KEYNOTE-024, Published in The New England
Journal of Medicine, Showed KEYTRUDA as Monotherapy Demonstrated
Superior Progression-Free and Overall Survival Compared to
Chemotherapy as First-Line Treatment in Patients with High Levels
of PD-L1 Expression
KEYNOTE-021, Cohort G, Published in The
Lancet Oncology, Showed KEYTRUDA in Combination with Chemotherapy
Demonstrated Superior Efficacy Compared to Chemotherapy Alone as
First-Line Treatment; Trial Enrolled Patients Regardless of PD-L1
Expression
Merck (NYSE:MRK), known as MSD outside the United States and
Canada, today announced results from two major studies of KEYTRUDA®
(pembrolizumab), the company’s anti-PD-1 therapy, in the first-line
treatment of patients with metastatic non-small cell lung cancer
(NSCLC) at the ESMO 2016 Congress, the annual meeting of the
European Society for Medical Oncology:
- In KEYNOTE-024, which evaluated
squamous and non-squamous NSCLC patients whose tumors expressed
high levels of PD-L1 (tumor proportion score, or TPS, of 50 percent
or more), KEYTRUDA provided a 50 percent reduction in the risk of
disease progression or death and a 40 percent reduction in the risk
of death compared to platinum doublet, the current standard of
care. These data were also published today in The New England
Journal of Medicine. Based upon the results observed from
KEYNOTE-024, to date KEYTRUDA is the only anti-PD-1 to demonstrate
superior progression-free survival (PFS) and overall survival (OS)
compared to chemotherapy for the first-line treatment of both
squamous and non-squamous NSCLC in patients whose tumors express
high levels of PD-L1 and do not express EGFR or ALK genetic
aberrations.
- In KEYNOTE-021, Cohort G, which
included patients with metastatic non-squamous NSCLC regardless of
PD-L1 expression level, KEYTRUDA (pembrolizumab) plus chemotherapy
(carboplatin plus pemetrexed) achieved a 55 percent objective
response rate (ORR) compared to 29 percent for chemotherapy alone,
the standard of care, and reduced the risk of disease progression
or death by 47 percent. To date, KEYTRUDA is the only anti-PD-1
therapy to demonstrate superior efficacy in combination with
chemotherapy compared to chemotherapy alone in patients receiving
first-line treatment. These data were published today in The Lancet
Oncology.
“Chemotherapy has been the standard treatment for most patients
with advanced non-small cell lung cancer for decades, but survival
rates remain low,” said Dr. Roger M. Perlmutter, president, Merck
Research Laboratories. “Our new data suggest that KEYTRUDA
treatment can offer meaningful improvement over chemotherapy in a
broad array of patients. In this sense, these studies may represent
a turning point in worldwide efforts to control lung cancer. We
sincerely thank the patients and the clinical investigators for
their participation in our studies. Together we are working to
improve the health of more and more patients with cancer.”
Merck has submitted KEYNOTE-024 data to regulatory agencies in
the United States, Europe, and Japan. The U.S. Food and Drug
Administration has granted Breakthrough Therapy Designation and
Priority Review, with a PDUFA, or target action, date of Dec. 24,
2016.
Merck is currently advancing multiple registration-enabling
studies in NSCLC with KEYTRUDA as monotherapy and in combination,
including the combination of KEYTRUDA plus a
platinum/pemetrexed-based chemotherapy regimen in patients with
previously untreated, non-squamous NSCLC in the ongoing phase 3
KEYNOTE-189 trial. The KEYTRUDA clinical development program
includes more than 350 clinical trials across more than 30 tumor
types, including more than 100 trials that combine KEYTRUDA with
other cancer treatments.
