Biomarker Analyses from Pivotal Phase 3 CLEAR
Trial in Patients with Advanced Renal Cell Carcinoma Will Be
Featured in an Oral Presentation
Additional Data From Eisai's Pipeline Provide
Insights Into Metastatic Breast Cancer and Other Solid
Tumors
NUTLEY, N.J., May 23, 2024 /PRNewswire/ -- Eisai announced
today the presentation of research across multiple types of cancer
from its oncology portfolio and pipeline during the 2024 American
Society of Clinical Oncology (ASCO) Annual Meeting (#ASCO24), which
is taking place virtually and in-person in Chicago, Illinois from May 31 to June 4.
Notable data include an oral presentation on biomarker analyses
from the pivotal Phase 3 CLEAR (Study 307)/KEYNOTE-581 trial
(NCT02811861), which evaluated lenvatinib (LENVIMA®),
the orally available multiple receptor tyrosine kinase inhibitor
discovered by Eisai, plus pembrolizumab (KEYTRUDA®),
Merck's anti-PD-1 therapy, versus sunitinib for the first-line
treatment of patients with advanced renal cell carcinoma (Abstract
#4504). An analysis of patterns of disease progression and
subsequent therapy from this trial will also be presented in a
poster presentation (Abstract #4524).
"At Eisai, we let the science drive us to new approaches that
accelerate progress in oncology, while also remaining grounded in
our human health care concept that reinforces our commitment
to prioritize the needs of patients and families impacted by a
cancer diagnosis," said Dr. Takashi
Owa, Chief Scientific Officer, Senior Vice President, Eisai
Co., Ltd. "With this in mind, we look forward to sharing research
that provides further insight into the role of lenvatinib plus
pembrolizumab as a first-line standard of care option in advanced
renal cell carcinoma, as well as research that explores various
modalities in our pipeline for the potential treatment of advanced
diseases with the goal of improving patients' lives."
Other key research of note from Eisai's pipeline include an oral
presentation of Phase 3 data from the JBCRG-M06/EMERALD study in
Japan evaluating trastuzumab and
pertuzumab in combination with Eisai's eribulin mesylate or a
taxane in patients with HER2-positive, locally advanced or
metastatic breast cancer (NCT03264547; Abstract #1007). Additional
pipeline research to be presented in poster sessions include an
overview of a Phase 2 study of BB-1701, an antibody drug conjugate
targeting HER2, in previously treated patients with HER2-positive
or HER2-low unresectable or metastatic breast cancer (NCT06188559;
Abstract #TPS1122), findings from a Phase 1b trial of tasurgratinib (development code:
E7090) with or without endocrine therapies for patients with ER
positive, HER2 negative recurrent/metastatic breast cancer after
receiving a CDK4/6 inhibitor (NCT04572295; Abstract #3103), as well
as the dose-expansion part of a Phase 1b global study of E7386 (a Wnt/β-catenin pathway
modulator) in combination with lenvatinib in patients with
hepatocellular carcinoma and other solid tumors including
endometrial cancer (NCT04008797; Abstract #TPS3169).
This release discusses investigational compounds and
investigational uses for FDA-approved products. It is not intended
to convey conclusions about efficacy and safety. There is no
guarantee that any investigational compounds or investigational
uses of FDA-approved products will successfully complete clinical
development or gain FDA approval.
The full list of Eisai presentations is included below. These
abstracts will be made available via the ASCO website on
Thursday, May 23, 2024, at
5:00 PM EDT.
Cancer
Type
|
Study/Compound
|
Abstract
Title
|
Abstract Type &
Details
|
Lenvatinib Plus
Pembrolizumab
|
Genitourinary
Cancer
|
CLEAR
|
Biomarker analyses in
patients with
advanced renal cell carcinoma (aRCC) from
the phase 3 CLEAR trial
|
Oral Abstract
Session
Abstract
#4504
June 3, 2024
10:00 AM EDT
/
9:00 AM CDT
|
Genitourinary
Cancer
|
CLEAR
|
Lenvatinib plus
pembrolizumab (L+P) vs
sunitinib (S) in advanced renal cell
carcinoma (aRCC): Patterns of progression
and subsequent therapy in the CLEAR trial
|
Poster
Session
Abstract
#4524
June 2, 2024
10:00 AM EDT
/
9:00 AM PM
CDT
|
Melanoma
|
LEAP-004
|
Lenvatinib (len) plus
pembrolizumab
(pembro) in patients with advanced
melanoma that progressed on anti-PD-(L)1
