Data Comparing KEYTRUDA to Chemotherapy
Shows Continued Benefit with Follow-Up Beyond 2.5 Years in
Patients with Ipilimumab-Refractory Advanced Melanoma
Merck (NYSE:MRK), known as MSD outside the United States and
Canada, today announced findings from the final overall survival
(OS) analysis from the KEYNOTE-002 study investigating the use of
KEYTRUDA® (pembrolizumab), the company’s anti-PD-1 therapy,
compared to investigator-choice chemotherapy with a crossover to
KEYTRUDA design, in patients with ipilimumab-refractory advanced
melanoma. Results presented at the ESMO 2016 Congress, the annual
meeting of the European Society for Medical Oncology, in Copenhagen
include follow-up of up to 35 months for the study’s co-primary
endpoints of OS and progression-free survival (PFS). Data showed
prolonged OS with KEYTRUDA (2 mg/kg and 10 mg/kg), with a median OS
of 13.4 months and 14.7 months and a two-year OS rate of 35.9
percent and 38.2 percent, respectively, compared to a median OS of
11.0 months and a two-year OS rate of 29.7 percent with
chemotherapy.
“Now, with longer follow-up, we continue to show clinically
meaningful outcomes with KEYTRUDA as monotherapy in these
ipilimumab-refractory patients,” said Dr. Roger Dansey, senior vice
president, oncology late-stage development, Merck Research
Laboratories. “These results provide further evidence supporting
the use of KEYTRUDA as a standard of care for patients with
advanced melanoma.”
Today, KEYTRUDA is approved for the treatment of advanced
melanoma in more than 50 countries, including the United States and
throughout Europe. The KEYTRUDA clinical development program
includes more than 30 tumor types in more than 350 clinical
studies, including more than 100 trials that combine KEYTRUDA
(pembrolizumab) with other cancer treatments.
The final analysis from KEYNOTE-002 is being presented at the
ESMO 2016 Congress by Dr. Omid Hamid, director of the Melanoma
Center at The Angeles Clinic and Research Institute, on Oct. 8 from
2:45 - 4:15 p.m. CEST (Abstract: #1107O).
Additional Findings from KEYNOTE-002
KEYNOTE-002 is a multicenter, randomized, controlled phase 2
study of KEYTRUDA (2 mg/kg or 10 mg/kg every three weeks) compared
to investigator’s choice chemotherapy (paclitaxel plus carboplatin,
paclitaxel, carboplatin, dacarbazine, or temozolomide) in patients
with ipilimumab-refractory advanced melanoma (n=540). The
co-primary endpoints were PFS and OS; secondary endpoints included
overall response rate (ORR), duration of response, and safety.
Tumor response was assessed at week 12, then every six weeks
through week 48, followed by every 12 weeks thereafter as assessed
by independent central review using Response Evaluation Criteria in
Solid Tumors (RECIST) v1.1. Per the study protocol, after three
months, patients who experienced disease progression on the
chemotherapy arm were eligible to cross over to receive KEYTRUDA.
In total, 55 percent (n=98/179) of patients in the chemotherapy arm
crossed over to receive KEYTRUDA monotherapy.
In the final analysis, which included the 98 patients who
crossed over from the chemotherapy arm to receive KEYTRUDA, the
median OS was 13.4 months with KEYTRUDA 2 mg/kg (95% CI, 11.0-16.4
months) and 14.7 months with KEYTRUDA 10 mg/kg (95% CI 11.3-19.5
months), compared to 11.0 months with chemotherapy (95% CI,
8.9-13.8 months) (hazard ratio: 0.86 [95% CI, 0.67-1.10; p=0.1173]
and hazard ratio: 0.74 [95% CI, 0.57-0.96; p=0.0106],
respectively); the two-year (24-month) OS rate was 35.9 percent and
38.2 percent with KEYTRUDA (2 mg/kg and 10 mg/kg, respectively),
compared to 29.7 percent with chemotherapy.
While improvements in OS between KEYTRUDA (2 mg/kg or 10 mg/kg)
and chemotherapy did not meet the protocol-specified significance
threshold, longer follow-up continued to show a clinically
meaningful improvement in PFS, the study’s co-primary endpoint,
with PFS of up to 31 months in patients treated with KEYTRUDA.
