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January 13, 2015 8:00 am ET

Combinations of KEYTRUDA® (pembrolizumab) with Alimta® (pemetrexed), Cyramza® (ramucirumab), or necitumumab to be explored

KENILWORTH, N.J. & INDIANAPOLIS–(BUSINESS WIRE)–Merck (NYSE:MRK), known as MSD outside the US and Canada, and Eli Lilly
and Company (NYSE:LLY) announced today an oncology clinical trial
collaboration to evaluate the safety, tolerability and efficacy of
KEYTRUDA® (pembrolizumab), Merck’s anti-PD-1 therapy, in combination
with Lilly compounds in multiple clinical trials:

• Merck will conduct a Phase 2 study examining the combination of
  pembrolizumab with pemetrexed in first-line non-squamous, non-small
  cell lung cancer (NSCLC). This study is currently enrolling.
• Lilly will conduct a multiple-arm Phase 1/2 study examining the
  combination of ramucirumab with pembrolizumab in multiple tumors. This
  study is anticipated to begin in 2015.
• Lilly will conduct a Phase 1/2 study examining the combination of
  necitumumab with pembrolizumab in NSCLC. This study is anticipated to
  begin in 2015.

The agreement is between Lilly and Merck, through a subsidiary.
Additional details of the collaboration were not disclosed.

“Cancer is not one disease but rather more than 200 diseases, all of
which have different causes and treatments,” said Richard Gaynor, M.D.,
senior vice president, product development and medical affairs, Lilly
Oncology. “Therefore research into combinations of immune-based
therapies with other agents that could address these different tumor
types is important. This collaboration between Lilly and Merck
represents each company’s strong commitment to patients fighting these
devastating diseases.”

“Our understanding of the immune system’s role and its impact in the
treatment of cancer continues to grow,” said Eric Rubin, M.D., vice
president, global clinical development, oncology, Merck Research
Laboratories. “Collaborations such as this one are important in
advancing the investigation of novel immuno-oncology combinations in
different cancers, and to achieving our shared goal of bringing
meaningful benefits to patients facing cancer.”

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.

About ALIMTA® (pemetrexed)

In 2004, ALIMTA received consecutive approvals: it was the first agent
to be approved in combination with cisplatin as a treatment for patients
with malignant pleural mesothelioma, whose disease is unresectable or
who are otherwise not candidates for curative surgery, and then as a
single agent for the second-line treatment of patients with locally
advanced or metastatic NSCLC after prior chemotherapy treatment.

In 2008, ALIMTA, in combination with cisplatin, was approved as a
first-line treatment for locally advanced or metastatic NSCLC for
patients with nonsquamous histology. At the time of the first-line
approval, the FDA also approved a change to the second-line indication.
ALIMTA is now indicated as a single agent for the treatment of patients
with locally advanced or metastatic, nonsquamous NSCLC after prior
chemotherapy.

In 2009, ALIMTA was approved as a maintenance therapy for locally
advanced or metastatic NSCLC, specifically for patients with a
nonsquamous histology whose disease has not progressed after four cycles
of platinum-based first-line chemotherapy.

In 2012, ALIMTA was approved by the FDA as a continuation maintenance
therapy for locally-advanced or metastatic NSCLC, following first-line
therapy with ALIMTA plus cisplatin in patients with a nonsquamous
histology.

ALIMTA is not indicated for treatment of patients with squamous cell
NSCLC. Myelosuppression is usually the dose-limiting toxicity with
ALIMTA therapy.

About CYRAMZA® (ramucirumab)

CYRAMZA as a single agent, or in combination with paclitaxel (a type of
chemotherapy), is approved for the treatment of people with advanced or
metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma
whose cancer has progressed on or after prior fluoropyrimidine- or
platinum-containing chemotherapy.

CYRAMZA is an antiangiogenic therapy. It is a vascular endothelial
growth factor (VEGF) Receptor 2 antagonist that specifically binds and
blocks activation of VEGF Receptor 2, by blocking the binding of VEGF
receptor ligands VEGF-A, VEGF-C, and VEGF-D. CYRAMZA inhibited
angiogenesis in an in vivo animal model.

