Early Findings Show DNA Mismatch
Repair-Deficient Colorectal and Other Tumors Highly Responsive to
Checkpoint Blockade with Anti-PD-1 Therapy
Merck Plans to Initiate Phase 2
Registrational Study with KEYTRUDA (KEYNOTE-164) to Evaluate
MMR-Deficiency in Colorectal Cancer
Merck (NYSE:MRK), known as MSD outside the United States and
Canada, today announced results from the first study evaluating the
correlation of benefit with an immunotherapy based on DNA mismatch
repair (MMR) deficiency, a well-established form of genetic
instability in many cancers characterized by the loss of function
of the MMR pathway. The Phase 2 study, led by researchers from
Johns Hopkins Kimmel Cancer Center, evaluated Merck’s anti-PD-1
therapy, KEYTRUDA® (pembrolizumab), in 48 evaluable, heavily
pre-treated patients with advanced colorectal cancer and other
solid tumors. In the colorectal cancer group with MMR-deficient
tumors, an objective response rate (ORR) of 62 percent was observed
(n=8/13). In contrast, no responses were observed in the colorectal
cancer group with MMR-proficient tumors (n=0/25). At the time of
analysis, the median progression-free survival (PFS) and overall
survival (OS) were not reached in the MMR-deficient colorectal
cancer group. These data, featured today in the American Society of
Clinical Oncology (ASCO) Press Program and published in the New
England Journal of Medicine, will be presented in an oral session
by Dr. Dung Le on Saturday, May 30 at the 2015 ASCO Annual
Meeting in Chicago (Abstract #LBA100).
Based on the encouraging results of this early study, Merck will
initiate a registrational Phase 2 study (KEYNOTE-164) to evaluate
the efficacy and safety of KEYTRUDA based on mismatch repair status
in locally advanced unresectable or metastatic (Stage IV)
colorectal cancers. This study is expected to begin enrolling
patients in mid-2015.
“These exciting results, while early, suggest that evidence of
DNA mismatch repair deficiency may be an important way of
identifying tumors that are responsive to checkpoint blockade,”
said Dr. Roger Dansey, therapeutic area head and senior vice
president, oncology late-stage development, Merck Research
Laboratories. “DNA mismatch repair deficiency is an established
biomarker in many types of cancer and these results open the door
for research with KEYTRUDA in colorectal cancer and other tumor
types with this potentially clinically meaningful tool. We look
forward to initiating a registrational Phase 2 study of KEYTRUDA in
patients with colorectal cancer to further explore this genomic
biomarker.”
Results from DNA Mismatch Repair Phase 2 Study with
KEYTRUDA
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
colorectal cancer (n=13), MMR-proficient colorectal cancer (n=25),
and MMR-deficient other cancers (n=10). Mismatch-repair status was
assessed using a standard polymerase chain reaction (PCR)-based
method for detection of microsatellite instability. The primary
endpoints of the study were immune-related PFS rate as assessed at
20 weeks and ORR; secondary endpoints included OS, PFS (as measured
by RECIST v1.1), and disease control rate. The data presented at
ASCO 2015 Annual Meeting were based on an analysis conducted as of
May 8, 2015.
In the group with MMR-deficient colorectal cancer, the ORR was
62 percent and the disease control rate (DCR) was 92 percent. No
responses were observed in the colorectal cancer group with
MMR-proficient tumors and the DCR was 16 percent. In the group with
MMR-deficient other cancers, the ORR was 60 percent and DCR was 70
percent. The median PFS and OS were not reached in the
MMR-deficient colorectal cancer group. In contrast, PFS was 2.3
months and OS was 7.6 months in the MMR-proficient colorectal
cancer group. The median duration of follow-up for all patients was
5.9 months (0.9 to 16.6); 8.3 months (2.2 to 16.6) in the
MMR-deficient colorectal group, 4.9 months (0.9 to 15.6) in the
MMR-proficient colorectal group, and 7.1 months (2.4 to 16.4) in
the MMR-deficient other cancers group. Of the responders, no
patients in the MMR-deficient colorectal cancer group and one
patient in MMR-deficient other cancers group had progressed at the
time of the analysis.
Treatment-related adverse events in the study were generally
consistent with previously reported safety data for KEYTRUDA
(n=41). The most common treatment-related adverse events (occurring
in greater than or equal to 10% of patients) included:
rash/pruritus (17%), pancreatitis (15%), and
thyroiditis/hypothyroidism (10%). Grade 3-4 treatment-related
adverse events occurred in 2 percent of patients (n=1).
About DNA Mismatch Repair and Microsatellite
Instability
DNA mismatch repair (MMR) is a process the body uses to
recognize and repair genetic mismatches generated during DNA
replication. A defective MMR system allows mismatch mutations to
persist. The average tumor has dozens of mutations; however tumors
with DNA MMR deficiency 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 “MSI high.” Overall, DNA
MMR-deficiency is present in approximately 15-20 percent 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 most hereditary colorectal
cancers associated with Lynch Syndrome.
About Colorectal Cancer1,2
Colorectal cancer starts in either the colon or the rectum, and
can also be referred to separately as colon cancer and rectal
cancer. An estimated 1,361,000 new cases of colorectal cancer were
diagnosed globally in 2012, and an estimated 694,000 people died.
Colorectal cancer is the third most common cancer found in men and
the second most common in women around the world. Overall, the
lifetime risk of developing colorectal cancer is about 1 in 20. The
five-year survival rates for advanced or metastatic colon or rectal
cancer (Stage IV) are estimated to be 11 and 12 percent,
respectively.
