In Addition, Longer Term Follow-Up
Single-Agent Data for KEYTRUDA Shows Continued Superior Overall
Response Rate and Progression Free Survival Compared to
Ipilimumab
Merck (NYSE:MRK), known as MSD outside the United States and
Canada, today announced findings from three studies investigating
the use of KEYTRUDA® (pembrolizumab), the company’s anti-PD-1
therapy, in combination with three other immunotherapies –
epacadostat, IMLYGICTM (talimogene laherparepvec), and ipilimumab –
in patients with advanced melanoma. The findings, which were
featured in separate oral presentations today at the Society for
Melanoma Research 2015 International Congress (SMR) in San
Francisco, showed robust anti-tumor activity with KEYTRUDA in all
three combinations studied.
“We have demonstrated the benefit of KEYTRUDA as a single agent
in advanced/metastatic melanoma and we are now also looking to
identify potential combinations for patients with this devastating
disease,” said Dr. Roger Dansey, senior vice president and
therapeutic area head, oncology late-stage development, Merck
Research Laboratories. “The combination data presented at SMR,
including KEYTRUDA combined with epacadostat or IMLYGIC, may
further our goal of improving outcomes without substantial
increased toxicity.”
Additionally, updated data presented at SMR from a Phase 3 study
of KEYTRUDA as a single agent showed superior overall response
rates (ORR) and progression free survival (PFS) compared to
ipilimumab in ipilimumab-naïve patients, with twice as many
patients achieving PFS on KEYTRUDA compared to ipilimumab. As
previously reported, the study met its endpoint of overall
survival. Patient-reported outcomes from the same study were also
presented. The KEYTRUDA clinical development program to date
includes patients with more than 30 tumor types in more than 160
clinical trials, including more than 80 trials that combine
KEYTRUDA with other cancer treatments.
Early Findings from the KEYNOTE-037 Study (KEYTRUDA with
Epacadostat)
KEYNOTE-037 is an ongoing Phase 1/2 study of KEYTRUDA
(pembrolizumab) in combination with epacadostat (INCB024360) – an
investigational selective IDO1 inhibitor – in patients with
advanced cancers. The trial is a collaboration between Merck and
Incyte Corporation. Data from the melanoma cohort of this study
were presented on Nov. 21 at 2:50 p.m. PST by Dr. Omid Hamid,
director, Melanoma Center, The Angeles Clinic and Research
Institute. These data were previously presented earlier this month
at the Society for Immunotherapy of Cancer Annual Meeting as part
of a presentation that included several tumor types. The SMR data
includes additional safety data.
Early data from this trial showed that in 19 patients with
advanced melanoma, the combination of KEYTRUDA (two doses studied –
2 mg/kg or 200 mg every three weeks) with epacadostat (four doses
studied – 25, 50, 100 or 300 mg twice daily) demonstrated an ORR of
53 percent (n=10/19), including three complete responses (CRs) and
seven partial responses (PRs). The disease control rate (DCR) was
74 percent (n=14/19).
Treatment-related adverse events were consistent with previously
reported safety data for KEYTRUDA as a single agent. Fifteen
percent (n=9/60) of patients assessed for safety across tumor types
experienced Grade 3 investigator-assessed, treatment-related
adverse events, including rash (8%), arthralgia (2%), AST increased
(2%), mucosal inflammation (2%) and nervous system disorder (2%).
Three patients discontinued treatment – one for Grade 3 arthralgia,
one for Grade 3 AST increased, and one for Grade 2 nervous system
disorder. No Grade 4 treatment-related adverse events or deaths
were observed.
As previously announced, based on these findings, a Phase 3
trial of this combination is planned.
Early Findings from the MASTERKEY-265 Study (KEYTRUDA with
IMLYGIC)
MASTERKEY-265 is an ongoing Phase 1b study evaluating the
safety, efficacy, and tolerability of KEYTRUDA in combination with
IMLYGIC – a herpes simplex virus-1 (HSV-1)-based oncolytic
immunotherapy – in patients with previously untreated, unresected
advanced melanoma. The trial is a collaboration between Merck and
Amgen. Data from this study were presented on Nov. 21 at 3:20 p.m.
