Lenvatinib Significantly Increases Progression Free Survival and Overall Response Rate When Used With Everolimus in Metastatic Renal Cell Carcinoma

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Eisai

01 Jun, 2015, 11:30 GMT

HATFIELD, England, June 1, 2015 /PRNewswire/ --

FOR EU MEDIA ONLY: NOT FOR SWISS AND US MEDIA 

Lenvatinib Significantly Increases Progression Free Survival and Overall Response Rate When Used With Everolimus in Metastatic Renal Cell Carcinoma 

Important phase II data for investigational use of lenvatinib in renal cancer to be presented in an oral session at American Society of Clinical Oncology (ASCO) 

A phase II trial of lenvatinib, when used in combination with everolimus, showed progression-free survival (PFS) was significantly extended in patients with metastatic renal cell carcinoma (mRCC) versus everolimus alone. The study met its primary endpoint of PFS as patients treated with the combination regimen experienced a median PFS of 14.6 months compared with 5.5 months for those who received everolimus alone (HR 0.40; 95% CI: 0.24-0.68; p<0.001).

The objective response rate (ORR) in both the lenvatinib plus everolimus group and the lenvatinib alone group demonstrated an improvement in ORR compared to the everolimus alone group (lenvatinib plus everolimus: 43% vs everolimus alone: 6%, lenvatinib alone: 27% vs everolimus alone: 6%). ORR is defined as the proportion of patients to see a tumour size reduction of a predefined amount for a minimum time period. In one of the study's secondary endpoints of overall survival (OS), an updated analysis carried out in December 2014 confirmed that lenvatinib plus everolimus extends OS, compared to everolimus alone (HR 0.51; 95% CI: 0.30-0.88). For lenvatinib in combination with everolimus, the most common treatment-emergent adverse events (TEAE) reported in the lenvatinib plus everolimus group were diarrhea, decreased appetite and fatigue. The most common TEAEs of Grade 3 or higher (Common Terminology Criteria for Adverse Events) included diarrhea, hypertension and fatigue.[1]

These data will be presented in an oral session at the 51st Annual Meeting of the American Society of Clinical Oncology (ASCO) on Monday 1 June at 11:45 CST (Abstract No. 4506).

Renal cell carcinoma is the most common form of kidney cancer. The standard treatment for metastatic or advanced renal cell carcinoma is molecular targeted drug therapy, which is designed to interfere with the specific molecules necessary for tumour growth and progression. Despite this, it remains a disease for which patients have very few treatment options. Progression free survival is important as it extends the period of time before which a tumour progresses and improves the overall prognosis for the patient.

Everolimus is a treatment recommended by the National Comprehensive Cancer Network guidelines as a 2nd-line therapy for unresectable advanced or metastatic renal cell carcinoma. Currently, no combination therapy for this indication has been approved anywhere in the world.

"For people with renal cell carcinoma, these data represent an encouraging step forward. In particular, the potential benefit in progression free survival will be welcomed by patients and clinicians alike, as this is an area of significant unmet need. Current treatment options often have a limited duration of benefit and these positive results show the potential role of lenvatinib in patients with advanced kidney cancer," commented James Larkin, Consultant Medical Oncologist at The Royal Marsden Hospital, London.

"Eisai is committed to exploring the potential clinical benefits of lenvatinib in order to further contribute to patients with cancer and their families," commented Kenichi Nomoto, President, Oncology Product Creation Unit at Eisai.

Further analyses on lenvatinib in the treatment of advanced thyroid cancer have also been presented at the Congress, using data from the phase III SELECT study unveiled at ASCO in 2014. SELECT is a randomised, double-blind, multicentre trial for people with progressive radioiodine-refractory differentiated thyroid cancer.[1],[2]  These data were presented on posters on Saturday 30 May:

  • The results of a study to determine the efficacy and safety of lenvatinib for the treatment of patients with 131I-refractory differentiated thyroid cancer, with and without prior VEGF-targeted therapy (Abstract No. 6013). In this study, lenvatinib conferred comparable efficacy in patients with and without prior exposure to VEGF-targeted therapy, with similar safety profiles. More than 75% of patients included within the SELECT study were naïve to tyrosine kinase inhibitor treatment and achieved a statistically significant progression free survival benefit of 18.7 months with lenvatinib when used as the first multiple tyrosine kinase inhibitor, compared to 3.6 months on placebo.
  • The results of a study to examine pharmacodynamic biomarkers of response and resistance in the Phase III study of lenvatinib in 131 I-refractory differentiated thyroid cancer, SELECT, (Abstract No. 6014). In this study, thyroglobulin changes were correlated with tumour shrinkage and overall response rate in the lenvatinib arm of SELECT. Increased levels of VEGF and FGF23 may indicate that lenvatinib is targeting these signalling networks in patients with refractory radioiodine differentiated thyroid cancer in SELECT.
  • The results of a study that examines the effect of age and lenvatinib treatment on overall survival for patients with 131I-refractory differentiated thyroid cancer in SELECT (Abstract No. 6048). The results of the SELECT analysis highlight that the effect of age was completely mitigated by lenvatinib treatment, resulting in improved overall survival for patients >65 years treated with lenvatinib.