therapy: Over 4 years of follow-up from the
phase 2 LEAP-004 study
|
Poster
Session
Abstract
#9559
June 1, 2024
2:30 PM EDT
/
1:30 PM CDT
|
Lenvatinib
|
Differentiated
Thyroid
Cancer
|
Real-World
Evidence
|
Patients with
radioiodine-refractory
differentiated thyroid cancer (RAI-R DTC)
with BRAF V600E and/or K601E mutation
status: A real-world view of effectiveness of
lenvatinib monotherapy
|
Poster
Session
Abstract
#6098
June 2, 2024
10:00 AM EDT
/
9:00 AM CDT
|
Gastrointestinal
Cancer
|
REFLECT
|
ctDNA analysis of
patients (pts) with
unresectable hepatocellular carcinoma
(uHCC) treated with lenvatinib (LEN) or
sorafenib (SOR) as 1L therapy
|
Poster
Session
Abstract
#4094
June 1, 2024
2:30 PM EDT
/
1:30 PM CDT
|
Eribulin
|
Breast
Cancer
|
JBCRG-M06/
EMERALD
|
Trastuzumab and
pertuzumab in
combination with eribulin mesylate or a
taxane as first-line chemotherapeutic
treatment for HER2-positive, locally
advanced or metastatic breast cancer:
Results of a multicenter, randomized, non-
inferiority phase 3 trial in Japan (JBCRG-
M06/EMERALD)
|
Oral Abstract
Session
Abstract
#1007
June 1, 2023
6:00 PM EDT
/
5:00 PM CDT
|
Pipeline
|
Breast
Cancer
|
BB-1701
|
An open-label,
multicenter, phase 2 study to
evaluate the safety and efficacy of BB-1701,
a novel antibody drug conjugate (ADC)
targeting human epidermal
growth factor receptor 2 (HER2), in
previously treated patients with HER2-
positive (HER2+) or HER2-low unresectable
or metastatic breast cancer (BC)
|
Poster
Session
Abstract
#TPS1122
June 2, 2024
10:00 AM EDT
/
9:00 AM CDT
|
tasurgratinib
|
Phase Ib trial of
tasurgratinib (E7090) with
or without endocrine therapies for patients
(pts) with ER+, HER2− recurrent/metastatic
breast cancer (BC) after receiving a CDK4/6
inhibitor
|
Poster
Session
Abstract
#3103
June 1, 2024
10:00 AM EDT / 9:00 AM
CDT
|
H3B-6545
|
H3B-6545 in women with
locally
advanced/metastatic estrogen receptor-
positive (ER+), HER2 negative (-) breast
cancer (BC)
|
Rapid Oral
Session
Abstract
#1015
June 3, 2024
12:36 PM EDT
/
11:36 AM CDT
|
H3B-6545
|
H3B-6545 + palbociclib
in patients (pts) with
locally advanced/metastatic estrogen
receptor-positive (ER+), HER2 negative (-)
breast cancer (BC)
|
Poster
Session
Abstract
#1051
June 2, 2024
10:00 AM EDT
/
9:00 AM CDT
|
Solid Tumors
|
E7386
|
Dose-expansion part of
a phase 1b global
study of E7386 in combination with
lenvatinib (LEN) in patients (pts) with
hepatocellular carcinoma (HCC) and other
solid tumors including endometrial cancer
(EC)
|
Poster
Session
Abstract
#TPS3169
June 1, 2024
10:00 AM EDT
/
9:00 AM CDT
|
In March 2018, Eisai and Merck (known as MSD
outside the United States and Canada), through an
affiliate, entered into a strategic collaboration for the worldwide
co-development and co-commercialization of lenvatinib, both as
monotherapy and in combination with Merck's anti-PD-1 therapy,
pembrolizumab. Eisai and Merck are studying the lenvatinib
plus pembrolizumab combination through the LEAP (LEnvatinib
And Pembrolizumab) clinical program in various tumor
types across multiple clinical trials.
In May 2023, Eisai entered into a
joint development agreement with Bliss Biopharmaceutical
(Hangzhou) Co., Ltd.
(Headquarters: Zhejiang Province,
China, "BlissBio"), for BB-1701, a
HER2-targeting antibody drug conjugate (ADC), with option rights
for a strategic collaboration. Eisai and BlissBio are currently
investigating BB-1701 in a Phase 2 clinical trial in Japan and the United
States for breast cancer, and a Phase 1/2 clinical trial in
the United States and China for HER2-expressing solid
tumors.
About BB-1701
BB-1701 is an antibody drug conjugate
(ADC) that is composed of Eisai's in-house developed cytotoxic
agent eribulin, and an anti-HER2 antibody using a linker, and is
expected to have anti-tumor effects on breast, lung and other solid
tumors that express HER2 through direct cytotoxicity (including
immunogenic cell death), a bystander effect* and immune
response-induced cell death.
*Bystander effect: When the cytotoxic agent and antibody parts
of an ADC are separated inside a targeted antigen-positive cancer
cell, the released cytotoxic agent also affects neighboring
antigen-negative cancer cells and the component cells of the cancer
microenvironment.