About KEYTRUDA® (pembrolizumab)
KEYTRUDA (pembrolizumab) is a humanized monoclonal antibody that
blocks the interaction between PD-1 and its ligands, PD-L1 and
PD-L2. By binding to the PD-1 receptor and blocking the interaction
with the receptor ligands, KEYTRUDA releases the PD-1
pathway-mediated inhibition of the immune response, including the
anti-tumor immune response.
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 unresectable or metastatic
melanoma and disease progression following ipilimumab and, if BRAF
V600 mutation positive, a BRAF inhibitor. 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.
Merck is advancing a broad and fast-growing clinical development
program for KEYTRUDA with more than 100 clinical trials – across
more than 30 tumor types and enrolling over 16,000 patients – both
as a monotherapy and in combination with other therapies.
Selected Important Safety Information for KEYTRUDA
Pneumonitis occurred in 12 (2.9%) of 411 patients with advanced
melanoma receiving KEYTRUDA (the approved indication in the United
States), including Grade 2 or 3 cases in 8 (1.9%) and 1 (0.2%)
patients, respectively. 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 pneumonitis.
Colitis (including microscopic colitis) occurred in 4 (1%) of
411 patients, including Grade 2 or 3 cases in 1 (0.2%) and 2 (0.5%)
patients respectively, 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 (including autoimmune hepatitis) occurred in 2 (0.5%)
of 411 patients, 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, including a
Grade 2 case in 1 and a Grade 4 case in 1 (0.2% each) patient,
receiving KEYTRUDA. Monitor for signs and symptoms of hypophysitis.
Administer corticosteroids for Grade 2 or greater hypophysitis.
Withhold KEYTRUDA for Grade 2; withhold or discontinue for Grade 3;
and permanently discontinue KEYTRUDA for Grade 4 hypophysitis.
Nephritis occurred in 3 (0.7%) patients receiving KEYTRUDA,
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.
Hyperthyroidism occurred in 5 (1.2%) of 411 patients, 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, including a Grade 3 case in 1 (0.2%) patient, receiving
KEYTRUDA. 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 corticosteroids for Grade 3 or greater
hyperthyroidism. Withhold KEYTRUDA for Grade 3; permanently
discontinue KEYTRUDA for Grade 4 hyperthyroidism. Isolated
hypothyroidism may be managed with replacement therapy without
treatment interruption and without corticosteroids.
Other clinically important immune-mediated adverse reactions can
occur. The following clinically significant, immune-mediated
adverse reactions occurred in less than 1% of patients treated with
KEYTRUDA: exfoliative dermatitis, uveitis, arthritis, myositis,
pancreatitis, hemolytic anemia, partial seizures arising in a
patient with inflammatory foci in brain parenchyma, adrenal
insufficiency, myasthenic syndrome, optic neuritis, and
rhabdomyolysis.
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. Restart KEYTRUDA if the
adverse reaction remains at Grade 1 or less. Permanently
discontinue KEYTRUDA for any severe or Grade 3 immune-mediated
adverse reaction that recurs and for any life-threatening
immune-mediated adverse reaction.
Based on its mechanism of action, KEYTRUDA may 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.
For the treatment of advanced melanoma, KEYTRUDA was
discontinued for adverse reactions in 6% of 89 patients who
received the recommended dose of 2 mg/kg and 9% of 411 patients
across all doses studied. Serious adverse reactions occurred in 36%
of patients receiving KEYTRUDA. The most frequent serious adverse
drug reactions reported in 2% or more of patients were renal
failure, dyspnea, pneumonia, and cellulitis.
The most common adverse reactions (reported in ≥20% of patients)
were fatigue (47%), cough (30%), nausea (30%), pruritus (30%), rash
(29%), decreased appetite (26%), constipation (21%), arthralgia
(20%), and diarrhea (20%).
The recommended dose of KEYTRUDA is 2 mg/kg administered as an
intravenous infusion over 30 minutes every three weeks until
disease progression or unacceptable toxicity. No formal
pharmacokinetic drug interaction studies have been conducted 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. Safety and
effectiveness of KEYTRUDA have not been established in pediatric
patients.
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, visit
www.merck.com/clinicaltrials.
About Merck
Today’s Merck is a global healthcare 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 healthcare through far-reaching policies, programs and
partnerships. For more information, visit www.merck.com and connect
with us on Twitter, Facebook and YouTube.
Forward-Looking Statement
This news release 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 Merck’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 healthcare
legislation in the United States and internationally; global trends
toward healthcare cost containment; technological advances, new
products and patents attained by competitors; challenges inherent
in new product development, including obtaining regulatory
approval; Merck’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 Merck’s patents and other
protections for innovative products; and the exposure to
litigation, including patent litigation, and/or regulatory
actions.
Merck 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 Merck’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.
___________________________
1 American Cancer Society. Colorectal Cancer. Available at:
http://www.cancer.org/acs/groups/cid/documents/webcontent/003096-pdf.pdf
2 World Health Organization. GLOBOCAN 2012: Estimated Cancer
Incidence, Mortality and Prevalence Worldwide in 2012. Available
at: http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx
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MerckMedia:Pamela Eisele, 267-664-0282Claire Mulhearn,
908-200-1889orInvestors:Joseph Romanelli, 908-740-1986Justin Holko,
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