This approval marks the fourth non-small
cell lung cancer (NSCLC) indication and the first indication in
earlier stages of NSCLC for KEYTRUDA in China
Merck (NYSE: MRK), known as MSD outside of the United States and
Canada, today announced KEYTRUDA, Merck’s anti-PD-1 therapy, has
been approved by the National Medical Products Administration
(NMPA) in China in combination with platinum-containing
chemotherapy as neoadjuvant treatment and then continued as
monotherapy as adjuvant treatment after surgery for patients with
resectable stage II, IIIA, or IIIB non-small cell lung cancer
(NSCLC).
“While there have been several advances in the treatment of
metastatic lung cancer over the past decade, lung cancer continues
to be the leading cause of cancer death in China,” said Dr. Heather
Wakelee, principal investigator for KEYNOTE-671, thoracic medical
oncologist and professor of medicine at Stanford University and
past president of the International Association for the Study of
Lung Cancer (IASLC). “This approval represents an important moment
for certain patients with resectable NSCLC in China, providing a
new option that has been shown in the KEYNOTE-671 study to
significantly improve overall survival in these patients.”
In October 2023, KEYTRUDA in combination with
platinum-containing chemotherapy as neoadjuvant treatment, then
continued as a single agent as adjuvant treatment for patients with
stage II, IIIA or IIIB NSCLC was approved in the U.S. based on
results from the KEYNOTE-671 trial. KEYTRUDA plus chemotherapy in
the neoadjuvant setting followed by KEYTRUDA as monotherapy after
surgical resection significantly improved overall survival (OS),
reducing the risk of death by 28% (HR=0.72 [95% CI, 0.56-0.93];
one-sided p=0.0103) in patients with NSCLC, regardless of PD-L1
expression, versus placebo plus chemotherapy in the neoadjuvant
setting followed by placebo after surgical resection. For patients
who received the KEYTRUDA-based regimen, median OS was not reached
(95% CI, NR-NR) versus 52.4 months (95% CI, 45.7-NR) for patients
who received the chemotherapy-placebo regimen. The KEYTRUDA-based
regimen also improved event-free survival (EFS), reducing the risk
of disease recurrence, progression or death by 42% (HR=0.58 [95%
CI, 0.46-0.72]; p<0.0001) compared to the chemotherapy-placebo
regimen. Adverse reactions occurring in patients with resectable
NSCLC receiving KEYTRUDA in combination with platinum-containing
chemotherapy, given as neoadjuvant treatment and continued as
single agent adjuvant treatment after surgery, were generally
similar to those occurring in patients across tumor types receiving
KEYTRUDA in combination with chemotherapy.
This milestone builds on the momentum for worldwide approvals
for KEYTRUDA in the perioperative setting for certain patients with
earlier stages of NSCLC, including the European Union and
Japan.
“This approval marks KEYTRUDA’s fourth lung cancer indication in
China, embarking on a new journey of treating certain patients with
earlier stage non-small cell lung cancer,” said Anna Van Acker,
Senior Vice President of MSD and President of MSD in China.
“KEYTRUDA has established an important role in immunotherapy for
advanced NSCLC with its three previously approved indications in
China, but there are still significant unmet medical needs for
certain patients with earlier stage NSCLC, as lung cancer remains
China's leading cause of cancer incidence and mortality. We are
thrilled to introduce this new treatment option and remain
committed to advancing innovation to help more Chinese
patients.”
