KEYTRUDA Is the First Single-Agent,
Anti-PD-1 Therapy Approved for the First-Line Treatment of These
Patients
Approval Received Less Than One Month
Following Submission of sBLA Application Based on Results of
KEYNOTE-177
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 KEYTRUDA, Merck’s anti-PD-1 therapy, as
monotherapy for the first-line treatment of patients with
unresectable or metastatic microsatellite instability-high (MSI-H)
or mismatch repair deficient (dMMR) colorectal cancer. The approval
is based on results from the Phase 3 KEYNOTE-177 trial, in which
KEYTRUDA significantly reduced the risk of disease progression or
death by 40% (HR=0.60 [95% CI, 0.45-0.80; p=0.0004]) compared with
chemotherapy, the current standard of care. In the study, treatment
with KEYTRUDA also more than doubled median progression-free
survival (PFS) compared with chemotherapy (16.5 months [95% CI,
5.4-32.4] versus 8.2 months [95% CI, 6.1-10.2]).
“Today’s approval has the potential to change the treatment
paradigm for the first-line treatment of patients with MSI-H
colorectal cancer, based on the important findings from KEYNOTE-177
that showed KEYTRUDA monotherapy demonstrated superior
progression-free survival compared to standard of care
chemotherapy,” said Dr. Roy Baynes, senior vice president and head
of global clinical development, chief medical officer, Merck
Research Laboratories. “Our commitment to pursuing biomarker
research continues to help us bring new treatments to patients,
particularly for those who have few available options.”
Immune-mediated adverse reactions, which may be severe or fatal,
can occur with KEYTRUDA, including pneumonitis, colitis, hepatitis,
endocrinopathies, nephritis and renal dysfunction, 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.
This approval was granted less than one month following the
submission of a new supplemental Biologics License Application
(sBLA), which was reviewed under the FDA’s Real-Time Oncology
Review (RTOR) pilot program. This review also was conducted under
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, Health Canada and Swissmedic on their ongoing
review of the application.
“Patients with unresectable or metastatic MSI-H colorectal
cancer have historically faced poor outcomes, and until today,
chemotherapy-containing regimens were the only FDA-approved
first-line treatment options,” said Luis A. Diaz, M.D., head of the
division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer
Center. “In patients who were treated with KEYTRUDA and responded
(n=67) in the KEYNOTE-177 trial, 43% of patients experienced a
duration of response lasting two years or longer. This approval
helps address the unmet need to provide a new monotherapy treatment
option for patients.”
Data Supporting the Approval
The approval was based on data from KEYNOTE-177 (NCT02563002), a
multi-center, randomized, open-label, active-controlled trial that
enrolled 307 patients with previously untreated unresectable or
metastatic MSI-H or dMMR colorectal cancer. Microsatellite
instability (MSI) or mismatch repair (MMR) tumor status was
determined locally using polymerase chain reaction or
immunohistochemistry, respectively. Patients with autoimmune
disease or a medical condition that required immunosuppression were
ineligible.
Patients were randomized 1:1 to receive KEYTRUDA 200 mg
intravenously every three weeks or investigator’s choice of the
following chemotherapy regimens given intravenously every two
weeks:
- mFOLFOX6 (oxaliplatin, leucovorin, and fluorouracil) or
mFOLFOX6 in combination with either bevacizumab or cetuximab:
oxaliplatin 85 mg/m2, leucovorin 400 mg/m2 (or levoleucovorin 200
mg/m2), and fluorouracil 400 mg/m2 bolus on Day 1, then
fluorouracil 2,400 mg/m2 over 46-48 hours; plus bevacizumab 5 mg/kg
on Day 1 or cetuximab 400 mg/m2 on first infusion, then 250 mg/m2
weekly.
- FOLFIRI (irinotecan, leucovorin, and fluorouracil) or FOLFIRI
in combination with either bevacizumab or cetuximab: irinotecan 180
mg/m2, leucovorin 400 mg/m2 (or levoleucovorin 200 mg/m2), and
fluorouracil 400 mg/m2 bolus on Day 1, then fluorouracil 2,400
mg/m2 over 46-48 hours; plus bevacizumab 5 mg/kg on Day 1 or
cetuximab 400 mg/m2 on first infusion, then 250 mg/m2 weekly.
Treatment with KEYTRUDA or chemotherapy continued until Response
Evaluation Criteria in Solid Tumors (RECIST) v1.1-defined
progression of disease as determined by the investigator or
unacceptable toxicity. Patients treated with KEYTRUDA without
disease progression could be treated for up to 24 months.
Assessment of tumor status was performed every nine weeks. Patients
randomized to chemotherapy were offered KEYTRUDA at the time of
disease progression. The main efficacy outcome measure was
progression-free survival (PFS) as assessed by blinded independent
central review (BICR) according to RECIST v1.1, modified to follow
a maximum of 10 target lesions and a maximum of five target lesions
per organ, and overall survival (OS). Additional efficacy outcome
measures were objective response rate (ORR) and duration of
response (DOR).
Patients were enrolled and randomized to KEYTRUDA (n=153) or
chemotherapy (n=154). The baseline characteristics of these 307
patients were: median age of 63 years (range, 24 to 93), 47% age 65
or older; 50% male; 75% White and 16% Asian; 52% had an Eastern
Cooperative Oncology Group (ECOG) performance status (PS) of 0, and
48% had an ECOG PS of 1; and 27% received prior adjuvant or
neoadjuvant chemotherapy. Among the 154 patients randomized to
receive chemotherapy, 143 received chemotherapy per the protocol.
