KEYTRUDA Plus LENVIMA Is Now Approved for
Two Types of Cancer, Including Advanced RCC
Based on Phase 3 CLEAR/KEYNOTE-581 Trial,
KEYTRUDA Plus LENVIMA Significantly Reduced Risk of Disease
Progression or Death by 61% Versus Sunitinib
Merck (NYSE: MRK), known as MSD outside the United States and
Canada, and Eisai today announced that the U.S. Food and Drug
Administration (FDA) has approved the combination of KEYTRUDA,
Merck’s anti-PD-1 therapy, plus LENVIMA, the orally available
multiple receptor tyrosine kinase inhibitor discovered by Eisai,
for the first-line treatment of adult patients with advanced renal
cell carcinoma (RCC). The approval is based on results from the
pivotal Phase 3 CLEAR (Study 307)/KEYNOTE-581 trial, in which
KEYTRUDA plus LENVIMA demonstrated statistically significant
improvements versus sunitinib in the efficacy outcome measures of
progression-free survival (PFS), overall survival (OS) and
confirmed objective response rate (ORR).
For PFS, KEYTRUDA plus LENVIMA reduced the risk of disease
progression or death by 61% (HR=0.39 [95% CI: 0.32-0.49];
p<0.0001) with a median PFS of 23.9 months versus 9.2 months for
sunitinib. For OS, KEYTRUDA plus LENVIMA reduced the risk of death
by 34% (HR=0.66 [95% CI: 0.49-0.88]; p=0.0049) versus sunitinib.
Additionally, the confirmed ORR was 71% (95% CI: 66-76) (n=252) for
patients who received KEYTRUDA plus LENVIMA versus 36% with
sunitinib (95% CI: 31-41) (n=129). KEYTRUDA plus LENVIMA achieved a
complete response (CR) rate of 16% and partial response (PR) rate
of 55% versus a CR rate of 4% and a PR rate of 32% for those who
received sunitinib.
Immune-mediated adverse reactions, which may be severe or fatal,
can occur in any organ system or tissue and can affect more than
one body system simultaneously. Immune-mediated adverse reactions
can occur at any time during or after treatment with KEYTRUDA,
including pneumonitis, colitis, hepatitis, endocrinopathies,
nephritis, dermatologic reactions, solid organ transplant
rejection, and complications of allogeneic hematopoietic stem cell
transplantation. Early identification and management of
immune-mediated adverse reactions are essential to ensure safe use
of KEYTRUDA. Based on the severity of the adverse reaction,
KEYTRUDA should be withheld or permanently discontinued and
corticosteroids administered if appropriate. KEYTRUDA can also
cause severe or life-threatening infusion-related reactions. Based
on its mechanism of action, KEYTRUDA can cause fetal harm when
administered to a pregnant woman. For more information, see
“Selected Important Safety Information” below.
Adverse reactions, some of which can be serious or fatal, may
occur with LENVIMA, including hypertension, cardiac dysfunction,
arterial thromboembolic events, hepatotoxicity, renal failure or
impairment, proteinuria, diarrhea, fistula formation and
gastrointestinal perforation, QT interval prolongation,
hypocalcemia, reversible posterior leukoencephalopathy syndrome,
hemorrhagic events, impairment of thyroid stimulating hormone
suppression/thyroid dysfunction, impaired wound healing,
osteonecrosis of the jaw, and embryo-fetal toxicity. Based on its
mechanism of action and data from animal reproduction studies,
LENVIMA can cause fetal harm when administered to a pregnant woman.
Females of reproductive potential should be advised to use
effective contraception. Based on the severity of the adverse
reaction, LENVIMA should be interrupted, reduced, and/or
discontinued. For more information, see “Selected Safety
Information” below.
“This approval is based in part on data demonstrating that
KEYTRUDA plus LENVIMA significantly reduced the risk of disease
progression or death versus sunitinib,” said Dr. Robert Motzer,
Jack and Dorothy Byrne Chair in Clinical Oncology, Kidney Cancer
Section Head, Genitourinary Oncology Service, Memorial Sloan
Kettering Cancer Center. “This is a significant milestone for newly
diagnosed patients with advanced renal cell carcinoma and
introduces a promising combination option in the first-line
setting.”
“This FDA approval reinforces the potential of KEYTRUDA plus
LENVIMA, which is now approved for two different types of cancer.
In the study, KEYTRUDA plus LENVIMA demonstrated a survival benefit
for patients with advanced renal cell carcinoma, supporting the
importance of this combination as a new first-line treatment option
for these patients,” said Dr. Gregory Lubiniecki, Vice President,
Oncology Clinical Research, Merck Research Laboratories. “At Merck,
we are focused on delivering meaningful innovations that extend the
lives of people with cancer. We are proud to see how our
collaboration with Eisai can now help to improve survival outcomes
for patients with advanced renal cell carcinoma and are committed
to further exploring KEYTRUDA plus LENVIMA in other
difficult-to-treat cancers.”
“This FDA approval is truly significant for the advanced renal
cell carcinoma community. The CLEAR/KEYNOTE-581 trial shows
treatment with KEYTRUDA plus LENVIMA resulted in superior outcomes
across progression-free survival, overall survival and objective
response rate versus sunitinib in patients with advanced renal cell
carcinoma,” said Dr. Takashi Owa, Chief Medicine Creation and Chief
Discovery Officer, Oncology Business Group at Eisai. “This
milestone is a testament to our dedication to developing new
therapeutic options for people living with advanced cancers, which
is fueled by our passion for aiming to improve cancer care for
patients, and amplified by the teamwork resulting from our
collaboration with Merck.”
This approval was reviewed under the FDA’s Real-Time Oncology
Review (RTOR) pilot program, which aims to improve the efficiency
of the review process for applications to ensure that treatments
are available to patients as early as possible.
Dr. Motzer has provided consulting and advisory services for
Merck and Eisai.
Data Supporting the Approval
The approval was based on data from the CLEAR (Study
307)/KEYNOTE-581 trial (ClinicalTrials.gov, NCT02811861), a Phase
3, multicenter, open-label, randomized trial conducted in 1,069
patients with advanced RCC in the first-line setting. Patients were
enrolled regardless of PD-L1 tumor expression status. Patients with
active autoimmune disease or a medical condition that required
immunosuppression were ineligible. Randomization was stratified by
geographic region (North America and Western Europe vs. “Rest of
the World”) and Memorial Sloan Kettering Cancer Center (MSKCC)
prognostic groups (favorable vs. intermediate vs. poor risk).
Patients were randomized (1:1:1) to one of the following
treatment arms:
- LENVIMA (20 mg orally once daily) in combination with KEYTRUDA
(200 mg intravenously [IV] every three weeks for up to 24 months);
or
- LENVIMA (18 mg orally once daily) in combination with
everolimus (5 mg orally once daily); or
- Sunitinib (50 mg orally once daily for four weeks on treatment,
followed by two weeks off treatment).
Treatment continued until unacceptable toxicity or disease
progression. Administration of KEYTRUDA plus LENVIMA was permitted
beyond Response Evaluation Criteria in Solid Tumors
(RECIST)-defined disease progression if the patient was clinically
stable and considered by the investigator to be deriving clinical
benefit. KEYTRUDA was continued for a maximum of 24 months;
however, treatment with LENVIMA could be continued beyond 24
months. Assessment of tumor status was performed at baseline and
then every eight weeks.
The study population characteristics were: median age of 62
years (range: 29 to 88 years), 42% age 65 or older; 75% male; 74%
White, 21% Asian, 1% Black, and 2% other races; 18% and 82% of
patients had a baseline Karnofsky Performance Status (KPS) of 70 to
80 and 90 to 100, respectively; patient distribution by MSKCC risk
categories was 27% favorable, 64% intermediate, and 9% poor. Common
sites of metastases in patients were lung (68%), lymph node (45%),
and bone (25%).
