Eisai and Merck Enter Collaboration to Explore Novel Combination Regimens of Anti-PD-1 Therapy with Multi-targeting RTK Inhibitor and Microtubule Dynamics Inhibitor in Multiple Types of Cancer
March 4, 2015 6:30 pm ET
Combination clinical studies of lenvatinib, eribulin and pembrolizumab to be explored
TOKYO & KENILWORTH, N.J.–(BUSINESS WIRE)–Eisai Co., Ltd. and Merck (NYSE:MRK), known as MSD outside the U.S. and
Canada, through a subsidiary, announced today a clinical trial
collaboration to evaluate the safety, tolerability and efficacy of
Merck’s anti-PD-1 therapy, pembrolizumab (marketed in the U.S. under the
brand name KEYTRUDA®), in combination with Eisai oncology
compounds lenvatinib mesylate (a multi-targeting RTK inhibitor marketed
in the U.S. under the brand name LENVIMA™, “lenvatinib”) and eribulin
mesylate (a microtubule dynamics inhibitor marketed in nearly 60
countries including Japan, the U.S., and Europe under the brand name
HALAVEN®, “eribulin”) in multiple clinical trials.
The planned studies include a multicenter, open-label Phase 1b/2 study
of lenvatinib plus pembrolizumab in select solid tumors and an
open-label, single-arm, multicenter Phase 1b/2 study to evaluate the
efficacy and safety of eribulin in combination with pembrolizumab in
metastatic triple-negative breast cancer. Eisai and Merck will establish
a Joint Development Committee to oversee clinical development
activities. The studies are expected to begin in the second half of
2015. Financial terms of the agreement were not disclosed.
“This collaboration could be a major step in the direction of developing
combination regimens in different types of cancer, potentially
maximizing the value of eribulin and lenvatinib,” said Kenichi Nomoto,
PhD, president, oncology product creation unit, Eisai Product Creation
Systems. “Together, Eisai and Merck seek to explore combination regimens
that have the potential to create synergistic effects between lenvatinib
and pembrolizumab as well as between eribulin and pembrolizumab. Our
hope is that we will bring treatments to market that make a difference
in the lives of people battling cancer.”
“Cancer is a complex disease that often requires different approaches to
help patients achieve the best possible outcome,” said Dr. Eric Rubin,
therapeutic area head, oncology early-stage development, Merck Research
Laboratories. “The collaboration with Eisai exemplifies Merck’s focus on
advancing breakthrough science in immuno-oncology. We look forward to
evaluating pembrolizumab in combination with eribulin and also with
lenvatinib in different tumor types.”
The combinations of lenvatinib and pembrolizumab, and eribulin and
pembrolizumab, are investigational. The efficacy and safety of these
combinations have not been established.
About LENVIMA™ (lenvatinib mesylate)
LENVIMA, discovered and developed by Eisai, is an oral molecular
targeted agent that selectively inhibits the kinase activities of
vascular endothelial growth factor (VEGF) receptors (VEGFR1 (FLT1),
VEGFR2 (KDR) and VEGFR3 (FLT4)), and fibroblast growth factor (FGF)
receptors FGFR1, 2, 3 and 4 in addition to other proangiogenic and
oncogenic pathway-related RTKs (including the platelet-derived growth
factor (PDGF) receptor PDGFRα; KIT; and RET) involved in tumor
proliferation. In particular, LENVIMA possesses a new binding mode (Type
V) to VEGFR2, as confirmed through X-ray crystal structural analysis,
and exhibits rapid and potent inhibition of kinase activity, according
to kinetic analysis.
LENVIMA was approved on February 13, 2015 and launched on February 26,
2015 for the treatment of patients with locally recurrent or metastatic,
progressive, radioactive iodine-refractory differentiated thyroid cancer
in the United States, and is currently undergoing regulatory review for
this indication in Japan, the EU, Switzerland, South Korea, Canada,
Singapore, Russia, Australia and Brazil. Meanwhile, Eisai is currently
conducting studies clinical studies of LENVIMA in several types of
cancer including hepatocellular carcinoma (Phase III), renal cell
carcinoma (Phase II), non-small cell lung cancer (Phase II) and
endometrial cancer (Phase II). Furthermore, lenvatinib has been granted
Orphan Drug Designation in Japan (for thyroid cancer), the United States
(for the treatment of follicular, medullary, anaplastic, and metastatic
or locally advanced papillary thyroid cancer), and Europe (for
follicular and papillary thyroid cancer).
