FDA Accepts Supplemental New Drug Application for Eisai's Lenvatinib for the Treatment of Liver Cancer

WOODCLIFF LAKE, N.J., Sept. 26, 2017 /PRNewswire/ -- Eisai Inc. today announced the U.S. Food and Drug Administration (FDA) accepted for review a supplemental New Drug Application (sNDA) for lenvatinib (marketed as Lenvima^®) for the potential use in the first-line treatment of patients with hepatocellular carcinoma (HCC), commonly referred to as liver cancer.

"Patients with advanced liver cancer face a debilitating, life-threatening disease and additional treatment options are needed for these patients," said Kenichi Nomoto, PhD, Chief Scientific Officer, Oncology Business Group, Eisai. "Given the importance of the REFLECT study results, in which lenvatinib was the first first-line systemic therapy to demonstrate positive results when compared to sorafenib in a Phase 3 trial in patients with HCC in more than a decade, we will work closely with the FDA in hopes of bringing a new treatment option to patients living with advanced liver cancer."

The sNDA submission is based on the positive results of the pivotal Phase 3 REFLECT trial. In this study, lenvatinib demonstrated a treatment effect on OS by statistical confirmation of non-inferiority to sorafenib.  This is the first positive Phase 3 study of a systemic treatment in comparison to sorafenib in this patient population. Additionally, patients experienced statistically significant and clinically meaningful improvements in the secondary efficacy endpoints of progression-free survival (PFS), time to progression (TTP) and objective response rate (ORR).

This release discusses an investigational use for an FDA-approved product. It is not intended to convey conclusions about safety or efficacy. There is no guarantee that any investigational uses of such FDA-approved product will gain FDA approval.

About the REFLECT Trial (Study 304)
REFLECT was an international, multicenter, open-label, randomized, non-inferiority Phase 3 study to compare the efficacy and safety of lenvatinib versus sorafenib as a first-line systemic treatment in patients with unresectable HCC. Patients (n=954) at 183 trial sites in 21 countries were randomized to receive lenvatinib 12 mg or 8 mg once a day depending on body weight (?60 kg or <60 kg) (n=478) or sorafenib 400 mg twice a day (n=476). Treatment was continued until disease progression or unacceptable toxicity. The primary endpoint of this study was OS. The secondary efficacy endpoints of this study were PFS, TTP and ORR.

The median OS for patients treated with lenvatinib was 13.6 months compared to 12.3 months for sorafenib (HR: 0.92; 95% CI: 0.79 ? 1.06). Median PFS was 7.4 months with lenvatinib with a median TTP of 8.9 months compared to median PFS of 3.7 months (HR: 0.66; 95% CI: 0.57 ? 0.77; p<0.00001) and median TTP of 3.7 months on sorafenib (HR 0.63; 95% CI; 0.53 ? 0.73; p<0.00001). In addition, lenvatinib demonstrated significantly higher ORR (24%) compared to sorafenib (9%) (odds ratio: 3.13; 95% CI: 2.15-4.56; p<0.00001). Endpoints were evaluated using mRECIST and determined by investigator assessment. Independent radiologic review is now complete.

In this study, the most common treatment-emergent adverse events (TEAEs) observed in the lenvatinib arm were hypertension, diarrhea, decreased appetite, decreased weight, and fatigue. In the sorafenib arm, the most common TEAEs were palmar-plantar erythrodysesthesia, diarrhea, hypertension, and decreased appetite. Patients who received lenvatinib had fewer instances of palmar-plantar erythrodysesthesia, diarrhea and alopecia, and more instances of hypertension, proteinuria, dysphonia, and hypothyroidism, than did patients who received sorafenib. Nine percent of patients treated with lenvatinib and 7% of patients treated with sorafenib discontinued treatment due to treatment-related adverse events. Forty-three percent of patients treated with lenvatinib and 30% of patients who received sorafenib experienced serious TEAEs.

About Hepatocellular Carcinoma (HCC)
Hepatocellular carcinoma is the most common type of liver cancer, accounting for about 90% of cases of primary liver cancer in the United States. In 2015, liver cancer accounted for approximately 788,000 deaths globally, making it the second leading cause of cancer-related deaths worldwide. The prevalence and mortality rate of liver cancer has been rising steadily over the past decade. This year, more than 40,710 Americans will be diagnosed and 28,920 will die from their disease. HCC patients with advanced stage disease may not be amenable for potentially curative therapeutic interventions such as a liver transplant, surgical resection or tumor ablation (typically radiofrequency ablation). Patients who cannot be treated with potentially curative approaches have a poor prognosis.

About LENVIMA^® (lenvatinib) 
LENVIMA^® (lenvatinib) is a kinase inhibitor that is indicated for:

• Differentiated Thyroid Cancer (DTC): single agent for patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory DTC.
• Renal Cell Cancer (RCC): in combination with everolimus for patients with advanced RCC following one prior anti-angiogenic therapy.

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 (PDGFR?), KIT, and RET.