About the KEYNOTE-671 study design
KEYNOTE-671 is a randomized, double-blind Phase 3 trial
(ClinicalTrials.gov, NCT03425643) evaluating KEYTRUDA in
combination with neoadjuvant chemotherapy, followed by surgery and
continued adjuvant treatment with KEYTRUDA as a single agent,
versus placebo plus neoadjuvant chemotherapy, followed by resection
and adjuvant placebo, in patients with resectable stage II, IIIA or
IIIB (T3-4N2) NSCLC (per the eight edition of the American Joint
Committee on Cancer [AJCC] Cancer Staging Manual). The trial’s dual
primary endpoints are EFS, per RECIST v1.1 by investigator
assessment, and OS. Key secondary endpoints include pathologic
complete response (pCR) and major pathological response (mPR). The
study enrolled 797 patients who were randomly assigned (1:1) to
receive either:
- KEYTRUDA (200 mg intravenously [IV] every three weeks [Q3W])
plus chemotherapy (cisplatin [75 mg/m2, IV; given on Day 1 of each
cycle] and either gemcitabine [1,000 mg/m2, IV; given on Days 1 and
8 of each cycle] or pemetrexed [500 mg/m2, IV; given on Day 1 of
each cycle]) for up to four cycles as neoadjuvant therapy prior to
surgery. Within 4-12 weeks following surgery, KEYTRUDA (200 mg) was
administered every three weeks for up to 13 cycles, or;
- Placebo (saline IV Q3W) plus chemotherapy (cisplatin [75 mg/m2,
IV; given on Day 1 of each cycle] and either gemcitabine [1,000
mg/m2, IV; given on Days 1 and 8 of each cycle] or pemetrexed [500
mg/m2, IV; given on Day 1 of each cycle]) for up to four cycles as
neoadjuvant therapy prior to surgery. Within 4‑12 weeks following
surgery, placebo was administered every three weeks for up to 13
cycles.
About lung cancer
Lung cancer is the leading cause of cancer death worldwide. In
2022, there were approximately 2.4 million new cases and 1.8
million deaths from lung cancer globally. In China alone, there
were more than one million new cases and about 733,200 deaths from
lung cancer in 2022. Patients diagnosed with lung cancer in China
have historically faced poor outcomes, as the five-year survival
rate for patients diagnosed with lung cancer in China is only
19.7%. Improving lung cancer survival remains an important goal in
China, as the Healthy China 2030 Planning Outline aims to increase
cancer’s overall five-year survival rate to 46.6%. Non-small cell
lung cancer is the most common type of lung cancer, accounting for
about 80% of all cases.
About Merck’s early-stage cancer clinical program
Finding cancer at an earlier stage may give patients a greater
chance of long-term survival. Many cancers are considered most
treatable and potentially curable in their earliest stage of
disease. Building on the strong understanding of the role of
KEYTRUDA in later-stage cancers, Merck is studying KEYTRUDA in
earlier disease states, with approximately 25 ongoing
registrational studies across multiple types of cancer.
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 1,600 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.
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.
KEYTRUDA is indicated for the treatment of patients with
resectable (tumors ≥4 cm or node positive) NSCLC in combination
with platinum-containing chemotherapy as neoadjuvant treatment, and
then continued as a single agent as adjuvant treatment after
surgery.
KEYTRUDA, as a single agent, is indicated as adjuvant treatment
following resection and platinum-based chemotherapy for adult
patients with Stage IB (T2a ≥4 cm), II, or IIIA NSCLC.
See additional selected KEYTRUDA indications in the U.S. after
the Selected Important Safety Information.
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 programmed death receptor-1 (PD-1) or
the programmed death ligand 1 (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.
Pneumonitis occurred in 7% (41/580) of adult patients with
resected NSCLC who received KEYTRUDA as a single agent for adjuvant
treatment of NSCLC, including fatal (0.2%), Grade 4 (0.3%), and
Grade 3 (1%) adverse reactions. Patients received high-dose
corticosteroids for a median duration of 10 days (range: 1 day to
2.3 months). Pneumonitis led to discontinuation of KEYTRUDA in 26
(4.5%) of patients. Of the patients who developed pneumonitis, 54%
interrupted KEYTRUDA, 63% discontinued KEYTRUDA, and 71% 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 (ALT) (20%) and increased
aspartate aminotransferase (AST) (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. The incidence of new or
worsening hyperthyroidism was higher in 580 patients with resected
NSCLC, occurring in 11% of patients receiving KEYTRUDA as a single
agent as adjuvant treatment, including Grade 3 (0.2%)
hyperthyroidism. The incidence of new or worsening hypothyroidism
was higher in 580 patients with resected NSCLC, occurring in 22% of
patients receiving KEYTRUDA as a single agent as adjuvant treatment
(KEYNOTE-091), including Grade 3 (0.3%) 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, other
transplant (including corneal graft) 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 treatments.
