FDA Approves Merck’s KEYTRUDA® (pembrolizumab) for Treatment of Refractory or Relapsed Primary Mediastinal Large B-Cell Lymphoma (PMBCL)

KEYTRUDA is the First Anti-PD-1 Therapy Approved for Adult and
Pediatric Patients with Refractory PMBCL or Who Have Relapsed After Two
or More Prior Lines of Therapy

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®, the company’s anti-PD-1 therapy, for the
treatment of adult and pediatric patients with refractory primary
mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after
two or more prior lines of therapy. This indication is approved under
the FDA’s accelerated approval regulations 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. With this
indication, KEYTRUDA becomes the first anti-PD-1 therapy to be approved
for the treatment of PMBCL, a type of non-Hodgkin lymphoma. This is the
second indication for KEYTRUDA for the treatment of a hematologic
malignancy.

Relapsed or refractory PMBCL is often a challenging disease to treat,
and many affected patients are young adults,” said Philippe Armand,
M.D., Ph.D., medical oncologist in the Hematologic Oncology Treatment
Center at Dana-Farber Cancer Institute. “In the clinical trial that
supported this approval, treatment with KEYTRUDA resulted in meaningful
responses, including complete disease remission in some patients. This
approval therefore provides another therapeutic option for patients with
PMBCL who have progressed on or after prior therapies.”

Immune-mediated adverse reactions occurred with KEYTRUDA, including
pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, severe
skin reactions and solid organ transplant rejection. Based on the
severity of the adverse reaction, KEYTRUDA should be withheld or
discontinued and corticosteroids administered if appropriate.
Immune-mediated complications, including fatal events, occurred in
patients with classical Hodgkin lymphoma (cHL) who underwent allogeneic
hematopoietic stem cell transplantation (HSCT) after treatment with
KEYTRUDA. Follow patients closely for early evidence of
transplant-related complications, and intervene promptly. In patients
with a history of allogeneic HSCT, acute graft-versus-host disease
(GVHD), including fatal GVHD, has been reported after treatment with
KEYTRUDA; consider the benefit of KEYTRUDA versus the risk of GVHD.
KEYTRUDA can also cause severe or life-threatening infusion-related
reactions. Monitor patients for signs and symptoms of infusion-related
reactions; for Grade 3 or 4 reactions, stop infusion and permanently
discontinue KEYTRUDA. Based on its mechanism of action, KEYTRUDA can
cause fetal harm when administered to a pregnant woman. Female patients
of reproductive potential should be advised of the potential hazard to a
fetus. For more information, see “Selected Important Safety Information”
below.

The approval of our anti-PD-1 therapy, KEYTRUDA, for the treatment of
refractory or relapsed PMBCL provides an important therapeutic option
for patients who have this rare disease,” said Jonathan Cheng, M.D.,
vice president, oncology clinical research, Merck Research Laboratories.
This approval reinforces Merck’s commitment to helping patients
diagnosed with hematologic cancers and marks the second indication for
KEYTRUDA in a hematologic malignancy.”

Data Supporting the Approval

The approval was based on data from KEYNOTE-170, a multicenter,
open-label, single-arm trial evaluating KEYTRUDA in 53 patients with
relapsed or refractory PMBCL. Patients were not eligible for the trial
if they had active non-infectious pneumonitis, allogeneic HSCT within
the past five years (or greater than 5 years but with symptoms of GVHD),
active autoimmune disease, a medical condition that required
immunosuppression, or an active infection requiring systemic therapy.
Patients received KEYTRUDA 200 mg every three weeks until unacceptable
toxicity or documented disease progression, or for up to 24 months for
patients who did not progress. Disease assessments were performed every
12 weeks and assessed by blinded independent central review according to
the 2007 revised International Working Group criteria. Efficacy was
based on overall response rate (ORR) and duration of response (DOR).

Among the 53 patients accrued in KEYNOTE-170, the baseline
characteristics were: median age of 33 years (range, 20 to 61 years); 43
percent were male; 92 percent were White; 43 percent had an ECOG
performance status (PS) of 0 and 57 percent had an ECOG PS of 1. The
median number of prior lines of therapy administered for the treatment
of PMBCL was three (range, 2 to 8). Thirty-six percent had primary
refractory disease, 49 percent had relapsed disease refractory to the
last prior therapy, and 15 percent had untreated relapse. Twenty-six
percent of patients had undergone prior autologous HSCT and 32 percent
of patients had prior radiation therapy. All patients had received
rituximab as part of a prior line of therapy.

