European Commission Approves KEYTRUDA® (pembrolizumab) for First-Line Treatment of Patients with Metastatic Non-Small Cell Lung Cancer (NSCLC) Whose Tumors Have High PD-L1 Expression with No EGFR or ALK Positive Tumor Mutations
January 31, 2017 4:00 pm ET
Approval Based on Data Showing Improved Overall Survival and Progression-Free Survival with KEYTRUDA Compared to Chemotherapy
First Anti-PD-1 Therapy Approved in Europe for Previously Untreated Patients with Metastatic NSCLC
KENILWORTH, N.J.–(BUSINESS WIRE)–Merck (NYSE:MRK), known as MSD outside the United States and Canada,
today announced that the European Commission has approved KEYTRUDA®
(pembrolizumab), the company’s anti-PD-1 therapy, for the first-line
treatment of metastatic non-small cell lung cancer (NSCLC) in adults
whose tumors have high PD-L1 expression (tumor proportion score [TPS] of
50 percent or more) with no EGFR or ALK positive tumor mutations.
“The approval of KEYTRUDA as a first treatment instead of chemotherapy
for patients who express high levels of PD-L1 has the potential to
transform the way metastatic non-small cell lung cancer is treated,”
said Dr. Roy Baynes, senior vice president, head of clinical
development, and chief medical officer, Merck Research Laboratories. “We
are committed to ensuring that patients in Europe – who are in need of
new treatment options – are able to quickly gain access to KEYTRUDA.”
The approval is based on phase 3 data which demonstrated superior
overall survival (OS) and progression-free survival (PFS) with KEYTRUDA
compared to chemotherapy, the current standard of care for advanced
NSCLC. The approval allows marketing of KEYTRUDA in all 28 EU member
states plus Iceland, Lichtenstein and Norway, at the approved dose of
200 mg every three weeks until disease progression or unacceptable
toxicity. In August 2016, KEYTRUDA (pembrolizumab) (2 mg/kg every three
weeks) was approved in Europe for previously-treated patients with
locally advanced or metastatic NSCLC whose tumors express PD-L1 (TPS of
1 percent or more) and who have received at least one prior chemotherapy
“The data demonstrate that KEYTRUDA provided meaningful improvements in
survival versus the current standard of care in patients whose tumors
express high levels of PD-L1,” said Dr. Luis Paz-Ares, chair of the
medical oncology department, Hospital Universitario Doce de Octubre,
Madrid, Spain. “These findings supporting the approval also provide
further rationale for biomarker testing in order to identify those
patients more likely to benefit the most from treatment with KEYTRUDA.”
The European Commission’s approval is based on data from KEYNOTE-024, a
randomized, open-label, phase 3 study evaluating KEYTRUDA monotherapy at
a fixed dose of 200 mg compared to standard of care platinum-containing
chemotherapy (pemetrexed+carboplatin, pemetrexed+cisplatin,
gemcitabine+cisplatin, gemcitabine+carboplatin, or
paclitaxel+carboplatin) for the treatment of patients with both squamous
and non-squamous metastatic NSCLC. The study enrolled 305 patients who
had not received prior systemic chemotherapy treatment for their
metastatic disease and whose tumors had high PD-L1 expression with no
EGFR or ALK aberrations. The primary endpoint was PFS; additional
efficacy outcome measures were OS and objective response rate (ORR).
In the study, KEYTRUDA reduced the risk of disease progression or death
by 50 percent compared to chemotherapy (HR, 0.50 [95% CI, 0.37, 0.68];
p<0.001). The median PFS for KEYTRUDA was 10.3 months (95% CI, 6.7-not
reached) compared to 6.0 months for chemotherapy (95% CI, 4.2-6.2). At
six months and 12 months, respectively, 62 percent and 48 percent of
patients treated with KEYTRUDA were alive and had no disease progression
compared to 50 percent and 15 percent of those receiving chemotherapy.
Additionally, KEYTRUDA resulted in a 40 percent reduction in the risk of
death compared to chemotherapy (HR, 0.60 [95% CI, 0.41, 0.89]; p=0.005);
this finding includes the 66 patients (43.7%) on the chemotherapy arm
who crossed over in-study to receive KEYTRUDA once their cancer had
progressed; median OS was not reached in either group. The OS rate at
six months and 12 months, respectively, was 80 percent and 70 percent in
patients treated with KEYTRUDA compared to 72 percent and 54 percent in
those receiving chemotherapy.
