Merck’s KEYTRUDA® (pembrolizumab) Plus Pemetrexed (ALIMTA®) and Platinum Chemotherapy Reduced the Risk of Death by Half Compared with Chemotherapy Alone as First-Line Treatment for Advanced Nonsquamous NSCLC in Phase 3 KEYNOTE-189 Study

KEYTRUDA Combination Improved Overall Survival in Patients Regardless
of PD-L1 Expression, Including Patients Who Tested Negative for PD-L1

Results Presented Today at AACR 2018 and Published in The New
England Journal of Medicine
Also Show Significant Improvement in
Progression-Free Survival, with Risk of Progression or Death Reduced by
Nearly Half

KENILWORTH, N.J.–(BUSINESS WIRE)–$MRK #MRK–Merck (NYSE: MRK), known as MSD outside the United States and Canada,
today announced results from KEYNOTE-189, a pivotal Phase 3 trial
evaluating KEYTRUDA®, 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). Findings showed that the
KEYTRUDA-pemetrexed-platinum chemotherapy combination significantly
improved overall survival (OS), reducing the risk of death by half
compared with chemotherapy alone (HR=0.49 [95% CI, 0.38-0.64];
p<0.00001). In pre-specified exploratory analyses, an OS benefit was observed regardless of PD-L1 expression in the three PD-L1 categories that were evaluated, including: patients whose tumors were negative for PD-L1 (HR=0.59 [95% CI, 0.38-0.92]); patients whose tumors had PD-L1 tumor proportion scores (TPS) of 1-49 percent (HR=0.55 [95% CI, 0.34-0.90]); and patients who had a TPS of greater than or equal to 50 percent (HR=0.42 [95% CI, 0.26-0.68]). The addition of KEYTRUDA to pemetrexed plus platinum chemotherapy also achieved a significant improvement in progression-free survival (PFS), with a reduction in the risk of progression or death of nearly half for patients in the KEYTRUDA combination arm, compared with chemotherapy alone (HR=0.52 [95% CI, 0.43-0.64]; p<0.00001). A PFS improvement in the KEYTRUDA combination group was observed in patients whose tumors were negative for PD-L1 (HR=0.75 [95% CI, 0.53-1.05]); patients with a TPS of 1-49 percent (HR=0.55 [95% CI, 0.37-0.81]); and patients with a TPS greater than or equal to 50 percent (HR=0.36 [95% CI, 0.25-0.52]). These results are being presented today in a plenary session at the American Association for Cancer Research (AACR) Annual Meeting 2018 (Abstract #CT075), with simultaneous publication in The New England Journal of Medicine.

In this trial, KEYTRUDA in combination with pemetrexed and platinum
chemotherapy, compared with chemotherapy alone, prolonged overall
survival and progression-free survival in patients with advanced
nonsquamous non-small cell lung cancer regardless of PD-L1 expression,”
said Dr. Leena Gandhi, director of thoracic medical oncology at NYU
Langone’s Perlmutter Cancer Center and lead author of The New England
Journal of Medicine
paper. “There is good scientific rationale for
combining KEYTRUDA with pemetrexed and platinum chemotherapy, and these
clinical data now suggest this combination as a new standard of care for
the first-line treatment of these nonsquamous non-small cell lung cancer
patients.”

Our goal is to extend the lives of patients with lung cancer, and the
unambiguous survival findings from KEYNOTE-189 showing the risk of death
was reduced by half in the KEYTRUDA arm are important not only for
patients but also for the medical community,” said Dr. Roger M.
Perlmutter, president, Merck Research Laboratories. “The results of this
trial have the potential to change the treatment paradigm for patients
with nonsquamous non-small cell lung cancer in the first-line setting,
including patients whose tumors are either PD-L1 negative or are
untested.”

