KEYTRUDA Is the First Anti-PD-1 Therapy
Approved for Adult Patients With Relapsed or Refractory cHL After
Frontline Therapy
KEYTRUDA Also Approved for Pediatric
Patients With Refractory cHL, or cHL That Has Relapsed After Two or
More Lines of Therapy
Merck (NYSE:MRK), known as MSD outside the United States and
Canada, today announced that the U.S. Food and Drug Administration
(FDA) has approved an expanded label for KEYTRUDA, Merck’s
anti-PD-1 therapy, as monotherapy for the treatment of adult
patients with relapsed or refractory classical Hodgkin lymphoma
(cHL). The approval is based on results from the Phase 3
KEYNOTE-204 trial in which KEYTRUDA significantly reduced the risk
of disease progression or death by 35% (HR=0.65 [95% CI, 0.48-0.88;
p<0.0027]) compared to brentuximab vedotin (BV). Additionally,
median progression-free survival (PFS) was 13.2 months (95% CI,
10.9-19.4) for patients treated with KEYTRUDA and 8.3 months (95%
CI, 5.7-8.8) for patients treated with BV. The FDA also approved an
updated pediatric indication for KEYTRUDA for the treatment of
pediatric patients with refractory cHL, or cHL that has relapsed
after two or more lines of therapy.
“An estimated 8,500 patients in the U.S., many of them 40 years
of age or younger, will be diagnosed with cHL this year. Now
patients with cHL who progress after frontline therapy have a new
option in KEYTRUDA, which has demonstrated a clinically meaningful
improvement in progression-free survival compared to brentuximab
vedotin,” said Dr. Vicki Goodman, vice president, clinical
research, Merck Research Laboratories. “At Merck, we are committed
to improving outcomes for patients with cancer. Today’s FDA
approval builds upon our growing range of options for people with
blood cancers.”
Immune-mediated adverse reactions, which may be severe or fatal,
can occur with KEYTRUDA, including pneumonitis, colitis, hepatitis,
endocrinopathies, nephritis, severe skin reactions, solid organ
transplant rejection, and complications of allogeneic hematopoietic
stem cell transplantation (HSCT). Based on the severity of the
adverse reaction, KEYTRUDA should be withheld or discontinued and
corticosteroids administered if appropriate. KEYTRUDA can also
cause severe or life-threatening infusion-related reactions. Based
on its mechanism of action, KEYTRUDA can cause fetal harm when
administered to a pregnant woman. For more information, see
“Selected Important Safety Information” below.
“The patients with cHL who do not achieve remission following
initial treatment or who relapse after transplantation face a poor
prognosis, reflecting the unmet need for improved therapies in the
relapsed/refractory setting,” said Dr. John Kuruvilla, hematologist
and associate professor of medicine, Princess Margaret Cancer
Centre and University of Toronto. “With this approval, KEYTRUDA has
the potential to change the current standard of care and help these
patients achieve better outcomes.”
KEYTRUDA was previously approved under the FDA’s accelerated
approval process for the treatment of adult and pediatric patients
with refractory cHL, or who have relapsed after three or more prior
lines of therapy based on data from the KEYNOTE-087 trial. In
accordance with accelerated approval regulations, continued
approval was contingent upon verification and description of
clinical benefit; these accelerated approval requirements have been
fulfilled with the data from KEYNOTE-204.
This approval was reviewed under the FDA’s Project Orbis, an
initiative of the FDA Oncology Center of Excellence that provides a
framework for concurrent submission and review of oncology drugs
among its international partners. For this application, a modified
Project Orbis was undertaken, and the FDA is collaborating with the
Australian Therapeutic Goods Administration and Health Canada on
their ongoing review of the application.
Data Supporting the Approval The approval was based on data from
KEYNOTE-204 (NCT02684292), a randomized, open-label,
active-controlled trial conducted in 304 patients with relapsed or
refractory cHL. The trial enrolled adults with relapsed or
refractory disease after at least one multi-agent chemotherapy
regimen. Patients were randomized 1:1 to receive either KEYTRUDA
200 mg intravenously every three weeks or BV 1.8 mg/kg
intravenously every three weeks.
Treatment was continued until unacceptable toxicity, documented
disease progression or a maximum of 35 cycles (up to approximately
two years). Disease assessment was performed every 12 weeks.
