Late-Breaker Presentation of Overall
Survival and Progression-Free Survival Results from Pivotal Phase 3
KEYNOTE-189 Trial with KEYTRUDA® (pembrolizumab) Plus
Pemetrexed and Platinum Chemotherapy in First-Line Treatment of
Advanced Nonsquamous Non-Small Cell Lung Cancer
First-Time KEYTRUDA Data Including
Recurrence-Free Survival from Phase 3 KEYNOTE-054 Study, in
Collaboration with EORTC, in Patients with Stage III Surgically
Resected High-Risk Melanoma
Additional Research with KEYTRUDA,
Investigational STING Agonist (MK-1454) and Merck’s Collaboration
with AstraZeneca for LYNPARZA® (olaparib) to be
Presented
Merck (NYSE:MRK), known as MSD outside the United States and
Canada, today announced that new research from Merck’s broad
oncology clinical program – across several major tumor types, as
monotherapy and in combination – will be presented at the American
Association for Cancer Research (AACR) Annual Meeting 2018 in
Chicago from April 14-18. For the first time, data from the pivotal
phase 3 KEYNOTE-189 trial with KEYTRUDA® (pembrolizumab), Merck’s
anti-PD-1 therapy, in combination with pemetrexed (ALIMTA®) and
cisplatin or carboplatin for the first-line treatment of metastatic
nonsquamous non-small cell lung cancer (NSCLC) will be presented
(Abstract #CT075). In January 2018, Merck announced the KEYNOTE-189
study met its dual primary endpoints, and the KEYTRUDA combination
resulted in significantly longer overall survival (OS) and
progression-free survival (PFS) than pemetrexed plus platinum
chemotherapy alone. In addition, results from the phase 3
KEYNOTE-054 trial, in collaboration with the European Organization
for Research and Treatment of Cancer (EORTC), studying KEYTRUDA in
adjuvant melanoma will be presented (Abstract #CT001). As
previously announced, this is the first KEYTRUDA trial to
demonstrate a significant recurrence-free survival (RFS) benefit in
the adjuvant treatment setting for stage III melanoma.
“Our global efforts in immuno-oncology research, anchored by
KEYTRUDA, are fueled by a commitment to improve the lives of
patients suffering from malignant disease,” said Dr. Roger M.
Perlmutter, president, Merck Research Laboratories. “New studies to
be presented at AACR, including our KEYNOTE-189 and -054 trials in
first-line lung cancer and adjuvant melanoma, respectively,
demonstrate the progress that we and our colleagues have made in
developing treatment regimens for a broad range of cancers.”
“The science of immunotherapy has advanced significantly in
recent years, and Merck is forging new ground through its research
efforts. At the Cancer Research Institute, we support the discovery
of new treatment options for people with cancer and we are very
excited about the new research with KEYTRUDA in first-line lung
cancer and other cancers to be presented at AACR,” said Jill
O'Donnell-Tormey, Ph.D., chief executive officer and director of
scientific affairs, Cancer Research Institute (CRI).
With KEYTRUDA (pembrolizumab) and a growing early pipeline of 20
novel mechanisms, Merck has become a leader in immuno-oncology
research with the largest clinical program in the industry. Data
from Merck’s broad portfolio including KEYTRUDA,
internally-discovered investigational STING agonist (MK-1454), and
several collaborations including with AstraZeneca for the PARP
inhibitor LYNPARZA® (olaparib), will be featured in more than 20
oral plenary and poster presentations.
Select data highlights at AACR include:
- KEYNOTE-189: Randomized,
double-blind, phase 3 study of pembrolizumab (pembro) or placebo
plus pemetrexed (pem) and platinum as first-line therapy for
metastatic NSCLC. Top-line results showed that the KEYTRUDA
combination improved OS and PFS in the first-line treatment of
nonsquamous NSCLC. Abstract #CT075. L Gandhi. Plenary Session:
Monday, April 16, 10:30 a.m.-12:30 p.m. CDT.
- KEYNOTE-054 (EORTC1325):
Pembrolizumab versus placebo after complete resection of high-risk
stage III melanoma: Efficacy and safety results from the EORTC
1325-MG/KEYNOTE-054 double-blinded phase III trial. In January
2018, Merck and EORTC announced the study met the primary endpoint
of RFS, showing significant benefit for patients with resected
stage III melanoma who received KEYTRUDA compared to placebo.
Abstract #CT001. A Eggermont. Plenary Session: Sunday, April 15,
9:30 a.m.-12:15 p.m. CDT.