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 treatments 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, when KEYTRUDA was administered as a single agent
to patients with stage III melanoma, 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-716, when
KEYTRUDA was administered as a single agent to patients with stage
IIB or IIC melanoma, adverse reactions occurring in patients with
stage IIB or IIC melanoma were similar to those occurring in 1011
patients with stage III melanoma from KEYNOTE-054.
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-671, adverse reactions occurring in patients with
resectable NSCLC receiving KEYTRUDA in combination with
platinum-containing chemotherapy, given as neoadjuvant treatment
and continued as single-agent adjuvant treatment, were generally
similar to those occurring in patients in other clinical trials
across tumor types receiving KEYTRUDA in combination with
chemotherapy.
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, insomnia,
palmar-plantar erythrodysesthesia, urinary tract infection, and
hypothyroidism.
In the neoadjuvant phase of KEYNOTE-671, when KEYTRUDA was
administered in combination with platinum-containing chemotherapy
as neoadjuvant treatment, serious adverse reactions occurred in 34%
of 396 patients. The most frequent (≥2%) serious adverse reactions
were pneumonia (4.8%), venous thromboembolism (3.3%), and anemia
(2%). Fatal adverse reactions occurred in 1.3% of patients,
including death due to unknown cause (0.8%), sepsis (0.3%), and
immune-mediated lung disease (0.3%). Permanent discontinuation of
any study drug due to an adverse reaction occurred in 18% of
patients who received KEYTRUDA in combination with
platinum-containing chemotherapy; the most frequent adverse
reactions (≥1%) that led to permanent discontinuation of any study
drug were acute kidney injury (1.8%), interstitial lung disease
(1.8%), anemia (1.5%), neutropenia (1.5%), and pneumonia
(1.3%).
Of the KEYTRUDA-treated patients who received neoadjuvant
treatment, 6% of 396 patients did not receive surgery due to
adverse reactions. The most frequent (≥1%) adverse reaction that
led to cancellation of surgery in the KEYTRUDA arm was interstitial
lung disease (1%).
In the adjuvant phase of KEYNOTE-671, when KEYTRUDA was
administered as a single agent as adjuvant treatment, serious
adverse reactions occurred in 14% of 290 patients. The most
frequent serious adverse reaction was pneumonia (3.4%). One fatal
adverse reaction of pulmonary hemorrhage occurred. Permanent
discontinuation of KEYTRUDA due to an adverse reaction occurred in
12% of patients who received KEYTRUDA as a single agent, given as
adjuvant treatment; the most frequent adverse reactions (≥1%) that
led to permanent discontinuation of KEYTRUDA were diarrhea (1.7%),
interstitial lung disease (1.4%), increased aspartate
aminotransferase (1%), and musculoskeletal pain (1%).
Adverse reactions observed in KEYNOTE-091 were generally similar
to those occurring in other patients with NSCLC receiving KEYTRUDA
as a single agent, with the exception of hypothyroidism (22%),
hyperthyroidism (11%), and pneumonitis (7%). Two fatal adverse
reactions of myocarditis occurred.
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-A39, when KEYTRUDA was administered in combination
with enfortumab vedotin to patients with locally advanced or
metastatic urothelial cancer (n=440), fatal adverse reactions
occurred in 3.9% of patients, including acute respiratory failure
(0.7%), pneumonia (0.5%), and pneumonitis/ILD (0.2%). Serious
adverse reactions occurred in 50% of patients receiving KEYTRUDA in
combination with enfortumab vedotin; the serious adverse reactions
in ≥2% of patients were rash (6%), acute kidney injury (5%),
pneumonitis/ILD (4.5%), urinary tract infection (3.6%), diarrhea
(3.2%), pneumonia (2.3%), pyrexia (2%), and hyperglycemia (2%).
Permanent discontinuation of KEYTRUDA occurred in 27% of patients.
The most common adverse reactions (≥2%) resulting in permanent
discontinuation of KEYTRUDA were pneumonitis/ILD (4.8%) and rash
(3.4%). The most common adverse reactions (≥20%) occurring in
patients treated with KEYTRUDA in combination with enfortumab
vedotin were rash (68%), peripheral neuropathy (67%), fatigue
(51%), pruritus (41%), diarrhea (38%), alopecia (35%), weight loss
(33%), decreased appetite (33%), nausea (26%), constipation (26%),
dry eye (24%), dysgeusia (21%), and urinary tract infection
(21%).
