Updated Findings from KEYNOTE-012 for KEYTRUDA® (pembrolizumab) Show Continued Benefit in Response Rates and Duration of Response Lasting Up to 30 Months in Patients with Previously Treated Recurrent or Metastatic Head and Neck Cancer
June 6, 2016 7:00 am ET
Response Rates from KEYNOTE-055 Show Nearly One in Five Patients Responding with KEYTRUDA; Results Confirm Findings from KEYNOTE-012
KENILWORTH, N.J.–(BUSINESS WIRE)–Merck (NYSE:MRK), known as MSD outside the United States and Canada,
today announced new data with KEYTRUDA® (pembrolizumab), the
company’s anti-PD-1 therapy, as a monotherapy from two studies
(KEYNOTE-012 and KEYNOTE-055) in heavily pre-treated patients with
recurrent or metastatic head and neck squamous cell carcinoma (HNSCC).
Data are being presented at the 52nd Annual Meeting of the
American Society of Clinical Oncology (ASCO) in Chicago.
In KEYNOTE-012, for the primary endpoint, findings showed an overall
response rate (ORR) of 18 percent (n=34/192) (95% CI, 13-24). At the
time of analysis, 65 percent of responders (n=22/34) were continuing to
respond – with responses observed in some patients for more than 30
months; median duration of response had not yet been reached. The
secondary endpoint results showed a median overall survival (OS) rate of
eight months (95% CI, 6-10) (Abstract #6012). The phase 1b KEYNOTE-012
study was the first clinical study investigating the role of a PD-1
inhibitor in recurrent or metastatic HNSCC. Based on the results of
KEYNOTE-012, Merck is seeking approval for KEYTRUDA (200 mg fixed dose
every three weeks) for previously treated recurrent or metastatic HNSCC.
The U.S. Food and Drug Administration (FDA) granted Priority Review with
a PDUFA, or action date, of August 9, 2016. The application will be
reviewed under the FDA’s Accelerated Approval program.
For the second study, KEYNOTE-055, which enrolled patients regardless of
PD-L1 tumor status, an analysis based on the first 50 patients showed an
ORR (confirmed, partial responses) in nearly one in five, or 18 percent
(n=9/50) (95% CI, 9-31) of patients treated with KEYTRUDA (Abstract
#6011). Findings from 92 patients with six months of follow-up or more
are also being presented. KEYNOTE-055 is a phase 2 study evaluating the
safety, tolerability, and anti-tumor activity of KEYTRUDA
(pembrolizumab) as a monotherapy (200 mg fixed dose every three weeks)
in patients with recurrent or metastatic HNSCC with disease progression
on platinum-based and cetuximab therapy.
“Head and neck cancer is an extremely difficult disease to treat – and
despite our best efforts, bringing forward meaningful treatment advances
has been challenging,” said Dr. Ranee Mehra, chief of head and neck
oncology, Fox Chase Cancer Center. “To see this level of response with
pembrolizumab in patients with head and neck cancer is encouraging and
provides further evidence of the potential for pembrolizumab in the
treatment of this disease.”
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. With four
registration-enabling studies, Merck currently has the largest
immuno-oncology clinical development program in head and neck cancer,
encompassing all stages of advanced disease, and is conducting research
investigating OS and progression-free survival (PFS) endpoints with
KEYTRUDA as a monotherapy, as well as in combination with chemotherapy
compared to standard of care.
“In Merck’s immuno-oncology clinical development program, we are rapidly
evaluating the potential for KEYTRUDA to play a role in managing a range
of difficult-to-treat cancers, and these data being presented at ASCO
are the result of this effort,” said Dr. Roger Dansey, senior vice
president and therapeutic area head, oncology late-stage development,
Merck Research Laboratories. “We look forward to bringing KEYTRUDA to
more patients with our application for advanced head and neck cancer.”