- KEYNOTE-040: Updated survival
results of the KEYNOTE-040 study of pembrolizumab vs
standard-of-care chemotherapy for recurrent or metastatic head and
neck squamous cell carcinoma. Updated OS results will be presented
at AACR. Abstract #CT115. D Soulières. Minisymposium: Monday, April
16, 3:00-5:00 p.m. CDT.
- Merck’s Early Pipeline:
Combining STING Agonists with an Anti-PD-1 Antagonist results in
Marked AntiTumor Activity in Immune-Excluded Tumors. MK-1454,
Merck’s investigational STING (stimulator of interferon genes)
agonist, is currently being evaluated in a phase 1 study as
monotherapy and in combination with KEYTRUDA in patients with
advanced solid tumors and lymphomas. Abstract #4721/24. S Perera.
Poster Presentation: Tuesday, April 17, 1:00-5:00 p.m. CDT.
- OlympiAD: OlympiAD final overall
survival: Olaparib versus chemotherapy treatment of physician’s
choice (TPC) in patients with HER2-negative metastatic breast
cancer (mBC) and a germline BRCA mutation (gBRCAm). Abstract
#CT038. M Robson. Minisymposium: Sunday, April 15, 3:00-5:00 p.m.
CDT.
Additional data to be presented for KEYTRUDA (pembrolizumab) and
from Merck’s collaboration with AstraZeneca for LYNPARZA (olaparib)
include:
Additional KEYTRUDA Data at
AACR
- Minisymposium: Safety, efficacy, and
immune correlates of alternative doses and schedules of entinostat
combined with pembrolizumab in patients with advanced solid tumors
- results from SNDX-275-0141 Phase I trial. AW Tolcher.
- Minisymposium: Biomarkers predictive of
response to pembrolizumab in head and neck cancer (HNSCC). TY
Seiwert.
- Minisymposium: Effect of JAK/STAT or
PI3Kδ plus PD-1 inhibition on the tumor microenvironment: Biomarker
results from a phase 1b study in patients with advanced solid
tumors. J.M. Kirkwood.
- Poster Presentation: Durability of
responses to the combination of SD-101 and pembrolizumab in
advanced metastatic melanoma: Results of a phase 1b, multicenter
study. A Ribas.
- Poster Presentation: Phase Ib/II,
open-label, multicenter study of intratumoral SD-101 in combination
with pembrolizumab in anti-PD-1 treatment-naïve patients with
recurrent or metastatic head and neck squamous cell carcinoma
(HNSCC). E Cohen.
- Poster Presentation: Imprime PGG, a
soluble yeast β-glucan PAMP, in combination with Pembrolizumab
induces infiltration and activation of both innate and adaptive
immune cells within tumor sites in melanoma and triple-negative
breast cancer (TNBC) patients. MT Uhlik.
- Poster Presentation: Comprehensive
investigation of Programmed Death Receptor Ligand 1 (PD-L1)
Expression and Associated Molecular Features in Gastric Cancer
patients. X Liu.
- Poster Presentation: Molecular
Biomarker Study of Programmed Death Receptor Ligand 1 (PD-L1) in
Korean Patients with Lung Adenocarcinoma. X Liu.
Additional LYNPARZA Data at
AACR
- Poster Presentation: A two-stage Simon
Design phase II study for NOn-BRCA metastatic BReast cancer (MBC)
patients with homologous recombination deficiency treated with
OLAparib single agent. (NOBROLA study). E Aguirre.
- Poster Presentation: Testing a
combination of AKT inhibitor (AZD5363) with PARP inhibitor Olaparib
plus Carboplatin in TNBC. JH Carlson.
- Poster Presentation: Patient derived
ovarian cancer xenograft (OC-PDX) to study the response of the PARP
inhibitor olaparib. F Bizzaro.
- Poster Presentation: Adaptive oncology
phase 1 study of first-in-class inhibitor of ataxia telangiectasia
mutated protein kinase (ATM), in combination with olaparib. Y
Chen.
- Poster Presentation: A pre-surgical
window of opportunity study to investigate the biomarker effects of
DNA damage response (DDR) agents in patients (pts) with Head and
Neck Squamous Cell Carcinoma (HNSCC). U Duvvuri.
- Poster Presentation: The PARP inhibitor
olaparib is synergistic with the ATR inhibitor AZD6738 in ATM
deficient cancer cells. R Lloyd.
- Poster Session: A head-to-head
comparison of the properties of five clinical PARP inhibitors
identifies new insights that can explain both the observed clinical
efficacy and safety profiles. E Leo.
For more information, including a complete list of abstract
titles, please see the AACR program
at http://www.abstractsonline.com/pp8/#!/4562.