The major efficacy outcome measures were PFS, as assessed by
independent radiologic review (IRC) according to RECIST v1.1, and
OS. Additional efficacy outcome measures included confirmed ORR as
assessed by IRC. KEYTRUDA in combination with LENVIMA demonstrated
statistically significant improvements in PFS, OS, and ORR compared
with sunitinib. Efficacy results showed:
Endpoint
KEYTRUDA 200 mg every 3 weeks
and LENVIMA 20 mg n=355
Sunitinib n=357
Progression-Free Survival (PFS)
Number of events, n (%)
160 (45%)
205 (57%)
Progressive disease
145 (41%)
196 (55%)
Death
15 (4%)
9 (3%)
Median PFS in months (95% CI)
23.9 (20.8, 27.7)
9.2 (6.0, 11.0)
Hazard ratio* (95% CI)
0.39 (0.32, 0.49)
p-Value†
<0.0001
Overall Survival (OS)
Number of deaths, n (%)
80 (23%)
101 (28%)
Median OS in months (95% CI)
NR (33.6, NR)
NR (NR, NR)
Hazard ratio* (95% CI)
0.66 (0.49, 0.88)
p-Value†
0.0049
Objective Response Rate
(Confirmed)
ORR, n (%)
252 (71%)
129 (36%)
(95% CI)
(66, 76)
(31, 41)
Complete response rate
16%
4%
Partial response rate
55%
32%
p-Value‡
<0.0001
Tumor assessments were based on RECIST
1.1; only confirmed responses are included for ORR. Data cutoff
date = 28 Aug 2020 CI = Confidence interval; NE= Not estimable; NR=
Not reached * Hazard ratio is based on a Cox Proportional Hazards
Model. Stratified by geographic region and MSKCC prognostic groups.
† Two-sided p-value based on stratified log-rank test. ‡ Two-sided
p-value based upon CMH test.
The median duration of exposure to the combination therapy of
KEYTRUDA and LENVIMA was 17 months (range: 0.1 to 39 months).
Fatal adverse reactions occurred in 4.3% of patients who
received KEYTRUDA in combination with LENVIMA, 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
KEYTRUDA plus LENVIMA. 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 either KEYTRUDA, LENVIMA, or both
due to an adverse reaction occurred in 37% of patients receiving
KEYTRUDA in combination with LENVIMA; 29% KEYTRUDA only, 26%
LENVIMA only and 13% both treatments. The most common adverse
reactions (≥2%) resulting in permanent discontinuation of KEYTRUDA,
LENVIMA, or the combination were pneumonitis (3%), myocardial
infarction (3%), hepatotoxicity (3%), acute kidney injury (3%),
rash (3%), and diarrhea (2%).
Dose interruptions of KEYTRUDA, LENVIMA, or both due to an
adverse reaction occurred in 78% of patients receiving KEYTRUDA in
combination with LENVIMA. KEYTRUDA was interrupted in 55% of
patients, LENVIMA was interrupted in 73% of patients, and both
treatments were interrupted in 39% of patients. The most common
adverse reactions (≥3%) resulting in interruption of KEYTRUDA were
diarrhea (10%), hepatotoxicity (8%), fatigue (7%), lipase increased
(5%), amylase increased (4%), musculoskeletal pain (3%),
hypertension (3%), rash (3%), acute kidney injury (3%), and
decreased appetite (3%). 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 syndrome (PPE) (11%),
nausea (9%), stomatitis (9%), musculoskeletal pain (8%), rash (8%),
increased lipase (7%), abdominal pain (6%), and vomiting (6%),
increased alanine aminotransferase (ALT) (5%), and increased
amylase (5%). Fifteen percent (15%) of patients treated with
KEYTRUDA in combination with LENVIMA received an oral prednisone
equivalent to ≥40 mg daily for an immune-mediated adverse reaction.
Grade 3 and 4 increased ALT or increased aspartate aminotransferase
(AST) was seen in 9% of patients. Grade ≥2 increased ALT or AST was
reported in 64 (18%) patients, of whom 20 (31%) received ≥40 mg
daily oral prednisone equivalent. Recurrence of Grade ≥2 increased
ALT or AST was observed in three patients on rechallenge in
patients receiving LENVIMA and 10 patients receiving both KEYTRUDA
and LENVIMA.
The most common adverse reactions (All Grades ≥20%) for KEYTRUDA
plus LENVIMA were fatigue (63%), diarrhea (62%), musculoskeletal
disorders (58%), hypothyroidism (57%), hypertension (56%),
stomatitis (43%), decreased appetite (41%), rash (37%), nausea
(36%), weight loss, dysphonia and proteinuria (30% each), PPE
syndrome (29%), hemorrhagic events and abdominal pain (27% each),
vomiting (26%), constipation and hepatotoxicity (25% each),
headache (23%), and acute kidney injury (21%). The most common
adverse reactions (Grades 3-4) for KEYTRUDA plus LENVIMA were
hypertension (29%), diarrhea (10%), fatigue and hepatotoxicity (9%
each), weight loss and proteinuria (8% each), acute kidney injury,
hemorrhagic events and rash (5% each), musculoskeletal disorders,
decreased appetite and PPE (4% each), nausea and vomiting (3%
each), stomatitis and abdominal pain (2% each), and constipation,
hypothyroidism and headache (1% each).
Clinically relevant adverse reaction (<20%) that occurred in
patients receiving KEYTRUDA plus LENVIMA were myocardial infarction
(3%) and angina pectoris (1%).
About Renal Cell Carcinoma (RCC)
Worldwide, it is estimated there were more than 431,000 new
cases of kidney cancer diagnosed and more than 179,000 deaths from
the disease in 2020. In the U.S. alone, it is estimated there will
be approximately 76,000 new cases of kidney cancer diagnosed and
almost 14,000 deaths from the disease in 2021. Renal cell carcinoma
is by far the most common type of kidney cancer; about nine out of
10 kidney cancer diagnoses are RCC. Renal cell carcinoma is about
twice as common in men as in women. Most cases of RCC are
discovered incidentally during imaging tests for other abdominal
diseases. Approximately 30% of patients with RCC will have
metastatic disease at diagnosis. Survival is highly dependent on
the stage at diagnosis, and the five-year survival rate is 13% for
patients diagnosed with metastatic disease.
About KEYTRUDA® (pembrolizumab) Injection, 100 mg
KEYTRUDA is an anti-programmed death receptor-1 (PD-1) therapy
that works by increasing the ability of the body’s immune system to
help detect and fight tumor cells. KEYTRUDA is a humanized
monoclonal antibody that blocks the interaction between PD-1 and
its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes
which may affect both tumor cells and healthy cells.
Merck has the industry’s largest immuno-oncology clinical
research program. There are currently more than 1,500 trials
studying KEYTRUDA across a wide variety of cancers and treatment
settings. The KEYTRUDA clinical program seeks to understand the
role of KEYTRUDA across cancers and the factors that may predict a
patient's likelihood of benefitting from treatment with KEYTRUDA,
including exploring several different biomarkers.
Selected KEYTRUDA® (pembrolizumab) Indications in the
U.S.
Melanoma
KEYTRUDA is indicated for the treatment of patients with
unresectable or metastatic melanoma.
KEYTRUDA is indicated for the adjuvant treatment of patients
with melanoma with involvement of lymph node(s) following complete
resection.
Non-Small Cell Lung Cancer
KEYTRUDA, in combination with pemetrexed and platinum
chemotherapy, is indicated for the first-line treatment of patients
with metastatic nonsquamous non-small cell lung cancer (NSCLC),
with no EGFR or ALK genomic tumor aberrations.
