KEYTRUDA Combination Improved Overall
Survival in Patients Regardless of PD-L1 Expression, Including
Patients Who Tested Negative for PD-L1
Results Presented Today at AACR 2018 and
Published in The New England Journal of Medicine Also Show
Significant Improvement in Progression-Free Survival, with Risk of
Progression or Death Reduced by Nearly Half
Merck (NYSE: MRK), known as MSD outside the United States and
Canada, today announced results from KEYNOTE-189, a pivotal Phase 3
trial evaluating KEYTRUDA®, Merck’s anti-PD-1 therapy, in
combination with pemetrexed (ALIMTA®) and cisplatin or carboplatin
for the first-line treatment of metastatic nonsquamous non-small
cell lung cancer (NSCLC). Findings showed that the
KEYTRUDA-pemetrexed-platinum chemotherapy combination significantly
improved overall survival (OS), reducing the risk of death by half
compared with chemotherapy alone (HR=0.49 [95% CI, 0.38-0.64];
p<0.00001). In pre-specified exploratory analyses, an OS benefit
was observed regardless of PD-L1 expression in the three PD-L1
categories that were evaluated, including: patients whose tumors
were negative for PD-L1 (HR=0.59 [95% CI, 0.38-0.92]); patients
whose tumors had PD-L1 tumor proportion scores (TPS) of 1-49
percent (HR=0.55 [95% CI, 0.34-0.90]); and patients who had a TPS
of greater than or equal to 50 percent (HR=0.42 [95% CI,
0.26-0.68]). The addition of KEYTRUDA to pemetrexed plus platinum
chemotherapy also achieved a significant improvement in
progression-free survival (PFS), with a reduction in the risk of
progression or death of nearly half for patients in the KEYTRUDA
combination arm, compared with chemotherapy alone (HR=0.52 [95% CI,
0.43-0.64]; p<0.00001). A PFS improvement in the KEYTRUDA
combination group was observed in patients whose tumors were
negative for PD-L1 (HR=0.75 [95% CI, 0.53-1.05]); patients with a
TPS of 1-49 percent (HR=0.55 [95% CI, 0.37-0.81]); and patients
with a TPS greater than or equal to 50 percent (HR=0.36 [95% CI,
0.25-0.52]). These results are being presented today in a plenary
session at the American Association for Cancer Research (AACR)
Annual Meeting 2018 (Abstract #CT075), with simultaneous
publication in The New England Journal of Medicine.
“In this trial, KEYTRUDA in combination with pemetrexed and
platinum chemotherapy, compared with chemotherapy alone, prolonged
overall survival and progression-free survival in patients with
advanced nonsquamous non-small cell lung cancer regardless of PD-L1
expression,” said Dr. Leena Gandhi, director of thoracic medical
oncology at NYU Langone’s Perlmutter Cancer Center and lead author
of The New England Journal of Medicine paper. “There is good
scientific rationale for combining KEYTRUDA with pemetrexed and
platinum chemotherapy, and these clinical data now suggest this
combination as a new standard of care for the first-line treatment
of these nonsquamous non-small cell lung cancer patients.”
“Our goal is to extend the lives of patients with lung cancer,
and the unambiguous survival findings from KEYNOTE-189 showing the
risk of death was reduced by half in the KEYTRUDA arm are important
not only for patients but also for the medical community,” said Dr.
Roger M. Perlmutter, president, Merck Research Laboratories. “The
results of this trial have the potential to change the treatment
paradigm for patients with nonsquamous non-small cell lung cancer
in the first-line setting, including patients whose tumors are
either PD-L1 negative or are untested.”
KEYTRUDA is the first immunotherapy to significantly extend
survival of patients with nonsquamous NSCLC in combination with
chemotherapy as a first-line treatment. KEYNOTE-189 is the
confirmatory trial for KEYNOTE-021 (Cohort G), a Phase 2 study that
made KEYTRUDA the only FDA-approved anti-PD-1 therapy in
combination with chemotherapy (pemetrexed plus carboplatin) for the
first-line treatment of patients with metastatic nonsquamous NSCLC,
regardless of PD-L1 expression. Merck is working to submit data
from KEYNOTE-189 to regulatory agencies in the United States and
around the world.
Merck has an extensive clinical development program in lung
cancer and is advancing multiple registration-enabling studies with
KEYTRUDA in combination with other treatments and as monotherapy.