Important Safety Information

Warnings and Precautions

• In DTC, hypertension was reported in 73% of patients on LENVIMA vs 16% with placebo (44% vs 4% grade ?3). In RCC, hypertension was reported in 42% of patients on LENVIMA + everolimus vs 10% with everolimus alone (13% vs 2% grade 3). Systolic blood pressure ?160 mmHg occurred in 29% of patients, and 21% of patients had a diastolic blood pressure ?100 mmHg in the LENVIMA + everolimus?treated group. Blood pressure should be controlled prior to treatment and monitored throughout. Withhold dose for grade 3 hypertension despite optimal antihypertensive therapy; resume at reduced dose when controlled at grade ?2. Discontinue for life-threatening hypertension
• In DTC, cardiac dysfunction was reported in 7% of patients on LENVIMA vs 2% with placebo (2% vs 0% grade ?3). In RCC, decreased ejection fraction and cardiac failure were reported in 10% of patients on LENVIMA + everolimus vs 6% with everolimus alone (3% vs 2% grade 3). Monitor for signs/symptoms of cardiac decompensation. Withhold LENVIMA for development of grade 3 cardiac dysfunction until improvement to grade 0, 1, or baseline. Resume at reduced dose or discontinue based on severity and persistence of cardiac dysfunction. Discontinue for grade 4 cardiac dysfunction
• In DTC, arterial thromboembolic events were reported in 5% of patients on LENVIMA vs 2% with placebo (3% vs 1% grade ?3). In RCC, arterial thromboembolic events were reported in 2% of patients on LENVIMA + everolimus vs 6% with everolimus alone (2% vs 4% 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
• Across clinical studies in which 1,160 patients received LENVIMA monotherapy, hepatic failure (including fatal events) was reported in 3 patients and acute hepatitis in 1 patient. In DTC, ALT and AST increases (grade ?3) occurred in 4% and 5% of patients on LENVIMA, respectively, vs 0% with placebo. In RCC, ALT and AST increases (grade ?3) occurred in 3% of patients on LENVIMA + everolimus vs 2% and 0% with everolimus alone, respectively. Monitor liver function before initiation, then every 2 weeks for the first 2 months, and at least monthly thereafter during treatment. Withhold dose for liver impairment grade ?3 until resolved to grade 0, 1, or baseline. Resume at reduced dose or discontinue based on severity/persistence of hepatotoxicity. Discontinue for hepatic failure
• In DTC, proteinuria was reported in 34% of patients on LENVIMA vs 3% with placebo (11% vs 0% grade 3). In RCC, proteinuria was reported in 31% of patients on LENVIMA + everolimus vs 14% with everolimus alone (8% vs 2% grade 3). Monitor for proteinuria before and during treatment. Withhold dose for proteinuria ?2 g/24 h. Resume at reduced dose when proteinuria is <2 g/24 h. Discontinue for nephrotic syndrome
• In RCC, diarrhea was reported in 81% of patients on LENVIMA + everolimus vs 34% with everolimus alone (19% vs 2% grade ?3). Initiate prompt medical management for the development of diarrhea. Monitor for dehydration. Withhold dose for diarrhea grade ?3. Resume at a reduced dose when diarrhea resolves to grade 1 or baseline. Permanently discontinue LENVIMA for grade 4 diarrhea despite medical management
• In DTC, events of renal impairment were reported in 14% of patients on LENVIMA vs 2% with placebo (3% vs 1% grade ?3). In RCC, events of renal impairment were reported in 18% of patients on LENVIMA + everolimus vs 12% with everolimus alone (10% vs 2% 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. Active management of diarrhea and any other gastrointestinal (GI) symptoms should be initiated for grade 1 events
• In DTC, events of GI perforation or fistula were reported in 2% of patients on LENVIMA vs 0.8% with placebo. In RCC, events of GI perforation, abscess, or fistula (grade ?3) were reported in 2% of patients on LENVIMA + everolimus vs 0% with everolimus alone. Discontinue in patients who develop GI perforation or life-threatening fistula
• In DTC, QT/QTc interval prolongation was reported in 9% of patients on LENVIMA vs 2% with placebo (2% vs 0% >500 ms). In RCC, QTc interval increases >60 ms were reported in 11% of patients on LENVIMA + everolimus (6% >500 ms) vs 0% with everolimus alone. Monitor electrocardiograms in patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or patients taking drugs known to prolong the QT interval. Monitor and correct electrolyte abnormalities in all patients. Withhold dose for QTc interval prolongation >500 ms. Resume at reduced dose when QTc prolongation resolves to baseline
• In DTC, hypocalcemia (grade ?3) was reported in 9% of patients on LENVIMA vs 2% with placebo. In RCC, hypocalcemia (grade ?3) was reported in 6% of patients on LENVIMA + everolimus vs 2% with everolimus alone. Monitor blood calcium levels at least monthly and replace calcium as necessary. Interrupt and adjust LENVIMA as necessary
• Across clinical studies in which 1,160 patients received LENVIMA monotherapy, reversible posterior leukoencephalopathy syndrome (RPLS) was reported in 4 patients. Withhold LENVIMA for RPLS until fully resolved. Resume at reduced dose or discontinue based on the severity and persistence of neurologic symptoms
• Across clinical studies in which 1,160 patients received LENVIMA monotherapy, hemorrhage (grade ?3) was reported in 2% of patients. In DTC, hemorrhagic events occurred in 35% of patients on LENVIMA vs 18% with placebo (2% vs 3% grade ?3). There was 1 fatal intracranial hemorrhage case among 16 patients who received LENVIMA and had central nervous system metastases at baseline. The most frequently reported hemorrhagic event was epistaxis (11% grade 1, 1% grade 2). Discontinuation due to hemorrhagic events occurred in 1% of patients on LENVIMA. In RCC, hemorrhagic events occurred in 34% of patients on LENVIMA + everolimus vs 26% with everolimus alone (8% vs 2% grade ?3). The most frequently reported hemorrhagic event was epistaxis (23% for LENVIMA + everolimus vs 24% with everolimus alone). There was 1 fatal cerebral hemorrhage case. Discontinuation due to hemorrhagic events occurred in 3% of patients on LENVIMA + everolimus. Consider the risk of severe or fatal hemorrhage associated with tumor invasion/infiltration of major blood vessels (eg, carotid artery). Withhold LENVIMA for the development of grade 3 hemorrhage until resolved to grade 0 or 1. Resume at reduced dose or discontinue based on severity/persistence of hemorrhage. Discontinue for grade 4 hemorrhage
• In DTC patients with normal baseline thyroid-stimulating hormone (TSH), elevation of TSH level above 0.5 mU/L was observed postbaseline in 57% of patients on LENVIMA vs 14% with placebo. In RCC, grade 1 or 2 hypothyroidism occurred in 24% of patients on LENVIMA + everolimus vs 2% with everolimus alone. In RCC patients with normal or low TSH at baseline, elevation of TSH was observed postbaseline in 60% of patients on LENVIMA + everolimus vs 3% with everolimus alone. Monitor thyroid function before initiation of and at least monthly throughout treatment. Treat hypothyroidism according to standard medical practice to maintain a euthyroid state
• LENVIMA can 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