KEYNOTE-024: Data Showed KEYTRUDA was Superior to
Chemotherapy for PFS and OS in First-Line Treatment of Metastatic
NSCLC
KEYNOTE-024 included 305 patients who were previously untreated
and whose tumors expressed high levels of PD-L1 (TPS of 50 percent
or more). Patients were randomized to receive a 200 mg fixed dose
of KEYTRUDA every three weeks (n=154) or four to six cycles of
investigator’s choice of one of five platinum-based chemotherapy
regimens (n=151): carboplatin or cisplatin plus pemetrexed,
carboplatin or cisplatin plus gemcitabine, or carboplatin plus
paclitaxel. Pemetrexed maintenance therapy was permitted for
patients with non-squamous histologies. Patients randomized to the
control arm had the option of crossing over to KEYTRUDA
(pembrolizumab) upon disease progression. The median follow-up was
11.2 months (range, 6.3-19.7). The primary endpoint was PFS;
secondary endpoints were OS, ORR, and safety.
The findings published in The New England Journal of Medicine
demonstrated that KEYTRUDA reduced the risk of 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, 62.1 percent of
patients treated with KEYTRUDA were alive and had no disease
progression (95% CI, 53.8-69.4) compared to 50.3 percent of those
receiving chemotherapy (95% CI, 41.9-58.2). This benefit was
observed in all study subgroups.
Additionally, KEYTRUDA resulted in a 40 percent reduction in the
risk of death compared with 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. Further, ORR was 44.8 percent for patients
receiving KEYTRUDA (95% CI, 36.8-53.0), including six complete
responses, compared to 27.8 percent with chemotherapy (95% CI,
20.8-35.7), including one complete response.
“These data from KEYNOTE-024 demonstrate the potential of
KEYTRUDA to change the way non-small cell lung cancer is currently
treated,” said Dr. Martin Reck, head of the thoracic oncology
dept., LungenClinic Grosshansdorf, Germany, and lead author of The
New England Journal of Medicine paper. “This provides additional
evidence that testing for PD-L1 levels should become standard in
lung cancer at first diagnosis to guide treatment decisions.”
Additional Findings and Safety Information from
KEYNOTE-024
The safety of KEYTRUDA was consistent with what has been seen in
previous trials among patients with metastatic NSCLC. The most
common treatment-related adverse events for KEYTRUDA were diarrhea
(n=22), fatigue (n=16), and pyrexia (n=16). Grade 3-5
treatment-related adverse events for KEYTRUDA included diarrhea
(n=6) and pneumonitis (n=4). There was one treatment-related death
in a patient receiving KEYTRUDA (cause unknown).
Additionally, based on an analysis of duration of response, a
pre-specified exploratory endpoint, the median duration of response
was not reached with KEYTRUDA (range, 1.9+ to 14.5+ months). The
median duration of response with the chemotherapy group was 6.3
months (range, 2.1+ to 12.6+). Median time to response was 2.2
months for both groups.
About KEYNOTE-024
KEYNOTE-024 is a randomized, phase 3 study (ClinicalTrials.gov,
NCT02142738) evaluating KEYTRUDA (pembrolizumab) as monotherapy
compared to standard of care platinum-based chemotherapy in the
treatment of patients with metastatic NSCLC. Patients enrolled were
those who had received no prior systemic chemotherapy treatment for
their advanced disease, whose tumors did not harbor an EGFR
sensitizing mutation or ALK translocation, and whose tumors
expressed high levels of PD-L1 (TPS of 50 percent or more) as
determined by a central laboratory using an FDA approved companion
diagnostic, the Dako PD-L1 IHC 22C3 PharmDx test, from Agilent
Technologies.
KEYNOTE-021, Cohort G: KEYTRUDA Combined with Chemotherapy
Showed Higher Response Rates Compared to Chemotherapy Alone as
First-Line Treatment of Metastatic NSCLC
KEYNOTE-021, Cohort G, included 123 previously untreated
patients with metastatic non-squamous NSCLC regardless of PD-L1
expression and whose tumors did not have EGFR mutations or ALK
translocations. Patients were randomized to receive KEYTRUDA plus
platinum doublet chemotherapy with pemetrexed and carboplatin
(n=60) or platinum doublet chemotherapy alone (n=63). Patients
randomized to the chemotherapy-only arm had the option of crossing
over to KEYTRUDA monotherapy upon disease progression. The median
follow-up was 10.6 months (range, 0.8-19.3).