About E7386
E7386 is a selective inhibitor of the
interaction between the cAMP response element-binding protein
(CREB) binding protein (CBP) / β-catenin and a modulator of the Wnt
/ β-catenin signaling pathway. E7386 is thought to block the
protein-protein interaction between a transcriptional co-activator,
CBP and β-catenin, resulting in the inhibition of Wnt / β-catenin
pathway-dependent gene expression. Since E7386 is thought to act on
the CBP / β-catenin transcription complex located at the most
downstream of the Wnt signaling, it is expected to inhibit not only
ligand-dependent activation but also activation caused by gene
mutations in Wnt signaling factors such as adenomatous polyposis
coli (APC) and β-catenin. E7386 is created through collaboration
research between Eisai and PRISM BioLab Co., Ltd. (Headquarters:
Kanagawa)
About HALAVEN® (eribulin mesylate) Injection (0.5
mg/mL)
HALAVEN (eribulin mesylate) Injection is indicated
for the treatment of patients with metastatic breast cancer (mBC)
who have previously received at least 2 chemotherapeutic regimens
for the treatment of metastatic disease. Prior therapy should have
included an anthracycline and a taxane in either the adjuvant or
metastatic setting. HALAVEN is also indicated for the treatment of
patients with unresectable or metastatic liposarcoma who have
received a prior anthracycline-containing regimen.
Eribulin is a microtubule dynamics inhibitor in the halichondrin
class with a novel mechanism of action, developed in-house by
Eisai. Structurally, eribulin is a simplified and synthetically
produced version of halichondrin B, a natural product isolated from
the marine sponge Halichondria okadai. Eribulin is believed to work
by inhibiting the growth phase of microtubule dynamics which
prevents cell division. In addition, non-clinical studies showed
eribulin's unique actions in the tumor microenvironment such as an
increase in vascular perfusion and permeability in tumor cores,
promotion of the epithelial state, decrease in capacity of breast
cancer cells to migrate, etc.
Important Safety Information for HALAVEN
Warnings and Precautions
Neutropenia: Severe neutropenia (ANC <500/mm3) lasting
>1 week occurred in 12% of patients with mBC. Febrile
neutropenia occurred in 5% of patients with mBC and 2 patients
(0.4%) died from complications. Patients with mBC with elevated
liver enzymes >3 × ULN and bilirubin >1.5 × ULN experienced a
higher incidence of Grade 4 neutropenia and febrile neutropenia
than patients with normal levels. Monitor complete blood cell
counts prior to each dose, and increase the frequency of monitoring
in patients who develop Grade 3 or 4 cytopenias. Delay
administration and reduce subsequent doses in patients who
experience febrile neutropenia or Grade 4 neutropenia lasting >7
days.
Peripheral Neuropathy: Grade 3 peripheral neuropathy
occurred in 8% of patients with mBC (Grade 4=0.4%) and 22%
developed a new or worsening neuropathy that had not recovered
within a median follow-up duration of 269 days (range 25-662 days).
Neuropathy lasting >1 year occurred in 5% of patients with mBC.
Patients should be monitored for signs of peripheral motor and
sensory neuropathy. Withhold HALAVEN in patients who experience
Grade 3 or 4 peripheral neuropathy until resolution to Grade 2 or
less.
Embryo-Fetal Toxicity: HALAVEN can cause fetal harm when
administered to a pregnant woman. Advise females of reproductive
potential to use effective contraception during treatment with
HALAVEN and for at least 2 weeks following the final dose. Advise
males with female partners of reproductive potential to use
effective contraception during treatment with HALAVEN and for 3.5
months following the final dose.
QT Prolongation: Monitor for prolonged QT intervals in
patients with congestive heart failure, bradyarrhythmias, drugs
known to prolong the QT interval, and electrolyte abnormalities.
Correct hypokalemia or hypomagnesemia prior to initiating HALAVEN
and monitor these electrolytes periodically during therapy. Avoid
in patients with congenital long QT syndrome.
Adverse Reactions
In patients with mBC receiving HALAVEN, the most common adverse
reactions (≥25%) were neutropenia (82%), anemia (58%),
asthenia/fatigue (54%), alopecia (45%), peripheral neuropathy
(35%), nausea (35%), and constipation (25%). Febrile neutropenia
(4%) and neutropenia (2%) were the most common serious adverse
reactions. The most common adverse reaction resulting in
discontinuation was peripheral neuropathy (5%).
In patients with liposarcoma and leiomyosarcoma receiving
HALAVEN, the most common adverse reactions (≥25%) reported in
patients receiving HALAVEN were fatigue (62%), nausea (41%),
alopecia (35%), constipation (32%), peripheral neuropathy (29%),
abdominal pain (29%), and pyrexia (28%). The most common (≥5%)
Grade 3-4 laboratory abnormalities reported in patients receiving
HALAVEN were neutropenia (32%), hypokalemia (5.4%), and
hypocalcemia (5%). Neutropenia (4.9%) and pyrexia (4.5%) were the
most common serious adverse reactions. The most common adverse
reactions resulting in discontinuation were fatigue and
thrombocytopenia (0.9% each).
Use in Specific Populations
Lactation: Because of the potential for serious
adverse reactions in breastfed infants from eribulin mesylate,
advise women not to breastfeed during treatment with HALAVEN and
for 2 weeks after the final dose.