Randomization was stratified by prior autologous HSCT (yes vs. no)
and disease status after frontline therapy (primary refractory vs.
relapse less than 12 months after completion vs. relapse 12 months
or more after completion). The main efficacy measure was PFS as
assessed by blinded independent central review (BICR) using 2007
revised International Working Group (IWG) criteria.
Patients were enrolled and randomized to KEYTRUDA (n=151) or BV
(n=153). The study population characteristics were median age of 35
years (range, 18 to 84); 57% male; 77% white, 9% Asian and 3.9%
Black. The median number of prior therapies was two (range, 1 to
10) in the KEYTRUDA arm and three (range, 1 to 11) in the BV arm,
with 18% in both arms having one prior line. Forty-two percent of
patients were refractory to the last prior therapy, 29% had primary
refractory disease, 37% had prior autologous HSCT, 5% had received
prior BV, and 39% had prior radiation therapy.
In KEYNOTE-204, KEYTRUDA reduced the risk of disease progression
or death by 35% (HR=0.65 [95% CI, 0.48-0.88; p=0.0027]) and showed
a median PFS of 13.2 months (95% CI, 10.9-19.4). Median PFS was 8.3
months (95% CI, 5.7-8.8) for patients treated with BV. For PFS, in
the KEYTRUDA arm, there were 81 patients (54%) with an event versus
88 patients (58%) in the BV arm. For patients treated with
KEYTRUDA, the objective response rate (ORR) was 66% (95% CI,
57-73), with a complete response rate of 25% and a partial response
rate of 41%. For patients treated with BV, the ORR was 54% (95% CI,
46-62), with a complete response rate of 24% and a partial response
rate of 30%. The difference in ORRs is not statistically
significant. Among the responding patients, median duration of
response (DOR) was 20.7 months (range, 0.0+ to 33.2+) with KEYTRUDA
and 13.8 months (range, 0.0+ to 33.9+) with BV.
In KEYNOTE-204, the median duration of exposure to KEYTRUDA was
10 months (range, 1 day to 2.2 years), with 68% receiving at least
six months of treatment and 48% receiving at least one year of
treatment. Serious adverse reactions occurred in 30% of patients
who received KEYTRUDA. Serious adverse reactions in those greater
than or equal to 1% of patients included pneumonitis, pneumonia,
pyrexia, myocarditis, acute kidney injury, febrile neutropenia and
sepsis. Three patients (2%) died from causes other than disease
progression: two from complications after allogeneic HSCT and one
from an unknown cause.
Permanent discontinuation of KEYTRUDA due to an adverse reaction
occurred in 14% of patients; 7% of patients discontinued treatment
due to pneumonitis. Dosage interruption of KEYTRUDA due to an
adverse reaction occurred in 30% of patients. Adverse reactions
that required dosage interruption in greater than or equal to 3% of
patients were upper respiratory tract infection, pneumonitis,
transaminase increase and pneumonia. Thirty-eight percent of
patients had an adverse reaction requiring systemic corticosteroid
therapy. The most common adverse reactions (greater than or equal
to 20%) were upper respiratory tract infection (41%),
musculoskeletal pain (32%), diarrhea (22%), and pyrexia, fatigue,
rash and cough (20% each).
About Hodgkin Lymphoma Hodgkin lymphoma is a type of lymphoma
that develops in the white blood cells called lymphocytes, which
are part of the immune system. Hodgkin lymphoma can start almost
anywhere – most often in lymph nodes in the upper part of the body,
with the most common sites being in the chest, neck or under the
arms. Worldwide, there were approximately 80,000 new cases of
Hodgkin lymphoma, and more than 26,000 people died from the disease
in 2018. In 2020, it is estimated nearly 8,500 people will be
diagnosed with Hodgkin lymphoma in the United States. Classical
Hodgkin lymphoma accounts for more than nine in 10 cases of Hodgkin
lymphoma in developed countries.
About KEYTRUDA® (pembrolizumab) Injection, 100 mg KEYTRUDA is an
anti-PD-1 therapy that works by increasing the ability of the
body’s immune system to help detect and fight tumor cells. KEYTRUDA
is a humanized monoclonal antibody that blocks the interaction
between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T
lymphocytes which may affect both tumor cells and healthy
cells.
Merck has the industry’s largest immuno-oncology clinical
research program. There are currently more than 1,200 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 Melanoma KEYTRUDA
is indicated for the treatment of patients with unresectable or
metastatic melanoma.