Merck Investor Event: Merck will hold an investor event
in conjunction with the 2018 AACR Annual Meeting on Monday, April
16 at 6:45 p.m. CDT (7:45 p.m. EDT). Those unable to attend in
person will be able to listen to a live audio webcast of the
presentation. Details of the event to be provided at a date closer
to the event at http://investors.merck.com/home/default.aspx.
About KEYTRUDA® (pembrolizumab) Injection
100mg
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, which currently involves more than 700 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.
KEYTRUDA (pembrolizumab) Indications and Dosing
Melanoma
KEYTRUDA is indicated for the treatment of patients with
unresectable or metastatic melanoma at a fixed dose of 200 mg every
three weeks until disease progression or unacceptable toxicity.
Lung Cancer
KEYTRUDA, as a single agent, is indicated for the first-line
treatment of patients with metastatic non-small cell lung cancer
(NSCLC) whose tumors have high PD-L1 expression [tumor proportion
score (TPS) ≥50%] as determined by an FDA-approved test, with no
EGFR or ALK genomic tumor aberrations.
KEYTRUDA, as a single agent, is also indicated for the treatment
of patients with metastatic NSCLC whose tumors express PD-L1 (TPS
≥1%) as determined by an FDA-approved test, with disease
progression on or after platinum-containing chemotherapy. Patients
with EGFR or ALK genomic tumor aberrations should have disease
progression on FDA-approved therapy for these aberrations prior to
receiving KEYTRUDA.
KEYTRUDA, in combination with pemetrexed and carboplatin, is
indicated for the first-line treatment of patients with metastatic
nonsquamous NSCLC. This indication is approved under accelerated
approval based on tumor response rate and progression-free
survival. Continued approval for this indication may be contingent
upon verification and description of clinical benefit in the
confirmatory trials.
In metastatic NSCLC, KEYTRUDA (pembrolizumab) is administered at
a fixed dose of 200 mg every three weeks until disease progression,
unacceptable toxicity, or up to 24 months in patients without
disease progression.
When administering KEYTRUDA in combination with chemotherapy,
KEYTRUDA should be administered prior to chemotherapy when given on
the same day. See also the Prescribing Information for pemetrexed
and carboplatin.
Head and Neck Cancer
KEYTRUDA 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. 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. In HNSCC, KEYTRUDA is administered at a fixed
dose of 200 mg every three weeks until disease progression,
unacceptable toxicity, or up to 24 months in patients without
disease progression.
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 three 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. In adults with cHL,
KEYTRUDA is administered at a fixed dose of 200 mg every three
weeks until disease progression or unacceptable toxicity, or up to
24 months in patients without disease progression. In pediatric
patients with cHL, KEYTRUDA is administered at a dose of 2 mg/kg
(up to a maximum of 200 mg) every three weeks until disease
progression or unacceptable toxicity, or up to 24 months in
patients without disease progression.
Urothelial Carcinoma
KEYTRUDA is indicated for the treatment of patients with locally
advanced or metastatic urothelial carcinoma who are not eligible
for cisplatin-containing chemotherapy. 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
the confirmatory trials.
KEYTRUDA (pembrolizumab) is also indicated for the treatment of
patients with locally advanced or metastatic urothelial carcinoma
who have disease progression during or following
platinum-containing chemotherapy or within 12 months of neoadjuvant
or adjuvant treatment with platinum-containing chemotherapy.
In locally advanced or metastatic urothelial carcinoma, KEYTRUDA
is administered at a fixed dose of 200 mg every three weeks until
disease progression or unacceptable toxicity, or up to 24 months in
patients without disease progression.
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.
In adult patients with MSI-H cancer, KEYTRUDA is administered at
a fixed dose of 200 mg every three weeks until disease progression,
unacceptable toxicity, or up to 24 months in patients without
disease progression. In children with MSI-H cancer, KEYTRUDA is
administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every
three weeks until disease progression or unacceptable toxicity, or
up to 24 months in patients without disease progression.
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 [Combined Positive Score (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. The recommended dose of KEYTRUDA
(pembrolizumab) is 200 mg every three weeks until disease
progression, unacceptable toxicity, or up to 24 months in patients
without disease progression.
Selected Important Safety Information for
KEYTRUDA® (pembrolizumab)
KEYTRUDA can cause immune-mediated pneumonitis, including fatal
cases. Pneumonitis occurred in 94 (3.4%) of 2799 patients receiving
KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%),
and 5 (0.1%) pneumonitis, and occurred more frequently in patients
with a history of prior thoracic radiation (6.9%) compared to those
without (2.9%). 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.
