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December 10, 2014 8:45 am ET

Collaborative Trial is First to Investigate an Anti-PD-1 Therapy, Pembrolizumab, Combined with Trastuzumab

Study to Explore Whether New Approach May Reverse Trastuzumab Resistance in Cancer with Significant Unmet Need

SAN ANTONIO–(BUSINESS WIRE)–The International Breast Cancer Study Group (IBCSG), Breast
International Group (BIG), and Merck, known as MSD outside the United
States and Canada, today announced the opening of the PANACEA study, a
global collaborative study exploring a new way to treat HER2+ breast
cancer that has become resistant to the current standard of care. The
PANACEA study will investigate the use of pembrolizumab (KEYTRUDA^®)
in combination with trastuzumab to evaluate whether the addition of an
anti-PD-1 therapy can reverse trastuzumab resistance in patients with
HER2+ breast cancer whose cancer has spread while on trastuzumab therapy.

Worldwide, breast cancer is the most common cancer among women.¹
About one in five patients with breast cancer have too much of a
growth-promoting protein known as HER2/neu (or just HER2) on the surface
of cancer cells. Breast cancers with too much of this protein tend to
grow and spread more aggressively.

“PANACEA is the first phase 2 immunotherapy trial not only in HER2+
breast cancer, but in the entire breast cancer field,” said Sherene Loi,
MD, PhD, study chair, division of cancer medicine, Peter MacCallum
Cancer Centre, Australia. “If successful, this may herald a new
treatment approach in certain types of breast cancer.”

“Traditionally, breast cancer has not been thought as an ‘immunogenic’
solid tumor, which is why immunotherapies have been initially evaluated
in melanoma and renal cancers,” said Fabrice André, MD, PhD, study
co-chair, department of medical oncology, Institut Gustave Roussy,
France. “However, a significant amount of preclinical and correlative
clinical data suggest that HER2+ breast cancer could be amenable to
immuno-therapeutic approaches. That’s what the many centers involved in
this worldwide collaborative study will try to prove in the next couple
of years.”

“Merck is committing its resources to advance the science of
immuno-oncology, so we can better understand the role of the PD-1 and
other immune pathways in the treatment of breast and other cancers,”
said Alise Reicin, MD, vice president, global clinical development,
oncology, Merck Research Laboratories. “This study will provide insight
into the role of the PD-1/PD-L1 pathway in HER2+ breast cancer, and we
are very pleased to be collaborating with IBCSG and BIG on the PANACEA
study.”

About PANACEA Study

The trial, “Anti-PD-1 Monoclonal Antibody in Advanced,
Trastuzumab-resistant, HER2+ Breast Cancer (PANACEA),” is a Phase 1b/2
study in patients with HER2+ breast cancer whose cancer has spread while
on treatment with trastuzumab. Primary outcome measures of the study are
recommended dose and efficacy and safety profile of pembrolizumab in
combination with trastuzumab. Response will be assessed by RECIST 1.1
criteria. Secondary outcome measures include safety and tolerability,
disease control, duration of response, time to progression,
progression-free survival and overall survival.

The study is enrolling adult females with unresectable or metastatic
breast adenocarcinoma with confirmed HER2-positivity. There are 10 sites
participating in the study across Europe and Australia: Peter MacCallum
Cancer Centre and Westmead Hospital in Australia; Medical University of
Vienna in Austria; Jules Bordet Institute and CHU Sart Tilman in
Belgium; Institut de Cancérologie de l’OUEST, Centre Léon Bérard and
Institut Gustave Roussy in France; and Istituto Europeo di Oncologia
Milano and Azienda USL4 Prato in Italy.

For more information on the PANACEA study, including how to enroll,
please visit: http://clinicaltrials.gov/ct2/show/NCT02129556?term=pembrolizumab+AND+breast&rank=1.

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 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.

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.

About the International Breast Cancer Study Group (IBCSG)

The International Breast Cancer Study Group is a non-profit research
organization dedicated to innovative clinical research designed to
improve the prognosis of women with breast cancer. Formed in 1977 as the
Ludwig Breast Cancer Study Group, IBCSG strives to conduct clinical
trials at the highest level of knowledge in breast cancer medicine,
trial methodology, data handling, and ethical conduct. Patients and
investigators from six continents (Europe, Australia/New Zealand,
Africa, Asia, North and South America) cooperate by participating in
extensive clinical trials in breast cancer populations, guided by the
highest scientific and ethical standards. IBCSG plays a key role in
disseminating practice-changing trial results to the breast cancer
community. For more information, visit www.ibcsg.org.

About Breast International Group (BIG)

The Breast International Group (BIG) is a non-profit organization for
academic breast cancer research groups from around the world, based in
Brussels, Belgium.

Founded by leading European opinion leaders in 1999, BIG now constitutes
a network of 55 collaborative groups from Europe, Canada, Latin America,
Asia and Australasia. These entities are tied to several thousand
specialized hospitals and research centers worldwide. More than 30
clinical trials are run or are under development under the BIG umbrella
at any one time. BIG also works closely with the US National Cancer
Institute (NCI) and the North American Breast Cancer Groups (NABCG), so
that together they act as a strong integrating force in the breast
cancer research arena.

To make significant scientific advances in breast cancer research,
reduce unnecessary duplication of effort, and optimally serve those
affected by the disease, global collaboration is crucial. Therefore BIG
facilitates breast cancer research at international level, by
stimulating cooperation between its members and other academic networks,
and collaborating with, but working independently from, the
pharmaceutical industry.
www.BIGagainstbreastcancer.org

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.

Merck’s Focus on Cancer

Our goal is to translate breakthrough science into biomedical
innovations to help people with cancer worldwide. For Merck Oncology,
helping people fight cancer is our passion, supporting accessibility to
our cancer medicines is our commitment, and pursuing research in
immuno-oncology is our focus to potentially bring new hope to people
with cancer. For more information about our oncology clinical trials,
visit www.merck.com/clinicaltrials.

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 2013 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.

KEYTRUDA^® is a registered trademark of Merck
& Co., Inc., Whitehouse Station, N.J., USA

¹ GLOBOCAN. Breast Cancer: Estimated Incidence, Mortality and
Prevalence Worldwide in 2012. Available at: http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx.
Accessibility verified on December 9, 2014.

Photos/Multimedia Gallery Available: http://www.businesswire.com/multimedia/home/20141210005070/en/

International Breast Cancer Study Group
Laura Cava Northrop, 617-632-3973
press@ibcsg.org
or
Breast International Group
Cecilia Waldvogel, +41 79 478-0238
cecilia.waldvogel@BIGagainstbc.org
or
Merck
Claire Mulhearn, 908-236-1118
claire.mulhearn@merck.com