KEYTRUDA is indicated for the adjuvant treatment of patients
with melanoma with involvement of lymph node(s) following complete
resection.
Non-Small Cell Lung Cancer KEYTRUDA, in combination with
pemetrexed and platinum chemotherapy, is indicated for the
first-line treatment of patients with metastatic nonsquamous
non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic
tumor aberrations.
KEYTRUDA, in combination with carboplatin and either paclitaxel
or paclitaxel protein-bound, is indicated for the first-line
treatment of patients with metastatic squamous NSCLC.
KEYTRUDA, as a single agent, is indicated for the first-line
treatment of patients with NSCLC expressing PD-L1 [tumor proportion
score (TPS) ≥1%] as determined by an FDA-approved test, with no
EGFR or ALK genomic tumor aberrations, and is stage III where
patients are not candidates for surgical resection or definitive
chemoradiation, or metastatic.
KEYTRUDA, as a single agent, is indicated for the treatment of
patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%)
as determined by an FDA-approved test, with disease progression on
or after platinum-containing chemotherapy. Patients with EGFR or
ALK genomic tumor aberrations should have disease progression on
FDA-approved therapy for these aberrations prior to receiving
KEYTRUDA.
Small Cell Lung Cancer KEYTRUDA is indicated for the treatment
of patients with metastatic small cell lung cancer (SCLC) with
disease progression on or after platinum-based chemotherapy and at
least 1 other prior line of therapy. This indication is approved
under accelerated approval based on tumor response rate and
durability of response. Continued approval for this indication may
be contingent upon verification and description of clinical benefit
in confirmatory trials.
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 head and neck squamous cell
carcinoma (HNSCC) with disease progression on or after
platinum-containing chemotherapy.
Classical Hodgkin Lymphoma KEYTRUDA is indicated for the
treatment of adult patients with relapsed or refractory classical
Hodgkin lymphoma (cHL).
KEYTRUDA is indicated for the treatment of pediatric patients
with refractory cHL, or cHL that has relapsed after 2 or more lines
of therapy.
Primary Mediastinal Large B-Cell Lymphoma KEYTRUDA is indicated
for the treatment of adult and pediatric patients with refractory
primary mediastinal large B-cell lymphoma (PMBCL), or who have
relapsed after 2 or more prior lines of therapy. KEYTRUDA is not
recommended for treatment of patients with PMBCL who require urgent
cytoreductive therapy.
Urothelial Carcinoma KEYTRUDA is indicated for the treatment of
patients with locally advanced or metastatic urothelial carcinoma
(mUC) who are not eligible for cisplatin-containing chemotherapy
and whose tumors express PD-L1 [combined positive score (CPS) ≥10],
as determined by an FDA-approved test, or in patients who are not
eligible for any platinum-containing chemotherapy regardless of
PD-L1 status. This indication is approved under accelerated
approval based on tumor response rate and duration of response.
Continued approval for this indication may be contingent upon
verification and description of clinical benefit in confirmatory
trials.
KEYTRUDA is indicated for the treatment of patients with locally
advanced or metastatic urothelial carcinoma (mUC) who have disease
progression during or following platinum-containing chemotherapy or
within 12 months of neoadjuvant or adjuvant treatment with
platinum-containing chemotherapy.
KEYTRUDA is indicated for the treatment of patients with
Bacillus Calmette-Guerin (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 that have progressed following prior treatment and
who have no satisfactory alternative treatment options, or
- colorectal cancer that has progressed following treatment with
fluoropyrimidine, oxaliplatin, and irinotecan.
This indication is approved under accelerated approval based on
tumor response rate and durability of response. Continued approval
for this indication may be contingent upon verification and
description of clinical benefit in the confirmatory trials. The
safety and effectiveness of KEYTRUDA in pediatric patients with
MSI-H central nervous system cancers have not been established.
Microsatellite Instability-High or Mismatch Repair Deficient
Colorectal Cancer KEYTRUDA is indicated for the first-line
treatment of patients with unresectable or metastatic MSI-H or dMMR
colorectal cancer (CRC).
Gastric Cancer KEYTRUDA is indicated for the treatment of
patients with recurrent locally advanced or metastatic gastric or
gastroesophageal junction (GEJ) adenocarcinoma whose tumors express
PD-L1 (CPS ≥1) as determined by an FDA-approved test, with disease
progression on or after two or more prior lines of therapy
including fluoropyrimidine- and platinum-containing chemotherapy
and if appropriate, HER2/neu-targeted therapy. This indication is
approved under accelerated approval based on tumor response rate
and durability of response. Continued approval for this indication
may be contingent upon verification and description of clinical
benefit in the confirmatory trials.