PST by Dr. Georgina Long, associate professor, Melanoma Institute
Australia, University of Sydney.
Data presented were of 16 evaluable patients and the first
analysis of this study; results showed that the combination of
KEYTRUDA (200 mg every two weeks) with IMLYGIC (up to 4 mL of 106
PFU/mL, then 108 PFU/mL every two weeks) resulted in an unconfirmed
ORR of 56.3 percent (n=9/16) (95% CI, 19.8, 70.1), including two
CRs and seven PRs. The DCR was 68.8 percent (n=11/16) (95% CI, 11,
58.7).
Treatment-related adverse events were consistent with previously
reported safety data for KEYTRUDA (pembrolizumab). All 21 patients
enrolled had at least one adverse event, and most were Grades 1 and
2. The most common adverse events (occurring in at least 30% of
patients) of any grade were fatigue (52%), pyrexia (48%), chills
(43%), rash (38%), headache (33%), and nausea (33%). Grade 3
adverse events included headache (5%) and diarrhea (5%).
Treatment-related Grade 3 adverse events occurring in 5 patients
included anemia, hyperglycemia, hypoglycemia, hypophosphatemia,
headache, macular rash and generalized rash. No dose-limiting
toxicities were reported.
Based on these findings, a Phase 3 part of this trial is
planned.
Early Findings from the KEYNOTE-029 Study (KEYTRUDA with
Ipilimumab)
KEYNOTE-029 is an ongoing Phase 1/2 study evaluating the safety,
efficacy, and tolerability of KEYTRUDA in combination with low-dose
ipilimumab in patients with advanced melanoma to investigate
whether lower doses of ipilimumab improve the tolerability of the
combination regimen. Early findings from this study were presented
on Nov. 21 at 2 p.m. PST by Dr. Georgina Long, associate professor,
Melanoma Institute Australia, University of Sydney.
Early findings in 72 evaluable patients with advanced melanoma
showed that KEYTRUDA (2 mg/kg every three weeks) in combination
with low-dose ipilimumab (1 mg/kg every three weeks for four doses)
demonstrated an ORR of 56 percent (95% CI, 43-67), including three
CRs and 37 PRs. The DCR was 79 percent (95% CI, 68-88).
Treatment-related adverse events were observed in 93 percent
(n=67/72) of patients. Grade 3-4 treatment-related adverse events
were observed in 36 percent of patients (n=26/72), including lipase
increased (8%), amylase increased (6%), ALT increased (6%), AST
increased (4%), rash (3%), and diarrhea (1%). Grade 3-4
immune-mediated adverse events included thyroiditis, hypophysitis,
type 1 diabetes mellitus, pneumonitis, colitis, hepatitis,
pancreatitis, severe skin reactions and renal events. There were no
treatment-related deaths.
Additional Findings from the KEYNOTE-006 Study
KEYNOTE-006 is a global, open-label, randomized, pivotal, Phase
3 study of patients with unresectable stage 3 or 4 advanced
melanoma who were naïve to ipilimumab and had no more than one
prior systemic therapy. Patients received KEYTRUDA 10 mg/kg every
two weeks (n=279), KEYTRUDA 10 mg/kg every three weeks (n=277), or
four cycles of ipilimumab 3 mg/kg every three weeks (n=278).
Today’s findings provide data on additional endpoints of ORR and
PFS based on six months of additional follow-up (median follow-up
of 13.8 months), as well as the first-time presentation of
patient-reported outcomes. Results were featured in two poster
sessions by Dr. Jacob Schachter, Ella Lemelbaum Institute for
Melanoma, Sheba Medical Center, and Dr. Teresa Petrella, Sunnybrook
Health Sciences Centre, University of Toronto.
Findings showed PFS rates for KEYTRUDA at 12 months were twice
as high as ipilimumab – 37.7 percent in the KEYTRUDA every two week
cohort and 36.3 percent in the every three week group, compared to
17.2 percent with ipilimumab (hazard ratio: 0.60 [95% CI,
0.49-0.74] and hazard ratio: 0.59 [95% CI, 0.48-0.73],
respectively). Additionally, the ORR was 36.2 and 36.1 percent in
patients receiving KEYTRUDA every two weeks or every three weeks,
respectively [(95% CI, 30.6-42.1) and (95% CI, 30.4-42.1),
respectively], compared to 12.9 percent for ipilimumab (95% CI,
9.2-17.5).
