (HR=0.21, [95% CI, 0.15-0.29]; p<0.0001), and bone metastasis median PFS: lenvatinib, NR; placebo, 7.4 months (HR=0.65, [95% CI, 0.11-4.07] p<0.0001).[1]

A second subgroup analysis of the SELECT data, to be presented at the annual meeting, finds that the PFS benefit is similar in 195 people in Europe with progressive RR-DTC (lenvatinib n=131 and placebo n=64) compared with the overall study population (HR=0.24, [95% CI, 0.16-0.35]; p<0.0001).[2] The median PFS with lenvatinib and placebo is 18.7 months and 3.7 months respectively.

Effective treatment
"The data from our subgroup analyses are consistent with the overall SELECT study and show that lenvatinib is effective in this rare and hard-to-treat cancer. We are excited to present these subgroup analyses at this European forum, as patients and physicians across Europe are in urgent need of options to treat this aggressive form of thyroid cancer," commented Kate Newbold, Primary Investigator and Consultant Clinical Oncologist at The Royal Marsden Hospital NHS Foundation Trust, UK.

Study design
The SELECT-study was a multicentre, randomised, double-blind, placebo-controlled Phase III study to compare the PFS of people with RR-DTC and radiographic evidence of disease progression within the prior 13 months, treated with once-daily, oral lenvatinib (24mg) versus placebo.[8] Secondary endpoints of the study included overall response rate or ORR, overall survival or OS and safety. 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 (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.

Adverse events
The 5 most common treatment-related adverse events (any grade) in the European subgroup were hypertension (68%), diarrhoea (59%), decreased appetite (50%), decreased weight (46%) and nausea (41%).

Lenvatinib, discovered and developed by Eisai, received accelerated European Medicines Agency (EMA) review on the 31 July 2014 and was filed in Europe and the U.S. on 18 August 2014. The drug received orphan drug designation or 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 U.S. and thyroid cancer in Japan.

For more information:
[1] Sherman S 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 (SELECT). Presented as an oral presentation at ETA 2014 [Website]
[2] 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 [Website]
[3] Brito JP, Morris JC, Montori VM. Thyroid cancer: zealous imaging has increased detection and treatment of low risk tumors. BMJ. 2013 Aug 27;347:f4706. doi: 10.1136/bmj.f4706.[Article][PubMed]
[4] Thyroid Cancer. International Agency for Research on Cancer. Estimated Incidence, Mortality & Prevalence (2012). Last accessed: September 4, 2014 [Website]
[5] Data on file, Eisai.Co.Ltd
[6] Zuccotto F, Ardini E, Casale E, Angiolini M. Through the “Gatekeeper Door”: Exploiting the Active Kinase Conformation. Journal of Medicinal Chemistry, 2010, 53;7 2681-2694.[Article]
[7] Liao L, Jie J. Molecular Recognition of Protein Kinase Binding Pockets for Design of Potent and Selective Kinase Inhibitors. Journal of Medicinal Chemistry, 2007, 50;3:409-422 [Article]
[8] Schlumberger M, Tahara M, Wirth LJ, Robinson B, Brose MS, Elisei R, Dutcus CE, 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 J Clin Oncol 32:5s, 2014 (suppl; abstr LBA6008) [Abstract]
[9] Matsui J, Funahashi Y, Uenaka T, Watanabe T, Tsuruoka A, Asada M. Multi-kinase inhibitor E7080 suppresses lymph node and lung metastases of human mammary breast tumor MDA-MB-231 via inhibition of vascular endothelial growth factor-receptor (VEGF-R) 2 and VEGF-R3 kinase. Clin Cancer Res. 2008 Sep 1;14(17):5459-65. doi: 10.1158/1078-0432.CCR-07-5270.[Article][PubMed]
[10] Matsui J, Yamamoto Y, Funahashi Y, Tsuruoka A, Watanabe T, Wakabayashi T, Uenaka T, Asada M. 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 Feb 1;122(3):664-71.[Article][PubMed]
[11] National Cancer Institute at the National Institute of Health General Information About Thyroid Cancer. Last accessed: September 4 2014 [Website]
[12] Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, Mazzaferri EL, et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2009 Nov;19(11):1167-214. doi: 10.1089/thy.2009.0110.[Article][PubMed]
[13] Thyroid Cancer Basics. 2011. [Website
[14] Gild ML, Bullock M, Robinson BG, Clifton-Bligh R. Multikinase inhibitors: a new option for the treatment of thyroid cancer. Nat Rev Endocrinol. 2011 Aug 23;7(10):617-24. doi: 10.1038/nrendo.2011.141.[Article][PubMed]
[15] Bible KC, Suman VJ, Molina JR, Smallridge RC, Maples WJ, Menefee ME, Rubin J, et al. Efficacy of pazopanib in progressive, radioiodine-refractory, metastatic differentiated thyroid cancers: results of a phase 2 consortium study. Lancet Oncol. 2010 Oct;11(10):962-72. doi: 10.1016/S1470-2045(10)70203-5.[Article][PubMed]

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