New Long-Term Data From KEYNOTE-021 (Cohort
G) Reinforce Use of KEYTRUDA in Certain Patients with Advanced
Nonsquamous NSCLC
Updated Data for Quavonlimab (MK-1308), a
Novel Investigational Anti-CTLA-4 Antibody, in Combination With
KEYTRUDA Were Presented; Phase 3 Study for the Combination Planned
in First-Line Advanced NSCLC
Merck (NYSE: MRK), known as MSD outside the United States and
Canada, today announced positive results from two studies from the
company’s leading lung cancer clinical development program
evaluating KEYTRUDA, Merck’s anti-PD-1 therapy: KEYTRUDA in
combination with chemotherapy (KEYNOTE-021 [Cohort G]) and KEYTRUDA
in combination with quavonlimab (MK-1308), Merck’s novel
investigational anti-CTLA-4 antibody.
In KEYNOTE-021 (Cohort G), first-line treatment with KEYTRUDA in
combination with chemotherapy (n=60) demonstrated a significant
improvement in objective response rates (58% vs. 33%),
progression-free survival (HR=0.54 [95% CI, 0.35-0.83]) and a
sustained, long-term survival benefit (HR=0.71 [95% CI, 0.45-1.12])
versus chemotherapy alone (n=63) in patients with advanced
nonsquamous non-small cell lung cancer (NSCLC) regardless of PD‑L1
expression (Featured Poster #OFP01.02). Patients in Cohort G had no
EGFR or ALK genomic tumor aberrations. These findings represent the
longest follow-up data for an anti-PD-1/PD‑L1 therapy in
combination with chemotherapy for the first-line treatment of
NSCLC. Additionally, updated follow-up data from a Phase 1/2 study
of quavonlimab in combination with KEYTRUDA showed encouraging
anti-tumor activity and an acceptable safety profile as first-line
treatment in patients with advanced NSCLC (Poster #TS01.02).
“Over the last five years, KEYTRUDA has become foundational in
the treatment of metastatic lung cancer. The long-term data from
KEYNOTE-021 (Cohort G) reinforce the use of KEYTRUDA in combination
with chemotherapy in certain advanced lung cancer patients, while
data from our oncology pipeline reflect our commitment to exploring
a number of new combinations with KEYTRUDA that we believe could
have a meaningful impact for more lung cancer patients,” said Dr.
Vicki Goodman, vice president, oncology clinical research, Merck
Research Laboratories. “Updated data from our anti-CTLA-4 antibody
quavonlimab in combination with KEYTRUDA support the continued
development of this new combination and a Phase 3 study of
quavonlimab coformulated with KEYTRUDA in advanced non-small cell
lung cancer is planned.”
Results from both studies were presented at the IASLC 2020 North
America Conference on Lung Cancer hosted by the International
Association for the Study of Lung Cancer on Friday, Oct. 16. Follow
Merck on Twitter via @Merck and keep up to date with NACLC news and
updates by using the hashtag #NACLC20.
KEYTRUDA in Combination With Chemotherapy: Long-Term Data in
Advanced NSCLC From KEYNOTE-021 (Cohort G) (Featured Poster
#OFP01.02) New data from Cohort G of KEYNOTE-021 (NCT02039674)
demonstrated a significant improvement in objective response rates
(ORR), progression-free survival (PFS) and a sustained, long-term
survival benefit with KEYTRUDA in combination with pemetrexed
(ALIMTA®) and platinum chemotherapy versus pemetrexed and platinum
chemotherapy alone after four years of median study follow-up (49.4
months; range, 43.5 to 55.4). Cohort G of the Phase 1/2,
multi-cohort, multi-center, open-label trial evaluated KEYTRUDA in
combination with chemotherapy (n=60) versus chemotherapy alone
(n=63) as first-line treatment in patients with advanced
nonsquamous NSCLC. Patients in Cohort G had no EGFR or ALK genomic
tumor aberrations.
Findings from KEYNOTE-021 (Cohort G) showed that 50% of patients
treated with KEYTRUDA in combination with chemotherapy were alive
at three years versus 37% of patients who received chemotherapy
alone. KEYTRUDA in combination with chemotherapy also reduced the
risk of death by 29% (HR=0.71 [95% CI, 0.45-1.12]) versus
chemotherapy alone, with a median overall survival (OS) of 34.5
versus 21.1 months. The OS benefit was observed despite a 70%
(n=43/61) effective crossover rate from chemotherapy to
anti‑PD‑1/PD‑L1 therapy, including 28 patients who were treated
with KEYTRUDA as part of the on-study crossover.
The ORR was 58% for KEYTRUDA in combination with chemotherapy
versus 33% for chemotherapy alone. KEYTRUDA also reduced the risk
of disease progression or death by 46% (HR=0.54 [95% CI,
0.35-0.83]) versus chemotherapy, with a median PFS of 24.5 months
(range, 9.7 to 36.3) versus 9.9 months (range, 6.2 to 15.2). The
estimated three-year PFS rate was 37% for patients who received
KEYTRUDA in combination with chemotherapy versus 16% for those who
received chemotherapy alone. The median duration of response (DOR)
was more than one year longer with KEYTRUDA in combination with
chemotherapy (36.3 months; range, 1.4+ to 49.3+) versus
chemotherapy alone (22.8 months; range, 2.8+ to 47.2+).