There continued to be no treatment-related deaths in the
KEYTRUDA arm and there were no treatment-related deaths in the
ipilimumab arm beyond one that was previously reported. Grade 3-5
treatment-related adverse events were lower for KEYTRUDA than for
ipilimumab – 15.1 and 12.6 percent of patients receiving KEYTRUDA
every two weeks and every three weeks had Grade 3-4 adverse events,
respectively, compared to 19.9 percent of those receiving
ipilimumab. Immune-mediated treatment-related adverse events were
consistent with previously reported safety data for KEYTRUDA and
included hypothyroidism, hyperthyroidism, colitis, hepatitis,
hypophysitis, pneumonitis, type 1 diabetes mellitus, uveitis,
myositis and nephritis.
Also reported at SMR from this study was a prespecified analysis
of new patient-reported health-related quality of life (HRQoL)
outcomes, based on measures such as physical, emotional, cognitive,
and social functioning (based on European Organization for Research
and Treatment of Cancer (EORTC) Core Quality of Life
Questionnaire). The study showed that HRQoL was maintained to a
greater degree with KEYTRUDA than with ipilimumab – the change from
baseline at week 12 (difference in least squares) for KEYTRUDA was
-2.3 (95% CI, -5.21 to 0.62) for the two-week group and -2.6 (95%
CI, -5.44 to 0.23) for the three-week group, respectively, compared
to -9.9 (95% CI, -13.01 to -6.72) for the ipilimumab arm.
In addition, KEYTRUDA was associated with a better symptom
profile. Patients in the KEYTRUDA arms had smaller increases from
baseline in fatigue, pain, dyspnea, appetite loss, and diarrhea,
indicating that although these symptoms worsened with KEYTRUDA,
they did so to a lesser degree than with ipilimumab. KEYTRUDA also
resulted in improvements over baseline in nausea and vomiting and
insomnia, whereas these symptoms worsened with ipilimumab.
About KEYTRUDA® (pembrolizumab) Injection 100
mg
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 in the United States at a dose of 2 mg/kg
administered as an intravenous infusion over 30 minutes every three
weeks 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. 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 also indicated at the same dosing for the treatment of patients
with unresectable or metastatic melanoma and disease progression
following ipilimumab and, if BRAF V600 mutation positive, a BRAF
inhibitor. These indications are 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 these indications may be
contingent upon verification and description of clinical benefit in
the confirmatory trials.
Selected Important Safety Information for
KEYTRUDA® (pembrolizumab)
Pneumonitis, including fatal cases, occurred in patients
receiving KEYTRUDA. Pneumonitis occurred in 12 (2.9%) of 411
melanoma patients, including Grade 2 or 3 cases in 8 (1.9%) and 1
(0.2%) patients, respectively, receiving KEYTRUDA. Pneumonitis
occurred in 19 (3.5%) of 550 patients with NSCLC, including Grade 2
(1.1%), 3 (1.3%), 4 (0.4%), or 5 (0.2%) pneumonitis in patients,
receiving KEYTRUDA. 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.
Colitis (including microscopic colitis) occurred in 4 (1%) of
411 patients with melanoma, including Grade 2 or 3 cases in 1
(0.2%) and 2 (0.5%) patients, respectively, receiving KEYTRUDA.
Colitis occurred in 4 (0.7 %) of 550 patients with NSCLC,
including Grade 2 (0.2%) or 3 (0.4%) colitis in patients receiving
KEYTRUDA. 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.
Hepatitis occurred in patients receiving KEYTRUDA. Hepatitis
(including autoimmune hepatitis) occurred in 2 (0.5%) of 411
patients with melanoma, including a Grade 4 case in 1 (0.2%)
patient, 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 2 (0.5%) of 411 patients with melanoma,
including a Grade 2 case in 1 and a Grade 4 case in 1 (0.2% each)
patient, receiving KEYTRUDA. Hypophysitis occurred in 1 (0.2 %) of
550 patients with NSCLC, 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 indicated. Withhold
KEYTRUDA (pembrolizumab) for Grade 2 and withhold or discontinue
for Grade 3 or Grade 4 hypophysitis.
