FDA Approves Merck’s KEYTRUDA® (pembrolizumab) in Combination With Inlyta® (axitinib) as First-Line Treatment for Patients With Advanced Renal Cell Carcinoma (RCC)

Approval Based on Results of KEYNOTE-426, Where KEYTRUDA in
Combination With Axitinib Reduced the Risk of Death by Nearly Half
Compared to Sunitinib

KENILWORTH, N.J.–(BUSINESS WIRE)–lt;a href=”https://twitter.com/search?q=%24MRK&src=ctag” target=”_blank”gt;$MRKlt;/agt; lt;a href=”https://twitter.com/hashtag/MRK?src=hash” target=”_blank”gt;#MRKlt;/agt;–Merck (NYSE: MRK), known as MSD outside the United States and Canada,
today announced that the U.S. Food and Drug Administration (FDA) has
approved KEYTRUDA, Merck’s anti-PD-1 therapy, in combination with Inlyta
(axitinib), a tyrosine kinase inhibitor, for the first-line treatment of
patients with advanced renal cell carcinoma (RCC). The approval is based
on findings from the pivotal Phase 3 KEYNOTE-426 trial, which
demonstrated significant improvements in overall survival (OS),
progression-free survival (PFS) and objective response rate (ORR) for
KEYTRUDA in combination with axitinib (KEYTRUDA-axitinib combination)
compared to sunitinib. Consistent results were observed across
pre-specified subgroups, IMDC risk categories and PD-L1 tumor expression
status. For the main efficacy outcome measures of OS and PFS, the
KEYTRUDA-axitinib combination reduced the risk of death by 47% compared
to sunitinib (HR=0.53 [95% CI, 0.38-0.74]; p<0.0001); for PFS, the
KEYTRUDA-axitinib combination showed a reduction in the risk of
progression of disease or death of 31% compared to sunitinib (HR=0.69
[95% CI, 0.57-0.84]; p=0.0001). The ORR, an additional efficacy outcome
measure, was 59% for patients who received the KEYTRUDA-axitinib
combination (95% CI, 54-64) and 36% for those who received sunitinib
(95% CI, 31-40) (p<0.0001). This is the first indication for KEYTRUDA in
advanced RCC, the most common type of kidney cancer, and the first
anti-PD-1 therapy FDA-approved as part of a combination regimen that
significantly improved OS, PFS, and ORR versus sunitinib in patients
with advanced RCC.

“This represents a new treatment option for patients with advanced renal
cell carcinoma, who will now have access to KEYTRUDA as part of a
first-line combination regimen,” said Dr. Scot Ebbinghaus, vice
president, clinical research, Merck Research Laboratories. “Today’s
approval reflects Merck’s commitment to patients with cancer and further
supports the use of KEYTRUDA to help improve survival outcomes for
patients with advanced renal cell carcinoma.”

Immune-mediated adverse reactions, which may be severe or fatal, can
occur with KEYTRUDA, including pneumonitis, colitis, hepatitis,
endocrinopathies, nephritis and renal dysfunction, severe skin
reactions, solid organ transplant rejection, and complications of
allogeneic hematopoietic stem cell transplantation (HSCT). Based on the
severity of the adverse reaction, KEYTRUDA should be withheld or
discontinued and corticosteroids administered if appropriate. KEYTRUDA
can also cause severe or life-threatening infusion-related reactions.
Based on its mechanism of action, KEYTRUDA can cause fetal harm when
administered to a pregnant woman. For more information, see “Selected
Important Safety Information” below.

“Given the aggressive nature of the disease, many patients with advanced
renal cell carcinoma need additional treatment options that can help
improve survival outcomes,” said Dr. Brian Rini, medical oncologist at
Cleveland Clinic Cancer Center and professor of medicine at the
Cleveland Clinic Lerner College of Medicine of Case Western Reserve
University. “Pembrolizumab in combination with axitinib offers an
important new therapeutic option for physicians to consider when
approaching initial treatment for patients newly diagnosed with advanced
renal cell carcinoma.” Dr. Rini reports consulting and research funding
from Merck.

About KEYNOTE-426

The approval was based on data from the pre-specified interim analysis
of the Phase 3 KEYNOTE-426 trial, a randomized, multi-center, open-label
trial conducted in 861 patients who had not received systemic therapy
for advanced RCC. Patients were enrolled regardless of PD-L1 tumor
expression status. Randomization was stratified by International
Metastatic RCC Database Consortium (IMDC) risk categories (favorable
versus intermediate versus poor) and geographic region (North America
versus Western Europe versus “Rest of the World”). Patients with active
autoimmune disease requiring systemic immunosuppression within the last
two years were ineligible.