In KEYNOTE-052, KEYTRUDA was discontinued due to adverse
reactions in 11% of 370 patients with locally advanced or
metastatic urothelial carcinoma. 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 metastatic
urothelial carcinoma. 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-158 and KEYNOTE-164, adverse reactions occurring in
patients with MSI-H or dMMR cancer were similar to those occurring
in patients with other solid tumors who received KEYTRUDA as a
single agent.
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 vs placebo, there was a difference of
≥5% incidence between patients treated with KEYTRUDA vs standard of
care for diarrhea (53% vs 44%) and nausea (49% vs 44%).
In KEYNOTE-859, when KEYTRUDA was administered in combination
with fluoropyrimidine- and platinum-containing chemotherapy,
serious adverse reactions occurred in 45% of 785 patients. Serious
adverse reactions in >2% of patients included pneumonia (4.1%),
diarrhea (3.9%), hemorrhage (3.9%), and vomiting (2.4%). Fatal
adverse reactions occurred in 8% of patients who received KEYTRUDA,
including infection (2.3%) and thromboembolism (1.3%). KEYTRUDA was
permanently discontinued due to adverse reactions in 15% of
patients. The most common adverse reactions resulting in permanent
discontinuation of KEYTRUDA (≥1%) were infections (1.8%) and
diarrhea (1.0%). The most common adverse reactions (reported in
≥20%) in patients receiving KEYTRUDA in combination with
chemotherapy were peripheral neuropathy (47%), nausea (46%),
fatigue (40%), diarrhea (36%), vomiting (34%), decreased appetite
(29%), abdominal pain (26%), palmar-plantar erythrodysesthesia
syndrome (25%), constipation (22%), and weight loss (20%).
In KEYNOTE-590, when KEYTRUDA was administered with cisplatin
and fluorouracil 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-A18, when KEYTRUDA was administered with CRT
(cisplatin plus external beam radiation therapy [EBRT] followed by
brachytherapy [BT]) to patients with FIGO 2014 Stage III-IVA
cervical cancer, fatal adverse reactions occurred in 1.4% of 292
patients, including 1 case each (0.3%) of large intestinal
perforation, urosepsis, sepsis, and vaginal hemorrhage. Serious
adverse reactions occurred in 30% of patients; those ≥1% included
urinary tract infection (2.7%), urosepsis (1.4%), and sepsis (1%).
KEYTRUDA was discontinued for adverse reactions in 7% of patients.
The most common adverse reaction (≥1%) resulting in permanent
discontinuation was diarrhea (1%). For patients treated with
KEYTRUDA in combination with CRT, the most common adverse reactions
(≥10%) were nausea (56%), diarrhea (50%), vomiting (33%), urinary
tract infection (32%), fatigue (26%), hypothyroidism (20%),
constipation (18%), decreased appetite and weight loss (17% each),
abdominal pain and pyrexia (12% each), hyperthyroidism, dysuria,
rash (11% each), and pelvic pain (10%).
In KEYNOTE-826, when KEYTRUDA was administered in combination
with paclitaxel and cisplatin or paclitaxel and carboplatin, with
or without bevacizumab (n=307), to patients with persistent,
recurrent, or first-line metastatic cervical cancer regardless of
tumor PD-L1 expression who had not been treated with chemotherapy
except when used concurrently as a radio-sensitizing agent, fatal
adverse reactions occurred in 4.6% of patients, including 3 cases
of hemorrhage, 2 cases each of sepsis and due to unknown causes,
and 1 case each of acute myocardial infarction, autoimmune
encephalitis, cardiac arrest, cerebrovascular accident, femur
fracture with perioperative pulmonary embolus, intestinal
perforation, and pelvic infection. Serious adverse reactions
occurred in 50% of patients receiving KEYTRUDA in combination with
chemotherapy with or without bevacizumab; those ≥3% were febrile
neutropenia (6.8%), urinary tract infection (5.2%), anemia (4.6%),
and acute kidney injury and sepsis (3.3% each).