KEYTRUDA, in combination with carboplatin and either paclitaxel
or paclitaxel protein-bound, is indicated for the first-line
treatment of patients with metastatic squamous NSCLC.
KEYTRUDA, as a single agent, is indicated for the first-line
treatment of patients with NSCLC expressing PD-L1 [tumor proportion
score (TPS) ≥1%] as determined by an FDA-approved test, with no
EGFR or ALK genomic tumor aberrations, and is
- stage III where patients are not candidates for surgical
resection or definitive chemoradiation, or
- metastatic.
KEYTRUDA, as a single agent, is indicated for the treatment of
patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%)
as determined by an FDA-approved test, with disease progression on
or after platinum-containing chemotherapy. Patients with EGFR or
ALK genomic tumor aberrations should have disease progression on
FDA-approved therapy for these aberrations prior to receiving
KEYTRUDA.
Head and Neck Squamous Cell Cancer
KEYTRUDA, in combination with platinum and fluorouracil (FU), is
indicated for the first-line treatment of patients with metastatic
or with unresectable, recurrent head and neck squamous cell
carcinoma (HNSCC).
KEYTRUDA, as a single agent, is indicated for the first-line
treatment of patients with metastatic or with unresectable,
recurrent HNSCC whose tumors express PD-L1 [combined positive score
(CPS) ≥1)] as determined by an FDA-approved test.
KEYTRUDA, as a single agent, is indicated for the treatment of
patients with recurrent or metastatic HNSCC with disease
progression on or after platinum-containing chemotherapy.
Classical Hodgkin Lymphoma
KEYTRUDA is indicated for the treatment of adult patients with
relapsed or refractory classical Hodgkin lymphoma (cHL).
KEYTRUDA is indicated for the treatment of pediatric patients
with refractory cHL, or cHL that has relapsed after 2 or more lines
of therapy.
Primary Mediastinal Large B-Cell Lymphoma
KEYTRUDA is indicated for the treatment of adult and pediatric
patients with refractory primary mediastinal large B-cell lymphoma
(PMBCL), or who have relapsed after 2 or more prior lines of
therapy. KEYTRUDA is not recommended for treatment of patients with
PMBCL who require urgent cytoreductive therapy.
Urothelial Carcinoma
KEYTRUDA is indicated for the treatment of patients with locally
advanced or metastatic urothelial carcinoma (mUC) who are not
eligible for cisplatin-containing chemotherapy and whose tumors
express PD-L1 (CPS ≥10), as determined by an FDA-approved test, or
in patients who are not eligible for any platinum-containing
chemotherapy regardless of PD-L1 status. This indication is
approved under accelerated approval based on tumor response rate
and duration of response. Continued approval for this indication
may be contingent upon verification and description of clinical
benefit in confirmatory trials.
KEYTRUDA is indicated for the treatment of patients with locally
advanced or mUC who have disease progression during or following
platinum-containing chemotherapy or within 12 months of neoadjuvant
or adjuvant treatment with platinum-containing chemotherapy.
KEYTRUDA is indicated for the treatment of patients with
Bacillus Calmette-Guerin-unresponsive, high-risk, non-muscle
invasive bladder cancer (NMIBC) with carcinoma in situ with or
without papillary tumors who are ineligible for or have elected not
to undergo cystectomy.
Microsatellite Instability-High or Mismatch Repair Deficient
Cancer
KEYTRUDA is indicated for the treatment of adult and pediatric
patients with unresectable or metastatic microsatellite
instability-high (MSI-H) or mismatch repair deficient (dMMR) solid
tumors that have progressed following prior treatment and who have
no satisfactory alternative treatment options.
This indication is approved under accelerated approval based on
tumor response rate and durability of response. Continued approval
for this indication may be contingent upon verification and
description of clinical benefit in the confirmatory trials. The
safety and effectiveness of KEYTRUDA in pediatric patients with
MSI-H central nervous system cancers have not been established.
Microsatellite Instability-High or Mismatch Repair Deficient
Colorectal Cancer
KEYTRUDA is indicated for the treatment of patients with
unresectable or metastatic MSI-H or dMMR colorectal cancer
(CRC).
Gastric Cancer
KEYTRUDA, in combination with trastuzumab, fluoropyrimidine- and
platinum-containing chemotherapy, is indicated for the first-line
treatment of patients with locally advanced unresectable or
metastatic HER2-positive gastric or gastroesophageal junction (GEJ)
adenocarcinoma. This indication is approved under accelerated
approval based on tumor response rate and durability of response.
Continued approval for this indication may be contingent upon
verification and description of clinical benefit in the
confirmatory trials.
Esophageal Cancer
KEYTRUDA is indicated for the treatment of patients with locally
advanced or metastatic esophageal or GEJ (tumors with epicenter 1
to 5 centimeters above the GEJ) carcinoma that is not amenable to
surgical resection or definitive chemoradiation either:
- in combination with platinum- and fluoropyrimidine-based
chemotherapy, or
- as a single agent after one or more prior lines of systemic
therapy for patients with tumors of squamous cell histology that
express PD-L1 (CPS ≥10) as determined by an FDA-approved test.
Cervical Cancer
KEYTRUDA is indicated for the treatment of patients with
recurrent or metastatic cervical cancer with disease progression on
or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as
determined by an FDA-approved test. This indication is approved
under accelerated approval based on tumor response rate and
durability of response. Continued approval for this indication may
be contingent upon verification and description of clinical benefit
in the confirmatory trials.
Hepatocellular Carcinoma
KEYTRUDA is indicated for the treatment of patients with
hepatocellular carcinoma (HCC) who have been previously treated
with sorafenib. This indication is approved under accelerated
approval based on tumor response rate and durability of response.
Continued approval for this indication may be contingent upon
verification and description of clinical benefit in the
confirmatory trials.
Merkel Cell Carcinoma
KEYTRUDA is indicated for the treatment of adult and pediatric
patients with recurrent locally advanced or metastatic Merkel cell
carcinoma (MCC). This indication is approved under accelerated
approval based on tumor response rate and durability of response.
Continued approval for this indication may be contingent upon
verification and description of clinical benefit in the
confirmatory trials.
Renal Cell Carcinoma
KEYTRUDA, in combination with axitinib, is indicated for the
first-line treatment of adult patients with advanced renal cell
carcinoma (RCC).
KEYTRUDA, in combination with LENVIMA, is indicated for the
first-line treatment of adult patients with advanced RCC.
Endometrial Carcinoma
KEYTRUDA, in combination with LENVIMA, is indicated for the
treatment of patients with advanced endometrial carcinoma that is
not MSI-H or dMMR, who have disease progression following prior
systemic therapy in any settings and are not candidates for
curative surgery or radiation.
Tumor Mutational Burden-High Cancer
KEYTRUDA is indicated for the treatment of adult and pediatric
patients with unresectable or metastatic tumor mutational
burden-high (TMB-H) [≥10 mutations/megabase] solid tumors, as
determined by an FDA-approved test, that have progressed following
prior treatment and who have no satisfactory alternative treatment
options. This indication is approved under accelerated approval
based on tumor response rate and durability of response. Continued
approval for this indication may be contingent upon verification
and description of clinical benefit in the confirmatory trials. The
safety and effectiveness of KEYTRUDA in pediatric patients with
TMB-H central nervous system cancers have not been established.
Cutaneous Squamous Cell Carcinoma
KEYTRUDA is indicated for the treatment of patients with
recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) or
locally advanced cSCC that is not curable by surgery or
radiation.
Triple-Negative Breast Cancer
KEYTRUDA is indicated for the treatment of patients with
high-risk early-stage TNBC in combination with chemotherapy as
neoadjuvant treatment, and then continued as a single agent as
adjuvant treatment after surgery.