In KEYNOTE-170, the ORR was 45 percent (95% CI, 32, 60), with a complete
response rate (CRR) of 11 percent and a partial response rate of 34
percent. Median DOR, based on 24 patients who responded, was not reached
(range, 1.1+ to 19.2+ months). For the 24 responders, the median time to
first objective response (complete or partial response) was 2.8 months
(range, 2.1 to 8.5 months). Median follow-up time was 9.7 months.

Among the 53 patients with PMBCL treated in KEYNOTE-170, KEYTRUDA was
discontinued due to adverse reactions in eight percent of patients, and
treatment was interrupted due to adverse reactions in 15 percent.
Twenty-five percent of patients had an adverse reaction requiring
systemic corticosteroid therapy. Serious adverse reactions occurred in
26 percent of patients, and included arrhythmia (4%), cardiac tamponade
(2%), myocardial infarction (2%), pericardial effusion (2%) and
pericarditis (2%). Six (11%) patients died within 30 days of start of
treatment. The most common adverse reactions (occurring in ≥20% of
patients) were musculoskeletal pain (30%), upper respiratory tract
infection and pyrexia (28% each), cough (26%), fatigue (23%) and dyspnea
(21%).

There is limited experience with KEYTRUDA in pediatric patients.
Efficacy for pediatric patients with PMBCL was extrapolated from the
results in the adult PMBCL population. In a study of 40 pediatric
patients with advanced melanoma, lymphoma, or PD-L1 positive advanced,
relapsed, or refractory solid tumors, patients were administered
KEYTRUDA 2 mg/kg every three weeks. Patients received KEYTRUDA for a
median of three doses (range, 1-17 doses), with 34 patients (85%)
receiving KEYTRUDA for two 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
pediatric patients when compared to adults under 65 years of age were
fatigue (45%), vomiting (38%), abdominal pain (28%),
hypertransaminasemia (28%) and hyponatremia (18%).

About KEYTRUDA® (pembrolizumab) Injection,
100 mg

KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of
the body’s immune system to help detect and fight tumor cells. KEYTRUDA
is a humanized monoclonal antibody that blocks the interaction between
PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes
which may affect both tumor cells and healthy cells.

Merck has the industry’s largest immuno-oncology clinical research
program, which currently involves more than 750 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.

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 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 pediatric
patients with PMBCL, 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.

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 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. 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.

Immune-mediated adverse reactions, which may be severe or fatal, can
occur in any organ system or tissue in patients receiving KEYTRUDA.
While immune-mediated adverse reactions usually occur during treatment
with PD-1/PD-L1 blocking antibodies, they may occur after
discontinuation of treatment. For suspected immune-mediated adverse
reactions, ensure adequate evaluation to confirm etiology or exclude
other causes. Based on the severity of the adverse reaction, withhold
KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or
less, initiate corticosteroid taper and continue to taper over at least
1 month. Based on limited data from clinical studies in patients whose
immune-related adverse reactions could not be controlled with
corticosteroid use, administration of other systemic immunosuppressants
can be considered. Resume KEYTRUDA when the adverse reaction remains at
Grade 1 or less following corticosteroid taper. Permanently discontinue
KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs
and for any life-threatening immune-mediated adverse reaction.

The following clinically significant immune-mediated adverse reactions
occurred in less than 1% (unless otherwise indicated) of 2799 patients:
arthritis (1.5%), uveitis, myositis, Guillain-Barré syndrome, myasthenia
gravis, vasculitis, pancreatitis, hemolytic anemia, sarcoidosis, and
encephalitis. In addition, myelitis and myocarditis were reported in
other clinical trials, including cHL, 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 treatment with KEYTRUDA. Of 23 patients
with cHL who proceeded to allogeneic HSCT after KEYTRUDA, 6 developed
graft-versus-host disease (GVHD) (one fatal case), and 2 developed
severe hepatic veno-occlusive disease (VOD) after reduced-intensity
conditioning (one fatal case). 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.
Follow patients closely for early evidence of transplant-related
complications such as hyperacute GVHD, Grade 3 to 4 acute GVHD,
steroid-requiring febrile syndrome, hepatic VOD, and other
immune-mediated adverse reactions, and intervene promptly.

Contacts

Merck
Media:
Pamela Eisele, 267-305-3558
or
Elizabeth
Sell, 267-305-3877
or
Investors:
Teri Loxam, 908-740-1986
or
Michael
DeCarbo, 908-740-1807

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