KEYTRUDA can cause immune-mediated colitis. Colitis occurred in
48 (1.7%) of 2799 patients receiving KEYTRUDA, including Grade 2
(0.4%), 3 (1.1%), and 4 (<0.1%) colitis. 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.
KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred
in 19 (0.7%) of 2799 patients receiving KEYTRUDA, including Grade 2
(0.1%), 3 (0.4%), and 4 (<0.1%) hepatitis. 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.
KEYTRUDA can cause hypophysitis. Hypophysitis occurred in 17
(0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2
(0.2%), 3 (0.3%), and 4 (<0.1%) hypophysitis. Monitor patients
for signs and symptoms of hypophysitis (including hypopituitarism
and adrenal insufficiency). Administer corticosteroids and hormone
replacement as clinically indicated. Withhold KEYTRUDA for Grade 2;
withhold or discontinue for Grade 3 or 4 hypophysitis.
KEYTRUDA can cause thyroid disorders, including hyperthyroidism,
hypothyroidism, and thyroiditis. Hyperthyroidism occurred in 96
(3.4%) of 2799 patients receiving KEYTRUDA, including Grade 2
(0.8%) and 3 (0.1%) hyperthyroidism. Hypothyroidism occurred in 237
(8.5%) of 2799 patients receiving KEYTRUDA, including Grade 2
(6.2%) and 3 (0.1%) hypothyroidism. The incidence of new or
worsening hypothyroidism was higher in patients with HNSCC,
occurring in 28 (15%) of 192 patients with HNSCC, including Grade 3
(0.5%) hypothyroidism. Thyroiditis occurred in 16 (0.6%) of 2799
patients receiving KEYTRUDA (pembrolizumab), including Grade 2
(0.3%) thyroiditis. Monitor patients for changes in thyroid
function (at the start of treatment, periodically during treatment,
and as indicated based on clinical evaluation) and for clinical
signs and symptoms of thyroid disorders. Administer replacement
hormones for hypothyroidism and manage hyperthyroidism with
thionamides and beta-blockers as appropriate. Withhold or
discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism.
KEYTRUDA can cause type 1 diabetes mellitus, including diabetic
ketoacidosis, which have been reported in 6 (0.2%) of 2799
patients. Monitor patients for hyperglycemia or other signs and
symptoms of diabetes. Administer insulin for type 1 diabetes, and
withhold KEYTRUDA and administer antihyperglycemics in patients
with severe hyperglycemia.
KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred
in 9 (0.3%) of 2799 patients receiving KEYTRUDA, including Grade 2
(0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Monitor patients for
changes in renal function. Administer corticosteroids for Grade 2
or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently
discontinue KEYTRUDA for Grade 3 or 4 nephritis.
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.
KEYTRUDA can cause other clinically important immune-mediated
adverse reactions. These immune-mediated reactions may occur in any
organ system. 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
(pembrolizumab) 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, and partial seizures arising in a patient with inflammatory
foci in brain parenchyma. In addition, myelitis and myocarditis
were reported in other clinical trials, including classical Hodgkin
lymphoma, and postmarketing use.
Solid organ transplant rejection has been reported in
postmarketing use of KEYTRUDA. Treatment with KEYTRUDA may increase
the risk of rejection in solid organ transplant recipients.
Consider the benefit of treatment with KEYTRUDA vs the risk of
possible organ rejection in these patients.
KEYTRUDA can cause severe or life-threatening infusion-related
reactions, including hypersensitivity and anaphylaxis, which have
been reported in 6 (0.2%) of 2799 patients. Monitor patients for
signs and symptoms of infusion-related reactions, including rigors,
chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia,
and fever. For Grade 3 or 4 reactions, stop infusion and
permanently discontinue KEYTRUDA.
Immune-mediated complications, including fatal events, occurred
in patients who underwent allogeneic hematopoietic stem cell
transplantation (HSCT) after being treated with KEYTRUDA. Of 23
patients with cHL who proceeded to allogeneic HSCT after treatment
with KEYTRUDA on any trial, 6 patients (26%) developed
graft-versus-host disease (GVHD), one of which was fatal, and 2
patients (9%) developed severe hepatic veno-occlusive disease (VOD)
after reduced-intensity conditioning, one of which was fatal. 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.
These complications may occur despite intervening therapy
between PD-1 blockade and allogeneic HSCT. Follow patients closely
for early evidence of transplant-related complications such as
hyperacute GVHD, severe (Grade 3 to 4) acute GVHD,
steroid-requiring febrile syndrome, hepatic VOD, and other
immune-mediated adverse reactions, and intervene promptly.
In clinical 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 clinical trials.