KEYTRUDA, in combination with chemotherapy, is indicated for the
treatment of patients with locally recurrent unresectable or
metastatic TNBC whose tumors express PD-L1 (CPS ≥10) as determined
by an FDA-approved test.
Selected Important Safety Information for KEYTRUDA
Severe and Fatal Immune-Mediated Adverse Reactions
KEYTRUDA is a monoclonal antibody that belongs to a class of
drugs that bind to either the PD-1 or the PD-L1, blocking the
PD-1/PD-L1 pathway, thereby removing inhibition of the immune
response, potentially breaking peripheral tolerance and inducing
immune-mediated adverse reactions. Immune-mediated adverse
reactions, which may be severe or fatal, can occur in any organ
system or tissue, can affect more than one body system
simultaneously, and can occur at any time after starting treatment
or after discontinuation of treatment. Important immune-mediated
adverse reactions listed here may not include all possible severe
and fatal immune-mediated adverse reactions.
Monitor patients closely for symptoms and signs that may be
clinical manifestations of underlying immune-mediated adverse
reactions. Early identification and management are essential to
ensure safe use of anti–PD-1/PD-L1 treatments. Evaluate liver
enzymes, creatinine, and thyroid function at baseline and
periodically during treatment. For patients with TNBC treated with
KEYTRUDA in the neoadjuvant setting, monitor blood cortisol at
baseline, prior to surgery, and as clinically indicated. In cases
of suspected immune-mediated adverse reactions, initiate
appropriate workup to exclude alternative etiologies, including
infection. Institute medical management promptly, including
specialty consultation as appropriate.
Withhold or permanently discontinue KEYTRUDA depending on
severity of the immune-mediated adverse reaction. In general, if
KEYTRUDA requires interruption or discontinuation, administer
systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or
equivalent) until improvement to Grade 1 or less. Upon improvement
to Grade 1 or less, initiate corticosteroid taper and continue to
taper over at least 1 month. Consider administration of other
systemic immunosuppressants in patients whose adverse reactions are
not controlled with corticosteroid therapy.
Immune-Mediated Pneumonitis
KEYTRUDA can cause immune-mediated pneumonitis. The incidence is
higher in patients who have received prior thoracic radiation.
Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients
receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3
(0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were
required in 67% (63/94) of patients. Pneumonitis led to permanent
discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9%
(26) of patients. All patients who were withheld reinitiated
KEYTRUDA after symptom improvement; of these, 23% had recurrence.
Pneumonitis resolved in 59% of the 94 patients.
Pneumonitis occurred in 8% (31/389) of adult patients with cHL
receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3%
of patients. Patients received high-dose corticosteroids for a
median duration of 10 days (range: 2 days to 53 months).
Pneumonitis rates were similar in patients with and without prior
thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA
in 5.4% (21) of patients. Of the patients who developed
pneumonitis, 42% interrupted KEYTRUDA, 68% discontinued KEYTRUDA,
and 77% had resolution.
Immune-Mediated Colitis
KEYTRUDA can cause immune-mediated colitis, which may present
with diarrhea. Cytomegalovirus infection/reactivation has been
reported in patients with corticosteroid-refractory immune-mediated
colitis. In cases of corticosteroid-refractory colitis, consider
repeating infectious workup to exclude alternative etiologies.
Immune-mediated colitis occurred in 1.7% (48/2799) of patients
receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%),
and Grade 2 (0.4%) reactions. Systemic corticosteroids were
required in 69% (33/48); additional immunosuppressant therapy was
required in 4.2% of patients. Colitis led to permanent
discontinuation of KEYTRUDA in 0.5% (15) and withholding in 0.5%
(13) of patients. All patients who were withheld reinitiated
KEYTRUDA after symptom improvement; of these, 23% had recurrence.
Colitis resolved in 85% of the 48 patients.
Hepatotoxicity and Immune-Mediated
Hepatitis
KEYTRUDA as a Single Agent
KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated
hepatitis occurred in 0.7% (19/2799) of patients receiving
KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2
(0.1%) reactions. Systemic corticosteroids were required in 68%
(13/19) of patients; additional immunosuppressant therapy was
required in 11% of patients. Hepatitis led to permanent
discontinuation of KEYTRUDA in 0.2% (6) and withholding in 0.3% (9)
of patients. All patients who were withheld reinitiated KEYTRUDA
after symptom improvement; of these, none had recurrence. Hepatitis
resolved in 79% of the 19 patients.
KEYTRUDA with Axitinib
KEYTRUDA in combination with axitinib can cause hepatic
toxicity. Monitor liver enzymes before initiation of and
periodically throughout treatment. Consider monitoring more
frequently as compared to when the drugs are administered as single
agents. For elevated liver enzymes, interrupt KEYTRUDA and
axitinib, and consider administering corticosteroids as needed.
With the combination of KEYTRUDA and axitinib, Grades 3 and 4
increased alanine aminotransferase (20%) and increased aspartate
aminotransferase (13%) were seen at a higher frequency compared to
KEYTRUDA alone. Fifty-nine percent of the patients with increased
ALT received systemic corticosteroids. In patients with ALT ≥3
times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved
to Grades 0-1 in 94%. Among the 92 patients who were rechallenged
with either KEYTRUDA (n=3) or axitinib (n=34) administered as a
single agent or with both (n=55), recurrence of ALT ≥3 times ULN
was observed in 1 patient receiving KEYTRUDA, 16 patients receiving
axitinib, and 24 patients receiving both. All patients with a
recurrence of ALT ≥3 ULN subsequently recovered from the event.
Immune-Mediated
Endocrinopathies
Adrenal Insufficiency
KEYTRUDA can cause primary or secondary adrenal insufficiency.
For Grade 2 or higher, initiate symptomatic treatment, including
hormone replacement as clinically indicated. Withhold KEYTRUDA
depending on severity. Adrenal insufficiency occurred in 0.8%
(22/2799) of patients receiving KEYTRUDA, including Grade 4
(<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) reactions. Systemic
corticosteroids were required in 77% (17/22) of patients; of these,
the majority remained on systemic corticosteroids. Adrenal
insufficiency led to permanent discontinuation of KEYTRUDA in
<0.1% (1) and withholding in 0.3% (8) of patients. All patients
who were withheld reinitiated KEYTRUDA after symptom
improvement.
Hypophysitis
KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis
can present with acute symptoms associated with mass effect such as
headache, photophobia, or visual field defects. Hypophysitis can
cause hypopituitarism. Initiate hormone replacement as indicated.
Withhold or permanently discontinue KEYTRUDA depending on severity.
Hypophysitis occurred in 0.6% (17/2799) of patients receiving
KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2
(0.2%) reactions. Systemic corticosteroids were required in 94%
(16/17) of patients; of these, the majority remained on systemic
corticosteroids. Hypophysitis led to permanent discontinuation of
KEYTRUDA in 0.1% (4) and withholding in 0.3% (7) of patients. All
patients who were withheld reinitiated KEYTRUDA after symptom
improvement.
Thyroid Disorders
KEYTRUDA can cause immune-mediated thyroid disorders.
Thyroiditis can present with or without endocrinopathy.
Hypothyroidism can follow hyperthyroidism. Initiate hormone
replacement for hypothyroidism or institute medical management of
hyperthyroidism as clinically indicated. Withhold or permanently
discontinue KEYTRUDA depending on severity. Thyroiditis occurred in
0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2
(0.3%). None discontinued, but KEYTRUDA was withheld in <0.1%
(1) of patients.
Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving
KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to
permanent discontinuation of KEYTRUDA in <0.1% (2) and
withholding in 0.3% (7) of patients. All patients who were withheld
reinitiated KEYTRUDA after symptom improvement. Hypothyroidism
occurred in 8% (237/2799) of patients receiving KEYTRUDA, including
Grade 3 (0.1%) and Grade 2 (6.2%). It led to permanent
discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.5%
(14) of patients. All patients who were withheld reinitiated
KEYTRUDA after symptom improvement. The majority of patients with
hypothyroidism required long-term thyroid hormone replacement. The
incidence of new or worsening hypothyroidism was higher in 1185
patients with HNSCC, occurring in 16% of patients receiving
KEYTRUDA as a single agent or in combination with platinum and FU,
including Grade 3 (0.3%) hypothyroidism. The incidence of new or
worsening hypothyroidism was higher in 389 adult patients with cHL
(17%) receiving KEYTRUDA as a single agent, including Grade 1
(6.2%) and Grade 2 (10.8%) hypothyroidism.
Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic
Ketoacidosis
Monitor patients for hyperglycemia or other signs and symptoms
of diabetes. Initiate treatment with insulin as clinically
indicated. Withhold KEYTRUDA depending on severity. Type 1 DM
occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to
permanent discontinuation in <0.1% (1) and withholding of
KEYTRUDA in <0.1% (1) of patients. All patients who were
withheld reinitiated KEYTRUDA after symptom improvement.
Immune-Mediated Nephritis With Renal
Dysfunction
KEYTRUDA can cause immune-mediated nephritis. Immune-mediated
nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA,
including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%)
reactions. Systemic corticosteroids were required in 89% (8/9) of
patients. Nephritis led to permanent discontinuation of KEYTRUDA in
0.1% (3) and withholding in 0.1% (3) of patients. All patients who
were withheld reinitiated KEYTRUDA after symptom improvement; of
these, none had recurrence. Nephritis resolved in 56% of the 9
patients.
Immune-Mediated Dermatologic Adverse
Reactions
KEYTRUDA can cause immune-mediated rash or dermatitis.
Exfoliative dermatitis, including Stevens-Johnson syndrome, drug
rash with eosinophilia and systemic symptoms, and toxic epidermal
necrolysis, has occurred with anti–PD-1/PD-L1 treatments. Topical
emollients and/or topical corticosteroids may be adequate to treat
mild to moderate nonexfoliative rashes. Withhold or permanently
discontinue KEYTRUDA depending on severity. Immune-mediated
dermatologic adverse reactions occurred in 1.4% (38/2799) of
patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2
(0.1%) reactions. Systemic corticosteroids were required in 40%
(15/38) of patients. These reactions led to permanent
discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6%
(16) of patients. All patients who were withheld reinitiated
KEYTRUDA after symptom improvement; of these, 6% had recurrence.
The reactions resolved in 79% of the 38 patients.
Other Immune-Mediated Adverse
Reactions
The following clinically significant immune-mediated adverse
reactions occurred at an incidence of <1% (unless otherwise
noted) in patients who received KEYTRUDA or were reported with the
use of other anti–PD-1/PD-L1 treatments. Severe or fatal cases have
been reported for some of these adverse reactions.
Cardiac/Vascular: Myocarditis, pericarditis, vasculitis; Nervous
System: Meningitis, encephalitis, myelitis and demyelination,
myasthenic syndrome/myasthenia gravis (including exacerbation),
Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy;
Ocular: Uveitis, iritis and other ocular inflammatory toxicities
can occur. Some cases can be associated with retinal detachment.
Various grades of visual impairment, including blindness, can
occur. If uveitis occurs in combination with other immune-mediated
adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome,
as this may require treatment with systemic steroids to reduce the
risk of permanent vision loss; Gastrointestinal: Pancreatitis, to
include increases in serum amylase and lipase levels, gastritis,
duodenitis; Musculoskeletal and Connective Tissue:
Myositis/polymyositis, rhabdomyolysis (and associated sequelae,
including renal failure), arthritis (1.5%), polymyalgia rheumatica;
Endocrine: Hypoparathyroidism; Hematologic/Immune: Hemolytic
anemia, aplastic anemia, hemophagocytic lymphohistiocytosis,
systemic inflammatory response syndrome, histiocytic necrotizing
lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune
thrombocytopenic purpura, solid organ transplant rejection.
Infusion-Related Reactions
KEYTRUDA can cause severe or life-threatening infusion-related
reactions, including hypersensitivity and anaphylaxis, which have
been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor
for signs and symptoms of infusion-related reactions. Interrupt or
slow the rate of infusion for Grade 1 or Grade 2 reactions. For
Grade 3 or Grade 4 reactions, stop infusion and permanently
discontinue KEYTRUDA.
Complications of Allogeneic Hematopoietic Stem Cell
Transplantation (HSCT)
Fatal and other serious complications can occur in patients who
receive allogeneic HSCT before or after anti–PD-1/PD-L1 treatment.
Transplant-related complications include hyperacute
graft-versus-host disease (GVHD), acute and chronic GVHD, hepatic
veno-occlusive disease after reduced intensity conditioning, and
steroid-requiring febrile syndrome (without an identified
infectious cause). These complications may occur despite
intervening therapy between anti–PD-1/PD-L1 treatment and
allogeneic HSCT. Follow patients closely for evidence of these
complications and intervene promptly. Consider the benefit vs risks
of using anti–PD-1/PD-L1 treatments prior to or after an allogeneic
HSCT.
Increased Mortality in Patients With Multiple Myeloma
In trials in patients with multiple myeloma, the addition of
KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in
increased mortality. Treatment of these patients with an
anti–PD-1/PD-L1 treatment in this combination is not recommended
outside of controlled trials.
Embryofetal Toxicity
Based on its mechanism of action, KEYTRUDA can cause fetal harm
when administered to a pregnant woman. Advise women of this
potential risk. In females of reproductive potential, verify
pregnancy status prior to initiating KEYTRUDA and advise them to
use effective contraception during treatment and for 4 months after
the last dose.
Adverse Reactions
In KEYNOTE-006, KEYTRUDA was discontinued due to adverse
reactions in 9% of 555 patients with advanced melanoma; adverse
reactions leading to permanent discontinuation in more than one
patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic
reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%).
The most common adverse reactions (≥20%) with KEYTRUDA were fatigue
(28%), diarrhea (26%), rash (24%), and nausea (21%).
In KEYNOTE-054, KEYTRUDA was permanently discontinued due to
adverse reactions in 14% of 509 patients; the most common (≥1%)
were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Serious
adverse reactions occurred in 25% of patients receiving KEYTRUDA.
The most common adverse reaction (≥20%) with KEYTRUDA was diarrhea
(28%).
In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed
and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA
was discontinued due to adverse reactions in 20% of 405 patients.
The most common adverse reactions resulting in permanent
discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney
injury (2%). The most common adverse reactions (≥20%) with KEYTRUDA
were nausea (56%), fatigue (56%), constipation (35%), diarrhea
(31%), decreased appetite (28%), rash (25%), vomiting (24%), cough
(21%), dyspnea (21%), and pyrexia (20%).
In KEYNOTE-407, when KEYTRUDA was administered with carboplatin
and either paclitaxel or paclitaxel protein-bound in metastatic
squamous NSCLC, KEYTRUDA was discontinued due to adverse reactions
in 15% of 101 patients. The most frequent serious adverse reactions
reported in at least 2% of patients were febrile neutropenia,
pneumonia, and urinary tract infection. Adverse reactions observed
in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with
the exception that increased incidences of alopecia (47% vs 36%)
and peripheral neuropathy (31% vs 25%) were observed in the
KEYTRUDA and chemotherapy arm compared to the placebo and
chemotherapy arm in KEYNOTE-407.
