European Approval Based on KEYNOTE-407 Study Results Demonstrating
Significant Improvement in Overall Survival with KEYTRUDA in Combination
with Chemotherapy Compared to Chemotherapy Alone
KEYTRUDA is First Anti-PD-1 Therapy Approved in Combination with
Chemotherapy in Europe for Adults with Metastatic Squamous NSCLC
Regardless of PD-L1 Expression
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 European Commission has approved KEYTRUDA, the
company’s anti-PD-1 therapy, in combination with carboplatin and either
paclitaxel or nab-paclitaxel, for the first-line treatment of adults
with metastatic squamous non-small cell lung cancer (NSCLC). This
approval is based on data from the Phase 3 KEYNOTE-407 trial, which
demonstrated that KEYTRUDA in combination with chemotherapy
significantly improved overall survival (OS) in adults with metastatic
squamous NSCLC regardless of PD-L1 tumor expression status, reducing the
risk of death by 36 percent compared to chemotherapy alone (HR=0.64 [95%
CI, 0.49-0.85]; p=0.0008).
“In KEYNOTE-407, first-line treatment with KEYTRUDA in combination with
chemotherapy resulted in significant improvements in overall survival
for patients with metastatic squamous non-small cell lung cancer,
regardless of PD-L1 expression,” said Dr. Luis Paz-Ares, chair of the
medical oncology department, Hospital Universitario Doce de Octubre,
Madrid, Spain. “Lung cancer is the leading cause of cancer death in
Europe, so this approval marks an important milestone for the patients
and families facing this difficult-to-treat type of lung cancer.”
The approval allows marketing of the KEYTRUDA combination 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 NSCLC, KEYTRUDA is also approved in Europe for
the:
-
First-line treatment of metastatic nonsquamous NSCLC in combination
with pemetrexed and platinum chemotherapy in adults whose tumors have
no EGFR or ALK positive mutations (KEYNOTE-189); -
First-line treatment of metastatic squamous or nonsquamous NSCLC as
monotherapy in adults whose tumors have high PD-L1 expression (tumor
proportion score [TPS] ≥50%) with no EGFR or ALK positive tumor
mutations (KEYNOTE-024); and -
Treatment of locally advanced or metastatic NSCLC in adults whose
tumors express PD-L1 (TPS ≥1%) and who have received at least one
prior chemotherapy regimen (KEYNOTE-010).
“KEYTRUDA provides a foundation for the treatment of lung cancer in
Europe, and this approval expands our first-line combination indications
to include adults with metastatic squamous non-small cell lung cancer,”
said Dr. Roy Baynes, senior vice president and head of global clinical
development, chief medical officer, Merck Research Laboratories. “This
is a meaningful treatment advance as an anti-PD-1 combination therapy is
now approved in Europe for this type of non-small cell lung cancer. With
this approval, more patients with non-small cell lung cancer may have
the opportunity to benefit from combination therapy with KEYTRUDA.”
Data Supporting the European Approval
The approval was based on data from KEYNOTE-407, a Phase 3, randomized,
double-blind, multicenter, placebo-controlled study evaluating KEYTRUDA
in combination with carboplatin-paclitaxel or nab-paclitaxel compared
with carboplatin-paclitaxel or nab-paclitaxel alone. The dual primary
endpoints are OS and progression-free survival (PFS); secondary
endpoints include objective response rate (ORR) and duration of response
(DOR). The study enrolled 559 patients who were randomized (1:1) to
receive one of the following treatments via intravenous infusion:
-
KEYTRUDA 200 mg and carboplatin AUC 6 mg/mL/min on Day 1 of each
21-day cycle for four cycles and paclitaxel 200 mg/m2
on Day 1 of each 21-day cycle for four cycles or nab-paclitaxel
100 mg/m2 on Days 1, 8 and 15 of each 21-day cycle for
four cycles, followed by KEYTRUDA 200 mg every three weeks. KEYTRUDA
was administered prior to chemotherapy on Day 1. -
Placebo and carboplatin AUC 6 mg/mL/min on Day 1 of each 21-day cycle
for four cycles and paclitaxel 200 mg/m2 on Day 1
of each 21-day cycle for four cycles or nab-paclitaxel 100 mg/m2
on Days 1, 8 and 15 of each 21-day cycle for four cycles, followed by
placebo every 3 weeks.