Esophageal Cancer KEYTRUDA is indicated for the treatment of
patients with recurrent locally advanced or metastatic squamous
cell carcinoma of the esophagus whose tumors express PD-L1 (CPS
≥10) as determined by an FDA-approved test, with disease
progression after one or more prior lines of systemic therapy.
Cervical Cancer KEYTRUDA is indicated for the treatment of
patients with recurrent or metastatic cervical cancer with disease
progression on or after chemotherapy whose tumors express PD-L1
(CPS ≥1) as determined by an FDA-approved test. This indication is
approved under accelerated approval based on tumor response rate
and durability of response. Continued approval for this indication
may be contingent upon verification and description of clinical
benefit in the confirmatory trials.
Hepatocellular Carcinoma KEYTRUDA is indicated for the treatment
of patients with hepatocellular carcinoma (HCC) who have been
previously treated with sorafenib. This indication is approved
under accelerated approval based on tumor response rate and
durability of response. Continued approval for this indication may
be contingent upon verification and description of clinical benefit
in the confirmatory trials.
Merkel Cell Carcinoma KEYTRUDA is indicated for the treatment of
adult and pediatric patients with recurrent locally advanced or
metastatic Merkel cell carcinoma (MCC). This indication is approved
under accelerated approval based on tumor response rate and
durability of response. Continued approval for this indication may
be contingent upon verification and description of clinical benefit
in the confirmatory trials.
Renal Cell Carcinoma KEYTRUDA, in combination with axitinib, is
indicated for the first-line treatment of patients with advanced
renal cell carcinoma (RCC).
Tumor Mutational Burden-High 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) that is not curable by surgery or
radiation.
Selected Important Safety Information for KEYTRUDA
Immune-Mediated Pneumonitis KEYTRUDA can cause
immune-mediated pneumonitis, including fatal cases. Pneumonitis
occurred in 3.4% (94/2799) of patients with various cancers
receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4
(0.3%), and 5 (0.1%). Pneumonitis occurred in 8.2% (65/790) of
NSCLC patients receiving KEYTRUDA as a single agent, including
Grades 3-4 in 3.2% of patients, and occurred more frequently in
patients with a history of prior thoracic radiation (17%) compared
to those without (7.7%). Pneumonitis occurred in 6% (18/300) of
HNSCC patients receiving KEYTRUDA as a single agent, including
Grades 3-5 in 1.6% of patients, and occurred in 5.4% (15/276) of
patients receiving KEYTRUDA in combination with platinum and FU as
first-line therapy for advanced disease, including Grades 3-5 in
1.5% of patients. Pneumonitis occurred in 8% (31/389) of patients
with cHL receiving KEYTRUDA as a single agent, including Grades 3-4
in 2.3% of patients.
Monitor patients for signs and symptoms of pneumonitis. Evaluate
suspected pneumonitis with radiographic imaging. Administer
corticosteroids for Grade 2 or greater pneumonitis. Withhold
KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3
or 4 or recurrent Grade 2 pneumonitis.
Immune-Mediated Colitis KEYTRUDA can cause
immune-mediated colitis. Colitis occurred in 1.7% (48/2799) of
patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%),
and 4 (<0.1%). Monitor patients for signs and symptoms of
colitis. Administer corticosteroids for Grade 2 or greater colitis.
Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue
KEYTRUDA for Grade 4 colitis.
Immune-Mediated Hepatitis (KEYTRUDA) and Hepatotoxicity
(KEYTRUDA in Combination With Axitinib) Immune-Mediated
Hepatitis KEYTRUDA can cause immune-mediated hepatitis. Hepatitis
occurred in 0.7% (19/2799) of patients receiving KEYTRUDA,
including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%). Monitor
patients for changes in liver function. Administer corticosteroids
for Grade 2 or greater hepatitis and, based on severity of liver
enzyme elevations, withhold or discontinue KEYTRUDA.
Hepatotoxicity in Combination With Axitinib KEYTRUDA in
combination with axitinib can cause hepatic toxicity with higher
than expected frequencies of Grades 3 and 4 ALT and AST elevations
compared to KEYTRUDA alone. With the combination of KEYTRUDA and
axitinib, Grades 3 and 4 increased ALT (20%) and increased AST
(13%) were seen. Monitor liver enzymes before initiation of and
periodically throughout treatment. Consider more frequent
monitoring of liver enzymes 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.
