FDA Approves Two New Indications for Merck’s KEYTRUDA® (pembrolizumab)

KEYTRUDA Now Approved for First-Line Treatment of Patients with
Metastatic or with Unresectable, Recurrent Head and Neck Squamous Cell
Carcinoma as Monotherapy for Patients Whose Tumors Express PD-L1 (CPS
≥1) or in Combination with Platinum and Fluorouracil (FU) Regardless of
PD-L1 Expression

KENILWORTH, N.J.–(BUSINESS WIRE)–$MRK #MRK–Merck (NYSE: MRK), known as MSD outside the United States and Canada,
today announced that the U.S. Food and Drug Administration (FDA) has
approved KEYTRUDA, Merck’s anti-PD-1 therapy, as monotherapy in patients
whose tumors express PD-L1 (Combined Positive Score [CPS] ≥1) or in
combination with platinum and fluorouracil (FU), a commonly used
chemotherapy regimen, for the first-line treatment of patients with
metastatic or with unresectable, recurrent head and neck squamous cell
carcinoma (HNSCC). The approval is based on results from the pivotal
Phase 3 KEYNOTE-048 trial, where KEYTRUDA demonstrated a significant
improvement in overall survival (OS) compared with the EXTREME regimen
(cetuximab with carboplatin or cisplatin plus FU), a standard treatment,
as monotherapy in patients whose tumors expressed PD-L1 (CPS ≥1)
(HR=0.78 [95% CI, 0.64-0.96]; p=0.0171) and in combination with
chemotherapy in the total study population (HR=0.77 [95% CI, 0.63-0.93];
p=0.0067). With these new indications, KEYTRUDA is the first anti-PD-1
therapy approved in the first-line setting as monotherapy in patients
whose tumors express PD-L1 (CPS ≥1) or in combination with chemotherapy
regardless of PD-L1 expression for patients with metastatic or with
unresectable, recurrent HNSCC and the first anti-PD-1 therapy to
demonstrate a statistically significant improvement in OS in these
patients.

“This approval is a very exciting milestone in the treatment of head and
neck cancer and has the potential to transform the way we treat patients
with this debilitating disease by offering important new therapeutic
options,” said Dr. Barbara Burtness, professor of medicine, Yale School
of Medicine and co-director, Development Therapeutics Research Program,
Yale Cancer Center. “Metastatic or recurrent head and neck cancer has
been an area of significant unmet need, so it is encouraging to have
immunotherapy regimens available for patients in the first-line setting.”

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.

“Head and neck squamous cell carcinoma has historically presented many
challenges to physicians and patients, including limited treatment
options and physical and functional issues caused by the disease and its
treatment,” said Dr. Jonathan Cheng, vice president, clinical research,
Merck Research Laboratories. “This approval is an important advance in
the management of this devastating cancer. The results of KEYNOTE-048,
which support this approval, demonstrated that KEYTRUDA monotherapy for
patients whose tumors expressed PD-L1 CPS greater than or equal to one
and KEYTRUDA in combination with chemotherapy regardless of PD-L1
expression significantly prolonged survival for patients with metastatic
or with unresectable, recurrent head and neck squamous cell carcinoma in
the first-line setting.”

KEYTRUDA was initially approved for the treatment of patients with
recurrent or metastatic HNSCC with disease progression on or after
platinum-containing chemotherapy in 2016 under the FDA’s accelerated
approval process based on objective response rate data from the Phase 1b
KEYNOTE-012 trial. In accordance with the accelerated approval process,
continued approval was contingent upon verification and description of
clinical benefit, which has now been demonstrated in KEYNOTE-048 and has
resulted in the FDA converting the accelerated approval to a full
(regular) approval.

Data Supporting the Approval

This approval is based on data from the pre-specified interim analysis
of the Phase 3 KEYNOTE-048 trial, a randomized, multi-center,
open-label, active-controlled trial conducted in 882 patients with
metastatic HNSCC who had not previously received systemic therapy and
who were considered incurable by local therapies. Randomization was
stratified by tumor PD-L1 expression (Tumor Proportion Score [TPS] ≥50%
or <50%) according to the PD-L1 IHC 22C3 pharmDx kit, HPV status
according to p16 IHC (positive or negative), and ECOG Performance Status
(PS) (0 vs. 1). Patients were randomized 1:1:1 to one of the following
treatment arms:

• KEYTRUDA 200 mg intravenously every three weeks;
• KEYTRUDA 200 mg intravenously every three weeks, carboplatin AUC 5
  mg/mL/min intravenously every three weeks or cisplatin 100 mg/m²
  intravenously every three weeks and FU 1000 mg/m²/day as a
  continuous intravenous infusion over 96 hours every three weeks
  (maximum of six cycles of platinum and FU);
• Cetuximab 400 mg/m² intravenously as the initial dose then
  250 mg/m² intravenously once weekly, carboplatin AUC 5
  mg/mL/min intravenously every three weeks or cisplatin 100 mg/m²
  intravenously every three weeks and FU 1000 mg/m²/day as a
  continuous intravenous infusion over 96 hours every three weeks
  (maximum of six cycles of platinum and FU).

Among the 882 patients, the study population characteristics were:
median age of 61 years (range, 20 to 94), 36% age 65 or older; 83% male;
73% White, 20% Asian, and 2.4% Black; 61% had ECOG PS of 1; and 79% were
former or current smokers. Twenty-two percent of patients’ tumors were
HPV positive; 23% had PD-L1 TPS ≥50%; and 95% had stage IV disease (19%
were stage IVA, 6% were stage IVB, and 70% were stage IVC). Eighty-five
percent of patients’ tumors had PD-L1 expression of CPS ≥1, and 43% had
CPS ≥20.

Treatment with KEYTRUDA continued until RECIST v1.1-defined progression
of disease as determined by the investigator, unacceptable toxicity or a
maximum of 24 months. A retrospective re-classification of patients’
tumor PD-L1 status according to CPS using the PD-L1 IHC 22C3 pharmDx kit
was conducted using the tumor specimens used for randomization.

The main efficacy outcome measures were OS and progression-free survival
(PFS) as assessed by blinded independent central review (BICR) according
to RECIST v1.1 (modified to follow a maximum of 10 target lesions and a
maximum of five target lesions per organ) sequentially tested in the
subgroup of patients with CPS ≥20, the subgroup of patients with CPS ≥1
and the overall population.

Efficacy Results for KEYTRUDA as a Single Agent in KEYNOTE-048
(CPS ≥1 and CPS ≥20)

Endpoint			CPS ≥1						CPS ≥20
			KEYTRUDA 200 mg every 3 weeks n=257			Cetuximab Platinum FU n=255			KEYTRUDA 200 mg every 3 weeks n=133			Cetuximab Platinum FU n=122
OS
Number of events (%)			177 (69%)			206 (81%)			82 (62%)			95 (78%)
Median in months (95% CI)			12.3 (10.8, 14.9)			10.3 (9.0,11.5)			14.9 (11.6, 21.5)			10.7 (8.8, 12.8)
Hazard ratio* (95% CI)			0.78 (0.64, 0.96)						0.61 (0.45, 0.83)
p-Value†			0.0171						0.0015
PFS
Number of events (%)			225 (88%)			231 (91%)			113 (85%)			111 (91%)
Median in months (95% CI)			3.2 (2.2, 3.4)			5.0 (4.8, 5.8)			3.4 (3.2, 3.8)			5.0 (4.8, 6.2)
Hazard ratio ‡ (95% CI)			1.15 (0.95, 1.38)						0.99 (0.75, 1.29)
Objective Response Rate
ORR‡ (95% CI)			19% (14.5, 24.4)			35% (29.1, 41.1)			23% (16.4, 31.4)			36% (27.6, 45.3)
Complete response rate			5%			3%			8%			3%
Partial response rate			14%			32%			16%			33%
Duration of Response
Median in months (range)			20.9 (1.5+, 34.8+)			4.5 (1.2+, 28.6+)			20.9 (2.7, 34.8+)			4.2 (1.2+, 22.3+)
* Based on the stratified Cox proportional hazard model † Based on a stratified log-rank test ‡ Response: Best objective response as confirmed complete response or partial response

