Positive Topline Results of Large Phase 3 Trial Show Eisai's Lenvatinib Meets Primary Endpoint in Unresectable Hepatocellular Carcinoma

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Jan 25, 2017, 07:00 ET

WOODCLIFF LAKE, N.J., Jan. 25, 2017 /PRNewswire/ -- Eisai Inc. today announced positive topline results from the randomized, multicenter Phase 3 trial (Study 304) evaluating the company's multiple receptor tyrosine kinase inhibitor, lenvatinib (marketed as Lenvima^®), for the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC). The trial achieved its primary endpoint by meeting the statistical criteria for non-inferiority of overall survival with lenvatinib compared to sorafenib, the current standard of care for systemic treatment in this setting. Eisai plans to present the results of this study at an upcoming medical meeting and discuss these data with regulatory authorities in the United States and worldwide.

Clinically meaningful and statistically significant improvements for lenvatinib were achieved in progression-free survival, time to progression and objective response rate, the secondary efficacy endpoints. In this study, the five most common adverse events observed in the lenvatinib arm were hypertension, diarrhea, decreased appetite, weight loss, and fatigue, which is consistent with the known side-effect profile of lenvatinib. Analyses of the remaining secondary endpoints of quality of life and plasma pharmacokinetics parameters, as well as safety, are ongoing.

"Although much progress has been made in cancer research, there remains a great need for more options in the treatment of unresectable hepatocellular carcinoma," said Alton Kremer, MD, PhD, Chief Clinical Officer and Chief Medical Officer, Oncology Business Group at Eisai. "The findings from this Phase 3 trial represent an important development for previously untreated patients with unresectable hepatocellular carcinoma who unfortunately face a poor prognosis."

Lenvatinib is approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer, and in combination with everolimus for patients with advanced renal cell carcinoma who were previously treated with an anti-angiogenic therapy. Lenvatinib is under investigation for unresectable hepatocellular carcinoma and the safety or effectiveness of the product for that use has not been established.

This international, multicenter, randomized, open-label, non-inferiority Phase 3 trial enrolled 954 patients with unresectable HCC who had not received prior systemic therapy. Patients were randomized to receive lenvatinib 12 mg or 8 mg once a day depending on body weight (n=478) or sorafenib 400 mg twice a day (n=476). Treatment was continued until disease progression or unacceptable toxicity.

HCC is the most common type of liver cancer, accounting for about 90% of cases of primary liver cancer in the United States. The rates of liver cancer and intrahepatic bile duct cancer have been rising steadily over the past decade, and more than 39,000 cases will be diagnosed in the United States this year. The liver cancer mortality rate has also been rising, with more than 27,000 deaths due to the disease estimated in 2016.

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 (PDGFRα), KIT, and RET. The combination of lenvatinib and everolimus showed increased anti-angiogenic and anti-tumor activity as demonstrated by decreased human endothelial cell proliferation, tube formation, and VEGF signaling in vitro and tumor volume in mouse xenograft models of human renal cell cancer greater than each drug alone.

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). 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, cardiac dysfunction was 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 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
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. Discontinue 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
In DTC, hemorrhagic events occurred in 35% of patients on Lenvima vs 18% with placebo (2% vs 3% grade ≥3). 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. There was 1 fatal intracranial hemorrhage case among 16 patients who received Lenvima and had central nervous system metastases at baseline. 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 dose for grade 3 hemorrhage. 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 prior to treatment initiation and monthly thereafter. 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 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 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%)
In RCC, adverse reactions led to dose reductions or interruption in 89% of patients receiving Lenvima + everolimus and in 54% of patients receiving everolimus. 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.