In KEYNOTE-042, KEYTRUDA was discontinued due to adverse
reactions in 19% of 636 patients with advanced NSCLC; the most
common were pneumonitis (3%), death due to unknown cause (1.6%),
and pneumonia (1.4%). The most frequent serious adverse reactions
reported in at least 2% of patients were pneumonia (7%),
pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion
(2.2%). The most common adverse reaction (≥20%) was fatigue
(25%).
In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to
adverse reactions in 8% of 682 patients with metastatic NSCLC; the
most common was pneumonitis (1.8%). The most common adverse
reactions (≥20%) were decreased appetite (25%), fatigue (25%),
dyspnea (23%), and nausea (20%).
In KEYNOTE-048, KEYTRUDA monotherapy was discontinued due to
adverse events in 12% of 300 patients with HNSCC; the most common
adverse reactions leading to permanent discontinuation were sepsis
(1.7%) and pneumonia (1.3%). The most common adverse reactions
(≥20%) were fatigue (33%), constipation (20%), and rash (20%).
In KEYNOTE-048, when KEYTRUDA was administered in combination
with platinum (cisplatin or carboplatin) and FU chemotherapy,
KEYTRUDA was discontinued due to adverse reactions in 16% of 276
patients with HNSCC. The most common adverse reactions resulting in
permanent discontinuation of KEYTRUDA were pneumonia (2.5%),
pneumonitis (1.8%), and septic shock (1.4%). The most common
adverse reactions (≥20%) were nausea (51%), fatigue (49%),
constipation (37%), vomiting (32%), mucosal inflammation (31%),
diarrhea (29%), decreased appetite (29%), stomatitis (26%), and
cough (22%).
In KEYNOTE-012, KEYTRUDA was discontinued due to adverse
reactions in 17% of 192 patients with HNSCC. Serious adverse
reactions occurred in 45% of patients. The most frequent serious
adverse reactions reported in at least 2% of patients were
pneumonia, dyspnea, confusional state, vomiting, pleural effusion,
and respiratory failure. The most common adverse reactions (≥20%)
were fatigue, decreased appetite, and dyspnea. Adverse reactions
occurring in patients with HNSCC were generally similar to those
occurring in patients with melanoma or NSCLC who received KEYTRUDA
as a monotherapy, with the exception of increased incidences of
facial edema and new or worsening hypothyroidism.
In KEYNOTE-204, KEYTRUDA was discontinued due to adverse
reactions in 14% of 148 patients with cHL. Serious adverse
reactions occurred in 30% of patients receiving KEYTRUDA; those ≥1%
were pneumonitis, pneumonia, pyrexia, myocarditis, acute kidney
injury, febrile neutropenia, and sepsis. Three patients died from
causes other than disease progression: 2 from complications after
allogeneic HSCT and 1 from unknown cause. The most common adverse
reactions (≥20%) were upper respiratory tract infection (41%),
musculoskeletal pain (32%), diarrhea (22%), and pyrexia, fatigue,
rash, and cough (20% each).
In KEYNOTE-087, KEYTRUDA was discontinued due to adverse
reactions in 5% of 210 patients with cHL. Serious adverse reactions
occurred in 16% of patients; those ≥1% were pneumonia, pneumonitis,
pyrexia, dyspnea, GVHD, and herpes zoster. Two patients died from
causes other than disease progression: 1 from GVHD after subsequent
allogeneic HSCT and 1 from septic shock. The most common adverse
reactions (≥20%) were fatigue (26%), pyrexia (24%), cough (24%),
musculoskeletal pain (21%), diarrhea (20%), and rash (20%).
In KEYNOTE-170, KEYTRUDA was discontinued due to adverse
reactions in 8% of 53 patients with PMBCL. Serious adverse
reactions occurred in 26% of patients and included arrhythmia (4%),
cardiac tamponade (2%), myocardial infarction (2%), pericardial
effusion (2%), and pericarditis (2%). Six (11%) patients died
within 30 days of start of treatment. The most common adverse
reactions (≥20%) were musculoskeletal pain (30%), upper respiratory
tract infection and pyrexia (28% each), cough (26%), fatigue (23%),
and dyspnea (21%).
In KEYNOTE-052, KEYTRUDA was discontinued due to adverse
reactions in 11% of 370 patients with locally advanced or mUC.
Serious adverse reactions occurred in 42% of patients; those ≥2%
were urinary tract infection, hematuria, acute kidney injury,
pneumonia, and urosepsis. The most common adverse reactions (≥20%)
were fatigue (38%), musculoskeletal pain (24%), decreased appetite
(22%), constipation (21%), rash (21%), and diarrhea (20%).
In KEYNOTE-045, KEYTRUDA was discontinued due to adverse
reactions in 8% of 266 patients with locally advanced or mUC. The
most common adverse reaction resulting in permanent discontinuation
of KEYTRUDA was pneumonitis (1.9%). Serious adverse reactions
occurred in 39% of KEYTRUDA-treated patients; those ≥2% were
urinary tract infection, pneumonia, anemia, and pneumonitis. The
most common adverse reactions (≥20%) in patients who received
KEYTRUDA were fatigue (38%), musculoskeletal pain (32%), pruritus
(23%), decreased appetite (21%), nausea (21%), and rash (20%).
In KEYNOTE-057, KEYTRUDA was discontinued due to adverse
reactions in 11% of 148 patients with high-risk NMIBC. The most
common adverse reaction resulting in permanent discontinuation of
KEYTRUDA was pneumonitis (1.4%). Serious adverse reactions occurred
in 28% of patients; those ≥2% were pneumonia (3%), cardiac ischemia
(2%), colitis (2%), pulmonary embolism (2%), sepsis (2%), and
urinary tract infection (2%). The most common adverse reactions
(≥20%) were fatigue (29%), diarrhea (24%), and rash (24%).
Adverse reactions occurring in patients with MSI-H or dMMR CRC
were similar to those occurring in patients with melanoma or NSCLC
who received KEYTRUDA as a monotherapy.
In KEYNOTE-811, when KEYTRUDA was administered in combination
with trastuzumab, fluoropyrimidine- and platinum-containing
chemotherapy, KEYTRUDA was discontinued due to adverse reactions in
6% of 217 patients with locally advanced unresectable or metastatic
HER2+ gastric or GEJ adenocarcinoma. The most common adverse
reaction resulting in permanent discontinuation was pneumonitis
(1.4%). In the KEYTRUDA arm versus placebo, there was a difference
of ≥5% incidence between patients treated with KEYTRUDA versus
standard of care for diarrhea (53% vs 44%) and nausea (49% vs
44%).
The most common adverse reactions (reported in ≥20%) in patients
receiving KEYTRUDA in combination with chemotherapy were
fatigue/asthenia, nausea, constipation, diarrhea, decreased
appetite, rash, vomiting, cough, dyspnea, pyrexia, alopecia,
peripheral neuropathy, mucosal inflammation, stomatitis, headache,
weight loss, abdominal pain, arthralgia, myalgia, and insomnia.
In KEYNOTE-590, when KEYTRUDA was administered with cisplatin
and FU to patients with metastatic or locally advanced esophageal
or GEJ (tumors with epicenter 1 to 5 centimeters above the GEJ)
carcinoma who were not candidates for surgical resection or
definitive chemoradiation, KEYTRUDA was discontinued due to adverse
reactions in 15% of 370 patients. The most common adverse reactions
resulting in permanent discontinuation of KEYTRUDA (≥1%) were
pneumonitis (1.6%), acute kidney injury (1.1%), and pneumonia
(1.1%). The most common adverse reactions (≥20%) with KEYTRUDA in
combination with chemotherapy were nausea (67%), fatigue (57%),
decreased appetite (44%), constipation (40%), diarrhea (36%),
vomiting (34%), stomatitis (27%), and weight loss (24%).