The program, which is comprised of nearly 9,000 patients across 15
clinical studies, is evaluating KEYTRUDA across multiple settings
and stages of the disease.
“The reality is, there remains a significant need for treatment
options for patients with lung cancer. At the Bonnie J. Addario
Lung Cancer Foundation (ALCF), we are devoted exclusively to
eradicating lung cancer through research, early detection,
education and treatment. And, the survival benefit achieved by the
KEYTRUDA combination in the KEYNOTE-189 study represents a
meaningful advance and may offer hope for patients newly diagnosed
with one of the most common and deadly cancers,” said Bonnie J.
Addario, a 14-year lung cancer survivor and ALCF founder.
Additional Data and Safety Information from KEYNOTE-189
(Abstract #CT075)KEYNOTE-189, a randomized, double-blind,
placebo-controlled, Phase 3 study, evaluated KEYTRUDA in
combination with pemetrexed and cisplatin or carboplatin, compared
with pemetrexed and cisplatin or carboplatin alone, in 616
untreated patients with metastatic nonsquamous NSCLC, regardless of
PD-L1 expression. Patients had no sensitizing EGFR or ALK genomic
tumor aberrations, and had not previously received systemic therapy
for advanced disease. The dual primary endpoints were OS and PFS;
secondary endpoints include overall response rate (ORR) and
duration of response (DOR).
With a median follow-up of 10.5 months (range, 0.2-20.4),
KEYTRUDA in combination with pemetrexed and a platinum chemotherapy
demonstrated superior improvements in OS, with a 51 percent
reduction in the risk of death, compared with pemetrexed plus
platinum chemotherapy alone (HR=0.49 [95% CI, 0.38-0.64];
p<0.00001). This finding includes the 50 percent of patients
randomized to the chemotherapy alone group who discontinued all
study therapy (n=170) and went on to receive subsequent anti-PD-1
or PD-L1 therapy, including 67 patients who received KEYTRUDA
monotherapy as part of study crossover. Median OS was not reached
in the KEYTRUDA combination group (95% CI, not estimable) and was
11.3 months in the chemotherapy alone group (95% CI, 8.7-15.1). In
the study, 69.2 percent of patients were estimated to be alive at
12 months in the KEYTRUDA treatment group (95% CI, 64.1-73.8%)
compared with 49.4 percent in the chemotherapy alone group (95% CI,
42.1-56.2%).
In KEYNOTE-189 there was also a significant improvement in PFS
for KEYTRUDA in combination with pemetrexed and platinum
chemotherapy with a 48 percent reduction in the risk of progression
or death compared with pemetrexed plus platinum chemotherapy alone
(HR=0.52 [95% CI, 0.43-0.64]; p<0.00001). The median PFS was 8.8
months for the KEYTRUDA combination (95% CI, 7.6-9.2) compared with
4.9 months for chemotherapy alone (95% CI, 4.7-5.5). The percentage
of patients who were alive with no progression of disease at 12
months was 34.1 percent in the KEYTRUDA combination group (95% CI,
28.8-39.5%), which was nearly double the percentage of the
pemetrexed plus platinum chemotherapy group (17.3 percent [95% CI,
12.0-23.5%]). In addition, improvements in OS and PFS were observed
in other patient subgroups evaluated, including age, sex, EGOG
performance-status score, smoking status, brain metastases at
baseline and type of platinum chemotherapy prescribed (carboplatin
or cisplatin).
In the study, KEYTRUDA plus pemetrexed and a platinum
chemotherapy also showed an ORR that was more than double the ORR
of chemotherapy alone (47.6 percent [95% CI, 42.6-52.5%] compared
to 18.9 percent [95% CI, 13.8-25.0%], respectively, p<0.00001).
Among patients in the KEYTRUDA arm, the median duration of response
was 11.2 months (range, 1.1+ to 18.0+ months) compared with 7.8
months in the chemotherapy alone group (range, 2.1+ to 16.4+
months). The improvement in response rate occurred in all PD-L1
patient subgroups.