Median PFS was approximately three months for each of the patient
groups (95% CI of 2.8-3.8 months with KEYTRUDA 2 mg/kg; 95% CI of
2.8-5.2 months with KEYTRUDA 10 mg/kg; and 95% CI of 2.6-2.8 months
with chemotherapy) (hazard ratio: 0.58 [95% CI, 0.46-0.73;
p<0.0001] and hazard ratio: 0.47 [95% CI, 0.37-0.60;
p<0.0001], respectively). The two-year PFS rate was 16.0 percent
and 21.9 percent with KEYTRUDA (pembrolizumab) (2 mg/kg and 10
mg/kg, respectively), compared to less than one percent (0.6
percent) of patients treated with chemotherapy.
ORR was 22.2 percent and 27.6 percent with KEYTRUDA (2 mg/kg and
10 mg/kg, respectively), compared to 4.5 percent with chemotherapy.
At the time of analysis, 50 percent and 58 percent of patients who
responded to KEYTRUDA (2 mg/kg and 10 mg/kg, respectively) were
alive with no subsequent progression or anti-tumor therapy,
compared to 12 percent of patients who responded to
chemotherapy.
With longer follow-up, adverse events have remained consistent
with previously reported safety data. Treatment-related
immune-mediated adverse events of Grade 3-4 were pneumonitis,
colitis (10 mg/kg only), adrenal insufficiency, severe skin
toxicity, hypophysitis, hepatitis, nephritis (2 mg/kg only),
pancreatitis (10 mg/kg only), and myasthenia (10 mg/kg only).
About Melanoma
Melanoma, the most serious form of skin cancer, is characterized
by the uncontrolled growth of pigment-producing cells. The
incidence of melanoma has been increasing over the past four
decades – approximately 232,000 new cases were diagnosed worldwide
in 2012. In the U.S., melanoma is one of the most common types of
cancer diagnosed and is responsible for the vast majority of skin
cancer deaths. In 2016, an estimated 76,380 people are expected to
be diagnosed and an estimated 10,130 people are expected to die of
the disease in the U.S. alone. The five-year survival rates for
advanced or metastatic melanoma (Stage IV) are estimated to be 15
to 20 percent.
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 (pembrolizumab) 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) in Melanoma
Immune-mediated pneumonitis, including fatal cases, occurred in
patients receiving KEYTRUDA. Pneumonitis occurred in 32 (2.0%) of
1567 patients, including Grade 1 (0.8%), 2 (0.8%), and 3 (0.4%)
pneumonitis. 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 31 (2%) of 1567 patients,
including Grade 2 (0.5%), 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
(pembrolizumab) for Grade 2 or 3; permanently discontinue KEYTRUDA
for Grade 4 colitis.
Immune-mediated hepatitis occurred in 16 (1%) of 1567 patients,
including Grade 2 (0.1%), 3 (0.7%), 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.
Hypophysitis occurred in 13 (0.8%) of 1567 patients, including
Grade 2 (0.3%), 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.
Hyperthyroidism occurred in 51 (3.3%) of 1567 patients,
including Grade 2 (0.6%) and 3 (0.1%) hyperthyroidism.
Hypothyroidism occurred in 127 (8.1%) of 1567 patients, including
Grade 3 (0.1%) 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 7 (0.4%) of 1567 patients,
including Grade 2 (0.2%), 3 (0.2%), 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.
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
(pembrolizumab) 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
1567 patients: arthritis (1.6%), exfoliative dermatitis, bullous
pemphigoid, uveitis, myositis, Guillain-Barré syndrome, myasthenia
gravis, vasculitis, pancreatitis, hemolytic anemia, and partial
seizures arising in a patient with inflammatory foci in brain
parenchyma.
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.
In KEYNOTE-002, KEYTRUDA was discontinued due to adverse
reactions in 12% of 357 patients; the most common (≥1%) were
general physical health deterioration (1%), asthenia (1%), dyspnea
(1%), pneumonitis (1%), and generalized edema (1%). Adverse
reactions leading to interruption of KEYTRUDA occurred in 14% of
patients; the most common (≥1%) were dyspnea (1%), diarrhea (1%),
and maculopapular rash (1%). The most common adverse reactions with
KEYTRUDA vs chemotherapy were fatigue (43% with KEYTRUDA), pruritus
(28% vs 8%), rash (24% vs 8%), constipation (22% vs 20%), nausea
(22% with KEYTRUDA), diarrhea (20% vs 20%), and decreased appetite
(20% with KEYTRUDA). Corresponding incidence rates are listed for
chemotherapy only for those adverse reactions that occurred at the
same or lower rate than with KEYTRUDA
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.
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
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toward health care cost containment; technological advances, new
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conditions; manufacturing difficulties or delays; financial
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The company undertakes no obligation to publicly update any
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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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