KEYTRUDA is the first immunotherapy to significantly extend survival of
patients with nonsquamous NSCLC in combination with chemotherapy as a
first-line treatment. KEYNOTE-189 is the confirmatory trial for
KEYNOTE-021 (Cohort G), a Phase 2 study that made KEYTRUDA the only
FDA-approved anti-PD-1 therapy in combination with chemotherapy
(pemetrexed plus carboplatin) for the first-line treatment of patients
with metastatic nonsquamous NSCLC, regardless of PD-L1 expression. Merck
is working to submit data from KEYNOTE-189 to regulatory agencies in the
United States and around the world.

Merck has an extensive clinical development program in lung cancer and
is advancing multiple registration-enabling studies with KEYTRUDA in
combination with other treatments and as monotherapy. The program, which
is comprised of nearly 9,000 patients across 15 clinical studies, is
evaluating KEYTRUDA across multiple settings and stages of the disease.

The reality is, there remains a significant need for treatment options
for patients with lung cancer. At the Bonnie J. Addario Lung Cancer
Foundation (ALCF), we are devoted exclusively to eradicating lung cancer
through research, early detection, education and treatment. And, the
survival benefit achieved by the KEYTRUDA combination in the KEYNOTE-189
study represents a meaningful advance and may offer hope for patients
newly diagnosed with one of the most common and deadly cancers,” said
Bonnie J. Addario, a 14-year lung cancer survivor and ALCF founder.

Additional Data and Safety Information from KEYNOTE-189 (Abstract
#CT075)

KEYNOTE-189, a randomized, double-blind,
placebo-controlled, Phase 3 study, evaluated KEYTRUDA in combination
with pemetrexed and cisplatin or carboplatin, compared with pemetrexed
and cisplatin or carboplatin alone, in 616 untreated patients with
metastatic nonsquamous NSCLC, regardless of PD-L1 expression. Patients
had no sensitizing EGFR or ALK genomic tumor aberrations,
and had not previously received systemic therapy for advanced disease.
The dual primary endpoints were OS and PFS; secondary endpoints include
overall response rate (ORR) and duration of response (DOR).

With a median follow-up of 10.5 months (range, 0.2-20.4), KEYTRUDA in
combination with pemetrexed and a platinum chemotherapy demonstrated
superior improvements in OS, with a 51 percent reduction in the risk of
death, compared with pemetrexed plus platinum chemotherapy alone
(HR=0.49 [95% CI, 0.38-0.64]; p<0.00001). This finding includes the 50 percent of patients randomized to the chemotherapy alone group who discontinued all study therapy (n=170) and went on to receive subsequent anti-PD-1 or PD-L1 therapy, including 67 patients who received KEYTRUDA monotherapy as part of study crossover. Median OS was not reached in the KEYTRUDA combination group (95% CI, not estimable) and was 11.3 months in the chemotherapy alone group (95% CI, 8.7-15.1). In the study, 69.2 percent of patients were estimated to be alive at 12 months in the KEYTRUDA treatment group (95% CI, 64.1-73.8%) compared with 49.4 percent in the chemotherapy alone group (95% CI, 42.1-56.2%).

In KEYNOTE-189 there was also a significant improvement in PFS for
KEYTRUDA in combination with pemetrexed and platinum chemotherapy with a
48 percent reduction in the risk of progression or death compared with
pemetrexed plus platinum chemotherapy alone (HR=0.52 [95% CI,
0.43-0.64]; p<0.00001). The median PFS was 8.8 months for the KEYTRUDA combination (95% CI, 7.6-9.2) compared with 4.9 months for chemotherapy alone (95% CI, 4.7-5.5). The percentage of patients who were alive with no progression of disease at 12 months was 34.1 percent in the KEYTRUDA combination group (95% CI, 28.8-39.5%), which was nearly double the percentage of the pemetrexed plus platinum chemotherapy group (17.3 percent [95% CI, 12.0-23.5%]). In addition, improvements in OS and PFS were observed in other patient subgroups evaluated, including age, sex, EGOG performance-status score, smoking status, brain metastases at baseline and type of platinum chemotherapy prescribed (carboplatin or cisplatin).