About HALAVEN® (eribulin mesylate)
HALAVEN, a halichondrin class microtubule dynamics inhibitor with a
novel mechanism of action, belongs to a class of antineoplastic agents,
the halichondrins, which are natural products isolated from the marine
sponge Halichondria okadai. It is believed to work by inhibiting
the growth phase of microtubule dynamics without affecting the
shortening phase and sequestering tubulin into nonproductive aggregates.
HALAVEN was first approved as a treatment for metastatic breast cancer
in the United States in November 2010, and is now approved in nearly 60
countries worldwide, including Japan and countries in the Americas,
Europe and Asia. In the United States, HALAVEN Injection is indicated
for patients with metastatic breast cancer who have received at least
two chemotherapeutic regimens for the treatment of metastatic breast
cancer. Prior therapy should have included an anthracycline and a taxane
in either the adjuvant or metastatic setting. In Japan, HALAVEN has been
approved to treat inoperable or recurrent breast cancer and was launched
in the country in July 2011. Since June 2014, Eisai has been obtaining
approval in countries in Europe and Asia for the indication expansion of
HALAVEN to contribute to earlier treatment of patients with locally
advanced or metastatic breast cancer who have progressed after at least
one chemotherapeutic regimen for advanced disease. Prior therapy should
have included an anthracycline and a taxane in either the adjuvant or
metastatic setting, unless patients were not suitable for these
treatments. In addition, HALAVEN has been designated as an orphan drug
for soft-tissue sarcoma in the United States and Japan.
About KEYTRUDA® (pembrolizumab)
KEYTRUDA (pembrolizumab) is a humanized monoclonal antibody that blocks
the interaction between PD-1 (programmed death receptor-1) and its
ligands, PD-L1 and PD-L2. KEYTRUDA is indicated in the United States at
a dose of 2 mg/kg administered as an intravenous infusion over 30
minutes every three weeks for the treatment of patients with
unresectable or metastatic melanoma and disease progression following
ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. This
indication is approved under accelerated approval based on tumor
response rate and durability of response. An improvement in survival or
disease-related symptoms has not yet been established. Continued
approval for this indication may be contingent upon verification and
description of clinical benefit in the confirmatory trials.
Merck is advancing a broad and fast-growing clinical development program
for KEYTRUDA with more than 70 clinical trials – across more than 30
tumor types and over 8,000 patients – both as a monotherapy and in
combination with other therapies.
Important Safety Information for LENVIMA™ (U.S. labeling) Warnings
Hypertension was reported in 73% of LENVIMA-treated patients (of which
44% were ≥ Grade 3) and 16% of patients in the placebo group. Control
blood pressure prior to treatment and monitor blood pressure after 1
week, then every 2 weeks for the first 2 months, and then at least
monthly during treatment. Withhold LENVIMA for Grade 3 hypertension;
resume at a reduced dose when hypertension is controlled at ≤ Grade 2.
Discontinue LENVIMA for life-threatening hypertension.
Cardiac dysfunction was reported in 7% of LENVIMA-treated patients (2%
Grade 3 or greater). Monitor patients for clinical symptoms or signs of
cardiac decompensation. Withhold LENVIMA for development of Grade 3
cardiac dysfunction until improved to Grade 0 or 1 or baseline. Resume
at a reduced dose or discontinue LENVIMA depending on the severity and
persistence of cardiac dysfunction. Discontinue LENVIMA for Grade 4
Arterial thromboembolic events were reported in 5% of LENVIMA-treated
patients; events of Grade 3 or greater were 3%. Discontinue LENVIMA
following an arterial thrombotic event. LENVIMA has not been studied in
patients who have had an arterial thromboembolic event within the
previous 6 months.
Four percent (4%) of LENVIMA-treated patients experienced an increase in
ALT and 5% experienced an increase in AST that was Grade 3 or greater.
Monitor liver function before initiation and during treatment with
LENVIMA. Withhold LENVIMA for the development of ≥ Grade 3 liver
impairment until resolved to Grade 0 to 1 or baseline. Resume at a
reduced dose or discontinue LENVIMA depending on the severity and
persistence of hepatotoxicity. Discontinue LENVIMA for hepatic failure.
