New KEYTRUDA® (pembrolizumab) Data from KEYNOTE-006 and KEYNOTE-001 in Advanced Melanoma, Including Updated Survival Data, To Be Presented at 2016 ASCO Annual Meeting
May 18, 2016 4:19 pm ET
Final Overall Survival Data from KEYNOTE-006 To Be Presented at ASCO; KEYTRUDA, the First Anti-PD-1 Monotherapy to Demonstrate Overall Survival Compared to Ipilimumab, Shows Continued Benefit with Longer Follow-Up
KEYNOTE-001 Findings Show Continued Benefit in Response Rates, Duration of Response, and Include New Three-Year Overall Survival Data for KEYTRUDA
Merck (NYSE:MRK), known as MSD outside the United States and Canada,
today announced final overall survival (OS) data from KEYNOTE-006 and
new findings from KEYNOTE-001, including updated response rates,
duration of response data and three-year OS data with KEYTRUDA®
(pembrolizumab), the company’s anti-PD-1 therapy, in patients with
unresectable or metastatic melanoma. Findings from the final OS analysis
from KEYNOTE-006, a phase 3 study evaluating KEYTRUDA as monotherapy
compared to ipilimumab, continue to show a significant survival benefit
compared to ipilimumab in the first-line setting for advanced melanoma.
These data will be presented at the 52nd Annual Meeting of
the American Society of Clinical Oncology (ASCO) in Chicago, June 3 – 7,
Long-term OS data from KEYNOTE-006 to be presented at ASCO showed that
with KEYTRUDA, 55.1 percent and 55.3 percent of patients were alive two
years after starting treatment (10 mg/kg every two weeks and three
weeks, respectively), compared to 43 percent of patients receiving
ipilimumab (hazard ratio: 0.68 [95% CI, 0.53-0.87; p=0.0008] and hazard
ratio: 0.68 [95% CI, 0.53-0.86; p=0.0008], respectively). These data
will be presented by Dr. Jacob Schachter, Ella Institute for Research
and Treatment of Melanoma, Sheba Medical Center, in an oral session on
Monday, June 6, from 2:27 to 2:39 p.m. CDT (Location: Arie Crown
Theater) (Abstract #9504).
Additionally, data from KEYNOTE-001, including the long-term, three-year
OS analysis, were featured in the official ASCO Press Program today and
will be presented at ASCO in Chicago. The primary efficacy measure in
KEYNOTE-001 was overall response rate (ORR), and secondary outcome
measures included duration of response, progression-free survival (PFS)
and OS. The data from KEYNOTE-001 discussed today will be presented
along with additional findings in an oral session by Dr. Caroline
Robert, Institut Gustave-Roussy, on Monday, June 6, from 2:15 to 2:27
p.m. CDT (Location: Arie Crown Theater) (Abstract #9503).
“With longer-term follow-up from two studies, including a head-to-head
trial demonstrating superior survival compared to another immunotherapy,
we are continuing to see durability of response with KEYTRUDA as
monotherapy,” said Dr. Roger Dansey, senior vice president and
therapeutic area head, oncology late-stage development, Merck Research
Laboratories. “These results add to the growing body of data supporting
the use of KEYTRUDA as first-line treatment in advanced melanoma, and
serve as an important reminder for what we are aiming to achieve through
our immuno-oncology development program – enhanced survival for people
Findings from the melanoma cohorts of the phase 1b KEYNOTE-001 trial,
which included 655 patients, showed an ORR of 33 percent (per RECIST
v1.1). At the time of the analysis, a response duration of two years or
more was observed in 73 percent of patients. Long-term OS data showed an
estimated 40 percent of patients were alive three years after starting
KEYTRUDA (pembrolizumab), with a median survival of 24.4 months (95% CI,
20.2-29.0). Median duration of response has not yet been reached (range,
1.3+ to 38.8+).
Data from KEYNOTE-001 served as the basis for the U.S. Food and Drug
Administration’s accelerated approval of KEYTRUDA in September 2014. The
label was subsequently updated to reflect data from the KEYNOTE-006
(phase 3) and KEYNOTE-002 (phase 2) trials, expanding the indication to
include treatment of first-line advanced melanoma regardless of BRAF
status. Today, KEYTRUDA is approved for the treatment of advanced
melanoma in more than 50 countries, including the United States and
The KEYTRUDA clinical development program includes more than 30 tumor
types in more than 270 clinical trials, including more than 100 trials
that combine KEYTRUDA with other cancer treatments.