Hepatic and Renal Impairment: A reduction in starting
dose is recommended for patients with mild or moderate hepatic
impairment and/or moderate or severe renal impairment.
For more information about HALAVEN, click here for the full
Prescribing Information.
HALAVEN® is a registered trademark used by Eisai Inc.
under license from Eisai R&D Management Co., Ltd.
About LENVIMA® (lenvatinib) Capsules
LENVIMA is indicated:
- For the treatment of adult patients with locally recurrent or
metastatic, progressive, radioactive iodine-refractory
differentiated thyroid cancer (DTC)
- In combination with pembrolizumab, for the first line treatment
of adult patients with advanced renal cell carcinoma (RCC)
- In combination with everolimus for the treatment of adult
patients with advanced renal cell carcinoma (RCC) following one
prior anti-angiogenic therapy
- For the first-line treatment of patients with unresectable
hepatocellular carcinoma (HCC)
- In combination with pembrolizumab, for the treatment of
patients with advanced endometrial carcinoma (EC) that is mismatch
repair proficient (pMMR), as determined by an FDA-approved test, or
not microsatellite instability-high (MSI-H), who have disease
progression following prior systemic therapy in any setting and are
not candidates for curative surgery or radiation.
LENVIMA, discovered and developed by Eisai, is a multiple
receptor tyrosine kinase inhibitor that inhibits the kinase
activities of vascular endothelial growth factor (VEGF) receptors
VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). LENVIMA inhibits
other kinases 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 (PDGFRA), KIT, and RET. Lenvatinib also exhibited
antiproliferative activity in hepatocellular carcinoma cell lines
dependent on activated FGFR signaling with a concurrent inhibition
of FGF-receptor substrate 2 alpha (FRS2) phosphorylation. In
syngeneic mouse tumor models, the combination of lenvatinib with an
anti-PD-1 monoclonal antibody decreased tumor-associated
macrophages, increased activated cytotoxic T cells, and
demonstrated greater antitumor activity compared to either
treatment alone. The combination of LENVIMA and everolimus showed
increased antiangiogenic and antitumor 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 for LENVIMA
Warnings and Precautions
Hypertension. In DTC (differentiated thyroid cancer),
hypertension occurred in 73% of patients on LENVIMA (44% grade
3-4). In RCC (renal cell carcinoma), hypertension occurred in 42%
of patients on LENVIMA + everolimus (13% grade 3). Systolic blood
pressure ≥160 mmHg occurred in 29% of patients, and 21% had
diastolic blood pressure ≥100 mmHg. In HCC (hepatocellular
carcinoma), hypertension occurred in 45% of LENVIMA-treated
patients (24% grade 3). Grade 4 hypertension was not reported in
HCC.
Serious complications of poorly controlled hypertension have
been reported. Control blood pressure prior to initiation. Monitor
blood pressure after 1 week, then every 2 weeks for the first 2
months, and then at least monthly thereafter during treatment.
Withhold and resume at reduced dose when hypertension is controlled
or permanently discontinue based on severity.
Cardiac Dysfunction. Serious and fatal cardiac
dysfunction can occur with LENVIMA. Across clinical trials in 799
patients with DTC, RCC, and HCC, grade 3 or higher cardiac
dysfunction occurred in 3% of LENVIMA-treated patients. Monitor for
clinical symptoms or signs of cardiac dysfunction. Withhold and
resume at reduced dose upon recovery or permanently discontinue
based on severity.
Arterial Thromboembolic Events. Among patients receiving
LENVIMA or LENVIMA + everolimus, arterial thromboembolic events of
any severity occurred in 2% of patients in RCC and HCC and 5% in
DTC. Grade 3-5 arterial thromboembolic events ranged from 2% to 3%
across all clinical trials.
Among patients receiving LENVIMA with pembrolizumab, arterial
thrombotic events of any severity occurred in 5% of patients in
CLEAR, including myocardial infarction (3.4%) and cerebrovascular
accident (2.3%).
Permanently discontinue following an arterial thrombotic event.
The safety of resuming 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.
Hepatotoxicity. Across clinical studies enrolling 1327
LENVIMA-treated patients with malignancies other than HCC, serious
hepatic adverse reactions occurred in 1.4% of patients. Fatal
events, including hepatic failure, acute hepatitis, and hepatorenal
syndrome, occurred in 0.5% of patients. In HCC, hepatic
encephalopathy occurred in 8% of LENVIMA-treated patients (5% grade
3-5). Grade 3-5 hepatic failure occurred in 3% of LENVIMA-treated
patients; 2% of patients discontinued LENVIMA due to hepatic
encephalopathy, and 1% discontinued due to hepatic failure.
Monitor liver function prior to initiation, then every 2 weeks
for the first 2 months, and at least monthly thereafter during
treatment. Monitor patients with HCC closely for signs of hepatic
failure, including hepatic encephalopathy. Withhold and resume at
reduced dose upon recovery or permanently discontinue based on
severity.