Further, ORR was 45 percent for patients receiving KEYTRUDA
(pembrolizumab) (95% CI, 37-53), including six complete responses,
compared to 28 percent with chemotherapy (95% CI, 21-36), including one
The safety analysis supporting the European approval of KEYTRUDA was
based on 2,953 patients with advanced melanoma or NSCLC across four
doses (2 mg/kg every three weeks, 200 mg every three weeks, or 10 mg/kg
every two or three weeks) in studies KEYNOTE-001, KEYNOTE-002,
KEYNOTE-010 and KEYNOTE-024 combined. The most common adverse reactions
(≥10%) with KEYTRUDA were fatigue (24%), rash (19%), pruritus (17%),
diarrhea (12%), nausea (11%) and arthralgia (10%). The majority of
adverse reactions reported were of Grade 1 or 2 severity. The most
serious adverse reactions were immune-related adverse reactions and
severe infusion-related reactions.
KEYTRUDA is a humanized monoclonal antibody that works by increasing the
ability of the body’s immune system to help detect and fight tumor
cells. KEYTRUDA 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.
KEYTRUDA is administered as an intravenous infusion over 30 minutes
every three weeks for the approved indications. KEYTRUDA for injection
is supplied in a 100 mg single use vial.
KEYTRUDA Indications and Dosing in the U.S.
KEYTRUDA is indicated for the treatment of patients with unresectable or
metastatic melanoma at a dose of 2 mg/kg every three weeks until disease
progression or unacceptable toxicity.
KEYTRUDA 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 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
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.
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.
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
KEYTRUDA (pembrolizumab) 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.
KEYTRUDA can cause other clinically important immune-mediated adverse
reactions. 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%), exfoliative dermatitis, bullous pemphigoid, rash
(1.4%), uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis,
vasculitis, pancreatitis, hemolytic anemia, and partial seizures arising
in a patient with inflammatory foci in brain parenchyma.
KEYTRUDA (pembrolizumab) can cause severe or life-threatening
infusion-related reactions, 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.
Based on its mechanism of action, KEYTRUDA can cause fetal harm when
administered to a pregnant woman. If used during pregnancy, or if the
patient becomes pregnant during treatment, apprise the patient of the
potential hazard to a fetus. Advise females of reproductive potential to
use highly effective contraception during treatment and for 4 months
after the last dose of KEYTRUDA.
KEYTRUDA was discontinued due to adverse reactions in 8% of 682 patients
with metastatic NSCLC. The most common adverse event resulting in
permanent discontinuation of KEYTRUDA was pneumonitis (1.8%). Adverse
reactions leading to interruption of KEYTRUDA occurred in 23% of
patients; the most common (≥1%) were diarrhea (1%), fatigue (1.3%),
pneumonia (1%), liver enzyme elevation (1.2%), decreased appetite
(1.3%), and pneumonitis (1%). The most common adverse reactions
(occurring in at least 20% of patients and at a higher incidence than
with docetaxel) were decreased appetite (25% vs 23%), dyspnea (23% vs
20%), and nausea (20% vs 18%).
It is not known whether KEYTRUDA is excreted in human milk. Because many
drugs are excreted in human milk, instruct women to discontinue nursing
during treatment with KEYTRUDA and for 4 months after the final dose.
Safety and effectiveness of KEYTRUDA have not been established in
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 suffering from highly advanced, metastatic
(Stage IV) lung cancers is estimated to be two percent.
Our Focus on Cancer
Our goal is to translate breakthrough science into innovative oncology
medicines to help people with cancer worldwide. At Merck, helping people
fight cancer is our passion and supporting accessibility to our cancer
medicines is our commitment. Our focus is on pursuing research in
immuno-oncology and we are accelerating every step in the journey – from
lab to clinic – to potentially bring new hope to people with cancer.
As part of our focus on cancer, Merck is committed to exploring the
potential of immuno-oncology with one of the fastest-growing development
programs in the industry. We are currently executing an expansive
research program that includes more than 400 clinical trials evaluating
our anti-PD-1 therapy across more than 30 tumor types. We also continue
to strengthen our immuno-oncology portfolio through strategic
acquisitions and are prioritizing the development of several promising
immunotherapeutic candidates with the potential to improve the treatment
of advanced cancers.
For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials.
For over a century, Merck has been a global health care leader working
to help the world be well. Merck is known as MSD outside the United
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For more information, visit www.merck.com
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Please see Prescribing Information for KEYTRUDA (pembrolizumab) at
Patient Information/Medication Guide for KEYTRUDA at
Pamela Eisele, 267-305-3558
Courtney Ronaldo, 908-236-1108
Teri Loxam, 908-740-1986
Amy Klug, 908-740-1898