Lenvatinib Delays Deterioration in Certain Domains of Quality of Life in Patients with Unresectable Hepatocellular Carcinoma as Compared to Sorafenib in Phase 3 REFLECT Study
WOODCLIFF LAKE, N.J., Sept. 10, 2017 /PRNewswire/ -- Eisai Inc. announced today a delay in the deterioration of five health-related quality of life domains that affect patients' daily lives was observed in patients treated with lenvatinib as compared to those treated with sorafenib in the Phase 3 REFLECT study evaluating lenvatinib compared to sorafenib in patients with unresectable hepatocellular carcinoma (HCC). Quality of life scores declined with both treatments over the course of the study. Lenvatinib (marketed as Lenvima(®)) is not approved for HCC by any regulatory authority. These data were presented in an oral proffered paper session today at the European Society of Medical Oncology (ESMO) 2017 Congress in Madrid, Spain (Abstract No. 618O).
"In the REFLECT study, health-related quality of life scores favored lenvatinib in various areas that have an impact on patients' daily lives, such as nutrition, diarrhea and pain," said Prof. Arndt Vogel, MD, Clinic of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany, and investigator of the study. "The finding that lenvatinib delayed the worsening of several quality of life domains for patients with hepatocellular carcinoma when compared with sorafenib could be meaningful."
The secondary endpoint of HRQOL was assessed using the EORTC QLQ-C30 questionnaire and the HCC-specific module (EORTC QLQ-HCC18). Treatment with lenvatinib resulted in a longer median time to delay in worsening in the QLQ-C30 domains of role function (2.0 months vs 1.9 months; nominal p=0.0098), pain (2.0 months vs 1.8 months; nominal p=0.006) and diarrhea (4.6 months vs 2.7 months; nominal p<0.0001), and in the QLQ-HCC18 domains of body image (2.8 months vs 1.9 months; nominal p=0.0041) and nutrition (4.1 months vs 2.8 months; nominal p=0.006). There were no nominally significant differences in the other domains of the two scales (QLQ-C30 and QLQ-HCC18). Baseline HRQOL scores were similar for patients receiving either treatment across all domains.
"Following the clinically meaningful results in overall survival and the secondary efficacy measures in the REFLECT study presented at ASCO, it is encouraging to see that health-related quality of life scores favor lenvatinib in these domains in patients with hepatocellular carcinoma," said Alton Kremer, MD, PhD, Chief Clinical Officer and Chief Medical Officer, Oncology Business Group at Eisai. "We look forward to further discussion with the oncology community about the significance of these results presented today at ESMO."
Data from the REFLECT study is included in a supplemental New Drug Application currently under review by the FDA.
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, randomized, open-label, non-inferiority Phase 3 study to compare the efficacy and safety of lenvatinib versus sorafenib as a first-line systemic treatment in patients with uHCC. 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 overall survival. The secondary efficacy endpoints of this study were progression-free survival, time to progression and objective response rate.
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 in the United States, more than 40,710 cases will be diagnosed and 28,920 people 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.
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