Proteinuria was reported in 34% of LENVIMA-treated patients (of which
11% were Grade 3). Monitor for proteinuria before initiation of, and
periodically during treatment. Obtain a 24 hour urine protein if urine
dipstick proteinuria ≥2+ is detected. Withhold LENVIMA for ≥ 2 grams of
proteinuria/24 hours and resume at a reduced dose when proteinuria is <2
gm/24 hours. Discontinue LENVIMA for nephrotic syndrome.
Events of renal impairment were reported in 14% of LENVIMA-treated
patients. Renal failure or impairment ≥ Grade 3 was 3% in
LENVIMA-treated patients. Withhold LENVIMA for development of Grade 3 or
4 renal failure / impairment until resolved to Grade 0 to 1 or baseline.
Resume at a reduced dose or discontinue LENVIMA depending on the
severity and persistence of renal impairment.
Events of gastrointestinal perforation or fistula were reported in 2% of
LENVIMA-treated patients. Discontinue LENVIMA in patients who develop
gastrointestinal perforation or life-threatening fistula.
QT/QTc interval prolongation was reported in 9% of LENVIMA-treated
patients (2% Grade 3 or greater). Monitor ECG in patients with
congenital long QT syndrome, CHF, bradyarrhythmias, or patients taking
drugs known to prolong the QT interval. Monitor and correct electrolyte
abnormalities in all patients. Withhold LENVIMA for the development of ≥
Grade 3 QT interval prolongation. Resume LENVIMA at a reduced dose when
QT prolongation resolves to Grade 0 or 1 or baseline.
Hypocalcemia ≥ Grade 3 was reported in 9% of LENVIMA-treated patients.
Monitor blood calcium levels at least monthly and replace calcium as
necessary during LENVIMA treatment. Interrupt and adjust LENVIMA dosing
as necessary depending on severity, presence of ECG changes, and
persistence of hypocalcemia.
Reversible posterior leukoencephalopathy syndrome (RPLS) was reported in
3 patients across clinical studies in which 1108 patients received
LENVIMA. Confirm the diagnosis of RPLS with MRI. Withhold LENMIVA for
RPLS until fully resolved. Resume at a reduced dose or discontinue
LENVIMA depending on the severity and persistence of neurologic symptoms.
Hemorrhagic events occurred in 35% of LENVIMA-treated patients and in
18% of the placebo group. The incidence of Grade 3-5 hemorrhage was
similar between arms at 2% and 3%, respectively. The most frequently
reported hemorrhagic event was epistaxis (11% Grade 1 and 1% Grade 2).
Discontinuation due to hemorrhagic events occurred in 1% of
LENVIMA-treated patients. There was one case of fatal intracranial
hemorrhage among 16 patients who received LENVIMA and had CNS metastases
at baseline. Withhold LENVIMA for the development of Grade 3 hemorrhage
until resolved to Grade 0 to 1. Resume at a reduced dose or discontinue
LENVIMA depending on the severity and persistence of hemorrhage.
Discontinue LENVIMA in patients who experience Grade 4 hemorrhage.
LENVIMA impairs exogenous thyroid suppression. Elevation of TSH level
above 0.5 mU/L was observed post baseline in 57% of LENVIMA-treated
patients. Monitor TSH levels monthly and adjust thyroid replacement
medication as needed.
LENVIMA can cause fetal harm when administered to a pregnant woman.
Advise pregnant women of the potential risk to a fetus. Advise females
of reproductive potential to use effective contraception during
treatment with LENVIMA and for at least 2 weeks following completion of
Advise women not to breastfeed during treatment with LENVIMA.
The most common adverse reactions observed in LENVIMA-treated patients
vs. placebo treated patients respectively were hypertension (73% vs
16%), fatigue (67% vs 35%), diarrhea (67% vs 17%), arthralgia/myalgia
(62% vs 28%), decreased appetite (54% vs 18%), weight decreased (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%).
Important Safety Information for HALAVEN®
Monitor complete blood 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 longer than 7 days.
Severe neutropenia (ANC <500/mm3) lasting more than 1
week occurred in 12% (62/503) of patients. Patients 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.
Grade 3 and Grade 4 neutropenia occurred in 28% and 29%, respectively,
of patients who received HALAVEN. Febrile neutropenia occurred in 5%
of patients and two patients (0.4%) died from complications.
Patients should be monitored closely for signs of peripheral motor and
Grade 3 peripheral neuropathy occurred in 8% of patients, and Grade 4
in 0.4% of patients who received HALAVEN. Delay administration of
HALAVEN until resolution to Grade 2 or less.