The findings published in The Lancet Oncology demonstrated that
ORR nearly doubled by adding KEYTRUDA to chemotherapy, with an ORR
of 55 percent (n=33/60) compared to 29 percent (n=18/63) for
chemotherapy alone (treatment difference 26%, 95% CI, 9-42%,
p=0.0016); all responses were partial. Median duration of response
was not reached in either group (range, 1.4+-13.0+ for KEYTRUDA
plus chemotherapy; 1.4+-15.2+ for chemotherapy alone). Responses in
both groups were durable, with 88 percent (n=29/33) of responders
in the KEYTRUDA plus chemotherapy group and 78 percent (n=14/18) of
responders in the chemotherapy alone group experiencing ongoing
response at the time of data cut-off.
Additionally, the KEYTRUDA combination significantly reduced the
risk of disease progression or death compared to chemotherapy alone
(hazard ratio 0.53, 95% CI, 0.31-0.91, p=0.0102). Median PFS was
13.0 months with KEYTRUDA plus chemotherapy compared to 8.9 months
with chemotherapy alone. OS was similar between the two arms, with
92 percent survival at six months in both, and 75 percent and 72
percent survival at 12 months in the KEYTRUDA combination and
chemotherapy alone, respectively.
Of treated patients on the KEYTRUDA (pembrolizumab) plus
chemotherapy arm, 47 percent remained on treatment as of the
cut-off date, compared to 31 percent on chemotherapy alone. Of the
treated patients who discontinued treatment on the
chemotherapy-only arm, 52 percent (n=32/62) subsequently received
anti-PD-L1 therapy, with 32 percent crossing over to KEYTRUDA
monotherapy as allowed by the study protocol and 19 percent
receiving it outside of study crossover.
“The results from KEYNOTE-021 show that pembrolizumab plus
chemotherapy nearly doubled the number of patients responding to
treatment than chemotherapy alone,” said Dr. Corey Langer, director
of thoracic oncology and professor of medicine at the Hospital of
the University of Pennsylvania and lead author of The Lancet
Oncology paper. “We are now gaining a better understanding that
pembrolizumab combined with chemotherapy may play an important role
in the first-line treatment of patients with non-small cell lung
cancer.”
Additional Safety Information from KEYNOTE-021, Cohort
G
The most common treatment-related adverse events (occurring in
at least 15% of patients) for KEYTRUDA plus chemotherapy were
fatigue, nausea, anemia, rash, vomiting, diarrhea, increased AST,
constipation, decreased appetite, increased ALT, dysgeusia, and
decreased neutrophils. Grade 3-4 treatment-related adverse events
in this arm included fatigue, nausea, anemia, rash, vomiting,
increased AST, increased ALT, and decreased neutrophils. The most
common immune-mediated adverse events in patients receiving
KEYTRUDA plus chemotherapy were hypothyroidism and hyperthyroidism.
Additionally, pneumonitis, infusion reactions, and severe skin
toxicity were noted. These immune-mediated adverse events occurred
at similar rates to patients receiving KEYTRUDA as a single agent.
There was one treatment-related death from sepsis in a patient
receiving KEYTRUDA plus chemotherapy, and two (one from sepsis and
one from pancytopenia) in patients receiving chemotherapy
alone.