Immune-Mediated Endocrinopathies KEYTRUDA can cause
adrenal insufficiency (primary and secondary), hypophysitis,
thyroid disorders, and type 1 diabetes mellitus. Adrenal
insufficiency occurred in 0.8% (22/2799) of patients, including
Grade 2 (0.3%), 3 (0.3%), and 4 (<0.1%). Hypophysitis occurred
in 0.6% (17/2799) of patients, including Grade 2 (0.2%), 3 (0.3%),
and 4 (<0.1%). Hypothyroidism occurred in 8.5% (237/2799) of
patients, including Grade 2 (6.2%) and 3 (0.1%). The incidence of
new or worsening hypothyroidism was higher in 1185 patients with
HNSCC (16%) 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
patients with cHL (17%) receiving KEYTRUDA as a single agent,
including Grade 1 (6.2%) and Grade 2 (10.8%) hypothyroidism.
Hyperthyroidism occurred in 3.4% (96/2799) of patients, including
Grade 2 (0.8%) and 3 (0.1%), and thyroiditis occurred in 0.6%
(16/2799) of patients, including Grade 2 (0.3%). Type 1 diabetes
mellitus, including diabetic ketoacidosis, occurred in 0.2%
(6/2799) of patients.
Monitor patients for signs and symptoms of adrenal
insufficiency, hypophysitis (including hypopituitarism), thyroid
function (prior to and periodically during treatment), and
hyperglycemia. For adrenal insufficiency or hypophysitis,
administer corticosteroids and hormone replacement as clinically
indicated. Withhold KEYTRUDA for Grade 2 adrenal insufficiency or
hypophysitis and withhold or discontinue KEYTRUDA for Grade 3 or
Grade 4 adrenal insufficiency or hypophysitis. Administer hormone
replacement for hypothyroidism and manage hyperthyroidism with
thionamides and beta-blockers as appropriate. Withhold or
discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism. Administer
insulin for type 1 diabetes, and withhold KEYTRUDA and administer
antihyperglycemics in patients with severe hyperglycemia.
Immune-Mediated Nephritis and Renal Dysfunction KEYTRUDA
can cause immune-mediated nephritis. Nephritis occurred in 0.3%
(9/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%),
3 (0.1%), and 4 (<0.1%) nephritis. Nephritis occurred in 1.7%
(7/405) of patients receiving KEYTRUDA in combination with
pemetrexed and platinum chemotherapy. Monitor patients for changes
in renal function. Administer corticosteroids for Grade 2 or
greater nephritis. Withhold KEYTRUDA for Grade 2; permanently
discontinue for Grade 3 or 4 nephritis.
Immune-Mediated Skin Reactions Immune-mediated rashes,
including Stevens-Johnson syndrome (SJS), toxic epidermal
necrolysis (TEN) (some cases with fatal outcome), exfoliative
dermatitis, and bullous pemphigoid, can occur. Monitor patients for
suspected severe skin reactions and based on the severity of the
adverse reaction, withhold or permanently discontinue KEYTRUDA and
administer corticosteroids. For signs or symptoms of SJS or TEN,
withhold KEYTRUDA and refer the patient for specialized care for
assessment and treatment. If SJS or TEN is confirmed, permanently
discontinue KEYTRUDA.
Other Immune-Mediated Adverse Reactions Immune-mediated
adverse reactions, which may be severe or fatal, can occur in any
organ system or tissue in patients receiving KEYTRUDA and may also
occur after discontinuation of treatment. For suspected
immune-mediated adverse reactions, ensure adequate evaluation to
confirm etiology or exclude other causes. Based on the severity of
the adverse reaction, withhold KEYTRUDA and administer
corticosteroids. Upon improvement to Grade 1 or less, initiate
corticosteroid taper and continue to taper over at least 1 month.
Based on limited data from clinical studies in patients whose
immune-related adverse reactions could not be controlled with
corticosteroid use, administration of other systemic
immunosuppressants can be considered. Resume KEYTRUDA when the
adverse reaction remains at Grade 1 or less following
corticosteroid taper. Permanently discontinue KEYTRUDA for any
Grade 3 immune-mediated adverse reaction that recurs and for any
life-threatening immune-mediated adverse reaction.
