Eisai's Lenvatinib Receives FDA Priority Review for the Potential Treatment of Advanced Renal Cell Carcinoma in Combination with Everolimus

Supplemental application based on progression-free survival data from Study 205, a three-arm Phase 2 study comparing lenvatinib in combination with everolimus, everolimus alone and lenvatinib alone in these patients

Agency granted lenvatinib Breakthrough Therapy designation for investigational indication in July 2015

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Eisai Inc.

Jan 17, 2016, 06:15 ET

WOODCLIFF LAKE, N.J., Jan. 17, 2016 /PRNewswire/ -- Eisai Inc. announced today that the U.S. Food and Drug Administration (FDA) has accepted for Priority Review the supplemental New Drug Application (sNDA) for lenvatinib for the potential treatment of patients with unresectable advanced or metastatic renal cell carcinoma (RCC) in combination with everolimus following one prior vascular endothelial growth factor (VEGF)-targeted therapy. The FDA had previously granted lenvatinib Breakthrough Therapy designation for this investigational indication. Breakthrough Therapy designation is reserved for drugs with preliminary clinical evidence that indicates the drug, alone or in combination, may demonstrate a substantial improvement over existing therapies for the treatment of a serious condition.

An application for a drug will receive Priority Review by the FDA if it is a drug that treats a serious condition and, if approved, would provide a significant improvement in safety or effectiveness.

More than 61,000 new cases of kidney cancer will be diagnosed in the U.S. this year. Approximately 16% of patients with renal cell carcinoma will have metastases at diagnosis and as many as 40% will develop metastasis after primary surgical treatment for localized RCC. The prognosis for these patients with advanced RCC is poor and additional treatment options are needed.

"With the FDA's acceptance of this supplemental application, we are one step closer to potentially providing the first tyrosine kinase and mTOR inhibitor combination therapy to patients with unresectable advanced or metastatic renal cell carcinoma," said Kenichi Nomoto, Ph.D., President, Oncology Product Creation Unit, Eisai Product Creation Systems. "We look forward to working with the FDA over the coming months as it considers this potential new option for patients with advanced RCC."

Lenvatinib, discovered and developed by Eisai, is a multiple receptor tyrosine kinase inhibitor. Sold under the brand name 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 unresectable advanced or metastatic renal cell carcinoma.

The information in this release includes discussion of an investigational use for an FDA-approved product. It is not intended to convey conclusions about efficacy or safety. There is no guarantee that this investigational use 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 were approximately 61,560 new cases of kidney cancer and about 14,080 people will die from the disease. Approximately 16% 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 5-12%, the prognosis for these patients is poor.

About Lenvatinib (Available as LENVIMA^®)

LENVIMA^® (lenvatinib) is indicated for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC).

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. 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 reported in 73% of patients on LENVIMA vs 16% for placebo (44% vs 4% ≥grade 3). Blood pressure should be controlled prior to treatment. Withhold dose for grade 3 hypertension despite optimal antihypertensive therapy; resume at reduced dose when controlled at ≤grade 2. Discontinue for life-threatening hypertension.
Cardiac dysfunction reported in 7% of patients on LENVIMA vs 2% for placebo (2% vs 0% ≥grade 3). Monitor for signs/symptoms of cardiac decompensation. Withhold for grade 3 cardiac dysfunction. Resume at reduced dose or discontinue based on severity and persistence of cardiac dysfunction. Discontinue for grade 4 cardiac dysfunction.
Arterial thromboembolic events reported in 5% of patients on LENVIMA vs 2% for placebo (3% vs 1% ≥grade 3). Discontinue following an arterial thrombotic event. The safety of resuming LENVIMA after an arterial thromboembolic event has not been established, and LENVIMA has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months.
ALT and AST increases (≥grade 3) occurred in 4% and 5% of patients on LENVIMA vs 0% for placebo. Across clinical studies in which 1108 patients received LENVIMA, hepatic failure (including fatal events) was reported in 3 patients and acute hepatitis in 1 patient. Monitor liver function before initiation, then every 2 weeks for first 2 months, and at least monthly thereafter during treatment. Withhold dose for liver impairment ≥grade 3. Resume at reduced dose or discontinue based on severity/persistence of hepatotoxicity. Discontinue for hepatic failure.
Proteinuria reported in 34% of patients on LENVIMA vs 3% for placebo (11% vs 0% ≥grade 3). Monitor for proteinuria before and during treatment. Withhold dose for ≥2 grams of proteinuria/24 hours. Resume at reduced dose when proteinuria is <2 gm/24 hours. Discontinue for nephrotic syndrome.
Events of renal impairment reported in 14% of patients on LENVIMA vs 2% for placebo (3% vs 1% ≥grade 3). Withhold LENVIMA for grade 3 or 4 renal failure/impairment. Resume at reduced dose or discontinue, depending on severity/persistence of renal impairment.
Events of gastrointestinal (GI) perforation or fistula reported in 2% of patients on LENVIMA^® (lenvatinib) vs 0.8% for placebo. Discontinue in patients who develop GI perforation or life-threatening fistula.
QT/QTc interval prolongation reported in 9% of patients on LENVIMA vs 2% for placebo (2% vs 0% ≥grade 3). 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 dose for ≥grade 3 QT interval prolongation. Resume at reduced dose when QT prolongation resolves to grade 0, 1, or baseline.
Hypocalcemia ≥grade 3 reported in 9% of patients on LENVIMA (2% for placebo). Monitor blood calcium levels at least monthly and replace calcium as necessary. Interrupt and adjust LENVIMA as necessary. In most cases, hypocalcemia responded to replacement and dose interruption/reduction.
Across clinical studies in which 1108 patients received LENVIMA, reversible posterior leukoencephalopathy syndrome (RPLS) was reported in 3 patients. Withhold LENVIMA for RPLS until fully resolved. Resume at reduced dose or discontinue based on the severity and persistence of neurologic symptoms.
Hemorrhagic events occurred in 35% of patients on LENVIMA vs 18% for placebo (2% vs 3% ≥grade 3). The most frequently reported hemorrhagic event was epistaxis (11% grade 1 and 1% grade 2). Discontinuation due to hemorrhagic events occurred in 1% of patients on LENVIMA. There was 1 fatal intracranial hemorrhage case among 16 patients who received LENVIMA and had CNS metastases at baseline. Withhold dose for grade 3 hemorrhage. Resume at reduced dose or discontinue, based on severity/persistence of hemorrhage. Discontinue for grade 4 hemorrhage.
LENVIMA impairs exogenous thyroid suppression. In patients with a normal baseline TSH, elevation of TSH level above 0.5 mU/L was observed post baseline in 57% of patients on LENVIMA (14% for placebo). Monitor TSH levels monthly and adjust thyroid replacement medication as needed in patients with DTC.
LENVIMA may cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for at least 2 weeks following completion of therapy.

Adverse Reactions

The most common adverse reactions observed in LENVIMA-treated patients vs placebo-treated patients 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%).

Use in Specific Populations

Because of the potential for serious adverse reactions in nursing infants, advise women to discontinue breastfeeding during treatment.
LENVIMA may result in reduced fertility in females of reproductive potential, and may result in damage to male reproductive tissues, leading to reduced fertility of unknown duration.

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 and Pennsylvania, as well as a global demand chain organization that includes 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.