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May 29, 2015 1:05 pm ET

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

KENILWORTH, N.J.–(BUSINESS WIRE)–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 Cancer^1,2

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
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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

Merck
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