The safety of KEYTRUDA was consistent with what has been seen in
previous trials among patients with metastatic NSCLC. Grade 3-5
adverse events from any cause occurred in 67.2 percent of patients
in the KEYTRUDA plus pemetrexed and platinum chemotherapy group and
65.8 percent in the chemotherapy alone arm. Adverse events of any
grade and from any cause with an incidence of 15 percent or more in
the KEYTRUDA group were nausea (55.6%), anemia (46.2%), fatigue
(40.7%), constipation (34.8%), diarrhea (30.9%), decreased appetite
(28.1%), neutropenia (27.2%), vomiting (24.2%), cough (21.5%),
dyspnea (21.2%), asthenia (20.5%), rash (20.2%), pyrexia (19.5%),
edema peripheral (19.3%), thrombocytopenia (18.0%) and increased
lacrimation (17.0%). The most common immune-mediated adverse events
of any grade in patients receiving KEYTRUDA plus pemetrexed and
platinum chemotherapy were hypothyroidism (6.7%), pneumonitis
(4.4%), hyperthyroidism (4.0%), infusion reactions (2.5%), colitis
(2.2%), severe skin toxicity (2.0%), nephritis (1.7%) and hepatitis
(1.2%). There were three treatment-related deaths from pneumonitis
in the KEYTRUDA plus pemetrexed and platinum chemotherapy
group.
About KEYNOTE-189KEYNOTE-189 (ClinicalTrials.gov,
NCT02578680) enrolled 616 patients who were randomized 2:1 to one
of two treatment groups, and were treated until disease
progression, unacceptable toxicity, physician decision or consent
withdrawal, as follows:
- KEYTRUDA (200 mg fixed dose every three
weeks) plus pemetrexed (500 mg/m2) (with vitamin supplementation)
plus cisplatin (75 mg/m2) or carboplatin AUC 5 mg/mL/min on day 1
every three weeks (Q3W) for four cycles, followed by KEYTRUDA 200
mg plus pemetrexed (500 mg/m2) Q3W; or
- Saline placebo plus pemetrexed (500
mg/m2) (with vitamin supplementation) plus cisplatin (75 mg/m2) or
carboplatin AUC 5 mg/mL/min on day 1 every three weeks (Q3W) for
four cycles, followed by placebo plus pemetrexed (500 mg/m2)
Q3W.
Patients on the control arm who experienced disease progression,
verified by central independent review, were permitted to undergo
treatment assignment unblinding and crossover to receive open-label
KEYTRUDA. The KEYNOTE-189 study was conducted in collaboration with
Eli Lilly and Company, the makers of pemetrexed (ALIMTA).
About Lung CancerLung cancer, which forms in the tissues
of the lungs, usually within cells lining the air passages, is the
leading cause of cancer death worldwide. Each year, more people die
of lung cancer than die of colon, breast and prostate cancers
combined. The two main types of lung cancer are non-small cell and
small cell. NSCLC is the most common type of lung cancer,
accounting for about 85 percent of all cases. The five-year
survival rate for patients diagnosed in the United States with any
stage of lung cancer is estimated to be 18 percent.
Merck Investor WebcastMerck will hold a live investor
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About KEYTRUDA® (pembrolizumab) Injection
100mgKEYTRUDA is an anti-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, which currently involves more than 700 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.
KEYTRUDA (pembrolizumab) Indications and Dosing
MelanomaKEYTRUDA is indicated for the treatment of patients with
unresectable or metastatic melanoma at a fixed dose of 200 mg every
three weeks until disease progression or unacceptable toxicity.
Lung CancerKEYTRUDA, as a single agent, is indicated for the
first-line treatment of patients with metastatic non-small cell
lung cancer (NSCLC) whose tumors have high PD-L1 expression [tumor
proportion score (TPS) ≥50%] as determined by an FDA-approved test,
with no EGFR or ALK genomic tumor aberrations.
KEYTRUDA, as a single agent, is also 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.
KEYTRUDA, in combination with pemetrexed and carboplatin, is
indicated for the first-line treatment of patients with metastatic
nonsquamous NSCLC. This indication is approved under accelerated
approval based on tumor response rate and progression-free
survival. Continued approval for this indication may be contingent
upon verification and description of clinical benefit in the
confirmatory trials.
In metastatic NSCLC, KEYTRUDA is administered at a fixed dose of
200 mg every three weeks until disease progression, unacceptable
toxicity, or up to 24 months in patients without disease
progression.
When administering KEYTRUDA in combination with chemotherapy,
KEYTRUDA should be administered prior to chemotherapy when given on
the same day. See also the Prescribing Information for pemetrexed
and carboplatin.
Head and Neck CancerKEYTRUDA is indicated for the treatment of
patients with recurrent or metastatic head and neck squamous cell
carcinoma (HNSCC) with disease progression on or after
platinum-containing chemotherapy. 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. In HNSCC, KEYTRUDA is administered at a fixed
dose of 200 mg every three weeks until disease progression,
unacceptable toxicity, or up to 24 months in patients without
disease progression.