Findings from the KEYNOTE-012 Study (Abstract #6012)
KEYNOTE-012 is an ongoing multicenter, non-randomized, open-label,
multi-cohort phase 1b trial evaluating KEYTRUDA as a monotherapy (10
mg/kg every two weeks or 200 mg fixed dose every three weeks) in
patients with various advanced cancers, including head and neck. The
head and neck cohorts include patients with recurrent or metastatic
HNSCC, regardless of tumor human papilloma virus (HPV) status (23%
positive; 77% negative). One cohort includes 60 patients who were
considered PD-L1 positive; a second cohort includes 132 patients,
regardless of PD-L1 tumor status. The primary endpoints include overall
safety, tolerability, and ORR (as measured by RECIST v1.1); secondary
endpoints include PFS, OS, and duration of response.
Findings presented at ASCO were based on long-term follow-up of a pooled
analysis of the total population of patients across the two head and
neck cohorts (n=192). Data showed an ORR (confirmed) of 18 percent
(n=34/192) (95% CI, 13-24) – including eight complete responses and 26
partial responses. Thirty-three patients had stable disease and 93
patients had progressive disease. In total, 60 percent of patients
experienced a decrease in their target lesions at the time of analysis.
The median time to response was two months (range, 2-17 months). While
median duration of response had not yet been reached (range, 2+ to 30+
months), 65 percent of responders (n=22/34) were continuing to respond
at the time of analysis (85 percent of responses lasted for six months
or more with 71 percent lasting for 12 months or more). An analysis of
the survival measurements showed a median PFS of two months (95% CI,
1.9-2.1) – with a six-month PFS rate of 25 percent and 12-month PFS rate
of 17 percent. The median OS was eight months (95% CI, 6-10) – with a
six-month OS rate of 58 percent and a 12-month OS rate of 38 percent.
The safety profile was consistent with that observed in previously
reported KEYTRUDA (pembrolizumab) studies. The treatment-related adverse
events observed in this trial (any grade occurring in 5 percent or more
of patients) were fatigue (n=42), hypothyroidism (n=19), rash (n=18),
pruritus (n=16), decreased appetite (n=16), pyrexia (n=12), and nausea
(n=11). Grade 3-4 treatment-related adverse events observed (occurring
in 2 or more patients) were ALT increase (n=3), AST increase (n=3),
fatigue (n=2), decreased appetite (n=2), hyponatremia (n=2), pneumonitis
(n=2), facial swelling (n=2), and hypothyroidism (n=2). Twelve patients
discontinued due to a treatment-related adverse event; there were no
These data are being presented today, June 6, in an oral session by Dr.
Ranee Mehra of Fox Chase Cancer Center from 12:18 – 12:30 p.m. CDT
Findings from the KEYNOTE-055 Study (Abstract #6011)
KEYNOTE-055 is an ongoing multicenter phase 2 trial evaluating KEYTRUDA
as a monotherapy (200 mg fixed dose every three weeks) in patients with
advanced HNSCC, regardless of PD-L1 status, who have progressed on
platinum-based and cetuximab therapy. The primary endpoints include
overall safety, tolerability, and ORR (as measured by RECIST v1.1);
secondary endpoints include PFS, OS, and duration of response.
Data presented at ASCO were based on an early analysis conducted on the
first 50 patients enrolled in the study to receive KEYTRUDA and on an
analysis of 92 patients with six months of follow-up or more. The first
analysis (n=50) showed an ORR (confirmed, partial responses) of 18
percent (n=9/50) (95% CI, 9-31); nine patients had stable disease and 30
had progressive disease.
The analysis of the results observed in patients with six or more months
follow-up (n=92) showed an ORR (confirmed, partial responses) of 17
percent (n=16/92) (95% CI, 10-27); 17 patients had stable disease and 51
had progressive disease. Analysis of results based on tumor HPV status
showed an ORR of 22 percent (n=4/18) (95% CI, 6-48) in HPV-positive
patients and 16 percent (n=12/74) (95% CI, 9-27) in HPV-negative
patients. An analysis based on PD-L1 expression showed an ORR of 17
percent (n=13/76) (95% CI, 9-28) in patients whose tumors expressed
PD-L1 and eight percent (n=1/13) (95% CI, 0.2-36) in patients whose
tumors did not express PD-L1. Overall, 54 percent experienced a decrease
in their target lesions. The median time to response was two months
(range, 2-5 months). Median follow-up duration was seven months (range,
0-14 months) with 75 percent of responders remaining in response at the
time of analysis. An analysis of the survival measurements showed a
median PFS of 2.1 months (95% CI, 2.0-2.3), with a six-month PFS rate of
24 percent, and a median OS of eight months (95% CI, 8-11), with a
six-month OS rate of 65 percent.