Neuropathy lasting more than 1 year occurred in 5% of patients.
Twenty-two percent of patients developed a new or worsening neuropathy
that had not recovered within a median follow-up duration of 269 days
(range 25-662 days).
Peripheral neuropathy (5%) was the most common adverse reaction
resulting in discontinuation.
Pregnancy Category D
HALAVEN is expected to cause fetal harm when administered to a
pregnant woman and patients should be advised of these risks.
In an uncontrolled ECG study in 26 patients, QT prolongation was
observed on Day 8, independent of eribulin concentration, with no
prolongation on Day 1. ECG monitoring is recommended for patients with
congestive heart failure; bradyarrhythmias; concomitant use of drugs
that prolong QT interval, including Class Ia and III antiarrhythmics;
and electrolyte abnormalities.
Correct hypokalemia or hypomagnesemia prior to initiating HALAVEN and
monitor electrolytes periodically during therapy. Avoid in patients
with congenital long QT syndrome.
Hepatic and Renal Impairment
For patients with mild (Child-Pugh A) or moderate (Child-Pugh B)
hepatic and/or moderate or severe (CrCl 15-49 mL/min) renal
impairment, a reduction in starting dose is recommended.
Most Common Adverse Reactions
Most common adverse reactions (≥25%) reported in patients receiving
HALAVEN were neutropenia (82%), anemia (58%), asthenia/fatigue (54%),
alopecia (45%), peripheral neuropathy (35%), nausea (35%), and
The most common serious adverse reactions reported in patients
receiving HALAVEN were febrile neutropenia (4%) and neutropenia (2%).
Selected Important Safety Information for KEYTRUDA®
Pneumonitis occurred in 12 (2.9%) of 411 patients with advanced melanoma
receiving KEYTRUDA (the approved indication in the United States),
including Grade 2 or 3 cases in 8 (1.9%) and 1 (0.2%) patients,
respectively. Monitor patients for signs and symptoms of pneumonitis.
Evaluate suspected pneumonitis with radiographic imaging. Administer
corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA
for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4
Colitis (including microscopic colitis) occurred in 4 (1%) of 411
patients, including Grade 2 or 3 cases in 1 (0.2%) and 2 (0.5%) patients
respectively, receiving KEYTRUDA. Monitor patients for signs and
symptoms of colitis. Administer corticosteroids for Grade 2 or greater
colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue
KEYTRUDA for Grade 4 colitis.
Hepatitis (including autoimmune hepatitis) occurred in 2 (0.5%) of 411
patients, including a Grade 4 case in 1 (0.2%) patient, receiving
KEYTRUDA. Monitor patients for changes in liver function. Administer
corticosteroids for Grade 2 or greater hepatitis and, based on severity
of liver enzyme elevations, withhold or discontinue KEYTRUDA.
Hypophysitis occurred in 2 (0.5%) of 411 patients, including a Grade 2
case in 1 and a Grade 4 case in 1 (0.2% each) patient, receiving
KEYTRUDA. Monitor for signs and symptoms of hypophysitis. Administer
corticosteroids for Grade 2 or greater hypophysitis. Withhold KEYTRUDA
for Grade 2; withhold or discontinue for Grade 3; and permanently
discontinue KEYTRUDA for Grade 4 hypophysitis.
Nephritis occurred in 3 (0.7%) patients receiving KEYTRUDA, consisting
of one case of Grade 2 autoimmune nephritis (0.2%) and two cases of
interstitial nephritis with renal failure (0.5%), one Grade 3 and one
Grade 4. Monitor patients for changes in renal function. Administer
corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for
Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 nephritis.
Hyperthyroidism occurred in 5 (1.2%) of 411 patients, including Grade 2
or 3 cases in 2 (0.5%) and 1 (0.2%) patients respectively, receiving
KEYTRUDA. Hypothyroidism occurred in 34 (8.3%) of 411 patients,
including a Grade 3 case in 1 (0.2%) patient, receiving KEYTRUDA.
Thyroid disorders can occur at any time during treatment. Monitor
patients for changes in thyroid function (at the start of treatment,
periodically during treatment, and as indicated based on clinical
evaluation) and for clinical signs and symptoms of thyroid disorders.
Administer corticosteroids for Grade 3 or greater hyperthyroidism.