Hyperthyroidism occurred in 5 (1.2%) of 411 patients with
melanoma, including Grade 2 or 3 cases in 2 (0.5%) and 1 (0.2%)
patients, respectively, receiving KEYTRUDA. Hypothyroidism occurred
in 34 (8.3%) of 411 patients with melanoma, including a Grade 3
case in 1 (0.2%) patient, receiving KEYTRUDA. Hyperthyroidism
occurred in 10 (1.8%) of 550 patients with NSCLC, including Grade 2
(0.7%) or 3 (0.3%). Hypothyroidism occurred in 38 (6.9%) of 550
patients with NSCLC, including Grade 2 (5.5%) or 3 (0.2%). 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 Grade
4 hyperthyroidism.
Type 1 diabetes mellitus, including diabetic ketoacidosis, has
occurred in patients receiving KEYTRUDA. 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.
Nephritis occurred in patients receiving KEYTRUDA. Nephritis
occurred in 3 (0.7%) patients with melanoma, consisting of one case
of Grade 2 autoimmune nephritis (0.2%) and two cases of
interstitial nephritis with renal failure (0.5%), one Grade 3 and
one Grade 4. 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 of the adverse
reaction to Grade 1 or less, initiate corticosteroid taper and
continue to taper over at least 1 month. Resume KEYTRUDA when the
adverse reaction remains at Grade 1 or less following steroid
taper. Permanently discontinue KEYTRUDA for any severe or Grade 3
immune-mediated adverse reaction that recurs and for any
life-threatening immune-mediated adverse reaction.
Across clinical studies with KEYTRUDA, the following clinically
significant, immune-mediated adverse reactions have occurred:
bullous pemphigoid and Guillain-Barré syndrome. The following
clinically significant, immune-mediated adverse reactions occurred
in less than 1% of patients with melanoma treated with KEYTRUDA
(pembrolizumab): exfoliative dermatitis, uveitis, arthritis,
myositis, pancreatitis, hemolytic anemia, and partial seizures
arising in a patient with inflammatory foci in brain parenchyma.
The following clinically significant, immune-mediated adverse
reactions occurred in less than 1% of 550 patients with NSCLC
treated with KEYTRUDA: rash, vasculitis, hemolytic anemia, serum
sickness, and myasthenia gravis.
Infusion-related reactions, including severe and
life-threatening reactions, have occurred in patients receiving
KEYTRUDA. Monitor patients for signs and symptoms of infusion
related reactions including rigors, chills, wheezing, pruritus,
flushing, rash, hypotension, hypoxemia, and fever. For severe or
life-threatening 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.
Among the 411 patients with metastatic melanoma, KEYTRUDA was
discontinued for adverse reactions in 9% of 411 patients. Adverse
reactions, reported in at least two patients, that led to
discontinuation of KEYTRUDA were: pneumonitis, renal failure, and
pain. Serious adverse reactions occurred in 36% of patients. The
most frequent serious adverse reactions, reported in 2% or more of
patients, were renal failure, dyspnea, pneumonia, and cellulitis.
The most common adverse reactions (reported in at least 20% of
patients) were fatigue (47%), cough (30%), nausea (30%), pruritus
(30%), rash (29%), decreased appetite (26%), constipation (21%),
arthralgia (20%), and diarrhea (20%).
Among the 550 patients with metastatic NSCLC, KEYTRUDA was
discontinued due to adverse reactions in 14% of patients. Serious
adverse reactions occurred in 38% of patients. The most frequent
serious adverse reactions reported in 2% or more 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%), decreased appetite
(25%), dyspnea (23%), and cough (29%).
No formal pharmacokinetic drug interaction studies have been
conducted 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. For more information about
our oncology clinical trials, visit
www.merck.com/clinicaltrials.
About Merck
Today's Merck is 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
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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 United States
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
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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 2014
Annual Report on Form 10-K and the company’s other filings with the
Securities and Exchange Commission (SEC) available at the SEC’s
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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 the Medication Guide for KEYTRUDA at
http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_mg.pdf
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