Based on its mechanism of action, KEYTRUDA (pembrolizumab) can
cause fetal harm when administered to a pregnant woman. If used
during pregnancy, or if the patient becomes pregnant during
treatment, apprise the patient of the potential hazard to a fetus.
Advise females of reproductive potential to use highly effective
contraception during treatment and for 4 months after the last dose
of KEYTRUDA.
In KEYNOTE-006, KEYTRUDA was discontinued due to adverse
reactions in 9% of 555 patients with advanced melanoma; adverse
reactions leading to 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%). Adverse
reactions leading to interruption of KEYTRUDA occurred in 21% of
patients; the most common (≥1%) was diarrhea (2.5%). The most
common adverse reactions with KEYTRUDA vs ipilimumab were fatigue
(28% vs 28%), diarrhea (26% with KEYTRUDA), rash (24% vs 23%), and
nausea (21% with KEYTRUDA). Corresponding incidence rates are
listed for ipilimumab only for those adverse reactions that
occurred at the same or lower rate than with KEYTRUDA.
In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to
adverse reactions in 8% of 682 patients with metastatic NSCLC. The
most common adverse event resulting in permanent discontinuation of
KEYTRUDA was pneumonitis (1.8%). Adverse reactions leading to
interruption of KEYTRUDA occurred in 23% of patients; the most
common (≥1%) were diarrhea (1%), fatigue (1.3%), pneumonia (1%),
liver enzyme elevation (1.2%), decreased appetite (1.3%), and
pneumonitis (1%). The most common adverse reactions (occurring in
at least 20% of patients and at a higher incidence than with
docetaxel) were decreased appetite (25% vs 23%), dyspnea (23% vs
20%), and nausea (20% vs 18%).
In KEYNOTE-021(G1), when KEYTRUDA was administered in
combination with carboplatin and pemetrexed (carbo/pem) in advanced
nonsquamous NSCLC, KEYTRUDA was discontinued in 10% of 59 patients.
The most common adverse reaction resulting in discontinuation of
KEYTRUDA (≥2%) was acute kidney injury (3.4%). Adverse reactions
leading to interruption of KEYTRUDA occurred in 39% of patients;
the most common (≥2%) were fatigue (8%), neutrophil count decreased
(8%), anemia (5%), dyspnea (3.4%), and pneumonitis (3.4%). The most
common adverse reactions (≥20%) with KEYTRUDA compared to carbo/pem
alone were fatigue (71% vs 50%), nausea (68% vs 56%), constipation
(51% vs 37%), rash (42% vs 21%), vomiting (39% vs 27%), dyspnea
(39% vs 21%), diarrhea (37% vs 23%), decreased appetite (31% vs
23%), headache (31% vs 16%), cough (24% vs 18%), dizziness (24% vs
16%), insomnia (24% vs 15%), pruritus (24% vs 4.8%), peripheral
edema (22% vs 18%), dysgeusia (20% vs 11%), alopecia (20% vs 3.2%),
upper respiratory tract infection (20% vs 3.2%), and arthralgia
(15% vs 24%). This study was not designed to demonstrate a
statistically significant difference in adverse reaction rates for
KEYTRUDA (pembrolizumab) as compared to carbo/pem alone for any
specified adverse reaction.
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
(reported in at least 20% of patients) 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, with the exception of increased incidences of
facial edema (10% all Grades; 2.1% Grades 3 or 4) and new or
worsening hypothyroidism.
In KEYNOTE-087, KEYTRUDA was discontinued due to adverse
reactions in 5% of 210 patients with cHL, and treatment was
interrupted due to adverse reactions in 26% of patients. Fifteen
percent (15%) of patients had an adverse reaction requiring
systemic corticosteroid therapy. Serious adverse reactions occurred
in 16% of patients. The most frequent serious adverse reactions
(≥1%) included pneumonia, pneumonitis, pyrexia, dyspnea, GVHD, and
herpes zoster. Two patients died from causes other than disease
progression; one from GVHD after subsequent allogeneic HSCT and one
from septic shock. The most common adverse reactions (occurring in
≥20% of patients) were fatigue (26%), pyrexia (24%), cough (24%),
musculoskeletal pain (21%), diarrhea (20%), and rash (20%).