The following clinically significant immune-mediated adverse
reactions occurred in less than 1% (unless otherwise indicated) of
2799 patients: arthritis (1.5%), uveitis, myositis, Guillain-Barré
syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic
anemia, sarcoidosis, and encephalitis. In addition, myelitis and
myocarditis were reported in other clinical trials, including
classical Hodgkin lymphoma, and post-marketing use.
Treatment with KEYTRUDA may increase the risk of rejection in
solid organ transplant recipients. Consider the benefit of
treatment vs the risk of possible organ rejection in these
patients.
Infusion-Related Reactions KEYTRUDA can cause severe or
life-threatening infusion-related reactions, including
hypersensitivity and anaphylaxis, which have been reported in 0.2%
(6/2799) of patients. Monitor patients for signs and symptoms of
infusion-related reactions. For Grade 3 or 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 hematopoietic stem
cell transplantation (HSCT) before or after being treated with a
PD-1/PD-L1 blocking antibody. Transplant-related complications
include hyperacute graft-versus-host disease (GVHD), acute GVHD,
chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced
intensity conditioning, and steroid-requiring febrile syndrome
(without an identified infectious cause). These complications may
occur despite intervening therapy between PD-1/PD-L1 blockade and
allogeneic HSCT. Follow patients closely for evidence of
transplant-related complications and intervene promptly. Consider
the benefit versus risk of treatment with a PD-1/PD-L1 blocking
antibody 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 a PD-1 or PD-L1
blocking antibody 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-002, KEYTRUDA was permanently discontinued due to
adverse reactions in 12% of 357 patients with advanced melanoma;
the most common (≥1%) were general physical health deterioration
(1%), asthenia (1%), dyspnea (1%), pneumonitis (1%), and
generalized edema (1%). The most common adverse reactions were
fatigue (43%), pruritus (28%), rash (24%), constipation (22%),
nausea (22%), diarrhea (20%), and decreased appetite (20%).
In KEYNOTE-054, KEYTRUDA was permanently discontinued due to
adverse reactions in 14% of 509 patients; the most common (≥1%)
were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Serious
adverse reactions occurred in 25% of patients receiving KEYTRUDA.
The most common adverse reaction (≥20%) with KEYTRUDA was diarrhea
(28%).
In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed
and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA
was discontinued due to adverse reactions in 20% of 405 patients.
The most common adverse reactions resulting in permanent
discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney
injury (2%). The most common adverse reactions (≥20%) with KEYTRUDA
were nausea (56%), fatigue (56%), constipation (35%), diarrhea
(31%), decreased appetite (28%), rash (25%), vomiting (24%), cough
(21%), dyspnea (21%), and pyrexia (20%).
In KEYNOTE-407, when KEYTRUDA was administered with carboplatin
and either paclitaxel or paclitaxel protein-bound in metastatic
squamous NSCLC, KEYTRUDA was discontinued due to adverse reactions
in 15% of 101 patients. The most frequent serious adverse reactions
reported in at least 2% of patients were febrile neutropenia,
pneumonia, and urinary tract infection. Adverse reactions observed
in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with
the exception that increased incidences of alopecia (47% vs 36%)
and peripheral neuropathy (31% vs 25%) were observed in the
KEYTRUDA and chemotherapy arm compared to the placebo and
chemotherapy arm in KEYNOTE-407.
In KEYNOTE-042, KEYTRUDA was discontinued due to adverse
reactions in 19% of 636 patients with advanced NSCLC; the most
common were pneumonitis (3%), death due to unknown cause (1.6%),
and pneumonia (1.4%). The most frequent serious adverse reactions
reported in at least 2% of patients were pneumonia (7%),
pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion
(2.2%). The most common adverse reaction (≥20%) was fatigue
(25%).
In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to
adverse reactions in 8% of 682 patients with metastatic NSCLC; the
most common was pneumonitis (1.8%). The most common adverse
reactions (≥20%) were decreased appetite (25%), fatigue (25%),
dyspnea (23%), and nausea (20%).
Adverse reactions occurring in patients with SCLC were similar
to those occurring in patients with other solid tumors who received
KEYTRUDA as a single agent.
