Merck’s KEYTRUDA® (pembrolizumab) Approved by the European Commission for Patients with Advanced Non-Small Cell Lung Cancer (NSCLC) Whose Tumors Express PD-L1
August 2, 2016 4:00 pm ET
Approval Based on Trial Results Demonstrating Superior Overall Survival Compared to Chemotherapy in Previously-Treated Patients
KENILWORTH, N.J.–(BUSINESS WIRE)–Merck (NYSE:MRK), known as MSD outside the United States and Canada,
today announced that the European Commission (EC) has approved KEYTRUDA®
(pembrolizumab), the company’s anti-PD-1 therapy, at a dose of 2 mg/kg
every three weeks, for patients with locally advanced or metastatic
non-small cell lung cancer (NSCLC) in patients whose tumors express
PD-L1 and who have received at least one prior chemotherapy regimen.
Patients with EGFR or ALK positive tumor mutations should also have
received approved therapy for these mutations prior to receiving
KEYTRUDA. The EC approval allows marketing of KEYTRUDA in all 28 EU
The approval is based on findings from KEYNOTE-010, a pivotal study
which showed KEYTRUDA significantly improved overall survival (OS)
compared to standard of care chemotherapy.
“This approval provides an important new treatment regimen for patients
in Europe with advanced lung cancer, one of the most common and
challenging cancers,” said Dr. Roger Dansey, senior vice president and
therapeutic area head, oncology late-stage development, Merck Research
Laboratories. “In the KEYNOTE-010 trial, patients with advanced lung
cancer who had failed prior regimens experienced improved overall
survival when treated with KEYTRUDA as compared with those treated with
“The survival benefit for KEYTRUDA observed in previously-treated
patients who express PD-L1 is promising,” said Dr. Luis Paz-Ares, chair
of the medical oncology department, Hospital Universitario, Madrid,
Spain. “There is a significant unmet need for lung cancer patients, and
with this approval, we now have a new personalized treatment option
which uses biomarker testing to predict which patients are most likely
to benefit from treatment.”
KEYNOTE-010 is a global, open-label, randomized, pivotal phase 2/3 study
evaluating KEYTRUDA (pembrolizumab) (2 mg/kg or 10 mg/kg every three
weeks) compared to standard of care chemotherapy (docetaxel, 75 mg/m2 every
three weeks) in 1,033 patients with squamous and non-squamous NSCLC who
experienced disease progression after platinum-containing systemic
therapy and whose tumors expressed PD-L1. The primary endpoints were OS
and progression-free survival (PFS) and were assessed based on patients
with any level of PD-L1 expression (greater than or equal to one
percent) and in patients whose tumors express higher levels of PD-L1
(greater than or equal to 50 percent) – as reflected by tumor proportion
In the total study population (all levels of PD-L1 expression), both
doses of KEYTRUDA studied significantly improved OS compared with
docetaxel. Specifically, KEYTRUDA resulted in a 29 percent improvement
in OS for the 2 mg/kg dose (HR 0.71 [95% CI, 0.58-0.88; P=0.001]) and a
39 percent improvement in OS for the 10 mg/kg dose (HR 0.61 [95% CI,
0.49-0.75; P<0.001]), compared to docetaxel. Median OS for KEYTRUDA was
10.4 months (95% CI, 9.4-11.9) and 12.7 months (95% CI, 10.0-17.3),
respectively, compared to 8.5 months for docetaxel (95% CI, 7.5-9.8).
Among patients with higher levels of PD-L1 expression (a TPS score of 50
percent or greater), OS was superior for both KEYTRUDA doses compared
with docetaxel. Specifically, KEYTRUDA improved OS by 46 percent for the
2 mg/kg dose (HR 0.54 [95% CI, 0.38-0.77; P=0.001]) and by 50 percent
for the 10 mg/kg dose (HR 0.50 [95% CI, 0.36-0.70; P<0.001]), compared
to docetaxel. Median OS for KEYTRUDA (2 mg/kg and 10 mg/kg,
respectively) was 14.9 months (95% CI, 10.4 to not reached) and 17.3
months (95% CI, 11.8 to not reached), compared to 8.2 months for
docetaxel (95% CI, 6.4-10.7).
Among patients in the total study population treated with KEYTRUDA (2
mg/kg and 10 mg/kg, respectively), median PFS was 3.9 months (95% CI,
3.1-4.1) and 4.0 months (95% CI, 2.6-4.3), compared to 4.0 months for
docetaxel (95% CI, 3.1-4.2). KEYTRUDA numerically reduced the risk of
progression or death (PFS) at both doses (HR 0.88 [95% CI, 0.73-1.04]
for 2 mg/kg; HR 0.79 [95% CI, 0.66-0.94] for 10 mg/kg). PFS results in
the overall population were not statistically significant for either
dose based on protocol-specified statistical testing requirements.