Lenvatinib, discovered and developed by Eisai, is an oral molecular tri-specific targeted therapy that possesses a potent selectivity and a binding mode different to other tyrosine kinase inhibitors (TKI). Lenvatinib simultaneously inhibits the activities of several different molecules including vascular endothelial growth factor receptors (VEGFR), fibroblast growth factor receptors (FGFR), RET, KIT and platelet-derived growth factor receptors (PDGFR).[3],[4] This potentially makes lenvatinib the first TKI that simultaneously inhibits the kinase activities of FGFR 1-4 as well as VEGFR 1-3. In addition, lenvatinib was found to have a new Type V binding mode of kinase inhibition that is distinct from existing compounds.[5]

Lenvatinib has today received Marketing Authorisation from the European Commission 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).

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

The development of lenvatinib underscores 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  

Lenvatinib (E7080) 

Eisai is currently conducting clinical studies of Lenvima in several types of cancer including hepatocellular carcinoma (Phase III), renal cell carcinoma (Phase II), non-small cell lung cancer (Phase II) and endometrial cancer (Phase II).

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

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.

About SELECT[1]

The SELECT (Study of (E7080) LEnvatinib in Differentiated Cancer of the Thyroid) 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 six most common lenvatinib treatment-related adverse events (TRAEs) of any grade were hypertension, diarrhea, fatigue, decreased appetite, weight loss and nausea. TRAEs of Grade 3 or higher included hypertension, proteinuria, weight loss, diarrhea, and decreased appetite.

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]).[6] The median PFS with lenvatinib and placebo were 18.7 months and 3.7 months respectively.  

Two recent subanalyses from the SELECT study have been presented at the Endocrine Society Congress 2015 (ENDO). The first reports the results of the open-label extension phase of SELECT and aims to assess the crossover of patients in the placebo arm to the optional open-label lenvatinib treatment period. The results highlight that patients who crossed over from the placebo arm achieved a median PFS of 12.4 months with open-label lenvatinib treatment. Although toxicities were substantial, these were generally managed with medications, dose interruption, and dose reductions.

The second abstract examines the relationship between thyroid abnormalities and their effect on the safety and efficacy outcomes in SELECT. The analysis shows that although an increase in thyroid-stimulating hormone (TSH) levels was a frequent complication, its direct relationship to lenvatinib therapy has not been established and there is no evidence TSH levels affect tumour responses to lenvatinib treatment.

About Renal Cell Carcinoma 

RCC is a type of kidney cancer that originates in the lining of the proximal convoluted tubule, the very small tubes in the kidney that filter the blood and remove waste products. This form of cancer also arises from the cortical collecting ducts in addition to the proximal tubule. The only tumours of the kidney that are not included in the definition of RCC are tumours of the renal pelvis and ureters.

RCC accounts for approximately 90% of all kidney malignancies and represents an estimated 2-3% of all cancer cases, with the highest incidence occurring in Western countries. During the last two decades, until recently, there has been an annual 2% increase in incidence of the disease worldwide.[7]

About Thyroid Cancer 

Thyroid cancer refers to cancer that forms in the tissues of the thyroid gland, located at the base of the throat near the trachea.[8] It is more common in women than in men and most are in their 40s or 50s at time of diagnosis.[7]

Thyroid cancer affects more than 52,000 people in Europe each year.[6]  The incidence of thyroid cancer has increased significantly in the last decade by 69% and 65% in men and women, respectively.[9] The most common types of thyroid cancer, papillary and follicular (including Hurthle cell), are classified as differentiated thyroid cancer (DTC) and account for approximately 90% of all cases.[9]  The remaining cases are classified as either medullary (5-7% of cases) or anaplastic (1-2% of cases).[10]

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. Schlumberger M et al. Lenvatinib versus placebo in radioiodine refractory differentiated thyroid cancer. NEJM 2015; 372: 621-630. Available at http://www.nejm.org/doi/full/10.1056/NEJMoa1406470 Accessed: May 2015
  2. 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
  3. Matsui J, et al. Clin Cancer Res 2008;14:5459-65
  4. Matsui J, et al. Int J Cancer 2008;122:664-671
  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. 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.  
  7. Ljungberg et al. Guidelines on Renal Cell Carcinoma. Available at: http://uroweb.org/wp-content/uploads/10-Renal-Cell-Carcinoma_LR-LV2-2015.pdf . Accessed May 2015
  8. National Cancer Institute at the National Institute of Health. Available at: http://www.cancer.gov/cancertopics/pdq/treatment/thyroid/Patient/page1/AllPages#1 Accessed: May 2015
  9. Cancer Research UK. Thyroid cancer incidence statistics. Available at: http://www.cancerresearchuk.org/cancer-info/cancerstats/types/thyroid/incidence/uk-thyroid-cancer-incidence-statistics  Accessed: May 2015
  10. Thyroid Cancer Basics. 2011. Available at: http://www.thyca.org. Accessed: May 2015

Date of preparation: May 2015

Job code: Lenvima-UK0024