FDA Grants Breakthrough Therapy Designation to Eisai's Lenvatinib for the Potential Treatment of Metastatic Renal Cell Carcinoma

WOODCLIFF LAKE, N.J., July 28, 2015 /PRNewswire/ -- Eisai Inc. announced today the U.S. Food and Drug Administration (FDA) granted lenvatinib, the company's multiple receptor tyrosine kinase inhibitor, Breakthrough Therapy designation for the investigational use in patients with advanced or metastatic renal cell carcinoma (RCC) who were previously treated with a vascular endothelial growth factor (VEGF)-targeted therapy. RCC is the most common type of kidney cancer, representing about 90% of cases in the U.S. Approximately 20-30% of patients with RCC will have metastatic (stage IV) disease at diagnosis and as many as 40% will demonstrate metastasis after primary surgical treatment for localized RCC. The prognosis for these patients is poor, with a 5-year survival rate ranging from 5-10%.

"We are excited and honored that the FDA has granted Breakthrough Therapy designation to lenvatinib for patients with metastatic renal cell carcinoma," said Kenichi Nomoto, Ph.D., President, Oncology Product Creation Unit at Eisai Inc. "We look forward to working closely with the FDA to expedite this clinical program and hope to offer an important additional treatment option to patients in need."

Lenvatinib, marketed under the brand name LENVIMA™, 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.

The FDA Breakthrough Therapy designation was established in 2012 to address unmet medical needs in the treatment of serious or life-threatening conditions. This designation is intended to expedite the development and review of drugs with preliminary clinical evidence that indicates the drug, alone or in combination, may demonstrate a substantial improvement over existing therapies and to help ensure patients have access to them as soon as possible.

Lenvatinib was designated as a Breakthrough Therapy based on results of a Phase 2 open-label, multicenter study involving 153 patients who 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. The results of this study were presented in an oral presentation at the 2015 American Society of Clinical Oncology (ASCO) annual meeting.

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

About Renal Cell Carcinoma
Renal cell carcinoma (RCC), also known as 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. In 2015, there will be approximately 61,560 new cases of kidney cancer and about 14,080 people will die from the disease. Approximately 20-30% of patients with RCC will have metastases at diagnosis and as many as 40% will demonstrate metastasis after primary surgical treatment for localized RCC.  With a 5-year survival rate ranging from 5-10%, the prognosis for these patients is poor.

About Lenvatinib (Available as LENVIMA™)
LENVIMA (lenvatinib) is approved for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC). LENVIMA (lenvatinib) has not been approved 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 VEGFR1-3. 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 FGFR1-4; the platelet derived growth factor receptor alpha (PDGFRα), KIT, and RET. LENVIMA (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 LENVIMA-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 LENVIMA for Grade 3 hypertension; resume at a reduced dose when hypertension is controlled at ≤ Grade 2. Discontinue LENVIMA for life-threatening hypertension.

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

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

4% of LENVIMA-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 LENVIMA. Withhold LENVIMA for the development of ≥ Grade 3 liver impairment until resolved to Grade 0 to 1 or baseline. Resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of hepatotoxicity. Discontinue LENVIMA for hepatic failure.

Proteinuria was reported in 34% of LENVIMA-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 LENVIMA for ≥ 2 grams of proteinuria/24 hours and resume at a reduced dose when proteinuria is <2 gm/24 hours. Discontinue LENVIMA for nephrotic syndrome.

Events of renal impairment were reported in 14% of LENVIMA-treated patients. Renal failure or impairment ≥ Grade 3 was 3% in LENVIMA-treated patients. Withhold LENVIMA 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 LENVIMA depending on the severity and persistence of renal impairment.

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

QT/QTc interval prolongation was reported in 9% of LENVIMA-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 LENVIMA for the development of ≥ Grade 3 QT interval prolongation. Resume LENVIMA at a reduced dose when QT prolongation resolves to Grade 0 or 1 or baseline.

Hypocalcemia ≥ Grade 3 was reported in 9% of LENVIMA-treated patients. Monitor blood calcium levels at least monthly and replace calcium as necessary during LENVIMA treatment. Interrupt and adjust LENVIMA 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 LENVIMA. Confirm the diagnosis of RPLS with MRI. Withhold LENVIMA for RPLS until fully resolved. Resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of neurologic symptoms.

Hemorrhagic events occurred in 35% of LENVIMA-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 LENVIMA-treated patients. There was one case of fatal intracranial hemorrhage among 16 patients who received LENVIMA and had CNS metastases at baseline. Withhold LENVIMA for the development of Grade 3 hemorrhage until resolved to Grade 0 to 1. Resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of hemorrhage. Discontinue LENVIMA in patients who experience Grade 4 hemorrhage.

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

LENVIMA 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 LENVIMA and for at least 2 weeks following completion of therapy.

Advise women not to breastfeed during treatment with LENVIMA.

Adverse Reactions

The most common adverse reactions observed in LENVIMA-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 LENVIMA, click here for the full Prescribing 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.