In KEYNOTE-052, KEYTRUDA was discontinued due to adverse
reactions in 11% of 370 patients with locally advanced or
metastatic urothelial carcinoma. The most common adverse reactions
(in ≥20% of patients) were fatigue (38%), musculoskeletal pain
(24%), decreased appetite (22%), constipation (21%), rash (21%),
and diarrhea (20%). Eighteen patients (5%) died from causes other
than disease progression. Five patients (1.4%) who were treated
with KEYTRUDA experienced sepsis which led to death, and 3 patients
(0.8%) experienced pneumonia which led to death. Adverse reactions
leading to interruption of KEYTRUDA occurred in 22% of patients;
the most common (≥1%) were liver enzyme increase, diarrhea, urinary
tract infection, acute kidney injury, fatigue, joint pain, and
pneumonia. Serious adverse reactions occurred in 42% of patients,
the most frequent (≥2%) of which were urinary tract infection,
hematuria, acute kidney injury, pneumonia, and urosepsis.
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 (pembrolizumab) was
pneumonitis (1.9%). Adverse reactions leading to interruption of
KEYTRUDA occurred in 20% of patients; the most common (≥1%) were
urinary tract infection (1.5%), diarrhea (1.5%), and colitis
(1.1%). The most common adverse reactions (≥20%) in patients who
received KEYTRUDA vs those who received chemotherapy were fatigue
(38% vs 56%), musculoskeletal pain (32% vs 27%), pruritus (23% vs
6%), decreased appetite (21% vs 21%), nausea (21% vs 29%), and rash
(20% vs 13%). Serious adverse reactions occurred in 39% of
KEYTRUDA-treated patients, the most frequent (≥2%) of which were
urinary tract infection, pneumonia, anemia, and pneumonitis.
It is not known whether KEYTRUDA is excreted in human milk.
Because many drugs are excreted in human milk, instruct women to
discontinue nursing during treatment with KEYTRUDA and for 4 months
after the final dose.
There is limited experience in pediatric patients. In a study,
40 pediatric patients (16 children aged 2 years to younger than 12
years and 24 adolescents aged 12 years to 18 years) with advanced
melanoma, lymphoma, or PD-L1–positive advanced, relapsed, or
refractory solid tumors 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 KEYTRUDA for 2 doses
or more. The safety profile in these pediatric patients was similar
to that seen in adults treated with KEYTRUDA. Toxicities 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%), hypertransaminasemia (28%),
and hyponatremia (18%).
About LYNPARZA® (olaparib)
LYNPARZA is the first FDA-approved oral poly ADP-ribose
polymerase (PARP) inhibitor and the first targeted treatment to
potentially exploit DNA damage response (DDR) pathway deficiencies,
such as BRCA mutations, to preferentially kill cancer cells.
Specifically, in vitro studies have shown that LYNPARZA-induced
cytotoxicity may involve inhibition of PARP enzymatic activity and
increased formation of PARP-DNA complexes, resulting in DNA damage
and cancer cell death.
Indications for LYNPARZA® (olaparib) in the
U.S.
LYNPARZA is a poly (ADP-ribose) polymerase (PARP) inhibitor
indicated:
For the maintenance treatment of adult patients with recurrent
epithelial ovarian, fallopian tube, or primary peritoneal cancer,
who are in complete or partial response to platinum-based
chemotherapy.
For the treatment of adult patients with deleterious or
suspected deleterious germline BRCA-mutated (gBRCAm) advanced
ovarian cancer who have been treated with 3 or more prior lines of
chemotherapy. Select patients for therapy based on an FDA-approved
companion diagnostic for LYNPARZA (olaparib).
In patients with deleterious or suspected
deleterious gBRCAm, human epidermal growth factor
receptor 2 (HER2)-negative metastatic breast cancer who have
previously been treated with chemotherapy in the neoadjuvant,
adjuvant or metastatic setting. Patients with hormone receptor
(HR)-positive breast cancer should have been treated with a prior
endocrine therapy or be considered inappropriate for endocrine
treatment. Select patients for therapy based on an FDA-approved
companion diagnostic for LYNPARZA.
Important Safety Information for LYNPARZA®
(olaparib)
Contraindications
There are no contraindications for LYNPARZA.
Warnings and Precautions
Myelodysplastic Syndrome/Acute Myeloid Leukemia
(MDS/AML): Occurred in <1.5% of patients exposed to
LYNPARZA monotherapy, and the majority of events had a fatal
outcome. The duration of therapy in patients who developed
secondary MDS/AML varied from <6 months to >2 years. All of
these patients had previous chemotherapy with platinum agents
and/or other DNA-damaging agents, including radiotherapy, and some
also had a history of more than one primary malignancy or of bone
marrow dysplasia.
Do not start LYNPARZA until patients have recovered from
hematological toxicity caused by previous chemotherapy (≤Grade 1).
Monitor complete blood count for cytopenia at baseline and monthly
thereafter for clinically significant changes during treatment. For
prolonged hematological toxicities, interrupt LYNPARZA and monitor
blood count weekly until recovery.