Adverse reactions occurring in patients with esophageal cancer
who received KEYTRUDA as a monotherapy were similar to those
occurring in patients with melanoma or NSCLC who received KEYTRUDA
as a monotherapy.
In KEYNOTE-158, KEYTRUDA was discontinued due to adverse
reactions in 8% of 98 patients with recurrent or metastatic
cervical cancer. Serious adverse reactions occurred in 39% of
patients receiving KEYTRUDA; the most frequent included anemia
(7%), fistula, hemorrhage, and infections [except urinary tract
infections] (4.1% each). The most common adverse reactions (≥20%)
were fatigue (43%), musculoskeletal pain (27%), diarrhea (23%),
pain and abdominal pain (22% each), and decreased appetite
(21%).
Adverse reactions occurring in patients with HCC were generally
similar to those in patients with melanoma or NSCLC who received
KEYTRUDA as a monotherapy, with the exception of increased
incidences of ascites (8% Grades 3-4) and immune-mediated hepatitis
(2.9%). Laboratory abnormalities (Grades 3-4) that occurred at a
higher incidence were elevated AST (20%), ALT (9%), and
hyperbilirubinemia (10%).
Among the 50 patients with MCC enrolled in study KEYNOTE-017,
adverse reactions occurring in patients with MCC were generally
similar to those occurring in patients with melanoma or NSCLC who
received KEYTRUDA as a monotherapy. Laboratory abnormalities
(Grades 3-4) that occurred at a higher incidence were elevated AST
(11%) and hyperglycemia (19%).
In KEYNOTE-426, when KEYTRUDA was administered in combination
with axitinib, fatal adverse reactions occurred in 3.3% of 429
patients. Serious adverse reactions occurred in 40% of patients,
the most frequent (≥1%) were hepatotoxicity (7%), diarrhea (4.2%),
acute kidney injury (2.3%), dehydration (1%), and pneumonitis (1%).
Permanent discontinuation due to an adverse reaction occurred in
31% of patients; KEYTRUDA only (13%), axitinib only (13%), and the
combination (8%); the most common were hepatotoxicity (13%),
diarrhea/colitis (1.9%), acute kidney injury (1.6%), and
cerebrovascular accident (1.2%). The most common adverse reactions
(≥20%) were diarrhea (56%), fatigue/asthenia (52%), hypertension
(48%), hepatotoxicity (39%), hypothyroidism (35%), decreased
appetite (30%), palmar-plantar erythrodysesthesia (28%), nausea
(28%), stomatitis/mucosal inflammation (27%), dysphonia (25%), rash
(25%), cough (21%), and constipation (21%).
In KEYNOTE-581, when KEYTRUDA was administered in combination
with LENVIMA to patients with advanced renal carcinoma (n=352),
fatal adverse reactions occurred in 4.3% of patients. Serious
adverse reactions occurred in 51% of patients, the most common
(≥2%) were hemorrhagic events (5%), diarrhea (4%), hypertension
(3%), myocardial infarction, pneumonitis, and vomiting (3% each),
acute kidney injury, adrenal insufficiency, dyspnea, and pneumonia
(2% each).
Permanent discontinuation of either of KEYTRUDA, LENVIMA, or
both due to an adverse reaction occurred in 37% of patients; 29%
KEYTRUDA only, 26% lenvatinib only, and 13% both. The most common
adverse reactions (≥2%) resulting in permanent discontinuation of
KEYTRUDA, LENVIMA, or the combination were pneumonitis (3%),
myocardial infarction, hepatotoxicity, acute kidney injury, and
rash (3% each), and diarrhea (2%).
The most common adverse reactions (≥20%) observed with KEYTRUDA
in combination with LENVIMA were fatigue (63%), diarrhea (62%),
musculoskeletal disorders (58%), hypothyroidism (57%), hypertension
(56%), stomatitis (43%), decreased appetite (41%), rash (37%),
nausea (36%), weight loss, dysphonia and proteinuria (30% each),
palmar-plantar erythrodysesthesia syndrome (29%), abdominal pain
and hemorrhagic events (27% each), vomiting (26%), constipation and
hepatotoxicity (25% each), headache (23%), and acute kidney injury
(21%).
In KEYNOTE-775, when KEYTRUDA was administered in combination
with LENVIMA to patients with advanced endometrial carcinoma that
were not MSI-H or dMMR (n=342), fatal adverse reactions occurred in
4.7% of patients. Serious adverse reactions occurred in 50% of
these patients; the most common (≥3%) were hypertension (4.4%) and
urinary tract infections (3.2%).
Discontinuation of KEYTRUDA, due to an adverse reaction occurred
in 15% of these patients. The most common adverse reaction leading
to discontinuation of KEYTRUDA (≥1%) was increased ALT (1.2%).
The most common adverse reactions for KEYTRUDA in combination
with LENVIMA (reported in ≥20% patients) were hypothyroidism and
hypertension (67% each), fatigue (58%), diarrhea (55%),
musculoskeletal disorders (53%), nausea (49%), decreased appetite
(44%), vomiting (37%), stomatitis (35%), abdominal pain and weight
loss (34% each), urinary tract infections (31%), proteinuria (29%),
constipation (27%), headache (26%), hemorrhagic events (25%),
palmar-plantar erythrodysesthesia (23%), dysphonia (22%), and rash
(20%).
Adverse reactions occurring in patients with TMB-H cancer were
similar to those occurring in patients with other solid tumors who
received KEYTRUDA as a single agent.
Adverse reactions occurring in patients with recurrent or
metastatic cSCC or locally advanced cSCC were similar to those
occurring in patients with melanoma or NSCLC who received KEYTRUDA
as a monotherapy.
In KEYNOTE-522, when KEYTRUDA was administered with neoadjuvant
chemotherapy (carboplatin and paclitaxel followed by doxorubicin or
epirubicin and cyclophosphamide) followed by surgery and continued
adjuvant treatment with KEYTRUDA as a single agent (n=778) to
patients with newly diagnosed, previously untreated, high-risk
early-stage TNBC, fatal adverse reactions occurred in 0.9% of
patients, including 1 each of adrenal crisis, autoimmune
encephalitis, hepatitis, pneumonia, pneumonitis, pulmonary
embolism, and sepsis in association with multiple organ dysfunction
syndrome and myocardial infarction. Serious adverse reactions
occurred in 44% of patients receiving KEYTRUDA; those ≥2% were
febrile neutropenia (15%), pyrexia (3.7%), anemia (2.6%), and
neutropenia (2.2%). KEYTRUDA was discontinued in 20% of patients
due to adverse reactions. The most common reactions (≥1%) resulting
in permanent discontinuation were increased ALT (2.7%), increased
AST (1.5%), and rash (1%). The most common adverse reactions (≥20%)
in patients receiving KEYTRUDA were fatigue (70%), nausea (67%),
alopecia (61%), rash (52%), constipation (42%), diarrhea and
peripheral neuropathy (41% each), stomatitis (34%), vomiting (31%),
headache (30%), arthralgia (29%), pyrexia (28%), cough (26%),
abdominal pain (24%), decreased appetite (23%), insomnia (21%), and
myalgia (20%).
In KEYNOTE-355, when KEYTRUDA and chemotherapy (paclitaxel,
paclitaxel protein-bound, or gemcitabine and carboplatin) were
administered to patients with locally recurrent unresectable or
metastatic TNBC who had not been previously treated with
chemotherapy in the metastatic setting (n=596), fatal adverse
reactions occurred in 2.5% of patients, including
cardio-respiratory arrest (0.7%) and septic shock (0.3%). Serious
adverse reactions occurred in 30% of patients receiving KEYTRUDA in
combination with chemotherapy; the serious reactions in ≥2% were
pneumonia (2.9%), anemia (2.2%), and thrombocytopenia (2%).