Renal Failure or Impairment. Serious including fatal
renal failure or impairment can occur with LENVIMA. Renal
impairment was reported in 14% and 7% of LENVIMA-treated patients
in DTC and HCC, respectively. Grade 3-5 renal failure or impairment
occurred in 3% of patients with DTC and 2% of patients with HCC,
including 1 fatal event in each study. In RCC, renal impairment or
renal failure was reported in 18% of LENVIMA + everolimus–treated
patients (10% grade 3).
Initiate prompt management of diarrhea or
dehydration/hypovolemia. Withhold and resume at reduced dose upon
recovery or permanently discontinue for renal failure or impairment
based on severity.
Proteinuria. In DTC and HCC, proteinuria was reported in
34% and 26% of LENVIMA-treated patients, respectively. Grade 3
proteinuria occurred in 11% and 6% in DTC and HCC, respectively. In
RCC, proteinuria occurred in 31% of patients receiving LENVIMA +
everolimus (8% grade 3). Monitor for proteinuria prior to
initiation and periodically during treatment. If urine dipstick
proteinuria ≥2+ is detected, obtain a 24-hour urine protein.
Withhold and resume at reduced dose upon recovery or permanently
discontinue based on severity.
Diarrhea. Of the 737 LENVIMA-treated patients in DTC and
HCC, diarrhea occurred in 49% (6% grade 3). In RCC, diarrhea
occurred in 81% of LENVIMA + everolimus–treated patients (19% grade
3). Diarrhea was the most frequent cause of dose
interruption/reduction, and diarrhea recurred despite dose
reduction. Promptly initiate management of diarrhea. Withhold and
resume at reduced dose upon recovery or permanently discontinue
based on severity.
Fistula Formation and Gastrointestinal Perforation. Of
the 799 patients treated with LENVIMA or LENVIMA + everolimus in
DTC, RCC, and HCC, fistula or gastrointestinal perforation occurred
in 2%. Permanently discontinue in patients who develop
gastrointestinal perforation of any severity or grade 3-4
fistula.
QT Interval Prolongation. In DTC, QT/QTc interval
prolongation occurred in 9% of LENVIMA-treated patients and QT
interval prolongation of >500 ms occurred in 2%. In RCC, QTc
interval increases of >60 ms occurred in 11% of patients
receiving LENVIMA + everolimus and QTc interval >500 ms occurred
in 6%. In HCC, QTc interval increases of >60 ms occurred in 8%
of LENVIMA-treated patients and QTc interval >500 ms occurred in
2%.
Monitor and correct electrolyte abnormalities at baseline and
periodically during treatment. Monitor electrocardiograms in
patients with congenital long QT syndrome, congestive heart
failure, bradyarrhythmias, or those who are taking drugs known to
prolong the QT interval, including Class Ia and III
antiarrhythmics. Withhold and resume at reduced dose upon recovery
based on severity.
Hypocalcemia. In DTC, grade 3-4 hypocalcemia occurred in
9% of LENVIMA-treated patients. In 65% of cases, hypocalcemia
improved or resolved following calcium supplementation with or
without dose interruption or dose reduction. In RCC, grade 3-4
hypocalcemia occurred in 6% of LENVIMA + everolimus–treated
patients. In HCC, grade 3 hypocalcemia occurred in 0.8% of
LENVIMA-treated patients. Monitor blood calcium levels at least
monthly and replace calcium as necessary during treatment. Withhold
and resume at reduced dose upon recovery or permanently discontinue
depending on severity.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS).
Across clinical studies of 1823 patients who received LENVIMA as a
single agent, RPLS occurred in 0.3%. Confirm diagnosis of RPLS with
MRI. Withhold and resume at reduced dose upon recovery or
permanently discontinue depending on severity and persistence of
neurologic symptoms.
Hemorrhagic Events. Serious including fatal hemorrhagic
events can occur with LENVIMA. In DTC, RCC, and HCC clinical
trials, hemorrhagic events, of any grade, occurred in 29% of the
799 patients treated with LENVIMA as a single agent or in
combination with everolimus. The most frequently reported
hemorrhagic events (all grades and occurring in at least 5% of
patients) were epistaxis and hematuria. In DTC, grade 3-5
hemorrhage occurred in 2% of LENVIMA-treated patients, including 1
fatal intracranial hemorrhage among 16 patients who received
LENVIMA and had CNS metastases at baseline. In RCC, grade 3-5
hemorrhage occurred in 8% of LENVIMA + everolimus–treated patients,
including 1 fatal cerebral hemorrhage. In HCC, grade 3-5 hemorrhage
occurred in 5% of LENVIMA-treated patients, including 7 fatal
hemorrhagic events. Serious tumor-related bleeds, including fatal
hemorrhagic events, occurred in LENVIMA-treated patients in
clinical trials and in the postmarketing setting. In postmarketing
surveillance, serious and fatal carotid artery hemorrhages were
seen more frequently in patients with anaplastic thyroid carcinoma
(ATC) than other tumors. Safety and effectiveness of LENVIMA in
patients with ATC have not been demonstrated in clinical
trials.
