WOODCLIFF LAKE, N.J.,
Feb. 15, 2018 /PRNewswire/
-- Eisai Inc. announced today that the positive results of a
Phase 3 study (REFLECT study, Study 304) of its in-house discovered
and developed anticancer agent lenvatinib mesylate (marketed as
Lenvima®) in patients with unresectable hepatocellular
carcinoma (HCC) have been published in the online version of The
Lancet, which is one of the world's most prestigious medical
journals and was recently ranked second in the world in terms of
Impact Factor (Lead author: Professor and Chairman Masatoshi Kudo of Kindai University Faculty of
Medicine, Title of paper: "Lenvatinib versus sorafenib in
first-line treatment of patients with unresectable hepatocellular
carcinoma: a randomised phase 3 non-inferiority trial"). Lenvatinib
is not approved for HCC by any regulatory
authority.
The REFLECT study reported on in the paper was a multicenter,
open-label, randomized, global Phase 3 study comparing the
efficacy and safety of lenvatinib versus sorafenib, a standard
treatment for advanced hepatocellular carcinoma, as a first-line
treatment in patients with unresectable HCC. In this study,
lenvatinib demonstrated a treatment effect on the primary endpoint
of Overall Survival (OS) by statistical confirmation of
non-inferiority to sorafenib. Additionally, lenvatinib showed
statistically significant and clinically meaningful improvements in
the secondary endpoints of progression-free survival (PFS), time to
progression (TTP) and objective response rate (ORR).
The paper also reported on the results of an exploratory
analysis of the secondary endpoints based on blinded independent
imaging review (IIR). The IIR was conducted using both RECIST 1.1,
which uses the traditional assessment of the effect on change in
tumor diameter, and mRECIST, which takes into account areas of
tumor necrosis in addition to the RECIST 1.1 criteria. Results of
the IIR analyses were consistent with and corroborated those for
the investigator assessments demonstrating an improvement in PFS
and TTP, as well as an increase in ORR as compared with
sorafenib.
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 safety
profile of lenvatinib.
Eisai submitted applications for lenvatinib for the treatment of
HCC in Japan (June 2017), the United
States and Europe
(July 2017), China (October
2017), Taiwan (December 2017) and other countries. Eisai remains
committed to providing additional clinical evidence for lenvatinib
aimed at maximizing the value of the drug to patients as it seeks
to contribute further to addressing the diverse needs of, and
increasing the benefits provided to, patients with cancer, their
families and healthcare providers.
This release discusses investigational uses for an FDA-approved
product. It is not intended to convey conclusions about efficacy or
safety. There is no guarantee that any investigational uses of such
FDA-approved product will gain FDA approval.
For more information, visit:
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)30207-1/fulltext?elsca1=tlxpr.
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, respectively) (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.
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<0.0001) and median TTP of 3.7
months on sorafenib (HR 0.63; 95% CI; 0.53 – 0.73; p<0.0001). In
addition, lenvatinib demonstrated significantly higher ORR (24.1%)
compared to sorafenib (9.2%) (odds ratio: 3.13; 95% CI: 2.15 –
4.56; p<0.0001). Endpoints were evaluated using mRECIST and
determined by investigator assessment. A health-related quality of
life assessment and a blinded independent imaging review that
confirmed the investigator assessment were also completed.
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 Unresectable Hepatocellular Carcinoma
(uHCC)
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. In 2018, in
the United States, an estimated
42,200 cases will be diagnosed and 30,200 people will die from
their disease. uHCC, which could be Stage 3 or 4 disease, is an
advanced stage of liver cancer that cannot be removed by surgery.
Approximately 45% of patients have Stage 3 or 4 HCC at diagnosis
and there are limited treatment options available for patients with
advanced disease.
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
(FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). 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.
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). Serious complications of
poorly controlled hypertension, including aortic dissection, have
been reported. 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
- Impaired wound healing, including fistula formation, has been
reported in patients receiving LENVIMA. Temporary interruption of
LENVIMA therapy should be considered in patients undergoing major
surgical procedures
- 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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