Classical Hodgkin LymphomaKEYTRUDA is indicated for the
treatment of adult and pediatric patients with refractory classical
Hodgkin lymphoma (cHL), or who have relapsed after three or more
prior lines of therapy. 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. In adults with cHL, KEYTRUDA is administered
at a fixed dose of 200 mg every three weeks until disease
progression or unacceptable toxicity, or up to 24 months in
patients without disease progression. In pediatric patients with
cHL, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum
of 200 mg) every three weeks until disease progression or
unacceptable toxicity, or up to 24 months in patients without
disease progression.
Urothelial CarcinomaKEYTRUDA is indicated for the treatment of
patients with locally advanced or metastatic urothelial carcinoma
who are not eligible for cisplatin-containing chemotherapy. 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 the confirmatory trials.
KEYTRUDA is also indicated for the treatment of patients with
locally advanced or metastatic urothelial carcinoma who have
disease progression during or following platinum-containing
chemotherapy or within 12 months of neoadjuvant or adjuvant
treatment with platinum-containing chemotherapy.
In locally advanced or metastatic urothelial carcinoma, KEYTRUDA
is administered at a fixed dose of 200 mg every three weeks until
disease progression or unacceptable toxicity, or up to 24 months in
patients without disease progression.
Microsatellite Instability-High (MSI-H) CancerKEYTRUDA 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, or
- colorectal cancer that has progressed
following treatment with fluoropyrimidine, oxaliplatin, and
irinotecan.
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.
In adult patients with MSI-H cancer, KEYTRUDA is administered at
a fixed dose of 200 mg every three weeks until disease progression,
unacceptable toxicity, or up to 24 months in patients without
disease progression. In children with MSI-H cancer, KEYTRUDA is
administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every
three weeks until disease progression or unacceptable toxicity, or
up to 24 months in patients without disease progression.
Gastric CancerKEYTRUDA is indicated for the treatment of
patients with recurrent locally advanced or metastatic gastric or
gastroesophageal junction (GEJ) adenocarcinoma whose tumors express
PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an
FDA-approved test, with disease progression on or after two or more
prior lines of therapy including fluoropyrimidine- and
platinum-containing chemotherapy and if appropriate,
HER2/neu-targeted therapy. 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 recommended dose of KEYTRUDA is 200 mg
every three weeks until disease progression, unacceptable toxicity,
or up to 24 months in patients without disease progression.
Selected Important Safety Information for
KEYTRUDA®KEYTRUDA can cause immune-mediated pneumonitis,
including fatal cases. Pneumonitis occurred in 94 (3.4%) of 2799
patients receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3
(0.9%), 4 (0.3%), and 5 (0.1%) pneumonitis, and occurred more
frequently in patients with a history of prior thoracic radiation
(6.9%) compared to those without (2.9%). 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 or recurrent Grade 2
pneumonitis.
KEYTRUDA can cause immune-mediated colitis. Colitis occurred in
48 (1.7%) of 2799 patients receiving KEYTRUDA, including Grade 2
(0.4%), 3 (1.1%), and 4 (<0.1%) colitis. 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.
KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred
in 19 (0.7%) of 2799 patients receiving KEYTRUDA, including Grade 2
(0.1%), 3 (0.4%), and 4 (<0.1%) hepatitis. 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.
KEYTRUDA can cause hypophysitis. Hypophysitis occurred in 17
(0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2
(0.2%), 3 (0.3%), and 4 (<0.1%) hypophysitis. Monitor patients
for signs and symptoms of hypophysitis (including hypopituitarism
and adrenal insufficiency). Administer corticosteroids and hormone
replacement as clinically indicated. Withhold KEYTRUDA for Grade 2;
withhold or discontinue for Grade 3 or 4 hypophysitis.
KEYTRUDA can cause thyroid disorders, including hyperthyroidism,
hypothyroidism, and thyroiditis. Hyperthyroidism occurred in 96
(3.4%) of 2799 patients receiving KEYTRUDA, including Grade 2
(0.8%) and 3 (0.1%) hyperthyroidism. Hypothyroidism occurred in 237
(8.5%) of 2799 patients receiving KEYTRUDA, including Grade 2
(6.2%) and 3 (0.1%) hypothyroidism. The incidence of new or
worsening hypothyroidism was higher in patients with HNSCC,
occurring in 28 (15%) of 192 patients with HNSCC, including Grade 3
(0.5%) hypothyroidism. Thyroiditis occurred in 16 (0.6%) of 2799
patients receiving KEYTRUDA, including Grade 2 (0.3%) thyroiditis.