Consider the risk of severe or fatal hemorrhage associated with
tumor invasion or infiltration of major blood vessels (eg, carotid
artery). Withhold and resume at reduced dose upon recovery or
permanently discontinue based on severity.
Impairment of Thyroid Stimulating Hormone Suppression/Thyroid
Dysfunction. LENVIMA impairs exogenous thyroid suppression. In
DTC, 88% of patients had baseline thyroid stimulating hormone (TSH)
level ≤0.5 mU/L. In patients with normal TSH at baseline, elevation
of TSH level >0.5 mU/L was observed post baseline in 57% of
LENVIMA-treated patients. In RCC and HCC, grade 1 or 2
hypothyroidism occurred in 24% of LENVIMA + everolimus–treated
patients and 21% of LENVIMA-treated patients, respectively. In
patients with normal or low TSH at baseline, elevation of TSH was
observed post baseline in 70% of LENVIMA-treated patients in HCC
and 60% of LENVIMA + everolimus–treated patients in RCC.
Monitor thyroid function prior to initiation and at least
monthly during treatment. Treat hypothyroidism according to
standard medical practice.
Impaired Wound Healing. Impaired wound healing has been
reported in patients who received LENVIMA. Withhold LENVIMA for at
least 1 week prior to elective surgery. Do not administer for at
least 2 weeks following major surgery and until adequate wound
healing. The safety of resumption of LENVIMA after resolution of
wound healing complications has not been established.
Osteonecrosis of the Jaw (ONJ). ONJ has been
reported in patients receiving LENVIMA. Concomitant exposure to
other risk factors, such as bisphosphonates, denosumab, dental
disease, or invasive dental procedures, may increase the risk of
ONJ.
Perform an oral examination prior to treatment with LENVIMA and
periodically during LENVIMA treatment. Advise patients regarding
good oral hygiene practices and to consider having preventive
dentistry performed prior to treatment with LENVIMA and throughout
treatment with LENVIMA.
Avoid invasive dental procedures, if possible, while on
LENVIMA treatment, particularly in patients at higher risk.
Withhold LENVIMA for at least 1 week prior to scheduled dental
surgery or invasive dental procedures, if possible. For patients
requiring invasive dental procedures, discontinuation of
bisphosphonate treatment may reduce the risk of ONJ.
Withhold LENVIMA if ONJ develops and restart based on clinical
judgement of adequate resolution.
Embryo-Fetal Toxicity. Based on its mechanism of action and
data from animal reproduction studies, LENVIMA can cause fetal harm
when administered to pregnant women. In animal reproduction
studies, oral administration of lenvatinib during organogenesis at
doses below the recommended clinical doses resulted in
embryotoxicity, fetotoxicity, and teratogenicity in rats and
rabbits. Advise pregnant women of the potential risk to a fetus and
advise females of reproductive potential to use effective
contraception during treatment with LENVIMA and for 30 days after
the last dose.
Adverse Reactions
In DTC, the most common adverse
reactions (≥30%) observed in LENVIMA-treated patients were
hypertension (73%), fatigue (67%), diarrhea (67%),
arthralgia/myalgia (62%), decreased appetite (54%), decreased
weight (51%), nausea (47%), stomatitis (41%), headache (38%),
vomiting (36%), proteinuria (34%), palmar-plantar
erythrodysesthesia syndrome (32%), abdominal pain (31%), and
dysphonia (31%). The most common serious adverse reactions (≥2%)
were pneumonia (4%), hypertension (3%), and dehydration (3%).
