Merck (NYSE: MRK), known as MSD outside of the United States and
Canada, today announced the discontinuation of the clinical
development programs for vibostolimab, an anti-TIGIT antibody, and
favezelimab, an anti-LAG-3 antibody. Vibostolimab is being
evaluated as an investigational fixed-dose combination with
pembrolizumab (KEYTRUDA®) in the KeyVibe program. Favezelimab is
being evaluated as an investigational fixed-dose combination with
pembrolizumab in the KEYFORM program.
Merck is discontinuing the Phase 3 KeyVibe-003 and KeyVibe-007
trials, which are evaluating the fixed-dose combination of
vibostolimab and pembrolizumab in certain patients with non-small
cell lung cancer (NSCLC), based on the recommendation of an
independent Data Monitoring Committee (DMC). In a pre-planned
analysis, both trials met the pre-specified futility criteria for
the primary endpoint of overall survival. In these studies, the
safety profile of vibostolimab/pembrolizumab was consistent with
that observed for vibostolimab and pembrolizumab in previously
reported studies, with no new safety signals identified. As
expected with dual checkpoint inhibitor therapy, more
immune-related adverse events were observed with the fixed-dose
combination than with pembrolizumab. Considering the totality of
data from the Phase 3 KeyVibe studies, including the efficacy
outcomes from KeyVibe-003 and KeyVibe-007, the company has decided
to discontinue the Phase 3 KeyVibe-006 trial and other vibostolimab
studies.
Separately, Merck has decided to end the favezelimab clinical
development program, and will stop enrollment in the Phase 3
KEYFORM-008 trial evaluating the fixed-dose combination of
favezelimab and pembrolizumab in patients with relapsed or
refractory classical Hodgkin lymphoma (cHL) whose disease has
progressed following prior anti-PD-1 therapy. Patients currently in
this trial may continue on therapy until study completion.
KEYFORM-008 is the only Phase 3 study in the KEYFORM clinical
development program for which results are not available. The
company has made this decision after a thorough evaluation of data
from the favezelimab clinical program and will prioritize the
development of other candidates in its comprehensive and
diversified oncology pipeline. This decision is not based on any
concerns about the safety of this fixed-dose combination.
Merck is informing study investigators for these clinical trials
and advises patients to speak to their study team and physician
regarding next steps and treatment options. Data analyses for the
Phase 3 trials are ongoing, and the results will be shared with the
scientific community.
"Following a careful analysis of the data, the decision has been
made to discontinue development of these candidates to prioritize
other ongoing programs. We are grateful to all the patients,
caregivers and investigators for their many contributions that made
these studies possible," said Dr. Marjorie Green, senior vice
president and head of oncology, global clinical development, Merck
Research Laboratories. "We continue to pursue the most promising
science with a focus on agents with the greatest potential to
improve outcomes for more patients with cancer."
About KeyVibe-003 KeyVibe-003 is a randomized,
double-blind Phase 3 trial (ClinicalTrials.gov, NCT04738487)
evaluating the fixed-dose combination of vibostolimab and
pembrolizumab (MK-7684A) versus pembrolizumab monotherapy, as a
first-line treatment for patients with PD-L1 positive metastatic
NSCLC. The primary endpoint is overall survival (OS) in
participants with PD-L1 TPS ≥50%. Secondary endpoints include OS in
participants with PD-L1 TPS ≥1% and TPS 1-49%, progression-free
survival (PFS), overall response rate (ORR), duration of response
(DOR), safety and quality of life. The trial enrolled 1,264
patients who were randomized (1:1) to receive:
- Vibostolimab/pembrolizumab fixed-dose combination
(pembrolizumab 200 mg and vibostolimab 200 mg intravenously [IV]
every three weeks [Q3W] for up to 35 administrations); or
- Pembrolizumab (200 mg IV Q3W for up to 35 administrations)
About KeyVibe-007 KeyVibe-007 is a randomized,
double-blind Phase 3 trial (ClinicalTrials.gov, NCT05226598)