Patients were randomized (1:1) to one of the following treatment arms:

• • KEYTRUDA 200 mg intravenously every three weeks up to 24 months in
    combination with axitinib 5 mg orally, twice daily (n=432).

• • Sunitinib 50 mg orally, once daily for four weeks and then off
    treatment for two weeks (n=429).

Among the 861 patients, the study population characteristics were:
median age of 62 years (range, 26 to 90); 38% age 65 or older; 73% male;
79% White and 16% Asian; 19% and 80% of patients had a baseline
Karnofsky Performance Status (KPS) of 70 to 80 and 90 to 100,
respectively; and patient distribution by IMDC risk categories was 31%
favorable, 56% intermediate, and 13% poor.

Treatment with the KEYTRUDA-axitinib combination continued until RECIST
v1.1 (modified to follow a maximum of 10 target lesions and a maximum of
5 target lesions per organ)-defined progression of disease or
unacceptable toxicity. The main efficacy outcome measures were OS and
PFS as assessed by BICR according to modified RECIST v1.1. Additional
efficacy outcome measures included ORR, as assessed by BICR.

The trial demonstrated statistically significant improvements in OS,
PFS, and ORR in patients randomized to receive the KEYTRUDA-axitinib
combination compared to sunitinib.

With a median follow-up time of 12.8 months (range, 0.1 to 22 months),
OS was significantly improved in patients who received the
KEYTRUDA-axitinib combination compared to sunitinib (HR=0.53 [95% CI,
0.38-0.74]; p<0.0001). Estimated 12-month OS rates were 90% (95% CI,
86-92) with the KEYTRUDA-axitinib combination versus 78% (95% CI, 74-82)
with sunitinib. Median OS was not reached with either treatment
regimen. Progression-free survival was also significantly improved with
the KEYTRUDA-axitinib combination compared to sunitinib (HR=0.69 [95%
CI, 0.57-0.84]; p=0.0001). Median PFS was 15.1 months (95% CI,
12.6-17.7) in patients receiving the KEYTRUDA-axitinib combination
versus 11.1 months (95% CI, 8.7-12.5) with sunitinib. In the study, the
ORR was 59% for patients who received the KEYTRUDA-axitinib combination
(95% CI, 54-64) and 36% for those who received sunitinib (95% CI, 31-40)
(p<0.0001), with a complete response rate of 6% and 2% and a partial
response rate of 53% and 34%, for patients receiving the
KEYTRUDA-axitinib combination versus sunitinib, respectively.

In KEYNOTE-426, the safety of KEYTRUDA in combination with axitinib was
investigated in patients with previously untreated, advanced RCC. The
median duration of exposure to the combination therapy of KEYTRUDA and
axitinib was 10.4 months (range, 1 day to 21.2 months). Fatal adverse
reactions occurred in 3.3% of patients receiving KEYTRUDA in combination
with axitinib. Serious adverse reactions occurred in 40% of patients
receiving KEYTRUDA in combination with axitinib. Serious adverse
reactions in ≥1% of patients receiving KEYTRUDA in combination with
axitinib included hepatotoxicity (7%), diarrhea (4.2%), acute kidney
injury (2.3%), dehydration (1%), and pneumonitis (1%). Permanent
discontinuation due to an adverse reaction of either KEYTRUDA or
axitinib occurred in 31% of patients; 13% KEYTRUDA only, 13% axitinib
only, and 8% both drugs. The most common adverse reaction (>1%)
resulting in permanent discontinuation of KEYTRUDA, axitinib or the
combination was hepatotoxicity (13%), diarrhea/colitis (1.9%), acute
kidney injury (1.6%), and cerebrovascular accident (1.2%). The most
common adverse reactions (≥20%) in patients receiving in patients
receiving KEYTRUDA and axitinib 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%).

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. There are currently more than 950 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. The recommended dose of KEYTRUDA in patients with
unresectable or metastatic melanoma is 200 mg administered as an
intravenous infusion over 30 minutes every three weeks until disease
progression or unacceptable toxicity.

KEYTRUDA is indicated for the adjuvant treatment of patients with
melanoma with involvement of lymph node(s) following complete resection.
The recommended dose of KEYTRUDA for the adjuvant treatment of adult
patients with melanoma is 200 mg administered as an intravenous infusion
over 30 minutes every three weeks until disease recurrence, unacceptable
toxicity, or for up to 12 months in patients without disease recurrence.