Adverse reactions led to dose reductions in 68% of LENVIMA-treated
patients; 18% discontinued LENVIMA. The most common adverse
reactions (≥10%) resulting in dose reductions 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 (≥20%) observed in
LENVIMA + pembrolizumab-treated patients were fatigue (63%),
diarrhea (62%), musculoskeletal pain (58%), hypothyroidism (57%),
hypertension (56%), stomatitis (43%), decreased appetite (41%),
rash (37%), nausea (36%), decreased weight (30%), dysphonia (30%),
proteinuria (30%), palmar-plantar erythrodysesthesia syndrome
(29%), abdominal pain (27%), hemorrhagic events (27%), vomiting
(26%), constipation (25%), hepatotoxicity (25%), headache (23%),
and acute kidney injury (21%). The most common serious adverse
reactions (≥2%) were hemorrhagic events (5%), diarrhea (4%),
hypertension (3%), myocardial infarction (3%), pneumonitis (3%),
vomiting (3%), acute kidney injury (2%), adrenal insufficiency
(2%), dyspnea (2%), and pneumonia (2%). Fatal adverse reactions
occurred in 4.3% of patients receiving LENVIMA in combination with
pembrolizumab, including cardio-respiratory arrest (0.9%), sepsis
(0.9%), and one case (0.3%) each of arrhythmia, autoimmune
hepatitis, dyspnea, hypertensive crisis, increased blood
creatinine, multiple organ dysfunction syndrome, myasthenic
syndrome, myocarditis, nephritis, pneumonitis, ruptured aneurysm
and subarachnoid hemorrhage. Serious adverse reactions occurred in
51% of patients receiving LENVIMA and pembrolizumab. Serious
adverse reactions in ≥2% of patients were hemorrhagic events (5%),
diarrhea (4%), hypertension (3%), myocardial infarction (3%),
pneumonitis (3%), vomiting (3%), acute kidney injury (2%), adrenal
insufficiency (2%), dyspnea (2%), and pneumonia (2%). Permanent
discontinuation of LENVIMA, pembrolizumab, or both due to an
adverse reaction occurred in 37% of patients; 26% LENVIMA only, 29%
pembrolizumab only, and 13% both drugs. The most common adverse
reactions (≥2%) leading to permanent discontinuation of LENVIMA,
pembrolizumab, or both were pneumonitis (3%), myocardial infarction
(3%), hepatotoxicity (3%), acute kidney injury (3%), rash (3%), and
diarrhea (2%). Dose interruptions of LENVIMA, pembrolizumab, or
both due to an adverse reaction occurred in 78% of patients
receiving LENVIMA in combination with pembrolizumab. LENVIMA was
interrupted in 73% of patients and both drugs were interrupted in
39% of patients. LENVIMA was dose reduced in 69% of patients. The
most common adverse reactions (≥5%) resulting in dose reduction or
interruption of LENVIMA were diarrhea (26%), fatigue (18%),
hypertension (17%), proteinuria (13%), decreased appetite (12%),
palmar-plantar erythrodysesthesia (11%), nausea (9%), stomatitis
(9%), musculoskeletal pain (8%), rash (8%), increased lipase (7%),
abdominal pain (6%), and vomiting (6%), increased ALT (5%), and
increased amylase (5%).
In RCC, the most common adverse reactions (≥30%) observed in
LENVIMA + everolimus–treated patients were diarrhea (81%), fatigue
(73%), arthralgia/myalgia (55%), decreased appetite (53%), vomiting
(48%), nausea (45%), stomatitis (44%), hypertension (42%),
peripheral edema (42%), cough (37%), abdominal pain (37%), dyspnea
(35%), rash (35%), decreased weight (34%), hemorrhagic events
(32%), and proteinuria (31%). The most common serious adverse
reactions (≥5%) were renal failure (11%), dehydration (10%), anemia
(6%), thrombocytopenia (5%), diarrhea (5%), vomiting (5%), and
dyspnea (5%). Adverse reactions led to dose reductions or
interruption in 89% of patients. The most common adverse reactions
(≥5%) resulting in dose reductions 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 HCC, the most common adverse reactions (≥20%) observed in
LENVIMA-treated patients were hypertension (45%), fatigue (44%),
diarrhea (39%), decreased appetite (34%), arthralgia/myalgia (31%),
decreased weight (31%), abdominal pain (30%), palmar-plantar
erythrodysesthesia syndrome (27%), proteinuria (26%), dysphonia
(24%), hemorrhagic events (23%), hypothyroidism (21%), and nausea
(20%). The most common serious adverse reactions (≥2%) were hepatic
encephalopathy (5%), hepatic failure (3%), ascites (3%), and
decreased appetite (2%). Adverse reactions led to dose reductions
or interruption in 62% of patients. The most common adverse
reactions (≥5%) resulting in dose reductions were fatigue (9%),
decreased appetite (8%), diarrhea (8%), proteinuria (7%),
hypertension (6%), and palmar-plantar erythrodysesthesia syndrome
(5%). Treatment discontinuation due to an adverse reaction occurred
in 20% of patients. The most common adverse reactions (≥1%)
resulting in discontinuation of LENVIMA were fatigue (1%), hepatic
encephalopathy (2%), hyperbilirubinemia (1%), and hepatic failure
(1%).
In EC, the most common adverse reactions (≥20%) observed in
LENVIMA and pembrolizumab–treated patients were hypothyroidism
(67%), hypertension (67%), fatigue (58%), diarrhea (55%),
musculoskeletal disorders (53%), nausea (49%), decreased appetite
(44%), vomiting (37%), stomatitis (35%), decreased weight (34%),
abdominal pain (34%), urinary tract infection (31%), proteinuria
(29%), constipation (27%), headache (26%), hemorrhagic events
(25%), palmar‐plantar erythrodysesthesia (23%), dysphonia (22%),
and rash (20%). Fatal adverse reactions occurred in 4.7% of those
treated with LENVIMA and pembrolizumab, including 2 cases of
pneumonia, and 1 case of the following: acute kidney injury, acute
myocardial infarction, colitis, decreased appetite, intestinal
perforation, lower gastrointestinal hemorrhage, malignant
gastrointestinal obstruction, multiple organ dysfunction syndrome,
myelodysplastic syndrome, pulmonary embolism, and right ventricular
dysfunction. Serious adverse reactions occurred in 50% of patients
receiving LENVIMA and pembrolizumab. Serious adverse reactions with
frequency ≥3% were hypertension (4.4%), and urinary tract infection
(3.2%). Discontinuation of LENVIMA due to an adverse reaction
occurred in 26% of patients. The most common (≥1%) adverse
reactions leading to discontinuation of LENVIMA were hypertension
(2%), asthenia (1.8%), diarrhea (1.2%), decreased appetite (1.2%),
proteinuria (1.2%), and vomiting (1.2%). Dose reductions of LENVIMA
due to adverse reactions occurred in 67% of patients. The most
common (≥5%) adverse reactions resulting in dose reduction of
LENVIMA were hypertension (18%), diarrhea (11%), palmar-plantar
erythrodysesthesia syndrome (9%), proteinuria (7%), fatigue (7%),
decreased appetite (6%), asthenia (5%), and weight decreased (5%).