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 replacement hormones for hypothyroidism and
manage hyperthyroidism with thionamides and beta-blockers as
appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4
hyperthyroidism.
KEYTRUDA can cause type 1 diabetes mellitus, including diabetic
ketoacidosis, which have been reported in 6 (0.2%) of 2799
patients. Monitor patients for hyperglycemia or other signs and
symptoms of diabetes. Administer insulin for type 1 diabetes, and
withhold KEYTRUDA and administer antihyperglycemics in patients
with severe hyperglycemia.
KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred
in 9 (0.3%) of 2799 patients receiving KEYTRUDA, including Grade 2
(0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. 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.
Immune-mediated rashes, including Stevens-Johnson syndrome
(SJS), toxic epidermal necrolysis (TEN) (some cases with fatal
outcome), exfoliative dermatitis, and bullous pemphigoid, can
occur. Monitor patients for suspected severe skin reactions and
based on the severity of the adverse reaction, withhold or
permanently discontinue KEYTRUDA and administer corticosteroids.
For signs or symptoms of SJS or TEN, withhold KEYTRUDA and refer
the patient for specialized care for assessment and treatment. If
SJS or TEN is confirmed, permanently discontinue KEYTRUDA.
KEYTRUDA can cause other clinically important immune-mediated
adverse reactions. These immune-mediated reactions may occur in any
organ system. 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 to Grade
1 or less, initiate corticosteroid taper and continue to taper over
at least 1 month. Based on limited data from clinical studies in
patients whose immune-related adverse reactions could not be
controlled with corticosteroid use, administration of other
systemic immunosuppressants can be considered. Resume KEYTRUDA when
the adverse reaction remains at Grade 1 or less following
corticosteroid taper. Permanently discontinue KEYTRUDA for any
Grade 3 immune-mediated adverse reaction that recurs and for any
life-threatening immune-mediated adverse reaction.
The following clinically significant immune-mediated adverse
reactions occurred in less than 1% (unless otherwise indicated) of
2799 patients: arthritis (1.5%), uveitis, myositis, Guillain-Barré
syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic
anemia, and partial seizures arising in a patient with inflammatory
foci in brain parenchyma. In addition, myelitis and myocarditis
were reported in other clinical trials, including classical Hodgkin
lymphoma, and postmarketing use.
Solid organ transplant rejection has been reported in
postmarketing use of KEYTRUDA. Treatment with KEYTRUDA may increase
the risk of rejection in solid organ transplant recipients.
Consider the benefit of treatment with KEYTRUDA vs the risk of
possible organ rejection in these patients.
KEYTRUDA can cause severe or life-threatening infusion-related
reactions, including hypersensitivity and anaphylaxis, which have
been reported in 6 (0.2%) of 2799 patients. Monitor patients for
signs and symptoms of infusion-related reactions, including rigors,
chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia,
and fever. For Grade 3 or 4 reactions, stop infusion and
permanently discontinue KEYTRUDA.
Immune-mediated complications, including fatal events, occurred
in patients who underwent allogeneic hematopoietic stem cell
transplantation (HSCT) after being treated with KEYTRUDA. Of 23
patients with cHL who proceeded to allogeneic HSCT after treatment
with KEYTRUDA on any trial, 6 patients (26%) developed
graft-versus-host disease (GVHD), one of which was fatal, and 2
patients (9%) developed severe hepatic veno-occlusive disease (VOD)
after reduced-intensity conditioning, one of which was fatal. Cases
of fatal hyperacute GVHD after allogeneic HSCT have also been
reported in patients with lymphoma who received a PD-1
receptor–blocking antibody before transplantation.
These complications may occur despite intervening therapy
between PD-1 blockade and allogeneic HSCT. Follow patients closely
for early evidence of transplant-related complications such as
hyperacute GVHD, severe (Grade 3 to 4) acute GVHD,
steroid-requiring febrile syndrome, hepatic VOD, and other
immune-mediated adverse reactions, and intervene promptly.
In clinical 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 a
PD-1 or PD-L1 blocking antibody in this combination is not
recommended outside of controlled clinical trials.