In the study, KEYTRUDA plus pemetrexed and a platinum chemotherapy also
showed an ORR that was more than double the ORR of chemotherapy alone
(47.6 percent [95% CI, 42.6-52.5%] compared to 18.9 percent [95% CI,
13.8-25.0%], respectively, p<0.00001). Among patients in the KEYTRUDA arm, the median duration of response was 11.2 months (range, 1.1+ to 18.0+ months) compared with 7.8 months in the chemotherapy alone group (range, 2.1+ to 16.4+ months). The improvement in response rate occurred in all PD-L1 patient subgroups.

The safety of KEYTRUDA was consistent with what has been seen in
previous trials among patients with metastatic NSCLC. Grade 3-5 adverse
events from any cause occurred in 67.2 percent of patients in the
KEYTRUDA plus pemetrexed and platinum chemotherapy group and 65.8
percent in the chemotherapy alone arm. Adverse events of any grade and
from any cause with an incidence of 15 percent or more in the KEYTRUDA
group were nausea (55.6%), anemia (46.2%), fatigue (40.7%), constipation
(34.8%), diarrhea (30.9%), decreased appetite (28.1%), neutropenia
(27.2%), vomiting (24.2%), cough (21.5%), dyspnea (21.2%), asthenia
(20.5%), rash (20.2%), pyrexia (19.5%), edema peripheral (19.3%),
thrombocytopenia (18.0%) and increased lacrimation (17.0%). The most
common immune-mediated adverse events of any grade in patients receiving
KEYTRUDA plus pemetrexed and platinum chemotherapy were hypothyroidism
(6.7%), pneumonitis (4.4%), hyperthyroidism (4.0%), infusion reactions
(2.5%), colitis (2.2%), severe skin toxicity (2.0%), nephritis (1.7%)
and hepatitis (1.2%). There were three treatment-related deaths from
pneumonitis in the KEYTRUDA plus pemetrexed and platinum chemotherapy
group.

About KEYNOTE-189
KEYNOTE-189 (ClinicalTrials.gov,
NCT02578680) enrolled 616 patients who were randomized 2:1 to one of two
treatment groups, and were treated until disease progression,
unacceptable toxicity, physician decision or consent withdrawal, as
follows:

  • KEYTRUDA (200 mg fixed dose every three weeks) plus pemetrexed (500
    mg/m2) (with vitamin supplementation) plus cisplatin (75
    mg/m2) or carboplatin AUC 5 mg/mL/min on day 1 every three
    weeks (Q3W) for four cycles, followed by KEYTRUDA 200 mg plus
    pemetrexed (500 mg/m2) Q3W; or
  • Saline placebo plus pemetrexed (500 mg/m2) (with vitamin
    supplementation) plus cisplatin (75 mg/m2) or carboplatin
    AUC 5 mg/mL/min on day 1 every three weeks (Q3W) for four cycles,
    followed by placebo plus pemetrexed (500 mg/m2) Q3W.

Patients on the control arm who experienced disease progression,
verified by central independent review, were permitted to undergo
treatment assignment unblinding and crossover to receive open-label
KEYTRUDA. The KEYNOTE-189 study was conducted in collaboration with Eli
Lilly and Company, the makers of pemetrexed (ALIMTA).

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, breast and prostate cancers combined. The two
main types of lung cancer are non-small cell and small cell. NSCLC is
the most common type of lung cancer, accounting for about 85 percent of
all cases. The five-year survival rate for patients diagnosed in the
United States with any stage of lung cancer is estimated to be 18
percent.

Merck Investor Webcast
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webcast in conjunction with the AACR 2018 Annual Meeting on Monday,
April 16 at 6:45 p.m. CDT (7:45 p.m. EDT). Those interested in
participating can register and join here.

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 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 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 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®
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, 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.

Contacts

Merck
Media:
Pamela Eisele, 267-305-3558
or
Kristen
Drake, 908-334-4688
or
Investors:
Teri Loxam, 908-740-1986
or
Michael
DeCarbo, 908-740-1807

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