evaluating the fixed-dose combination of vibostolimab and
pembrolizumab with chemotherapy in treatment-naïve patients with
metastatic NSCLC. The primary endpoint is OS in participants with
PD-L1 TPS ≥1%. Secondary endpoints include OS in all participants,
PFS, ORR and DOR in TPS ≥ 1% and all participants, safety and
patient reported outcomes. The trial enrolled 739 patients who were
randomized (1:1) to receive:
- Vibostolimab/pembrolizumab fixed-dose combination
(pembrolizumab 200mg and vibostolimab 200 mg IV) plus platinum
doublet chemotherapy (Q3W for 4 cycles); then
vibostolimab/pembrolizumab (200mg/200mg IV) for up to 31 cycles
(plus pemetrexed 500mg/m2 Q3W maintenance for nonsquamous
histology)
- Pembrolizumab (200 mg IV) plus platinum doublet chemotherapy
(Q3W for 4 cycles); then pembrolizumab (200mg IV) for up to 31
cycles (plus pemetrexed 500mg/m2 Q3W maintenance for nonsquamous
histology)
About KeyVibe-006 KeyVibe-006 is a randomized, open-label
Phase 3 trial (ClincialTrials.gov, NCT05298423) evaluating the
fixed-dose combination of vibostolimab and pembrolizumab with
concurrent chemoradiotherapy followed by vibostolimab and
pembrolizumab versus concurrent chemoradiotherapy followed by
durvalumab in patients with stage III NSCLC. The primary endpoints
are PFS and OS for all participants and for participants with TPS ≥
1%. The secondary endpoints are ORR, DOR, safety and patient
reported outcomes. The trial enrolled approximately 580 patients
who were randomized (1:1) to receive:
- Vibostolimab/pembrolizumab (200mg/200mg IV) plus platinum
doublet (1 cycle); then platinum doublet plus
vibostolimab/pembrolizumab (2 cycles) plus thoracic radiotherapy;
then vibostolimab/pembrolizumab (200mg/200mg IV Q3W for 17 cycles);
or
- Platinum doublet (1 cycle); then platinum doublet (2 cycles)
plus thoracic radiotherapy; then durvalumab (10 mg/kg Q2W for 26
cycles)
About KEYFORM-008 KEYFORM-008 is a randomized, open-label Phase
3 trial (ClinicalTrials.gov, NCT05508867) evaluating the fixed-dose
combination of favezelimab and pembrolizumab (MK-4280A) versus
physician's choice chemotherapy for the treatment of patients with
PD-1 relapsed or refractory classical Hodgkin lymphoma. The primary
endpoint is PFS per Lugano Response Criteria as assessed by Blinded
Independent Central Review (BICR). The secondary endpoints are OS,
ORR, DOR and safety. The trial enrolled 169 patients who were
randomized (1:1) to receive:
- Favezelimab/pembrolizumab (800 mg/200 mg IV on day 1, then Q3W
for up to 35 infusions); or
- Physician's choice of either bendamustine (between 90-120 mg/m2
IV on day 1 and day 2 of either a 3- or 4-week cycle for up to 6
cycles); or gemcitabine (between 800-1,200 mg/m2 IV on day 1 and
day 8 of a Q3W cycle for up to 6 cycles)
About vibostolimab Vibostolimab (MK-7684) is an
investigational humanized anti-TIGIT antibody discovered and
developed by Merck. Vibostolimab restores antitumor activity by
blocking the TIGIT receptor from binding to its ligands (CD112 and
CD155), thereby activating T lymphocytes that help destroy tumor
cells.
About favezelimab Favezelimab (MK-4280) is an
investigational anti-lymphocyte activation gene-3 (LAG-3) antibody.
LAG-3 is a cell surface immunomodulatory receptor expressed on
various immune cells that down-regulates T cell proliferation and
activation. Favezelimab aims to restore T cell effector function by
preventing LAG-3 from binding to its primary ligand, major
histocompatibility complex (MHC) class II molecules.
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.
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.
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.
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.
Merck’s focus on cancer 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 https://www.merck.com/research/oncology.
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/20241216638631/en/
Media Contacts:
Robert Josephson (203) 914-2372
Sienna Choi (908) 873-4311
Investor Contacts:
Peter Dannenbaum (732) 594-1579
Steven Graziano (732) 594-1583
Merck (NYSE:MRK)
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