The safety profile was consistent with that observed in previously
KEYTRUDA (pembrolizumab) studies. The treatment-related adverse events
observed in this trial (any grade occurring in five percent or more of
patients) were fatigue (n=20), hypothyroidism (n=13), diarrhea (n=10),
decreased appetite (n=9), nausea (n=9), AST increase (n=9), and rash
(n=9). Grade 3-5 treatment-related adverse events observed (occurring in
2 or more patients) were anemia (n=2), AST increase (n=2), Alkaline
Phosphatase increase (n=2), and hepatitis (n=2). There was one
treatment-related death due to pneumonitis; three additional patients
discontinued due to a treatment-related adverse event.
These data are being presented today, June 6, in an oral session by Dr.
Joshua Bauml of the University of Pennsylvania from 12:06 – 12:18 p.m.
CDT (Location: S100bc).
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 (pembrolizumab) 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
Immune-mediated pneumonitis, including fatal cases, occurred in patients
receiving KEYTRUDA. Pneumonitis occurred in 32 (2.0%) of 1567 patients
with melanoma, including Grade 1 (0.8%), 2 (0.8%), and 3 (0.4%)
pneumonitis. 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 and more frequently in patients with a history of
asthma/chronic obstructive pulmonary disease (5.4%) or prior thoracic
radiation (6.0%). 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 with
melanoma, including Grade 2 (0.5%), 3 (1.1%), and 4 (0.1%) colitis.
Immune-mediated colitis occurred in 4 (0.7%) of 550 patients with NSCLC,
including Grade 2 (0.2%) or 3 (0.4%) 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 patients receiving KEYTRUDA.
Hepatitis occurred in 16 (1%) of 1567 patients with melanoma, 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 with melanoma,
including Grade 2 (0.3%), 3 (0.3%), and 4 (0.1%) hypophysitis.
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 clinically
indicated. Withhold KEYTRUDA (pembrolizumab) for Grade 2; withhold or
discontinue for Grade 3 or 4 hypophysitis.
Hyperthyroidism occurred in 51 (3.3%) of 1567 patients with melanoma,
including Grade 2 (0.6%) and 3 (0.1%) hyperthyroidism. Hypothyroidism
occurred in 127 (8.1%) of 1567 patients with melanoma, including Grade 3
(0.1%) hypothyroidism. Hyperthyroidism occurred in 10 (1.8%) of 550
patients with NSCLC, including Grade 2 (0.7%) or 3 (0.3%)
hyperthyroidism. Hypothyroidism occurred in 38 (6.9%) of 550 patients
with NSCLC, including Grade 2 (5.5%) or 3 (0.2%) 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 patients receiving KEYTRUDA.
Nephritis occurred in 7 (0.4%) of 1567 patients with melanoma 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 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
with melanoma: 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. The
following clinically significant, immune-mediated adverse reactions
occurred in less than 1% of 550 patients with NSCLC: rash, vasculitis,
hemolytic anemia, serum sickness, and myasthenia gravis.
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 with advanced melanoma; 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 with KEYTRUDA.
In Trial 2, KEYTRUDA was discontinued due to adverse reactions in 12% of
357 patients with advanced melanoma; 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 maculo-papular 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
KEYTRUDA was discontinued due to adverse reactions in 14% of 550
patients with NSCLC. Serious adverse reactions occurred in 38% of
patients. The most frequent serious adverse reactions reported at least
2% 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%), cough (29%), decreased
appetite (25%), and dyspnea (23%).
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 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
Patient Information/Medication Guide for KEYTRUDA at
Pamela Eisele, 267-305-3558
An Phan, 908-255-6325
Teri Loxam, 908-740-1986
Justin Holko, 908-740-1879