In KEYNOTE-407, KEYTRUDA in combination with carboplatin and either
paclitaxel or nab-paclitaxel significantly improved OS, reducing the
risk of death by 36 percent compared to chemotherapy alone (HR=0.64 [95%
CI, 0.49-0.85]; p<0.0008). The KEYTRUDA combination also demonstrated
improved PFS, with a reduction in the risk of progression or death of 44
percent compared to chemotherapy alone (HR=0.56 [95% CI, 0.45-0.70];
p<0.0001). Among patients who received the KEYTRUDA combination, the ORR
was 58 percent (95% CI, 52-64) compared to 38 percent (95% CI, 33-44)
for patients who received chemotherapy alone (p<0.0001). The median DOR
was 7.7 months (range, 1.1+ to 14.7+ months) for patients who received
the KEYTRUDA combination compared to 4.8 months (range, 1.3+ to 15.8+
months) for patients who received chemotherapy alone.
The safety of KEYTRUDA in combination with chemotherapy has been
evaluated in 791 patients with NSCLC receiving 200 mg, 2 mg/kg or 10
mg/kg KEYTRUDA every three weeks, in clinical studies. In this patient
population, the most frequent adverse reactions were nausea (49%),
anemia (48%), fatigue (38%), constipation (34%), diarrhea (31%),
neutropenia (29%), and decreased appetite (28%). Incidences of Grade 3-5
adverse reactions were 67 percent for the KEYTRUDA combination and 66
percent for chemotherapy alone.
About Lung Cancer in Europe (NSCLC)
Lung cancer, which forms in the tissues of the lungs, usually within
cells lining the air passages, is the leading cause of cancer death in
Europe and worldwide. In 2018, there were nearly 388,000 deaths from
lung cancer in Europe. 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. There are several subtypes
of NSCLC, including adenocarcinoma (accounting for 40% of lung cancers),
squamous cell carcinoma (25 to 30%) and large cell carcinoma (10 to 15%).
About KEYTRUDA® (pembrolizumab) Injection
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 900 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 in the U.S.
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
nab-paclitaxel, 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 metastatic 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 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, 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 is
administered as an intravenous infusion over 30 minutes 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 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 is administered as an
intravenous infusion over 30 minutes 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 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 is administered as an intravenous
infusion over 30 minutes 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 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 is
administered as an intravenous infusion over 30 minutes 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 as an
intravenous infusion over 30 minutes 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 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 an intravenous infusion over 30 minutes of 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 an intravenous infusion over
30 minutes of 200 mg 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 an intravenous infusion over 30 minutes of 200 mg 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.
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 receiving KEYTRUDA,
including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%),
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.
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
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.
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. Hyperthyroidism occurred
in 3.4% (96/2799) of patients, including Grade 2 (0.8%) and 3 (0.1%),
and thyroiditis occurred in 0.6% (16/2799) of patients, including Grade
2 (0.3%). Type 1 diabetes mellitus, including diabetic ketoacidosis,
occurred in 0.2% (6/2799) of patients.
Monitor patients for signs and symptoms of hypophysitis (including
hypopituitarism and adrenal insufficiency), thyroid function (prior to
and periodically during treatment), and hyperglycemia. For hypophysitis,
administer corticosteroids and hormone replacement as clinically
indicated. Withhold KEYTRUDA for Grade 2 and withhold or discontinue for
Grade 3 or 4 hypophysitis. Administer hormone replacement for
hypothyroidism and manage hyperthyroidism with thionamides and
beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade
3 or 4 hyperthyroidism. Administer insulin for type 1 diabetes, and
withhold KEYTRUDA and administer antihyperglycemics in patients with
severe hyperglycemia.
Immune-Mediated Nephritis and Renal Dysfunction
KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 0.3%
(9/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3
(0.1%), and 4 (<0.1%) nephritis. Nephritis occurred in 1.7% (7/405) of
patients receiving KEYTRUDA in combination with pemetrexed and platinum
chemotherapy. Monitor patients for changes in renal function. Administer
corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for
Grade 2; permanently discontinue for Grade 3 or 4 nephritis.
Immune-Mediated Skin Reactions
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.
Other Immune-Mediated Adverse Reactions
Immune-mediated adverse reactions, which may be severe or fatal, can
occur in any organ system or tissue in patients receiving KEYTRUDA and
may also 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.
Contacts
Media:
Pamela Eisele
(267) 305-3558
Kristen Drake
(908) 740-1679
Investors:
Teri Loxam
(908) 740-1986
Michael DeCarbo
(908) 740-1807