Results from Phase 2 Study of Lenvatinib when Combined with Everolimus in Metastatic Renal Cell Carcinoma to be Presented in Oral Session at ASCO

WOODCLIFF LAKE, N.J., June 1, 2015 /PRNewswire/ -- Eisai Inc. announced today results from an investigational Phase 2 trial which showed that lenvatinib, when used in combination with everolimus, significantly extended progression-free survival (PFS) 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 (n=51) experienced a median PFS of 14.6 months compared with 5.5 months for those who received everolimus alone (n=50) (HR 0.40). When administered as a monotherapy, patients who received lenvatinib alone (n=52) experienced 7.4 months of PFS. These data will be presented in an oral session at the 51^st Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago on Monday, June 1 at 11:45 a.m. CT (Abstract No. 4506).

"Additional treatments for metastatic renal cell carcinoma are needed for patients with this difficult-to-treat cancer," said Robert Motzer, M.D., Memorial Sloan Kettering Cancer Center, New York, and a principal investigator of the study. "These positive investigational study results show the potential role of lenvatinib in patients with metastatic renal cell carcinoma."

A total of 153 patients were enrolled in the open-label, multicenter study. Patients were previously treated with a VEGF-targeted therapy and randomized 1:1:1 to receive lenvatinib and everolimus (18+5 mg once a day), lenvatinib (24 mg once a day) or everolimus (10 mg once a day). Nearly all patients (99%) had received one prior VEGF-targeted therapy, 1% had received two prior VEGF-targeted therapies, and 18% had received prior immunotherapy treatment. For lenvatinib in combination with everolimus, the most common any-grade treatment-emergent adverse events (TEAEs) were diarrhea, decreased appetite and fatigue. The most common grade 3 or higher TEAEs were diarrhea, hypertension and fatigue.

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

The information discussed in this release presents an investigational use for lenvatinib. It is not intended to convey conclusions about efficacy and safety. There is no guarantee that the investigational use of this FDA-approved product will successfully complete clinical development or gain FDA approval.

About Renal Cell Carcinoma
Renal cell carcinoma (RCC), also known as kidney cancer, renal cell cancer or renal cell adenocarcinoma, is the most common type of kidney cancer, representing about 90% of cases in the United States. Renal cell carcinoma occurs when malignant cells are found in the lining of the tubules in the kidney. While RCC usually grows as a single tumor within a kidney, there may also be two or more tumors in one or both kidneys. In 2015, there will be approximately 61,560 new cases of kidney cancer and about 14,080 people will die from the disease. Approximately 25% of patients with kidney cancer will have metastases at diagnosis and the prognosis for these patients and other patients who develop metastases after diagnosis is poor.

About Lenvatinib (Available as LENVIMA™)
Lenvatinib is indicated for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC). Lenvatinib is not indicated for patients with metastatic renal cell carcinoma.

Lenvatinib, discovered and developed by Eisai, is a receptor tyrosine kinase (RTK) inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). Lenvatinib also inhibits other RTKs that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4; the platelet derived growth factor receptor alpha (PDGFRα), KIT, and RET. Lenvatinib was approved under Priority Review designation for locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer by the FDA in February 2015. Eisai was granted Orphan Drug Designation (ODD) for lenvatinib in various types of thyroid cancer in the United States, Japan, and Europe.

Important Safety Information

Warnings and Precautions

Hypertension was reported in 73% of lenvatinib-treated patients (of which 44% were ≥ Grade 3) and 16% of patients in the placebo group. Control blood pressure prior to treatment and monitor blood pressure after 1 week, then every 2 weeks for the first 2 months, and then at least monthly during treatment. Withhold lenvatinib for Grade 3 hypertension; resume at a reduced dose when hypertension is controlled at ≤ Grade 2. Discontinue lenvatinib for life-threatening hypertension.

Cardiac dysfunction was reported in 7% of lenvatinib-treated patients (2% Grade 3 or greater). Monitor patients for clinical symptoms or signs of cardiac decompensation. Withhold lenvatinib for development of Grade 3 cardiac dysfunction until improved to Grade 0 or 1 or baseline. Resume at a reduced dose or discontinue lenvatinib depending on the severity and persistence of cardiac dysfunction. Discontinue lenvatinib for Grade 4 cardiac dysfunction.

Arterial thromboembolic events were reported in 5% of lenvatinib-treated patients; events of Grade 3 or greater were 3%. Discontinue lenvatinib following an arterial thrombotic event. Lenvatinib has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months.

4% of lenvatinib-treated patients experienced an increase in ALT and 5% experienced an increase in AST that was Grade 3 or greater. Monitor liver function before initiation and during treatment with lenvatinib. Withhold lenvatinib for the development of ≥ Grade 3 liver impairment until resolved to Grade 0 to 1 or baseline. Resume at a reduced dose or discontinue lenvatinib depending on the severity and persistence of hepatotoxicity. Discontinue lenvatinib for hepatic failure.