About Necitumumab

Necitumumab is an investigational recombinant human IgG1 monoclonal
antibody that is designed to block the ligand binding site of the human
epidermal growth factor receptor 1 (EGFR). Activation of EGFR has been
correlated with malignant progression, induction of angiogenesis and
inhibition of apoptosis or cell death.

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.

Important Safety Information for ALIMTA® (pemetrexed for injection)

Myelosuppression is usually the dose-limiting toxicity with ALIMTA
therapy.

Contraindication

ALIMTA is contraindicated in patients who have a history of severe
hypersensitivity reaction to pemetrexed.

Warnings and Precautions

Prior to treatment with ALIMTA, patients must be instructed to initiate
supplementation with oral folic acid. Additionally, intramuscular
injections of vitamin B₁₂ are also required prior to ALIMTA
treatment. Folic acid and vitamin B₁₂ supplementation should
be continued throughout treatment as they may reduce the severity of
treatment-related hematologic and GI toxicities. Dexamethasone or its
equivalent should be administered the day before, the day of, and the
day after ALIMTA treatment.

ALIMTA can suppress bone marrow function, as manifested by neutropenia,
thrombocytopenia, and anemia (or pancytopenia). Reduce doses for
subsequent cycles based on hematologic and nonhematologic toxicities.

ALIMTA should not be administered to patients with a creatinine
clearance <45 mL/min. One patient with severe renal impairment
(creatinine clearance 19 mL/min) who did not receive folic acid and
vitamin B₁₂ died of drug-related toxicity following
administration of ALIMTA alone.

Caution should be used when administering NSAIDs concurrently with
ALIMTA to patients with mild to moderate renal insufficiency (creatinine
clearance from 45 to 79 mL/min). Patients with mild to moderate renal
insufficiency should avoid taking NSAIDs with short elimination
half-lives for a period of 2 days before, the day of, and 2 days
following administration of ALIMTA. In the absence of data regarding
potential interaction between ALIMTA and NSAIDs with longer half-lives,
all patients taking these NSAIDs should interrupt dosing for at least 5
days before, the day of, and 2 days following ALIMTA administration. If
concomitant administration of NSAIDs is necessary, patients should be
monitored closely for toxicity, especially myelosuppression, renal, and
gastrointestinal toxicity. No dose adjustment of ALIMTA is needed with
concomitant NSAIDs in patients with normal renal function.

Do not initiate a cycle of treatment in patients unless the ANC is ≥1500
cells/mm³, the platelet count is ≥100,000 cells/mm³,
and creatinine clearance is ≥45 mL/min.

Pregnancy Category D—ALIMTA may cause fetal harm when administered to a
pregnant woman. Women should be apprised of the potential hazard to the
fetus and should be advised to use effective contraceptive measures to
prevent pregnancy during treatment with ALIMTA.

Drug Interactions

See Warnings and Precautions for specific information regarding NSAID
administration in patients with renal insufficiency.

Concomitant administration of nephrotoxic drugs or substances that are
tubularly secreted could result in delayed clearance of ALIMTA.

Use in Specific Patient Populations

It is recommended that nursing be discontinued if the mother is being
treated with ALIMTA or discontinue the drug, taking into account the
importance of the drug for the mother.

Efficacy of ALIMTA in pediatric patients has not been demonstrated. The
most common toxicities reported in the studied pediatric patients were
hematological (leukopenia, neutropenia/granulocytopenia, anemia,
thrombocytopenia, and lymphopenia), liver function abnormalities
(increased ALT/AST), fatigue, and nausea.

Dosage and Administration Guidelines

Complete blood cell counts, including platelet counts and periodic
chemistry tests, which include renal and hepatic function tests, should
be performed on all patients receiving ALIMTA.

Dose adjustments at the start of a subsequent cycle should be based on
nadir hematologic counts or maximum nonhematologic toxicity from the
preceding cycle of therapy. Modify or suspend therapy according to the
Dosage Reduction Guidelines in the full Prescribing Information.

