New Data from Phase 2 Study Evaluating KEYTRUDA® (pembrolizumab) for the Treatment of Cancers Deficient in DNA Mismatch Repair Show Durable Responses Across a Range of Cancers
June 5, 2016 12:43 pm ET
Merck (NYSE: MRK), known as MSD outside the United States and Canada,
today announced updated findings from a study evaluating KEYTRUDA®
(pembrolizumab), the company’s anti-PD-1 therapy, in patients with
advanced cancers characterized as deficient for DNA mismatch repair
(MMR). Results showed that among previously treated patients with
MMR-deficient tumors, there was an overall response rate (ORR) of 53
percent (n=16/30) (95% CI, 36-70) in patients with a range of advanced
non-colorectal solid tumors and an ORR of 57 percent (n=16/28) (95% CI,
39-73) in patients with advanced colorectal cancer; in contrast, no
responses were observed in patients with advanced colorectal cancer
whose tumors were characterized as MMR-proficient (n=0/25). The
findings, from a phase 2 study led by researchers from Johns Hopkins
Kimmel Cancer Center in collaboration with Merck, were presented at the
52nd Annual Meeting of the American Society of Clinical
Oncology (ASCO) in Chicago (Abstracts #3003, #103).
“We continue to be encouraged by the findings of this ongoing study
evaluating KEYTRUDA in patients with mismatch repair deficient tumors,”
said Dr. Roger Dansey, senior vice president and therapeutic area head,
oncology late-stage development, Merck Research Laboratories.
“Characterization of biomarkers with the potential to predict clinical
outcomes for patients receiving immune therapy for cancer is an
important element of our clinical program for KEYTRUDA.”
Merck is conducting a phase 2 registration study (KEYNOTE-164) to
evaluate the efficacy and safety of KEYTRUDA monotherapy in patients
with previously treated, locally advanced unresectable or metastatic
(Stage IV) MMR-deficient or microsatellite instability-high (MSI-H)
colorectal cancer and a phase 3 study (KEYNOTE-177) in a treatment-naïve
patient population. An additional phase 2 clinical trial (KEYNOTE-158)
is evaluating patients with advanced tumors classified as MSI-H,
excluding colorectal carcinoma.
The KEYTRUDA (pembrolizumab) 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.
Updated Findings from Non-Colorectal Cancer Cohort (Abstract #3003)
and Colorectal Cancer Cohort (Abstract #103)
The phase 2 study evaluated the clinical activity of KEYTRUDA
monotherapy (10 mg/kg every two weeks) in patients with previously
treated, progressive metastatic disease with or without MMR-deficiency.
Three groups were evaluated: MMR-deficient non-colorectal cancers
(n=30), MMR-deficient colorectal cancer (n=28), and MMR-proficient
colorectal cancer (n=25). MMR status was assessed locally using a
standard immunohistochemistry (IHC) or polymerase chain reaction
(PCR)-based method for detection of microsatellite instability. The key
endpoints of the study were ORR, duration of response (DOR),
progression-free survival (PFS) measured by RECIST v1.1, and overall
Abstract #3003 described findings from a cohort of patients with
MMR-deficient non-colorectal cancers (including ampullary/biliary,
endometrial, gastric, pancreatic, prostate, sarcoma, and small bowel)
who received KEYTRUDA. Results demonstrated an ORR of 53 percent
(n=16/30) (95% CI, 36-70) – 30 percent were complete responses (n=9/30)
and 23 percent were partial responses (n=7/30). Additionally, 17 percent
of patients had stable disease (n=5/30), and the disease control rate
was 70 percent (n=21/30) (95% CI, 52-83). Median PFS and OS were not
reached at the time of analysis; median duration of follow-up was 10
Abstract #103 described findings from two cohorts of patients with
colorectal cancer (MMR-deficient and MMR-proficient) who received
KEYTRUDA. Among those patients with MMR-deficient tumors, an ORR of 57
percent was observed (n=16/28) (95% CI, 39-73) – 11 percent were
complete responses (n=3/28) and 46 percent were partial responses
(n=13/28). Additionally, 32 percent of patients had stable disease
(n=9/28) and the disease control rate was 89 percent (n=25/28) (95% CI,
73-96). The median PFS and OS were not reached; median duration of
follow-up was 9.3 months. Among patients with MMR-proficient tumors, no
responses were observed (n=0/25) and the disease control rate was 16
percent (n=4/25) (95% CI, 6-35); 16 percent had stable disease (n=4/25).
Additionally, in patients with MMR-proficient tumors, the median PFS was
2.3 months and the median OS was 5.98 months; median duration of
follow-up was 6 months.
The safety profile of KEYTRUDA (pembrolizumab) was consistent with that
observed in previously reported studies. For patients in the
MMR-deficient non-colorectal cancers cohort, Grade 3-4 treatment-related
adverse events included diarrhea/colitis (n=3) and pancreatitis (n=1).
For patients in the colorectal cancer cohorts (MMR-deficient and
MMR-proficient), Grade 3-4 treatment-related adverse events included
diarrhea/colitis (n=1), pancreatitis (n=2), rash/pruritus (n=1), anemia
(n=1), leukopenia (n=1), and thrombocytopenia (n=1).
Initial findings from this study evaluating KEYTRUDA (41 patients) were
presented at the 2015 ASCO Annual Meeting and simultaneously published
online in the New England Journal of Medicine (Le et al. New Eng. J.
Med. 372, 26, 2509). On November 2, 2015, Merck announced that the
U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy
Designation to KEYTRUDA for the treatment of patients with MSI-H
metastatic colorectal cancer.
About DNA Mismatch Repair and Microsatellite Instability
Analysis of tumor DNA for microsatellite instability can be used to
identify tumors with defective DNA mismatch repair (MMR) systems. DNA
MMR is a process that in normal cells permits the recognition and repair
of genetic mismatches generated during DNA replication. A defective MMR
system results in the persistence of DNA mismatches that may then be
incorporated into the genetic code as mutations. The average tumor has
dozens of mutations; however, tumors with DNA MMR-deficiency may harbor
thousands, especially in regions of repetitive DNA known as
microsatellites. Tumors that are found to have mutations in select
microsatellite sequences, called microsatellite instability (MSI), are
considered DNA MMR-deficient. These tumors are referred to as being
“MSI-high.” Overall, DNA MMR-deficiency is present in approximately
15-20 percent of tumors in Stage II disease, 10 percent in Stage III
disease and approximately 5 percent or less in Stage IV disease. In
colorectal cancers, MMR-deficiency is seen in approximately 15-20
percent of non-hereditary colorectal cancers and in most hereditary
colorectal cancers associated with Lynch Syndrome.
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 (pembrolizumab) is indicated for the treatment of patients with
unresectable or metastatic melanoma.
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
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
(pembrolizumab) 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
(pembrolizumab) 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
Kim Hamilton, 908-740-1863
Teri Loxam, 908-740-1986
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