Patients with higher levels of PD-L1 expression who were treated with
KEYTRUDA had significantly prolonged PFS compared to docetaxel (HR 0.58
[95% CI, 0.43-0.77; P=0.001] for 2 mg/kg; HR 0.59 [95% CI, 0.45-0.78;
P<0.001] for 10 mg/kg). Among patients treated with KEYTRUDA
(pembrolizumab) (2 mg/kg and 10 mg/kg, respectively), median PFS was 5.2
months (95% CI, 4.0-6.5) and 5.2 months (95% CI, 4.1-8.1), compared to
4.1 months for docetaxel (95% CI, 3.6-4.3).
The safety analysis supporting the European approval of KEYTRUDA was
based on 2,799 patients with advanced melanoma or NSCLC across three
doses (2 mg/kg every three weeks or 10 mg/kg every two or three weeks)
in studies KEYNOTE-001, KEYNOTE-002 and KEYNOTE-010 combined. The most
common adverse reactions (>10%) with KEYTRUDA were fatigue (24%), rash
(19%), pruritus (18%), 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.
“We are thrilled that the European Union will now have a new treatment
option for certain patients with advanced non-small cell lung cancer who
have not responded to chemotherapy,” said Stefania Vallone, president,
Lung Cancer Europe. “Lung cancer represents the leading cause of cancer
death worldwide, and this milestone underscores the importance of
innovation and commitment to developing new treatments that can have a
positive impact for patients living with this disease.”
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
relative survival rate for patients suffering from highly advanced,
metastatic (Stage IV) lung cancers is estimated to be two percent.
100 mg in the U.S.
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 indicated for the treatment of patients with unresectable or
KEYTRUDA (pembrolizumab) is also indicated for the treatment of patients
with advanced non-small cell lung cancer (NSCLC) whose tumors express
PD-L1 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 is administered at a dose of 2 mg/kg as an intravenous infusion
over 30 minutes every three weeks for the approved indications.
Selected Important Safety Information for KEYTRUDA
Immune-mediated pneumonitis occurred in 19 (3.5%) of 550 patients,
including Grade 2 (1.1%), 3 (1.3%), 4 (0.4%), or 5 (0.2%) pneumonitis
and occurred more frequently in patients with a history of
asthma/chronic obstructive pulmonary disease (5.4%) or prior thoracic
radiation (6.0%). 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 occurred in 4 (0.7%) of 550 patients, including
Grade 2 (0.2%) or 3 (0.4%) 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.
Immune-mediated hepatitis occurred in patients receiving KEYTRUDA.
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.
Hypophysitis occurred in 1 (0.2%) of 550 patients, which was Grade 3 in
severity. 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
Hyperthyroidism occurred in 10 (1.8%) of 550 patients, including Grade 2
(0.7%) or 3 (0.3%) hyperthyroidism. Hypothyroidism occurred in 38 (6.9%)
of 550 patients, including Grade 2 (5.5%) or 3 (0.2%) hypothyroidism.
Thyroid disorders can occur at any time during treatment. 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.
Type 1 diabetes mellitus, including diabetic ketoacidosis, occurred in 3
(0.1%) of 2117 patients. Monitor patients for hyperglycemia or other
signs and symptoms of diabetes. Administer insulin for type 1 diabetes,
and withhold KEYTRUDA (pembrolizumab) and administer anti-hyperglycemics
in patients with severe hyperglycemia.
Immune-mediated nephritis occurred in patients receiving KEYTRUDA.
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.
Other clinically important immune-mediated adverse reactions can occur.
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% of 550 patients: rash, vasculitis, hemolytic
anemia, serum sickness, and myasthenia gravis.
Severe and life-threatening infusion-related reactions have been
reported in 3 (0.1%) of 2117 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
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 14% of 550
patients. Serious adverse reactions occurred in 38% of patients. The
most frequent serious adverse reactions reported in at least 2% of
patients were pleural effusion, pneumonia, dyspnea, pulmonary embolism,
and pneumonitis. The most common adverse reactions (reported in at least
20% of patients) were fatigue (44%), cough (29%), decreased appetite
(25%), and dyspnea (23%).
No formal pharmacokinetic drug interaction studies have been conducted
with KEYTRUDA (pembrolizumab).
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
Our Focus on Cancer
Our goal is to translate breakthrough science into innovative oncology
medicines to help people with cancer worldwide. At Merck Oncology,
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
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 300 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 125 years, Merck has been a global health care leader working to
help the world be well. Merck is known as MSD outside the United States
and Canada. Through our prescription medicines, vaccines, biologic
therapies, and animal health products, we work with customers and
operate in more than 140 countries to deliver innovative health
solutions. We also demonstrate our commitment to increasing access to
health care through far-reaching policies, programs and partnerships.
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
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