Additionally, 51% of patients treated with KEYTRUDA in combination
with chemotherapy had responses lasting three years versus 47% with
chemotherapy alone.
Notably, 92% of patients who completed two years of treatment
with KEYTRUDA were alive at three years (n=11/12). All 12 patients
experienced an objective response and the estimated three-year DOR
rate was 100% (median DOR not reached [NR]; range, 11.7+ to 49.3+
months).
No new safety signals for KEYTRUDA in combination with
chemotherapy were identified with long-term follow-up. Among all
those treated, 39% of those who received KEYTRUDA in combination
with chemotherapy and 31% of those who received chemotherapy alone
experienced Grade 3-5 treatment-related adverse events (TRAEs).
Grade 3-5 TRAEs that led to discontinuation occurred in 17% of
patients who received KEYTRUDA in combination with chemotherapy and
16% of those who received chemotherapy alone. Grade 3-5 TRAEs that
led to death occurred in 2% (n=1) of patients who received KEYTRUDA
in combination with chemotherapy and 3% (n=2) of those who received
chemotherapy alone.
The KEYNOTE-021 (Cohort G) trial was conducted in collaboration
with Eli Lilly and Company, the makers of pemetrexed (ALIMTA®).
Quavonlimab (anti-CLTA-4) in Combination With KEYTRUDA: Phase
1/2 Results in Advanced NSCLC (Poster #TS01.02) In this
first-in-human, open-label, multi-arm Phase 1/2 study
(NCT03179436), quavonlimab, Merck’s novel anti-CTLA-4 therapy, was
evaluated in combination with KEYTRUDA as a first-line treatment in
patients with advanced NSCLC. In the dose-confirmation phase,
patients received quavonlimab (25 mg or 75 mg) every three weeks
(Q3W) or every six weeks (Q6W) in combination with KEYTRUDA (200 mg
Q3W for up to 35 cycles). The primary objective of the study was
safety and tolerability; secondary and exploratory objectives
included ORR per RECIST v1.1 by blinded independent central review
(BICR), PFS, OS and DOR. Response based on PD-L1 status was
retrospectively evaluated using tumor proportion score (TPS) as a
continuous variable.
Findings showed that quavonlimab in combination with KEYTRUDA
had an acceptable safety profile with no unexpected toxicities and
suggested encouraging anti-tumor activity. Any-grade adverse events
occurred in 98% of patients; TRAEs occurred 85% of patients. Grade
≥3 TRAEs occurred in 36% of patients across all treatment arms and
the most common TRAEs (>10% in any
arm) were increased alanine aminotransferase (8%), pneumonitis (8%)
and increased aspartate aminotransferase (6%).
With 16.9 months of median follow-up (range, 7.0 to 21.3),
results from the study showed the effect of quavonlimab in
combination with KEYTRUDA across secondary and exploratory
endpoints, including ORR, PFS, OS and DOR. Responses to quavonlimab
in combination with KEYTRUDA were observed regardless of PD-L1
expression with higher TPS scores significantly associated with
better response (one-sided p=0.015). These safety and efficacy data
support the 25 mg Q6W dose as the recommended Phase 2 dose of
quavonlimab when used in combination with KEYTRUDA.
Quavonlimab 25 mg Q6W +
KEYTRUDA n=40
Quavonlimab 25 mg Q3W +
KEYTRUDA n=40
Quavonlimab 75 mg Q6W +
KEYTRUDA n=40
Quavonlimab 75 mg Q3W +
KEYTRUDA n=14
Total N=134
ORR, % (95%, CI)
37.5 (22.7-54.2)
40 (24.9-56.7)
27.5 (14.6-43.9)
35.7 (12.8-64.9)
35.1 (27.0-43.8)
PFS, median (95%, CI),
mo
7.8 (4.2-14.8)
6.0 (2.0-8.3)
6.0 (3.5-8.1)
3.4 (1.8-NE)
6.1 (4.2-7.3)
OS, median (95%, CI),
mo
18.1 (14.2-NE)
18.1 (9.1-21.8)
17.1 (9.0-NE)
13.7 (3.5-NE)
16.5 (14.2-21.8)
DOR, median (95%, CI),
mo
NR (4.0 to 21.6+)
7.9 (2.8 to 21.4+)
15.9 (3.4 to 21.4+)
NR (8.8+ to 16.3+)
13.6 (2.8 to 21.6+)
About Lung Cancer Lung cancer, which forms in the tissues
of the lungs, usually within cells lining the air passages, is the
leading cause of cancer death worldwide. Each year, more people die
of lung cancer than die of colon and breast cancers combined. The
two main types of lung cancer are non-small cell and small cell.
Non-small cell lung cancer (NSCLC) is the most common type of lung
cancer, accounting for about 85% of all cases. Small cell lung
cancer (SCLC) accounts for about 10% to 15% of all lung cancers.
Before 2014, the five-year survival rate for patients diagnosed in
the U.S. with NSCLC and SCLC was estimated to be 5% and 6%,
respectively.
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.
About Quavonlimab (MK-1308) Quavonlimab is a novel
humanized IgG1 monoclonal antibody that binds to CTLA-4 and blocks
interaction with its ligands, CD80 and CD86. Quavonlimab is
currently being evaluated in combination with KEYTRUDA across
multiple solid tumors as part of ongoing Phase 1 and 2 trials. A
Phase 3 trial of quavonlimab coformulated with KEYTRUDA in advanced
non-small cell lung cancer is planned.
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 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 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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