Efficacy Results for KEYTRUDA plus Platinum/Fluorouracil in
KEYNOTE-048

Endpoint			KEYTRUDA 200 mg every 3 weeks Platinum FU n=281			Cetuximab Platinum FU n=278
OS
Number (%) of patients with event			197 (70%)			223 (80%)
Median in months (95% CI)			13.0 (10.9, 14.7)			10.7 (9.3, 11.7)
Hazard ratio* (95% CI)			0.77 (0.63, 0.93)
p-Value†			0.0067
PFS
Number of patients with event (%)			244 (87%)			253 (91%)
Median in months (95% CI)			4.9 (4.7, 6.0)			5.1 (4.9, 6.0)
Hazard ratio* (95% CI)			0.92 (0.77, 1.10)
p-Value†			0.3394
Objective Response Rate
ORR‡ (95% CI)			36% (30.0, 41.5)			36% (30.7, 42.3)
Complete response rate			6%			3%
Partial response rate			30%			33%
Duration of Response
Median in months (range)			6.7 (1.6+, 30.4+)			4.3 (1.2+, 27.9+)
* Based on the stratified Cox proportional hazard model † Based on stratified log-rank test ‡ Response: Best objective response as confirmed complete response or partial response

In KEYNOTE-048, the safety of KEYTRUDA, as a single agent and in
combination with platinum (cisplatin or carboplatin) and FU
chemotherapy, was investigated in patients with previously untreated,
recurrent or metastatic HNSCC. The median duration of exposure to
KEYTRUDA 200 mg every three weeks was 3.5 months (range, 1 day to 24.2
months) in the KEYTRUDA single agent arm and was 5.8 months (range, 3
days to 24.2 months) in the combination arm.

KEYTRUDA was discontinued for adverse reactions in 12% of patients in
the KEYTRUDA single agent arm. The most common adverse reactions
resulting in permanent discontinuation of KEYTRUDA were sepsis (1.7%)
and pneumonia (1.3%). Adverse reactions leading to the interruption of
KEYTRUDA occurred in 31% of patients; the most common adverse reactions
leading to the interruption of KEYTRUDA (≥2%) were pneumonia (2.3%),
pneumonitis (2.3%) and hyponatremia (2%). The most common adverse
reactions (≥20%) with KEYTRUDA as a single agent were fatigue (33%),
constipation (20%), and rash (20%).

KEYTRUDA was discontinued for adverse reactions in 16% of patients in
the combination arm. The most common adverse reactions resulting in
permanent discontinuation of KEYTRUDA were pneumonia (2.5%), pneumonitis
(1.8%) and septic shock (1.4%). Adverse reactions leading to the
interruption of KEYTRUDA occurred in 45% of patients; the most common
adverse reactions leading to interruption of KEYTRUDA (≥2%) were
neutropenia (14%), thrombocytopenia (10%), anemia (6%), pneumonia (4.7%)
and febrile neutropenia (2.9%). The most common adverse reactions (≥20%)
with KEYTRUDA in combination with platinum and FU were nausea (51%),
fatigue (49%), constipation (37%), vomiting (32%), mucosal inflammation
(31%), diarrhea (29%), decreased appetite (29%), stomatitis (26%) and
cough (22%).

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 1,000 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 NSCLC expressing PD-L1 [Tumor Proportion Score (TPS)
≥1%] as determined by an FDA-approved test, with no EGFR or ALK genomic
tumor aberrations, and is:

• stage III where patients are not candidates for surgical resection or
  definitive chemoradiation, or
• metastatic.

KEYTRUDA, as a single agent, is indicated for the treatment of patients
with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined
by an FDA-approved test, with disease progression on or after
platinum-containing chemotherapy. Patients with EGFR or ALK genomic
tumor aberrations should have disease progression on FDA-approved
therapy for these aberrations prior to receiving KEYTRUDA.

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, in combination with platinum and fluorouracil (FU), is
indicated for the first-line treatment of patients with metastatic or
with unresectable, recurrent head and neck squamous cell carcinoma
(HNSCC).

KEYTRUDA, as a single agent, is indicated for the first line treatment
of patients with metastatic or unresectable, recurrent HNSCC whose
tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by
an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients
with recurrent or metastatic HNSCC with disease progression on or after
platinum-containing chemotherapy.

In HNSCC, the recommended dose of KEYTRUDA is 200 mg administered as an
intravenous infusion over 30 minutes every 3 weeks until disease
progression, unacceptable toxicity, or up to 24 months in patients
without disease progression.

When administering KEYTRUDA in combination with chemotherapy, administer
KEYTRUDA prior to chemotherapy when given on the same day. Refer to the
Prescribing Information for the chemotherapy agents administered in
combination with KEYTRUDA for recommended dosing information, as
appropriate.

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
[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 (RCC).

Contacts

Media Contacts:
Pamela Eisele
(267) 305-3558

Ayn
Wisler
(908) 740-5590

Investor Contacts:
Teri Loxam
(908)
740-1986

Michael DeCarbo
(908) 740-1807

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