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 stage III NSCLC who are not candidates for surgical
resection or definitive chemoradiation, or metastatic NSCLC, and whose
tumors express PD-L1 [tumor proportion score (TPS) ≥1%] as determined by
an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.

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.

In NSCLC, the recommended dose of KEYTRUDA is 200 mg administered as an
intravenous infusion over 30 minutes 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 the chemotherapy agents
administered in combination with KEYTRUDA, as appropriate.

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 200 mg
is administered as an intravenous infusion over 30 minutes 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 3 or more prior lines of therapy. This indication is approved
under accelerated approval based on tumor response rate and durability
of response. Continued approval for this indication may be contingent
upon verification and description of clinical benefit in the
confirmatory trials. In adults with cHL, KEYTRUDA 200 mg is administered
as an intravenous infusion over 30 minutes 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 as an intravenous infusion over 30 minutes 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.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients
with refractory primary mediastinal large B-cell lymphoma (PMBCL), or
who have relapsed after 2 or more prior lines of therapy. This
indication is approved under accelerated approval based on tumor
response rate and durability of response. Continued approval for this
indication may be contingent upon verification and description of
clinical benefit in confirmatory trials. KEYTRUDA is not recommended for
the treatment of patients with PMBCL who require urgent cytoreductive
therapy.

In adults with PMBCL, KEYTRUDA 200 mg is administered as an intravenous
infusion over 30 minutes every three weeks until disease progression,
unacceptable toxicity, or up to 24 months in patients without disease
progression. In pediatric patients with PMBCL, KEYTRUDA is administered
as an intravenous infusion over 30 minutes 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 (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 the 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.

In locally advanced or metastatic urothelial carcinoma, KEYTRUDA 200 mg
is administered as an intravenous infusion over 30 minutes 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 200 mg is administered as
an intravenous infusion over 30 minutes every three weeks until disease
progression, unacceptable toxicity, or up to 24 months in patients
without disease progression. In pediatric patients with MSI-H cancer,
KEYTRUDA is administered as an intravenous infusion over 30 minutes 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 (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 as an intravenous infusion over 30 minutes every
three weeks until disease progression, unacceptable toxicity, or up to
24 months in patients without disease progression.

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. The recommended dose of KEYTRUDA is 200 mg as an intravenous
infusion over 30 minutes every three weeks until disease progression,
unacceptable toxicity or up to 24 months in patients without disease
progression.

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. The recommended dose of
KEYTRUDA is 200 mg as an intravenous infusion over 30 minutes every
three weeks until disease progression, unacceptable toxicity, or up to
24 months in patients without disease progression.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients
with recurrent locally advanced or metastatic Merkel cell carcinoma.
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 in adults is 200 mg administered as an intravenous infusion
over 30 minutes every three weeks until disease progression,
unacceptable toxicity, or up to 24 months in patients without disease
progression. The recommended dose of KEYTRUDA in pediatric patients is 2
mg/kg (up to a maximum of 200 mg), administered as an intravenous
infusion over 30 minutes every three weeks until disease progression or
unacceptable toxicity, or up to 24 months in patients without disease
progression.

Renal Cell Carcinoma

KEYTRUDA, in combination with axitinib, is indicated for the first-line
treatment of patients with advanced renal cell carcinoma. In renal cell
carcinoma, KEYTRUDA 200 mg is administered as an intravenous infusion
over 30 minutes every 3 weeks in combination with 5 mg axitinib orally
twice daily until disease progression, unacceptable toxicity, or for
KEYTRUDA, up to 24 months in patients without disease progression. When
axitinib is used in combination with KEYTRUDA, dose escalation of
axitinib above the initial 5 mg dose may be considered at intervals of
six weeks or longer. See also the Prescribing Information for
recommended axitinib dosing information.

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%).

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, or Hepatoxicity (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. Grades 3 and 4 increased ALT and
AST were seen in 20% and 13% of patients, respectively. Monitor liver
enzymes before initiation of and periodically throughout treatment.
Consider more frequent monitoring of liver enzymes as compared to when
the drugs are used in monotherapy. For elevated liver enzymes, interrupt
KEYTRUDA and axitinib, and consider administering corticosteroids as
needed.

Immune-Mediated Endocrinopathies

KEYTRUDA can cause hypophysitis, thyroid disorders, and type 1 diabetes
mellitus. 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 patients with
HNSCC, occurring in 15% (28/192) of patients.

Contacts

Media:
Pamela Eisele
(267) 305-3558

Investor:
Teri Loxam
(908) 740-1986

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