Dose interruptions of LENVIMA due to an adverse reaction occurred
in 58% of these patients. The most common (≥2%) adverse reactions
leading to interruption of LENVIMA were hypertension (11%),
diarrhea (11%), proteinuria (6%), decreased appetite (5%), vomiting
(5%), increased alanine aminotransferase (3.5%), fatigue (3.5%),
nausea (3.5%), abdominal pain (2.9%), weight decreased (2.6%),
urinary tract infection (2.6%), increased aspartate
aminotransferase (2.3%), asthenia (2.3%), and palmar-plantar
erythrodysesthesia (2%).
Use in Specific Populations
Because of the potential
for serious adverse reactions in breastfed children, advise women
to discontinue breastfeeding during treatment and for 1 week after
the last dose. LENVIMA may impair fertility in males and females of
reproductive potential.
No dose adjustment is recommended for patients with mild (CLcr
60-89 mL/min) or moderate (CLcr 30-59 mL/min) renal impairment.
LENVIMA concentrations may increase in patients with DTC, RCC, or
EC and severe (CLcr 15-29 mL/min) renal impairment. Reduce the dose
for patients with DTC, RCC, or EC and severe renal impairment.
There is no recommended dose for patients with HCC and severe renal
impairment. LENVIMA has not been studied in patients with end-stage
renal disease.
No dose adjustment is recommended for patients with HCC and mild
hepatic impairment (Child-Pugh A). There is no recommended dose for
patients with HCC with moderate (Child-Pugh B) or severe
(Child-Pugh C) hepatic impairment. No dose adjustment is
recommended for patients with DTC, RCC, or EC and mild or moderate
hepatic impairment. LENVIMA concentrations may increase in patients
with DTC, RCC, or EC and severe hepatic impairment. Reduce the dose
for patients with DTC, RCC, or EC and severe hepatic
impairment.
LENVIMA (lenvatinib) is available as 10 mg and 4 mg
capsules.
Please see Prescribing Information for LENVIMA (lenvatinib) at
http://www.lenvima.com/pdfs/prescribing-information.pdf
About the Eisai and Merck Strategic Collaboration
In
March 2018, Eisai and Merck, known as
MSD outside the United States and
Canada, through an affiliate,
entered into a strategic collaboration for the worldwide
co-development and co-commercialization of LENVIMA. Under the
agreement, the companies jointly develop, manufacture and
commercialize LENVIMA, both as monotherapy and in combination with
Merck's anti-PD-1 therapy KEYTRUDA. Eisai and Merck are studying
the KEYTRUDA plus LENVIMA combination through the LEAP
(LEnvatinib And Pembrolizumab) clinical
program in various tumor types across multiple clinical trials.
About Eisai
Eisai's Corporate Concept is "to give
first thought to patients and people in the daily living domain,
and to increase the benefits that health care provides." Under this
Concept [also known as our human health care (hhc)
Concept], we aim to effectively achieve social good in the form of
relieving anxiety over health and reducing health disparities. With
a global network of R&D facilities, manufacturing sites and
marketing subsidiaries, we strive to create and deliver innovative
products to target diseases with high unmet medical needs, with a
particular focus in our strategic areas of Neurology and
Oncology.
In addition, our continued commitment to the elimination of
neglected tropical diseases (NTDs), which is a target (3.3) of the
United Nations Sustainable Development Goals (SDGs), is
demonstrated by our work on various activities together with global
partners.
For more information about Eisai, please visit
www.eisai.com (for global headquarters: Eisai Co., Ltd.),
us.eisai.com (for U.S. headquarters: Eisai Inc.) or
www.eisai.eu (for Europe,
Middle East, Africa, Russia, Australia, and New
Zealand headquarters: Eisai Europe Ltd.), and connect with
us on Twitter (U.S. and global) and LinkedIn (for
U.S. and EMEA).
LENVIMA® is a registered trademark used by Eisai Inc.
under license from Eisai R&D Management Co., Ltd.
©2024 Eisai Inc. All Rights Reserved.
KEYTRUDA® is a registered trademark of Merck Sharp
& Dohme LLC, a subsidiary of Merck & Co., Inc.,
Rahway, N.J., U.S.A.
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SOURCE Eisai Inc.