Withhold KEYTRUDA for Grade 3; permanently discontinue KEYTRUDA for
Grade 4 hyperthyroidism. Isolated hypothyroidism may be managed with
replacement therapy without treatment interruption and without
Other clinically important immune-mediated adverse reactions can occur.
The following clinically significant, immune-mediated adverse reactions
occurred in less than 1% of patients treated with KEYTRUDA: exfoliative
dermatitis, uveitis, arthritis, myositis, pancreatitis, hemolytic
anemia, partial seizures arising in a patient with inflammatory foci in
brain parenchyma, adrenal insufficiency, myasthenic syndrome, optic
neuritis, and rhabdomyolysis.
For suspected immune-mediated adverse reactions, ensure adequate
evaluation to confirm etiology or exclude other causes. Based on the
severity of the adverse reaction, withhold KEYTRUDA and administer
corticosteroids. Upon improvement of the adverse reaction to Grade 1 or
less, initiate corticosteroid taper and continue to taper over at least
1 month. Restart KEYTRUDA if the adverse reaction remains at Grade 1 or
less. Permanently discontinue KEYTRUDA for any severe or Grade 3
immune-mediated adverse reaction that recurs and for any
life-threatening immune-mediated adverse reaction.
Based on its mechanism of action, KEYTRUDA may cause fetal harm when
administered to a pregnant woman. If used during pregnancy, or if the
patient becomes pregnant during treatment, apprise the patient of the
potential hazard to a fetus. Advise females of reproductive potential to
use highly effective contraception during treatment and for 4 months
after the last dose of KEYTRUDA.
For the treatment of advanced melanoma, KEYTRUDA was discontinued for
adverse reactions in 6% of 89 patients who received the recommended dose
of 2 mg/kg and 9% of 411 patients across all doses studied. Serious
adverse reactions occurred in 36% of patients receiving KEYTRUDA. The
most frequent serious adverse drug reactions reported in 2% or more of
patients were renal failure, dyspnea, pneumonia, and cellulitis.
The most common adverse reactions (reported in ≥20% of patients) were
fatigue (47%), cough (30%), nausea (30%), pruritus (30%), rash (29%),
decreased appetite (26%), constipation (21%), arthralgia (20%), and
The recommended dose of KEYTRUDA is 2 mg/kg administered as an
intravenous infusion over 30 minutes every three weeks until disease
progression or unacceptable toxicity. No formal pharmacokinetic drug
interaction studies have been conducted with KEYTRUDA. It is not known
whether KEYTRUDA is excreted in human milk. Because many drugs are
excreted in human milk, instruct women to discontinue nursing during
treatment with KEYTRUDA. Safety and effectiveness of KEYTRUDA have not
been established in pediatric patients.
Please see Prescribing Information for KEYTRUDA (pembrolizumab) at http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf
and the Medication Guide for KEYTRUDA at http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_mg.pdf
About Eisai in Oncology
Eisai is dedicated to discovering, developing and producing innovative
oncology therapies that may make a difference and impact the lives of
patients and their families. This passion for people is part of Eisai’s human
health care (hhc) mission, which strives for better
understanding of the needs of patients and their families to help
increase the benefits health care provides. Our commitment to meaningful
progress in oncology research, built on scientific expertise, is
supported by a global capability to conduct discovery and preclinical
research, and develop small molecules and biologic agents across various
types of cancer.
About Eisai Co., Ltd.
Eisai Co., Ltd. is a leading global research and development-based
pharmaceutical company headquartered in Japan. We define our corporate
mission as “giving first thought to patients and their families and to
increasing the benefits health care provides,” which we call our human
health care (hhc) philosophy. With over 10,000 employees
working across our global network of R&D facilities, manufacturing sites
and marketing subsidiaries, we strive to realize our hhc
philosophy by delivering innovative products in various therapeutic
areas with high unmet medical needs, including Oncology and Neurology.
As a global pharmaceutical company, our mission extends to patients
around the world through our investment and participation in
partnership-based initiatives to improve access to medicines in
developing and emerging countries.
For more information about Eisai Co., Ltd., please visit www.eisai.com.
Merck’s Focus on Cancer
Our goal is to translate breakthrough science into biomedical
innovations to help people with cancer worldwide. For Merck Oncology,
helping people fight cancer is our passion, supporting accessibility to
our cancer medicines is our commitment, and pursuing research in
immuno-oncology and other areas of breakthrough science is our focus to
potentially bring new hope to people with cancer. For more information
about our oncology clinical trials, visit www.merck.com/clinicaltrials.
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