About KEYNOTE-021, Cohort G
Cohort G of the multicenter, open-label, phase 1/2 multi-cohort
KEYNOTE-021 study evaluated the efficacy and safety of KEYTRUDA in
combination with pemetrexed and carboplatin compared with
pemetrexed and carboplatin in patients with metastatic,
non-squamous, EGFR- and ALK-negative NSCLC in the first-line
treatment setting. Patients were randomized 1:1 to four cycles of
KEYTRUDA (200 mg plus carboplatin AUC 5 (5 mg/mL/min) plus
pemetrexed 500 mg/m2 every three weeks), or carboplatin plus
pemetrexed alone, followed by maintenance pemetrexed with or
without KEYTRUDA. Randomization was stratified by PD-L1 expression
(positive expression defined as TPS of one percent or more;
negative expression defined as TPS of less than one percent).
Patients randomized to the chemotherapy arm were allowed to cross
over to KEYTRUDA (pembrolizumab) monotherapy if they experienced
disease progression. Response was assessed by blinded, independent
central review using RECIST 1.1 every six weeks for the first 18
weeks, every nine weeks through the first year, and every 12 weeks
in the second year. The primary endpoint was ORR; secondary
endpoints included PFS, duration of response, and OS.
About KEYTRUDA® (pembrolizumab)
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
Melanoma
KEYTRUDA is indicated for the treatment of patients with
unresectable or metastatic melanoma at a dose of 2 mg/kg every
three weeks.
Lung Cancer
KEYTRUDA is indicated for the treatment of patients with
metastatic 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, at a dose
of 2 mg/kg every three weeks. Patients with EGFR or ALK genomic
tumor aberrations should have disease progression on FDA-approved
therapy for these aberrations prior to receiving KEYTRUDA. This
indication is approved under accelerated approval based on tumor
response rate and durability of response. An improvement in
survival or disease-related symptoms has not yet been established.
Continued approval for this indication may be contingent upon
verification and description of clinical benefit in the
confirmatory trials.
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 at a fixed dose of 200 mg every three weeks. 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.
Selected Important Safety Information for
KEYTRUDA® (pembrolizumab)
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 hypophysitis.
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 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 (pembrolizumab) 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 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 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%).
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 pediatric patients.
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 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 350 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.
About Merck
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 and connect with us on Twitter, Facebook, YouTube and
LinkedIn.
Forward-Looking Statement of Merck & Co., Inc.,
Kenilworth, N.J., USA
This news release of Merck & Co., Inc., Kenilworth, N.J.,
USA (the “company”) includes “forward-looking statements” within
the meaning of the safe harbor provisions of the U.S. Private
Securities Litigation Reform Act of 1995. These statements are
based upon the current beliefs and expectations of the company’s
management and are subject to significant risks and uncertainties.
There can be no guarantees with respect to pipeline products that
the products will receive the necessary regulatory approvals or
that they will prove to be commercially successful. If underlying
assumptions prove inaccurate or risks or uncertainties materialize,
actual results may differ materially from those set forth in the
forward-looking statements.
Risks and uncertainties include but are not limited to, general
industry conditions and competition; general economic factors,
including interest rate and currency exchange rate fluctuations;
the impact of pharmaceutical industry regulation and health care
legislation in the United States and internationally; global trends
toward health care cost containment; technological advances, new
products and patents attained by competitors; challenges inherent
in new product development, including obtaining regulatory
approval; the company’s ability to accurately predict future market
conditions; manufacturing difficulties or delays; financial
instability of international economies and sovereign risk;
dependence on the effectiveness of the company’s patents and other
protections for innovative products; and the exposure to
litigation, including patent litigation, and/or regulatory
actions.
The company undertakes no obligation to publicly update any
forward-looking statement, whether as a result of new information,
future events or otherwise. Additional factors that could cause
results to differ materially from those described in the
forward-looking statements can be found in the company’s 2015
Annual Report on Form 10-K and the company’s other filings with the
Securities and Exchange Commission (SEC) available at the SEC’s
Internet site (www.sec.gov).
Please see Prescribing Information for KEYTRUDA
(pembrolizumab)
at http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf and
Patient Information/Medication Guide for KEYTRUDA
at http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_mg.pdf.
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