If the levels have not recovered to Grade 1 or less after 4
weeks, refer the patient to a hematologist for further
investigations, including bone marrow analysis and blood sample for
cytogenetics. Discontinue LYNPARZA if MDS/AML is confirmed.
Pneumonitis: Occurred in <1% of patients exposed
to LYNPARZA (olaparib), and some cases were fatal. If patients
present with new or worsening respiratory symptoms such as dyspnea,
cough, and fever, or a radiological abnormality occurs, interrupt
LYNPARZA treatment and initiate prompt investigation. Discontinue
LYNPARZA if pneumonitis is confirmed and treat patient
appropriately.
Embryo-Fetal Toxicity: Based on its mechanism of
action and findings in animals, LYNPARZA can cause fetal harm. A
pregnancy test is recommended for females of reproductive potential
prior to initiating treatment. Advise females of reproductive
potential of the potential risk to a fetus and to use effective
contraception during treatment and for 6 months following the last
dose. Advise male patients with female partners of
reproductive potential or who are pregnant to use effective
contraception during treatment and for 3 months following the last
dose of LYNPARZA and to not donate sperm during this time.
Adverse Reactions—Maintenance Setting
Most common adverse reactions (Grades 1-4) in ≥20% of patients
in clinical trials of LYNPARZA (olaparib) in the maintenance
setting for SOLO-2: nausea (76%), fatigue (including
asthenia) (66%), anemia (44%), vomiting (37%),
nasopharyngitis/upper respiratory tract infection (URI)/influenza
(36%), diarrhea (33%), arthralgia/myalgia (30%), dysgeusia (27%),
headache (26%), decreased appetite (22%), and stomatitis (20%).
Study 19: nausea (71%), fatigue (including asthenia) (63%),
vomiting (35%), diarrhea (28%), anemia (23%), respiratory tract
infection (22%), constipation (22%), headache (21%), and decreased
appetite (21%).
Most common laboratory abnormalities (Grades 1-4) in ≥25% of
patients in clinical trials of LYNPARZA in the maintenance
setting (SOLO-2/Study 19) were: increase in mean corpuscular volume
(89%/82%), decrease in hemoglobin (83%/82%), decrease in leukocytes
(69%/58%), decrease in lymphocytes (67%/52%), decrease in absolute
neutrophil count (51%/47%), increase in serum creatinine (44%/45%),
and decrease in platelets (42%/36%).
Adverse Reactions—Advanced gBRCAm Ovarian Cancer
Most common adverse reactions (Grades 1-4) in ≥20% of patients
in clinical trials of LYNPARZA for advanced gBRCAm ovarian
cancer after 3 or more lines of chemotherapy (pooled from 6
studies) were: fatigue (including asthenia) (66%), nausea (64%),
vomiting (43%), anemia (34%), diarrhea (31%), nasopharyngitis/upper
respiratory tract infection (URI) (26%), dyspepsia (25%), myalgia
(22%), decreased appetite (22%), and arthralgia/musculoskeletal
pain (21%).
Most common laboratory abnormalities (Grades 1-4) in ≥25% of
patients in clinical trials of LYNPARZA (olaparib)
for advanced gBRCAm ovarian cancer (pooled from 6
studies) were: decrease in hemoglobin (90%), increase in mean
corpuscular volume (57%), decrease in lymphocytes (56%), increase
in serum creatinine (30%), decrease in platelets (30%), and
decrease in absolute neutrophil count (25%).
Adverse Reactions—gBRCAm, HER2-Negative Breast Cancer
Most common adverse reactions (Grades 1-4) in ≥20% of patients
in OlympiAD were: nausea (58%), anemia (40%), fatigue
(including asthenia) (37%), vomiting (30%), neutropenia (27%),
respiratory tract infection (27%), leukopenia (25%), diarrhea
(21%), and headache (20%).
Most common laboratory abnormalities (Grades 1-4) in ≥25% of
patients in OlympiAD were: decrease in hemoglobin (82%),
decrease in lymphocytes (73%), decrease in leukocytes (71%),
increase in mean corpuscular volume (71%), decrease in absolute
neutrophil count (46%), and decrease in platelets (33%).
Drug Interactions
Anticancer Agents: Clinical studies of LYNPARZA in
combination with other myelosuppressive anticancer agents,
including DNA-damaging agents, indicate a potentiation and
prolongation of myelosuppressive toxicity.