KEYTRUDA was discontinued in 15% of patients due to adverse
reactions. The most common adverse reaction resulting in permanent
discontinuation (≥1%) was colitis (1%).
For patients treated with KEYTRUDA, chemotherapy, and
bevacizumab (n=196), the most common adverse reactions (≥20%) were
peripheral neuropathy (62%), alopecia (58%), anemia (55%),
fatigue/asthenia (53%), nausea and neutropenia (41% each), diarrhea
(39%), hypertension and thrombocytopenia (35% each), constipation
and arthralgia (31% each), vomiting (30%), urinary tract infection
(27%), rash (26%), leukopenia (24%), hypothyroidism (22%), and
decreased appetite (21%).
For patients treated with KEYTRUDA in combination with
chemotherapy with or without bevacizumab, the most common adverse
reactions (≥20%) were peripheral neuropathy (58%), alopecia (56%),
fatigue (47%), nausea (40%), diarrhea (36%), constipation (28%),
arthralgia (27%), vomiting (26%), hypertension and urinary tract
infection (24% each), and rash (22%).
In KEYNOTE-158, KEYTRUDA was discontinued due to adverse
reactions in 8% of 98 patients with previously treated 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%).
In KEYNOTE-394, KEYTRUDA was discontinued due to adverse
reactions in 13% of 299 patients with previously treated
hepatocellular carcinoma. The most common adverse reaction
resulting in permanent discontinuation of KEYTRUDA was ascites
(2.3%). The most common adverse reactions in patients receiving
KEYTRUDA (≥10%) were pyrexia (18%), rash (18%), diarrhea (16%),
decreased appetite (15%), pruritus (12%), upper respiratory tract
infection (11%), cough (11%), and hypothyroidism (10%).
In KEYNOTE-966, when KEYTRUDA was administered in combination
with gemcitabine and cisplatin, KEYTRUDA was discontinued for
adverse reactions in 15% of 529 patients with locally advanced
unresectable or metastatic biliary tract cancer. The most common
adverse reaction resulting in permanent discontinuation of KEYTRUDA
(≥1%) was pneumonitis (1.3%). Adverse reactions leading to the
interruption of KEYTRUDA occurred in 55% of patients. The most
common adverse reactions or laboratory abnormalities leading to
interruption of KEYTRUDA (≥2%) were decreased neutrophil count
(18%), decreased platelet count (10%), anemia (6%), decreased white
blood cell count (4%), pyrexia (3.8%), fatigue (3.0%), cholangitis
(2.8%), increased ALT (2.6%), increased AST (2.5%), and biliary
obstruction (2.3%).
In KEYNOTE-017 and KEYNOTE-913, adverse reactions occurring in
patients with MCC (n=105) were generally similar to those occurring
in patients with melanoma or NSCLC who received KEYTRUDA as a
single agent.
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-564, when KEYTRUDA was administered as a single agent
for the adjuvant treatment of renal cell carcinoma, serious adverse
reactions occurred in 20% of patients receiving KEYTRUDA; the
serious adverse reactions (≥1%) were acute kidney injury, adrenal
insufficiency, pneumonia, colitis, and diabetic ketoacidosis (1%
each). Fatal adverse reactions occurred in 0.2% including 1 case of
pneumonia. Discontinuation of KEYTRUDA due to adverse reactions
occurred in 21% of 488 patients; the most common (≥1%) were
increased ALT (1.6%), colitis (1%), and adrenal insufficiency (1%).
The most common adverse reactions (≥20%) were musculoskeletal pain
(41%), fatigue (40%), rash (30%), diarrhea (27%), pruritus (23%),
and hypothyroidism (21%).