• In DTC, the most common adverse reactions (?30%) 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 decrease (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%)
• In DTC, adverse reactions led to dose reductions in 68% of patients receiving LENVIMA and in 5% of patients receiving placebo; 18% of patients discontinued LENVIMA and 5% discontinued placebo for adverse reactions. The most common adverse reactions (?10%) resulting in dose reductions of LENVIMA were hypertension (13%), proteinuria (11%), decreased appetite (10%), and diarrhea (10%); the most common adverse reactions (?1%) resulting in discontinuation of LENVIMA were hypertension (1%) and asthenia (1%)
• In RCC, the most common adverse reactions (>30%) observed in patients treated with LENVIMA + everolimus vs everolimus alone were diarrhea (81% vs 34%), fatigue (73% vs 40%), arthralgia/myalgia (55% vs 32%), decreased appetite (53% vs 18%), vomiting (48% vs 12%), nausea (45% vs 16%), stomatitis/oral inflammation (44% vs 50%), hypertension/increased blood pressure (42% vs 10%), peripheral edema (42% vs 20%), cough (37% vs 30%), abdominal pain (37% vs 8%), dyspnea/exertional dyspnea (35% vs 28%), rash (35% vs 40%), weight decreased (34% vs 8%), hemorrhagic events (32% vs 26%), and proteinuria/urine protein present (31% vs 14%). The most common serious adverse reactions (?5%) were renal failure (11%), dehydration (10%), anemia (6%), thrombocytopenia (5%), diarrhea (5%), vomiting (5%), and dyspnea (5%)
• In RCC, adverse reactions led to dose reductions or interruption in 89% of patients receiving LENVIMA + everolimus and in 54% of patients receiving everolimus alone. The most common adverse reactions (?5%) resulting in dose reductions in the LENVIMA + everolimus?treated group were diarrhea (21%), fatigue (8%), thrombocytopenia (6%), vomiting (6%), nausea (5%), and proteinuria (5%). Treatment discontinuation due to an adverse reaction occurred in 29% of patients in the LENVIMA + everolimus?treated group and in 12% of patients in the everolimus-treated group

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 (hhc) is our goal. We give our first thought 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 discover and develop innovative therapies to help address unmet medical needs.

Eisai is a fully integrated pharmaceutical business that operates in two global business groups: oncology and neurology (dementia-related diseases and neurodegenerative diseases). Each group functions as an end-to-end global business with discovery, development, and marketing capabilities. Our U.S. headquarters, commercial and clinical development organizations are located in New Jersey; our discovery labs are in Massachusetts and Pennsylvania; and our global demand chain organization resides in Maryland and North Carolina. To learn more about Eisai Inc., please visit us at www.eisai.com/US.

SOURCE Eisai Inc.