Merck Announces Initial Results for KEYTRUDA® (pembrolizumab) with Novel Immunotherapy Combinations from Three Investigational Studies Presented at the Society for Melanoma Research International Congress
November 21, 2015 4:30 pm ET
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%
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
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
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®
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
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
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
with cancer. For more information about our oncology clinical trials,
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,
and connect with us on Twitter,
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 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 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 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 the Medication Guide for KEYTRUDA at http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_mg.pdf
Pamela Eisele, (267) 305-3558
An Phan, (908) 255-6325
Teri Loxam, (908) 740-1986
Justin Holko, (908) 740-1879