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; those ≥1% included
pneumonitis, pneumonia, pyrexia, myocarditis, acute kidney injury,
febrile neutropenia, and sepsis. Three patients died from causes
other than disease progression. The most common adverse reactions
(≥20%) were upper respiratory tract infection (41%),
musculoskeletal pain (32%), diarrhea (22%), and pyrexia, fatigue,
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% included pneumonia,
pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. Two
patients died from causes other than disease progression; 1 from
GVHD after subsequent allogeneic HSCT and 1 from septic shock. The
most common adverse reactions (≥20%) were fatigue (26%), pyrexia
(24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and
rash (20%).
In KEYNOTE-170, KEYTRUDA was discontinued due to adverse
reactions in 8% of 53 patients with PMBCL. Serious adverse
reactions occurred in 26% of patients and included arrhythmia (4%),
cardiac tamponade (2%), myocardial infarction (2%), pericardial
effusion (2%), and pericarditis (2%). Six (11%) patients died
within 30 days of start of treatment. The most common adverse
reactions (≥20%) were musculoskeletal pain (30%), upper respiratory
tract infection and pyrexia (28% each), cough (26%), fatigue (23%),
and dyspnea (21%).
In KEYNOTE-052, KEYTRUDA was discontinued due to adverse
reactions in 11% of 370 patients with locally advanced or
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.
Adverse reactions occurring in patients with gastric cancer were
similar to those occurring in patients with melanoma or NSCLC who
received KEYTRUDA as a monotherapy.
Adverse reactions occurring in patients with esophageal cancer
were similar to those occurring in patients with melanoma or NSCLC
who received KEYTRUDA as a monotherapy.
In KEYNOTE-158, KEYTRUDA was discontinued due to adverse
reactions in 8% of 98 patients with recurrent or metastatic
cervical cancer. Serious adverse reactions occurred in 39% of
patients receiving KEYTRUDA; the most frequent included anemia
(7%), fistula, hemorrhage, and infections [except urinary tract
infections] (4.1% each). The most common adverse reactions (≥20%)
were fatigue (43%), musculoskeletal pain (27%), diarrhea (23%),
pain and abdominal pain (22% each), and decreased appetite
(21%).
Adverse reactions occurring in patients with hepatocellular
carcinoma (HCC) were generally similar to those in patients with
melanoma or NSCLC who received KEYTRUDA as a monotherapy, with the
exception of increased incidences of ascites (8% Grades 3-4) and
immune-mediated hepatitis (2.9%). Laboratory abnormalities (Grades
3-4) that occurred at a higher incidence were elevated AST (20%),
ALT (9%), and hyperbilirubinemia (10%).
Among the 50 patients with MCC enrolled in study KEYNOTE-017,
adverse reactions occurring in patients with MCC were generally
similar to those occurring in patients with melanoma or NSCLC who
received KEYTRUDA as a monotherapy. Laboratory abnormalities
(Grades 3-4) that occurred at a higher incidence were elevated AST
(11%) and hyperglycemia (19%).
In KEYNOTE-426, when KEYTRUDA was administered in combination
with axitinib, fatal adverse reactions occurred in 3.3% of 429
patients. Serious adverse reactions occurred in 40% of patients,
the most frequent (≥1%) were hepatotoxicity (7%), diarrhea (4.2%),
acute kidney injury (2.3%), dehydration (1%), and pneumonitis (1%).
Permanent discontinuation due to an adverse reaction occurred in
31% of patients; KEYTRUDA only (13%), axitinib only (13%), and the
combination (8%); the most common were hepatotoxicity (13%),
diarrhea/colitis (1.9%), acute kidney injury (1.6%), and
cerebrovascular accident (1.2%). The most common adverse reactions
(≥20%) were diarrhea (56%), fatigue/asthenia (52%), hypertension
(48%), hepatotoxicity (39%), hypothyroidism (35%), decreased
appetite (30%), palmar-plantar erythrodysesthesia (28%), nausea
(28%), stomatitis/mucosal inflammation (27%), dysphonia (25%), rash
(25%), cough (21%), and constipation (21%).
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 cSCC were similar
to those occurring in patients with melanoma or NSCLC who received
KEYTRUDA as a monotherapy.
Lactation Because of the potential for serious adverse
reactions in breastfed children, advise women not to breastfeed
during treatment and for 4 months after the final dose.
Pediatric Use In KEYNOTE-051, 161 pediatric patients (62
pediatric patients aged 6 months to younger than 12 years and 99
pediatric patients aged 12 years to 17 years) were administered
KEYTRUDA 2 mg/kg every 3 weeks. The median duration of exposure was
2.1 months (range: 1 day to 24 months).
