Merck Announces Longer-Term Follow-Up of Overall Survival Data for KEYTRUDA® (pembrolizumab) in Patients with Advanced Melanoma from KEYNOTE-002 Presented at ESMO 2016 Congress
October 8, 2016 7:45 am ET
Data Comparing KEYTRUDA to Chemotherapy Shows Continued Benefit with Follow-Up Beyond 2.5 Years in Patients with Ipilimumab-Refractory Advanced Melanoma
KENILWORTH, N.J.–(BUSINESS WIRE)–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
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).
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.
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
KEYTRUDA is indicated for the treatment of patients with unresectable or
metastatic melanoma at a dose of 2 mg/kg every three weeks.
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
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
Selected Important Safety Information for KEYTRUDA
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 (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
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
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 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.
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