Based on its mechanism of action, KEYTRUDA can 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.
In KEYNOTE-006, KEYTRUDA was discontinued due to adverse
reactions in 9% of 555 patients with advanced melanoma; adverse
reactions leading to 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%). Adverse
reactions leading to interruption of KEYTRUDA occurred in 21% of
patients; the most common (≥1%) was diarrhea (2.5%). The most
common adverse reactions with KEYTRUDA vs ipilimumab were fatigue
(28% vs 28%), diarrhea (26% with KEYTRUDA), rash (24% vs 23%), and
nausea (21% with KEYTRUDA). Corresponding incidence rates are
listed for ipilimumab only for those adverse reactions that
occurred at the same or lower rate than with KEYTRUDA.
In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to
adverse reactions in 8% of 682 patients with metastatic NSCLC. The
most common adverse event resulting in permanent discontinuation of
KEYTRUDA was pneumonitis (1.8%). Adverse reactions leading to
interruption of KEYTRUDA occurred in 23% of patients; the most
common (≥1%) were diarrhea (1%), fatigue (1.3%), pneumonia (1%),
liver enzyme elevation (1.2%), decreased appetite (1.3%), and
pneumonitis (1%). The most common adverse reactions (occurring in
at least 20% of patients and at a higher incidence than with
docetaxel) were decreased appetite (25% vs 23%), dyspnea (23% vs
20%), and nausea (20% vs 18%).
In KEYNOTE-021(G1), when KEYTRUDA was administered in
combination with carboplatin and pemetrexed (carbo/pem) in advanced
nonsquamous NSCLC, KEYTRUDA was discontinued in 10% of 59 patients.
The most common adverse reaction resulting in discontinuation of
KEYTRUDA (≥2%) was acute kidney injury (3.4%). Adverse reactions
leading to interruption of KEYTRUDA occurred in 39% of patients;
the most common (≥2%) were fatigue (8%), neutrophil count decreased
(8%), anemia (5%), dyspnea (3.4%), and pneumonitis (3.4%). The most
common adverse reactions (≥20%) with KEYTRUDA compared to carbo/pem
alone were fatigue (71% vs 50%), nausea (68% vs 56%), constipation
(51% vs 37%), rash (42% vs 21%), vomiting (39% vs 27%), dyspnea
(39% vs 21%), diarrhea (37% vs 23%), decreased appetite (31% vs
23%), headache (31% vs 16%), cough (24% vs 18%), dizziness (24% vs
16%), insomnia (24% vs 15%), pruritus (24% vs 4.8%), peripheral
edema (22% vs 18%), dysgeusia (20% vs 11%), alopecia (20% vs 3.2%),
upper respiratory tract infection (20% vs 3.2%), and arthralgia
(15% vs 24%). This study was not designed to demonstrate a
statistically significant difference in adverse reaction rates for
KEYTRUDA as compared to carbo/pem alone for any specified adverse
reaction.
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
(reported in at least 20% of patients) 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, with the exception of increased incidences of
facial edema (10% all Grades; 2.1% Grades 3 or 4) and new or
worsening hypothyroidism.
In KEYNOTE-087, KEYTRUDA was discontinued due to adverse
reactions in 5% of 210 patients with cHL, and treatment was
interrupted due to adverse reactions in 26% of patients. Fifteen
percent (15%) of patients had an adverse reaction requiring
systemic corticosteroid therapy. Serious adverse reactions occurred
in 16% of patients. The most frequent serious adverse reactions
(≥1%) included pneumonia, pneumonitis, pyrexia, dyspnea, GVHD, and
herpes zoster. Two patients died from causes other than disease
progression; one from GVHD after subsequent allogeneic HSCT and one
from septic shock. The most common adverse reactions (occurring in
≥20% of patients) were fatigue (26%), pyrexia (24%), cough (24%),
musculoskeletal pain (21%), diarrhea (20%), and rash (20%).
In KEYNOTE-052, KEYTRUDA was discontinued due to adverse
reactions in 11% of 370 patients with locally advanced or
metastatic urothelial carcinoma. The most common adverse reactions
(in ≥20% of patients) were fatigue (38%), musculoskeletal pain
(24%), decreased appetite (22%), constipation (21%), rash (21%),
and diarrhea (20%). Eighteen patients (5%) died from causes other
than disease progression. Five patients (1.4%) who were treated
with KEYTRUDA experienced sepsis which led to death, and 3 patients
(0.8%) experienced pneumonia which led to death. Adverse reactions
leading to interruption of KEYTRUDA occurred in 22% of patients;
the most common (≥1%) were liver enzyme increase, diarrhea, urinary
tract infection, acute kidney injury, fatigue, joint pain, and
pneumonia. Serious adverse reactions occurred in 42% of patients,
the most frequent (≥2%) of which were urinary tract infection,
hematuria, acute kidney injury, pneumonia, and urosepsis.