Adverse reactions that occurred at a ≥10% higher rate in
pediatric patients when compared to adults were pyrexia (33%),
vomiting (30%), leukopenia (30%), upper respiratory tract infection
(29%), neutropenia (26%), headache (25%), and Grade 3 anemia
(17%).
Merck’s Focus on Cancer Our goal is to translate breakthrough
science into innovative oncology medicines to help people with
cancer worldwide. At Merck, the potential to bring new hope to
people with cancer drives our purpose and supporting accessibility
to our cancer medicines is our commitment. As part of our focus on
cancer, Merck is committed to exploring the potential of
immuno-oncology with one of the largest development programs in the
industry across more than 30 tumor types. We also continue to
strengthen our portfolio through strategic acquisitions and are
prioritizing the development of several promising oncology
candidates with the potential to improve the treatment of advanced
cancers. For more information about our oncology clinical trials,
visit www.merck.com/clinicaltrials.
About the Merck Access Program for KEYTRUDA At Merck, we
are committed to supporting accessibility to our cancer medicines.
Merck provides multiple programs to help appropriate patients who
are prescribed KEYTRUDA have access to our anti-PD-1 therapy. The
Merck Access Program provides reimbursement support for patients
receiving KEYTRUDA, including information to help with
out-of-pocket costs and co-pay assistance for eligible patients.
More information is available by calling 855-257-3932 or visiting
www.merckaccessprogram-keytruda.com.
About Merck’s Patient Support Program for KEYTRUDA Merck
is committed to helping provide patients and their caregivers
support throughout their treatment with KEYTRUDA. The KEY+YOU
Patient Support Program provides a range of resources and support.
For further information and to sign up, eligible patients may call
85-KEYTRUDA (855-398-7832) or visit www.keytruda.com.
About Merck For more than 125 years, Merck, known as MSD
outside of the United States and Canada, has been inventing for
life, bringing forward medicines and vaccines for many of the
world’s most challenging diseases in pursuit of our mission to save
and improve lives. We demonstrate our commitment to patients and
population health by increasing access to health care through
far-reaching policies, programs and partnerships. Today, Merck
continues to be at the forefront of research to prevent and treat
diseases that threaten people and animals – including cancer,
infectious diseases such as HIV and Ebola, and emerging animal
diseases – as we aspire to be the premier research-intensive
biopharmaceutical company in the world. For more information, visit
www.merck.com and connect with us on Twitter, Facebook, Instagram,
YouTube and LinkedIn.
Forward-Looking Statement of Merck & Co., Inc.,
Kenilworth, N.J., USA This news release of Merck & Co.,
Inc., Kenilworth, N.J., USA (the “company”) includes
“forward-looking statements” within the meaning of the safe harbor
provisions of the U.S. Private Securities Litigation Reform Act of
1995. These statements are based upon the current beliefs and
expectations of the company’s management and are subject to
significant risks and uncertainties. There can be no guarantees
with respect to pipeline products that the products will receive
the necessary regulatory approvals or that they will prove to be
commercially successful. If underlying assumptions prove inaccurate
or risks or uncertainties materialize, actual results may differ
materially from those set forth in the forward-looking
statements.
Risks and uncertainties include but are not limited to, general
industry conditions and competition; general economic factors,
including interest rate and currency exchange rate fluctuations;
the impact of the global outbreak of novel coronavirus disease
(COVID-19); the impact of pharmaceutical industry regulation and
health care legislation in the United States and internationally;
global trends toward health care cost containment; technological
advances, new products and patents attained by competitors;
challenges inherent in new product development, including obtaining
regulatory approval; the company’s ability to accurately predict
future market conditions; manufacturing difficulties or delays;
financial instability of international economies and sovereign
risk; dependence on the effectiveness of the company’s patents and
other protections for innovative products; and the exposure to
litigation, including patent litigation, and/or regulatory
actions.
The company undertakes no obligation to publicly update any
forward-looking statement, whether as a result of new information,
future events or otherwise. Additional factors that could cause
results to differ materially from those described in the
forward-looking statements can be found in the company’s 2019
Annual Report on Form 10-K and the company’s other filings with the
Securities and Exchange Commission (SEC) available at the SEC’s
Internet site (www.sec.gov).
Please see Prescribing Information for KEYTRUDA
(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.
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