Key Findings from the KEYNOTE-006 Study
KEYNOTE-006 is a global, open-label, randomized, pivotal, phase 3 study
evaluating KEYTRUDA (pembrolizumab) compared to ipilimumab in patients
with unresectable stage III or IV advanced melanoma with no more than
one prior systemic therapy. The study randomized 834 patients to receive
KEYTRUDA 10 mg/kg every three weeks, KEYTRUDA 10 mg/kg every two weeks,
or four cycles of ipilimumab 3 mg/kg every three weeks. The co-primary
endpoints were PFS and OS; secondary endpoints were ORR, duration of
response and safety, with an exploratory analysis for health-related
quality of life (QoL). Tumor response was assessed at week 12, then
every 6 weeks thereafter per RECIST v1.1 by independent, central,
blinded radiographic review and investigator-assessed, immune-related
Based on data to be presented at ASCO, KEYTRUDA (10 mg/kg every two or
three weeks) continued to provide superior OS, PFS and ORR compared to
ipilimumab. Specifically, long-term OS data showed 55.1 percent and 55.3
percent of patients were alive two years after starting treatment with
KEYTRUDA (every two weeks and three weeks, respectively) compared to 43
percent of patients receiving ipilimumab (hazard ratio: 0.68 [95% CI,
0.53-0.87; p=0.0008] and hazard ratio: 0.68 [95% CI, 0.53-0.86;
p=0.0008], respectively). Median OS was not reached for KEYTRUDA; for
ipilimumab, median OS was 16 months.
Additionally, an estimated 31.2 percent and 27.8 percent of patients
receiving KEYTRUDA (every two weeks and three weeks, respectively) were
alive and were disease progression-free at two years compared to 13.5
percent of patients receiving ipilimumab (hazard ratio: 0.61 [95% CI,
0.50-0.75; p<0.0001] for both). For patients receiving KEYTRUDA, ORR was
36.9 percent and 36.1 percent (every two weeks and three weeks,
respectively) compared to 13.3 percent for patients receiving ipilimumab
(p<0.0001 for both groups).
With longer follow-up, adverse events have remained consistent with
previously reported safety data. There was one treatment-related death
(due to sepsis) in the KEYTRUDA every two week group.
Key Findings from the KEYNOTE-001 Study
KEYNOTE-001 is a phase 1b multicenter, open-label, multi-cohort trial
evaluating KEYTRUDA in various advanced cancers, including advanced
melanoma. Patients in the melanoma cohorts received 2 mg/kg or 10 mg/kg
of KEYTRUDA every three weeks or 10 mg/kg of KEYTRUDA every two weeks
until unacceptable toxicity or disease progression. The major efficacy
outcome measure was confirmed ORR as assessed by blinded independent
central review using RECIST v1.1. Tumor response was assessed every 12
weeks. The secondary outcome measures included PFS, OS and duration of
The findings to be presented at ASCO include updated response rates and
duration of response data, as well as three-year OS data from the 655
patients with unresectable or metastatic melanoma and progression of
disease. All patients were followed for at least two years, with some
being followed for almost four years (with median follow-up duration of
Of those patients who responded to treatment with KEYTRUDA
(pembrolizumab), a complete response (CR) was observed in 10 percent of
patients. Among the 61 patients who stopped treatment once a complete
response had occurred, the response duration ranged from 17+ to 44+
months (median duration not reached). Only two patients who had a
complete response experienced disease progression after stopping
treatment. In addition, long-term survival data showed that 40 percent
of patients survived three years after starting treatment with KEYTRUDA
With longer follow-up, adverse events have remained consistent with
previously reported safety data. Immune-mediated treatment-related
adverse events observed in this trial were hypothyroidism (9.6%),
pneumonitis (4.3%), hyperthyroidism (2.3%), colitis (2.3%), uveitis
(1.5%), hepatitis (0.9%), and nephritis (0.5%).
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 for the treatment of patients with unresectable or
KEYTRUDA is also 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. 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.
KEYTRUDA is administered at a dose of 2 mg/kg as an intravenous infusion
over 30 minutes every three weeks for the approved indications.
Selected Important Safety Information for KEYTRUDA® (pembrolizumab)
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
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 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 (pembrolizumab) 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 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
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 Trial 6, KEYTRUDA was discontinued due to adverse reactions in 9% of
555 patients; adverse reactions leading to discontinuation in more than
one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic
reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%).
Adverse reactions leading to interruption of KEYTRUDA occurred in 21% of
patients; the most common (≥1%) was diarrhea (2.5%). The most common
adverse reactions with KEYTRUDA vs ipilimumab were fatigue (28% vs 28%),
diarrhea (26% with KEYTRUDA), rash (24% vs 23%), and nausea (21% with
KEYTRUDA). Corresponding incidence rates are listed for ipilimumab only
for those adverse reactions that occurred at the same or lower rate than
In Trial 2, 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 (pembrolizumab) occurred in 14% of patients; the most common
(≥1%) were dyspnea (1%), diarrhea (1%), and maculo-papular rash (1%).
The most common adverse reactions with KEYTRUDA (pembrolizumab) 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
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
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 270 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.
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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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