In KEYNOTE-045, KEYTRUDA was discontinued due to adverse
reactions in 8% of 266 patients with locally advanced or metastatic
urothelial carcinoma. The most common adverse reaction resulting in
permanent discontinuation of KEYTRUDA was pneumonitis (1.9%).
Adverse reactions leading to interruption of KEYTRUDA occurred in
20% of patients; the most common (≥1%) were urinary tract infection
(1.5%), diarrhea (1.5%), and colitis (1.1%). The most common
adverse reactions (≥20%) in patients who received KEYTRUDA vs those
who received chemotherapy were fatigue (38% vs 56%),
musculoskeletal pain (32% vs 27%), pruritus (23% vs 6%), decreased
appetite (21% vs 21%), nausea (21% vs 29%), and rash (20% vs 13%).
Serious adverse reactions occurred in 39% of KEYTRUDA-treated
patients, the most frequent (≥2%) of which were urinary tract
infection, pneumonia, anemia, and pneumonitis.
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 and for 4 months
after the final dose.
There is limited experience in pediatric patients. In a study,
40 pediatric patients (16 children aged 2 years to younger than 12
years and 24 adolescents aged 12 years to 18 years) with advanced
melanoma, lymphoma, or PD-L1–positive advanced, relapsed, or
refractory solid tumors were administered KEYTRUDA 2 mg/kg every 3
weeks. Patients received KEYTRUDA for a median of 3 doses (range
1–17 doses), with 34 patients (85%) receiving KEYTRUDA for 2 doses
or more. The safety profile in these pediatric patients was similar
to that seen in adults treated with KEYTRUDA. Toxicities that
occurred at a higher rate (≥15% difference) in these patients when
compared to adults under 65 years of age were fatigue (45%),
vomiting (38%), abdominal pain (28%), hypertransaminasemia (28%),
and hyponatremia (18%).
Merck’s Focus on CancerOur goal is to translate
breakthrough science into innovative oncology medicines to help
people with cancer worldwide. At Merck, helping people fight cancer
is our passion and supporting accessibility to our cancer medicines
is our commitment. Our focus is on pursuing research in
immuno-oncology and we are accelerating every step in the journey –
from lab to clinic – to potentially bring new hope to people with
cancer.
As part of our focus on cancer, Merck is committed to exploring
the potential of immuno-oncology with one of the fastest-growing
development programs in the industry. We are currently executing an
expansive research program evaluating our anti-PD-1 therapy across
more than 30 tumor types. We also continue to strengthen our
immuno-oncology portfolio through strategic acquisitions and are
prioritizing the development of several promising immunotherapeutic
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 MerckFor more than a century, Merck, a leading
global biopharmaceutical company 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. Through our prescription medicines, vaccines, biologic
therapies and animal health products, we work with customers and
operate in more than 140 countries to deliver innovative health
solutions. We also demonstrate our commitment to increasing access
to health care through far-reaching policies, programs and
partnerships. Today, Merck continues to be at the forefront of
research to advance the prevention and treatment of diseases that
threaten people and communities around the world - including
cancer, cardio-metabolic diseases, emerging animal diseases,
Alzheimer’s disease and infectious diseases including HIV and
Ebola. For more information, visit www.merck.com
and connect with us
on Twitter, Facebook, Instagram, YouTube
and LinkedIn.
Forward-Looking Statement of Merck & Co., Inc.,
Kenilworth, N.J., USAThis 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 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 2017
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).
Please see Prescribing Information for KEYTRUDA at
https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf
andPatient Information/Medication Guide for KEYTRUDA
at
https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_mg.pdf.
ALIMTA® is a registered trademark of Eli Lilly and
Company.
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version on businesswire.com: https://www.businesswire.com/news/home/20180416005456/en/
MerckMedia:Pamela Eisele, 267-305-3558orKristen Drake,
908-334-4688orInvestors:Teri Loxam, 908-740-1986orMichael DeCarbo,
908-740-1807
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