Proteinuria was reported in 34% of lenvatinib-treated patients (of which 11% were Grade 3). Monitor for proteinuria before initiation of, and periodically during treatment. Obtain a 24 hour urine protein if urine dipstick proteinuria ≥2+ is detected. Withhold lenvatinib for ≥ 2 grams of proteinuria/24 hours and resume at a reduced dose when proteinuria is <2 gm/24 hours. Discontinue lenvatinib for nephrotic syndrome.

Events of renal impairment were reported in 14% of lenvatinib-treated patients. Renal failure or impairment ≥ Grade 3 was 3% in lenvatinib-treated patients. Withhold lenvatinib for development of Grade 3 or 4 renal failure/impairment until resolved to Grade 0 to 1 or baseline. Resume at a reduced dose or discontinue lenvatinib depending on the severity and persistence of renal impairment.

Events of gastrointestinal perforation or fistula were reported in 2% of lenvatinib-treated patients. Discontinue lenvatinib in patients who develop gastrointestinal perforation or life-threatening fistula.

QT/QTc interval prolongation was reported in 9% of lenvatinib-treated patients (2% Grade 3 or greater). Monitor ECG in patients with congenital long QT syndrome, CHF, bradyarrhythmias, or patients taking drugs known to prolong the QT interval. Monitor and correct electrolyte abnormalities in all patients. Withhold lenvatinib for the development of ≥ Grade 3 QT interval prolongation. Resume lenvatinib at a reduced dose when QT prolongation resolves to Grade 0 or 1 or baseline.

Hypocalcemia ≥ Grade 3 was reported in 9% of lenvatinib-treated patients. Monitor blood calcium levels at least monthly and replace calcium as necessary during lenvatinib treatment. Interrupt and adjust lenvatinib dosing as necessary depending on severity, presence of ECG changes, and persistence of hypocalcemia.

Reversible posterior leukoencephalopathy syndrome (RPLS) was reported in 3 patients across clinical studies in which 1108 patients received lenvatinib. Confirm the diagnosis of RPLS with MRI. Withhold lenvatinib for RPLS until fully resolved. Resume at a reduced dose or discontinue lenvatinib depending on the severity and persistence of neurologic symptoms.

Hemorrhagic events occurred in 35% of lenvatinib-treated patients and in 18% of the placebo group. The incidence of Grade 3-5 hemorrhage was similar between arms at 2% and 3%, respectively. The most frequently reported hemorrhagic event was epistaxis (11% Grade 1 and 1% Grade 2). Discontinuation due to hemorrhagic events occurred in 1% of lenvatinib-treated patients. There was one case of fatal intracranial hemorrhage among 16 patients who received lenvatinib and had CNS metastases at baseline. Withhold lenvatinib for the development of Grade 3 hemorrhage until resolved to Grade 0 to 1. Resume at a reduced dose or discontinue lenvatinib depending on the severity and persistence of hemorrhage. Discontinue lenvatinib in patients who experience Grade 4 hemorrhage.

Lenvatinib impairs exogenous thyroid suppression. Elevation of TSH level above 0.5 mU/L was observed post baseline in 57% of lenvatinib-treated patients. Monitor TSH levels monthly and adjust thyroid replacement medication as needed.

Lenvatinib can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with lenvatinib and for at least 2 weeks following completion of therapy.

Advise women not to breastfeed during treatment with lenvatinib.

Adverse Reactions

The most common adverse reactions observed in lenvatinib-treated patients vs. placebo treated patients respectively were hypertension (73% vs 16%), fatigue (67% vs 35%), diarrhea (67% vs 17%), arthralgia/myalgia (62% vs 28%), decreased appetite (54% vs 18%), weight decreased (51% vs 15%), nausea (47% vs 25%), stomatitis (41% vs 8%), headache (38% vs 11%), vomiting (36% vs 15%), proteinuria (34% vs 3%), palmar-plantar erythrodysesthesia syndrome (32% vs 1%), abdominal pain (31% vs 11%), and dysphonia (31% vs 5%).

For more information about lenvatinib, click here for the full Product Information.

About Eisai Inc.
At Eisai Inc., human health care is our goal. We give our first thoughts to patients and their families, and helping to increase the benefits health care provides. As the U.S. pharmaceutical subsidiary of Tokyo-based Eisai Co., Ltd., we have a passionate commitment to patient care that is the driving force behind our efforts to help address unmet medical needs. We are a fully integrated pharmaceutical business with discovery, clinical, manufacturing and marketing capabilities. Our key areas of commercial focus include oncology and specialty care (Alzheimer's disease, epilepsy and metabolic disorders). To learn more about Eisai Inc., please visit us at www.eisai.com/US.

Eisai Inc. has affiliates that are part of a global product creation organization that includes R&D facilities in Massachusetts, New Jersey, North Carolina and Pennsylvania, as well as a global demand chain organization that includes manufacturing facilities in Maryland and North Carolina. Eisai's global areas of R&D focus include neuroscience; oncology; metabolic disorders; vascular, inflammatory and immunological reaction; and antibody-based programs.

SOURCE Eisai Inc.

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