CYP3A Inhibitors: Avoid concomitant use of strong or
moderate CYP3A inhibitors. If a strong or moderate CYP3A inhibitor
must be co-administered, reduce the dose of LYNPARZA. Advise
patients to avoid grapefruit, grapefruit juice, Seville oranges,
and Seville orange juice during LYNPARZA treatment.
CYP3A Inducers: Avoid concomitant use of strong or
moderate CYP3A inducers when using LYNPARZA (olaparib). If a
moderate inducer cannot be avoided, there is a potential for
decreased efficacy of LYNPARZA.
Use in Specific Populations
Lactation: No data are available regarding the
presence of olaparib in human milk, its effects on the breastfed
infant or on milk production. Because of the potential for serious
adverse reactions in the breastfed infant, advise a lactating woman
not to breastfeed during treatment with LYNPARZA (olaparib) and for
1 month after receiving the final dose.
Pediatric Use: The safety and efficacy of LYNPARZA
have not been established in pediatric patients.
Hepatic Impairment: No adjustment to the starting
dose is required in patients with mild hepatic impairment
(Child-Pugh classification A). There are no data in patients with
moderate or severe hepatic impairment.
Renal Impairment: No adjustment to the starting dose
is necessary in patients with mild renal impairment (CLcr=51-80
mL/min). In patients with moderate renal impairment (CLcr=31-50
mL/min), reduce the dose to 200 mg twice daily. There are no data
in patients with severe renal impairment or end-stage renal disease
(CLcr ≤30 mL/min).
Dosing and Administration
To avoid substitution errors and overdose, do not
substitute LYNPARZA tablets with LYNPARZA capsules on
a milligram-to-milligram basis due to differences in the dosing and
bioavailability of each formulation. Recommended tablet dose is 300
mg, taken orally twice daily, with or without food. Continue
treatment until disease progression or unacceptable toxicity. For
adverse reactions, consider dose interruption or dose
reduction.
About the AstraZeneca and Merck Strategic Oncology
Collaboration
In July 2017, AstraZeneca and Merck (known as MSD outside the
United States and Canada) announced a global strategic oncology
collaboration to co-develop and co-commercialize LYNPARZA, the
world’s first PARP inhibitor, and potential new medicine
selumetinib, a MEK inhibitor, for multiple cancer types. The
collaboration is based on increasing evidence that PARP and MEK
inhibitors can be combined with PD-L1/PD-1 inhibitors for a range
of tumor types. Working together, the companies will jointly
develop LYNPARZA and selumetinib in combination with other
potential new medicines and as a monotherapy. Independently, the
companies will develop LYNPARZA and selumetinib in combination with
their respective PD-L1 and PD-1 medicines.
Merck’s Focus on Cancer
Our goal is to translate breakthrough science into innovative
oncology medicines to help people with cancer worldwide. At Merck,
helping people fight cancer is our passion and supporting
accessibility to our cancer medicines is our commitment. Our focus
is on pursuing research in immuno-oncology and we are accelerating
every step in the journey – from lab to clinic – to potentially
bring new hope to people with cancer.
As part of our focus on cancer, Merck is committed to exploring
the potential of immuno-oncology with one of the fastest-growing
development programs in the industry. We are currently executing an
expansive research program evaluating our anti-PD-1 therapy across
more than 30 tumor types. We also continue to strengthen our
immuno-oncology portfolio through strategic acquisitions and are
prioritizing the development of several promising immunotherapeutic
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 a century, Merck, a leading global
biopharmaceutical company 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.
Through our prescription medicines, vaccines, biologic therapies
and animal health products, we work with customers and operate in
more than 140 countries to deliver innovative health solutions. We
also demonstrate our commitment to increasing access to health care
through far-reaching policies, programs and partnerships. Today,
Merck continues to be at the forefront of research to advance the
prevention and treatment of diseases that threaten people and
communities around the world - including cancer, cardio-metabolic
diseases, emerging animal diseases, Alzheimer’s disease and
infectious diseases including HIV and Ebola. 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 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 2017
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
https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf
and Patient Information/Medication Guide for KEYTRUDA
at
https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_mg.pdf.
Please see complete Prescribing Information for LYNPARZA
(olaparib)
tabletshttps://www.azpicentral.com/lynparza_tb/pi_lynparza_tb.pdf#page=1
and complete Prescribing Information for LYNPARZA
capsules,https://www.azpicentral.com/Lynparza/pi_lynparza.pdf#page=1
including Patient Information (Medication Guides).
ALIMTA® is a registered trademark of Eli Lilly and
Company.
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MerckMedia:Pamela Eisele, 267-305-3558orCourtney Ronaldo,
908-740-6132orInvestors:Teri Loxam, 908-740-1986orMichael DeCarbo,
908-740-1807
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