In KEYNOTE-868, when KEYTRUDA was administered in combination
with chemotherapy (paclitaxel and carboplatin) to patients with
advanced or recurrent endometrial carcinoma (n=382), serious
adverse reactions occurred in 35% of patients receiving KEYTRUDA in
combination with chemotherapy, compared to 19% of patients
receiving placebo in combination with chemotherapy (n=377). Fatal
adverse reactions occurred in 1.6% of patients receiving KEYTRUDA
in combination with chemotherapy, including COVID-19 (0.5%) and
cardiac arrest (0.3%). KEYTRUDA was discontinued for an adverse
reaction in 14% of patients. Adverse reactions occurring in
patients treated with KEYTRUDA and chemotherapy were generally
similar to those observed with KEYTRUDA alone or chemotherapy
alone, with the exception of rash (33% all Grades; 2.9% Grades
3-4).
Adverse reactions occurring in patients with MSI-H or dMMR
endometrial carcinoma who received KEYTRUDA as a single agent were
similar to those occurring in patients with melanoma or NSCLC who
received KEYTRUDA as a single agent.
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 last dose.
Pediatric Use
In KEYNOTE-051, 173 pediatric patients (65 pediatric patients
aged 6 months to younger than 12 years and 108 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 25 months).
Adverse reactions that occurred at a ≥10% higher rate in
pediatric patients when compared to adults were pyrexia (33%),
leukopenia (30%), vomiting (29%), neutropenia (28%), headache
(25%), abdominal pain (23%), thrombocytopenia (22%), Grade 3 anemia
(17%), decreased lymphocyte count (13%), and decreased white blood
cell count (11%).
Geriatric Use
Of the 564 patients with locally advanced or metastatic
urothelial cancer treated with KEYTRUDA in combination with
enfortumab vedotin, 44% (n=247) were 65-74 years and 26% (n=144)
were 75 years or older. No overall differences in safety or
effectiveness were observed between patients 65 years of age or
older and younger patients. Patients 75 years of age or older
treated with KEYTRUDA in combination with enfortumab vedotin
experienced a higher incidence of fatal adverse reactions than
younger patients. The incidence of fatal adverse reactions was 4%
in patients younger than 75 and 7% in patients 75 years or
older.
Additional Selected KEYTRUDA 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 adult and
pediatric (12 years and older) patients with Stage IIB, IIC, or III
melanoma following complete resection.
Malignant Pleural Mesothelioma
KEYTRUDA, in combination with pemetrexed and platinum
chemotherapy, is indicated for the first-line treatment of adult
patients with unresectable advanced or metastatic malignant pleural
mesothelioma (MPM).
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 Cancer
KEYTRUDA, in combination with enfortumab vedotin, is indicated
for the treatment of adult patients with locally advanced or
metastatic urothelial cancer.
KEYTRUDA, as a single agent, is indicated for the treatment of
patients with locally advanced or metastatic urothelial
carcinoma:
- who are not eligible for any platinum-containing chemotherapy,
or
- who have disease progression during or following
platinum-containing chemotherapy or within 12 months of neoadjuvant
or adjuvant treatment with platinum-containing chemotherapy.
KEYTRUDA, as a single agent, is indicated for the treatment of
patients with Bacillus Calmette-Guerin (BCG)-unresponsive,
high-risk, non-muscle invasive bladder cancer (NMIBC) with
carcinoma in situ (CIS) 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, as determined by an FDA-approved test, that have progressed
following prior treatment and who have no satisfactory alternative
treatment options.
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) as
determined by an FDA-approved test.
Gastric Cancer
KEYTRUDA, in combination with trastuzumab, fluoropyrimidine- and
platinum-containing chemotherapy, is indicated for the first-line
treatment of adults with locally advanced unresectable or
metastatic HER2-positive gastric or gastroesophageal junction (GEJ)
adenocarcinoma 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
of this indication may be contingent upon verification and
description of clinical benefit in the confirmatory trials.
KEYTRUDA, in combination with fluoropyrimidine- and
platinum-containing chemotherapy, is indicated for the first-line
treatment of adults with locally advanced unresectable or
metastatic HER2-negative gastric or gastroesophageal junction (GEJ)
adenocarcinoma.
Esophageal Cancer
KEYTRUDA is indicated for the treatment of patients with locally
advanced or metastatic esophageal or gastroesophageal junction
(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, in combination with chemoradiotherapy (CRT), is
indicated for the treatment of patients with FIGO 2014 Stage
III-IVA cervical cancer.