KEYTRUDA was discontinued in 11% of patients due to adverse
reactions. The most common reactions resulting in permanent
discontinuation (≥1%) were increased ALT (2.2%), increased AST
(1.5%), and pneumonitis (1.2%). The most common adverse reactions
(≥20%) in patients receiving KEYTRUDA in combination with
chemotherapy were: fatigue (48%), nausea (44%), alopecia (34%),
diarrhea and constipation (28% each), vomiting and rash (26% each),
cough (23%), decreased appetite (21%), and headache (20%).
Lactation
Because of the potential for serious adverse reactions in
breastfed children, advise women not to breastfeed during treatment
and for 4 months after the final dose.
Pediatric Use
In KEYNOTE-051, 161 pediatric patients (62 pediatric patients
aged 6 months to younger than 12 years and 99 pediatric patients
aged 12 years to 17 years) were administered KEYTRUDA 2 mg/kg every
3 weeks. The median duration of exposure was 2.1 months (range: 1
day to 24 months).
Adverse reactions that occurred at a ≥10% higher rate in
pediatric patients when compared to adults were pyrexia (33%),
vomiting (30%), leukopenia (30%), upper respiratory tract infection
(29%), neutropenia (26%), headache (25%), and Grade 3 anemia
(17%).
Please see Prescribing Information for KEYTRUDA
(pembrolizumab) at
http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf
and Medication Guide for KEYTRUDA at
http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_mg.pdf.
About LENVIMA® (lenvatinib); available as 10 mg and 4 mg
capsules
LENVIMA® (lenvatinib) is a kinase inhibitor that is
indicated:
- For the treatment of patients with locally recurrent or
metastatic, progressive, radioactive iodine-refractory
differentiated thyroid cancer (DTC)
- In combination with KEYTRUDA, 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 KEYTRUDA, for the treatment of patients
with advanced endometrial carcinoma (EC) that is not microsatellite
instability-high (MSI-H) or mismatch repair deficient (dMMR), 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 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 (PDGFRα), KIT, and
RET. The combination of LENVIMA and everolimus showed increased
anti-angiogenic and anti-tumor activity as demonstrated by
decreased human endothelial cell proliferation, tube formation, and
VEGF signaling in vitro and tumor volume in mouse xenograft models
of human renal cell cancer greater than each drug alone. In
syngeneic mouse tumor models, lenvatinib decreased tumor-associated
macrophages, increased activated cytotoxic T cells, and
demonstrated greater antitumor activity in combination with an
anti-PD-1 monoclonal antibody compared to either treatment
alone.
Selected 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 at least 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 + 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 infants, advise women to discontinue breastfeeding during
treatment and for at least 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.
Please see Prescribing Information for LENVIMA (lenvatinib)
at
https://us.eisai.com/-/media/Files/USEisai/792710051-2021-08-11.
About the Merck and Eisai 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
will jointly develop, manufacture and commercialize LENVIMA, both
as monotherapy and in combination with Merck’s anti-PD-1 therapy
KEYTRUDA.
In addition to ongoing clinical studies evaluating the KEYTRUDA
plus LENVIMA combination across several different tumor types, the
companies have jointly initiated new clinical studies through the
LEAP (LEnvatinib And Pembrolizumab) clinical program and are
evaluating the combination in 13 different tumor types across more
than 20 clinical trials.
Merck’s Focus on Cancer
Our goal is to translate breakthrough science into innovative
oncology medicines to help people with cancer worldwide. At Merck,
the potential to bring new hope to people with cancer drives our
purpose and supporting accessibility to our cancer medicines is our
commitment. As part of our focus on cancer, Merck is committed to
exploring the potential of immuno-oncology with one of the largest
development programs in the industry across more than 30 tumor
types. We also continue to strengthen our portfolio through
strategic acquisitions and are prioritizing the development of
several promising oncology candidates with the potential to improve
the treatment of advanced cancers. For more information about our
oncology clinical trials, visit www.merck.com/clinicaltrials.
About Merck
For 130 years, Merck, known as MSD outside of the United States
and Canada, has been inventing for life, bringing forward medicines
and vaccines for many of the world’s most challenging diseases in
pursuit of our mission to save and improve lives. We demonstrate
our commitment to patients and population health by increasing
access to health care through far-reaching policies, programs and
partnerships. Today, Merck continues to be at the forefront of
research to prevent and treat diseases that threaten people and
animals – including cancer, infectious diseases such as HIV and
Ebola, and emerging animal diseases – as we aspire to be the
premier research-intensive biopharmaceutical company in the world.
For more information, visit www.merck.com and connect with us on
Twitter, Facebook, Instagram, YouTube and LinkedIn.
Eisai’s Focus on Cancer
Eisai focuses on the development of anticancer drugs, targeting
the tumor microenvironment (with experience and knowledge from
existing in-house discovered compounds) and the driver gene
mutation and aberrant splicing (leveraging RNA Splicing Platform)
as areas (Ricchi) where real patient needs are still unmet, and
where Eisai can aim to become a frontrunner in oncology. Eisai
aspires to discover innovative new drugs with new targets and
mechanisms of action from these Ricchi, with the aim of
contributing to the cure of cancers.
About Eisai
Eisai is a leading global research and development-based
pharmaceutical company headquartered in Japan, with approximately
10,000 employees worldwide. 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. We strive to realize our hhc
philosophy by delivering innovative products in therapeutic areas
with high unmet medical needs, including Oncology and Neurology. In
the spirit of hhc, we take that commitment even further by applying
our scientific expertise, clinical capabilities and patient
insights to discover and develop innovative solutions that help
address society’s toughest unmet needs, including neglected
tropical diseases and the Sustainable Development Goals.
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).
Forward-Looking Statement of Merck & Co., Inc.,
Kenilworth, N.J., USA
This news release of Merck & Co., Inc., Kenilworth, N.J.,
USA (the “company”) includes “forward-looking statements” within
the meaning of the safe harbor provisions of the U.S. Private
Securities Litigation Reform Act of 1995. These statements are
based upon the current beliefs and expectations of the company’s
management and are subject to significant risks and uncertainties.
There can be no guarantees with respect to pipeline products that
the products will receive the necessary regulatory approvals or
that they will prove to be commercially successful. If underlying
assumptions prove inaccurate or risks or uncertainties materialize,
actual results may differ materially from those set forth in the
forward-looking statements.
Risks and uncertainties include but are not limited to, general
industry conditions and competition; general economic factors,
including interest rate and currency exchange rate fluctuations;
the impact of the global outbreak of novel coronavirus disease
(COVID-19); the impact of pharmaceutical industry regulation and
health care legislation in the United States and internationally;
global trends toward health care cost containment; technological
advances, new products and patents attained by competitors;
challenges inherent in new product development, including obtaining
regulatory approval; the company’s ability to accurately predict
future market conditions; manufacturing difficulties or delays;
financial instability of international economies and sovereign
risk; dependence on the effectiveness of the company’s patents and
other protections for innovative products; and the exposure to
litigation, including patent litigation, and/or regulatory
actions.
The company undertakes no obligation to publicly update any
forward-looking statement, whether as a result of new information,
future events or otherwise. Additional factors that could cause
results to differ materially from those described in the
forward-looking statements can be found in the company’s 2020
Annual Report on Form 10-K and the company’s other filings with the
Securities and Exchange Commission (SEC) available at the SEC’s
Internet site (www.sec.gov).
View source
version on businesswire.com: https://www.businesswire.com/news/home/20210811005902/en/
Merck Media Relations Melissa Moody: (215) 407-3536 Nikki
Sullivan: (718) 644-0730
Merck Investor Relations Peter Dannenbaum: (908) 740-1037
Raychel Kruper: (908) 740-2107
Eisai Inc. Media Relations Michele Randazzo: (551)
579-4465
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