Of these 143 patients, 56% received mFOLFOX6, 44% received FOLFIRI,
70% received bevacizumab plus mFOLFOX6 or FOLFIRI, and 11% received
cetuximab plus mFOLFOX6 or FOLFIRI. The median follow-up time was
27.6 months (range, 0.2 to 48.3 months).
In this study, KEYTRUDA monotherapy significantly reduced the
risk of disease progression or death by 40% (HR=0.60 [95% CI,
0.45-0.80; p=0.0004]) and showed a median PFS of 16.5 months (95%
CI, 5.4-32.4) compared with 8.2 months (95% CI, 6.1-10.2) for
patients treated with chemotherapy. For PFS, in the KEYTRUDA arm,
there were 82 patients (54%) with an event versus 113 patients
(73%) in the chemotherapy arm. At the time of the PFS analysis, the
OS data were not mature (66% of the required number of events for
the OS final analysis). For patients treated with KEYTRUDA, the ORR
was 44% (95% CI, 35.8-52.0), with a complete response rate of 11%
and a partial response rate of 33%, and for patients treated with
chemotherapy, the ORR was 33% (95% CI, 25.8-41.1), with a complete
response rate of 4% and a partial response rate of 29%. Median DOR
was not reached (range, 2.3+ to 41.4+) with KEYTRUDA versus 10.6
months (range, 2.8 to 37.5+) with chemotherapy. Based on 67
patients with a response in the KEYTRUDA arm and 51 patients with a
response in the chemotherapy arm, 75% in the KEYTRUDA arm had a
duration of response greater than or equal to 12 months versus 37%
in the chemotherapy arm, and 43% in the KEYTRUDA arm had a duration
of response greater than or equal to 24 months versus 18% in the
chemotherapy arm.
Among the 153 patients with MSI-H or dMMR colorectal cancer
treated with KEYTRUDA, the median duration of exposure to KEYTRUDA
was 11.1 months (range, 1 day to 30.6 months). Adverse reactions
occurring in patients with MSI-H or dMMR colorectal cancer were
similar to those occurring in 2,799 patients with melanoma or
non-small cell lung cancer treated with KEYTRUDA as a single
agent.
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 and pediatric
patients with refractory classical Hodgkin lymphoma (cHL), or who
have relapsed after 3 or more prior lines of therapy. This
indication is approved under accelerated approval based on tumor
response rate and durability of response. Continued approval for
this indication may be contingent upon verification and description
of clinical benefit in the confirmatory trials.
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. 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.
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 (MSI-H) 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.
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 (TMB-H)
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.
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. 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 postmarketing 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)
Immune-mediated complications, including fatal events, occurred
in patients who underwent allogeneic HSCT after treatment with
KEYTRUDA. Of 23 patients with cHL who proceeded to allogeneic HSCT
after KEYTRUDA, 6 (26%) developed graft-versus-host disease (GVHD)
(1 fatal case) and 2 (9%) developed severe hepatic veno-occlusive
disease (VOD) after reduced-intensity conditioning (1 fatal case).
Cases of fatal hyperacute GVHD after allogeneic HSCT have also been
reported in patients with lymphoma who received a PD-1
receptor–blocking antibody before transplantation. Follow patients
closely for early evidence of transplant-related complications such
as hyperacute graft-versus-host disease (GVHD), Grade 3 to 4 acute
GVHD, steroid-requiring febrile syndrome, hepatic veno-occlusive
disease (VOD), and other immune-mediated adverse reactions.
In patients with a history of allogeneic HSCT, acute GVHD
(including fatal GVHD) has been reported after treatment with
KEYTRUDA. Patients who experienced GVHD after their transplant
procedure may be at increased risk for GVHD after KEYTRUDA.
Consider the benefit of KEYTRUDA vs the risk of GVHD in these
patients.
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-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
There is limited experience in pediatric patients. In a trial,
40 pediatric patients (16 children aged 2 years to younger than 12
years and 24 adolescents aged 12 years to 18 years) with various
cancers, including unapproved usages, were administered KEYTRUDA 2
mg/kg every 3 weeks. Patients received KEYTRUDA for a median of 3
doses (range 1–17 doses), with 34 patients (85%) receiving 2 doses
or more. The safety profile in these pediatric patients was similar
to that seen in adults; adverse reactions that occurred at a higher
rate (≥15% difference) in these patients when compared to adults
under 65 years of age were fatigue (45%), vomiting (38%), abdominal
pain (28%), increased transaminases (28%), and hyponatremia
(18%).
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 recent 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).
Dr. Diaz is an uncompensated consultant for Merck. Dr. Diaz is
also an inventor on a patent related to MSI as a predictor of
response to PD-1 blockade.
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/20200629005810/en/
Media Contacts:
Pamela Eisele (267) 305-3558
Kristen Drake (908) 740-1679
Investor Contacts:
Peter Dannenbaum (908) 740-1037
Courtney Ronaldo (908) 740-6132
Merck (NYSE:MRK)
Historical Stock Chart
From Mar 2024 to Apr 2024
Merck (NYSE:MRK)
Historical Stock Chart
From Apr 2023 to Apr 2024