KEYTRUDA, in combination with chemotherapy, with or without
bevacizumab, is indicated for the treatment of patients with
persistent, recurrent, or metastatic cervical cancer whose tumors
express PD-L1 (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 cervical cancer with disease
progression on or after chemotherapy whose tumors express PD-L1
(CPS ≥1) as determined by an FDA-approved test.
Hepatocellular Carcinoma
KEYTRUDA is indicated for the treatment of patients with
hepatocellular carcinoma (HCC) secondary to hepatitis B who have
received prior systemic therapy other than a PD-1/PD-L1-containing
regimen.
Biliary Tract Cancer
KEYTRUDA, in combination with gemcitabine and cisplatin, is
indicated for the treatment of patients with locally advanced
unresectable or metastatic biliary tract cancer (BTC).
Merkel Cell Carcinoma
KEYTRUDA is indicated for the treatment of adult and pediatric
patients with recurrent locally advanced or metastatic Merkel cell
carcinoma (MCC).
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 is indicated for the adjuvant treatment of patients
with RCC at intermediate-high or high risk of recurrence following
nephrectomy, or following nephrectomy and resection of metastatic
lesions.
Endometrial Carcinoma
KEYTRUDA, in combination with carboplatin and paclitaxel,
followed by KEYTRUDA as a single agent, is indicated for the
treatment of adult patients with primary advanced or recurrent
endometrial carcinoma.
KEYTRUDA, as a single agent, is indicated for the treatment of
adult patients with advanced endometrial carcinoma that is MSI-H or
dMMR, as determined by an FDA-approved test, who have disease
progression following prior systemic therapy in any setting 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 (mut/Mb)] 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 triple-negative breast cancer (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.
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Every day, we follow the science as we work to discover
innovations that can help patients, no matter what stage of cancer
they have. As a leading oncology company, we are pursuing research
where scientific opportunity and medical need converge, underpinned
by our diverse pipeline of more than 25 novel mechanisms. With one
of the largest clinical development programs across more than 30
tumor types, we strive to advance breakthrough science that will
shape the future of oncology. By addressing barriers to clinical
trial participation, screening and treatment, we work with urgency
to reduce disparities and help ensure patients have access to
high-quality cancer care. Our unwavering commitment is what will
bring us closer to our goal of bringing life to more patients with
cancer. For more information, visit
www.merck.com/clinicaltrials.
About Merck’s research in lung cancer
Merck is advancing research aimed at transforming the way lung
cancer is treated, with a goal of improving outcomes for patients
affected by this deadly disease. Through nearly 200 clinical trials
evaluating more than 36,000 patients around the world, Merck is at
the forefront of lung cancer research. In NSCLC, KEYTRUDA has six
approved U.S. indications and is approved for advanced disease in
more than 95 countries. Among Merck’s research efforts are trials
focused on evaluating KEYTRUDA in earlier stages of lung cancer as
well as identifying new combinations and coformulations with
KEYTRUDA.
About Merck
At Merck, known as MSD outside of the United States and Canada,
we are unified around our purpose: We use the power of leading-edge
science to save and improve lives around the world. For more than
130 years, we have brought hope to humanity through the development
of important medicines and vaccines. We aspire to be the premier
research-intensive biopharmaceutical company in the world – and
today, we are at the forefront of research to deliver innovative
health solutions that advance the prevention and treatment of
diseases in people and animals. We foster a diverse and inclusive
global workforce and operate responsibly every day to enable a
safe, sustainable and healthy future for all people and
communities. For more information, visit www.merck.com and connect
with us on X (formerly Twitter), Facebook, Instagram, YouTube and
LinkedIn.
Forward-Looking Statement of Merck & Co., Inc., Rahway,
N.J., USA
This news release of Merck & Co., Inc., Rahway, 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 candidates that
the candidates 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 Annual
Report on Form 10-K for the year ended December 31, 2023 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
(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.
View source
version on businesswire.com: https://www.businesswire.com/news/home/20241216178312/en/
Media Contacts: Julie Cunningham (617) 519-6264 Sienna Choi
(908) 873-4311 Investor Contacts: Peter Dannenbaum (732) 594-1579
Steven Graziano (732) 594-1583
Merck (NYSE:MRK)
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