Abbreviated Adverse Reactions (% incidence) – 1st-line advanced
nonsquamous non-small cell lung cancer (NS NSCLC)

The most severe adverse reactions (grades 3-4) with ALIMTA in
combination with cisplatin versus gemcitabine in combination with
cisplatin, respectively, for the 1st-line treatment of patients with
advanced nonsquamous non-small cell lung cancer (NSCLC) were neutropenia
(15% vs 27%); leukopenia (5% vs 8%); thrombocytopenia (4% vs 13%);
anemia (6% vs 10%); fatigue (7% vs 5%); nausea (7% vs 4%); vomiting (6%
vs 6%); anorexia (2% vs 1%); creatinine elevation (1% vs 1%); and
diarrhea (1% vs 2%).

Common adverse reactions (all grades) with ALIMTA in combination with
cisplatin versus gemcitabine in combination with cisplatin,
respectively, were nausea (56% vs 53%); fatigue (43% vs 45%); vomiting
(40% vs 36%); anemia (33% vs 46%); neutropenia (29% vs 38%); anorexia
(27% vs 24%); constipation (21% vs 20%); leukopenia (18% vs 21%);
stomatitis/pharyngitis (14% vs 12%); alopecia (12% vs 21%); diarrhea
(12% vs 13%); thrombocytopenia (10% vs 27%); neuropathy/sensory (9% vs
12%); taste disturbance (8% vs 9%); rash/desquamation (7% vs 8%);
dyspepsia/heartburn (5% vs 6%); and creatinine elevation (10% vs 7%).

Abbreviated Adverse Reactions (% incidence) – Maintenance in advanced
NS NSCLC following non-ALIMTA containing, platinum-based induction
therapy

The most severe adverse reactions (grades 3-4) with ALIMTA as a single
agent versus placebo, respectively, for the maintenance treatment of
patients with locally advanced nonsquamous non-small cell lung cancer
(NS NSCLC) following non-ALIMTA containing platinum-based induction
therapy were anemia (3% vs 1%); neutropenia (3% vs 0%); leukopenia (2%
vs 1%); fatigue (5% vs 1%); nausea (1% vs 1%); anorexia (2% vs 0%);
mucositis/stomatitis (1% vs 0%); diarrhea (1% vs 0%); infection (2% vs
0%); and neuropathy-sensory (1% vs 0%).

Common adverse reactions (all grades) with ALIMTA as a single agent
versus placebo, respectively, after non-ALIMTA containing platinum-based
induction therapy were anemia (15% vs 6%); neutropenia (6% vs 0%);
leukopenia (6% vs 1%); increased ALT (10% vs 4%); increased AST (8% vs
4%); fatigue (25% vs 11%); nausea (19% vs 6%); anorexia (19% vs 5%);
vomiting (9% vs 1%); mucositis/stomatitis (7% vs 2%); diarrhea (5% vs
3%); infection (5% vs 2%); neuropathy-sensory (9% vs 4%); and
rash/desquamation (10% vs 3%).

Abbreviated Adverse Reactions (% incidence) – Maintenance in advanced
NS NSCLC following ALIMTA plus cisplatin induction therapy

The most severe adverse reactions (grades 3-4) with ALIMTA as a single
agent versus placebo, respectively, for the maintenance treatment of
patients with locally advanced nonsquamous non-small cell lung cancer
(NS NSCLC) following ALIMTA plus cisplatin induction therapy were anemia
(4.8% vs 0.6%); neutropenia (3.9% vs 0%); and fatigue (4.5% vs 0.6%).

Common adverse reactions (all grades) with ALIMTA as a single agent
versus placebo, respectively, following ALIMTA plus cisplatin induction
therapy were anemia (15% vs 4.8%); neutropenia (9% vs 0.6%); fatigue
(18% vs 11%); nausea (12% vs 2.4%); vomiting (6% vs 1.8%);
mucositis/stomatitis (5% vs 2.4%); and edema (5% vs 3.6%).

Abbreviated Adverse Reactions (% incidence) – 2nd-line advanced NS
NSCLC

The most severe adverse reactions (grades 3-4) with ALIMTA as a single
agent versus docetaxel, respectively, for the 2nd-line treatment of
patients with advanced non-small cell lung cancer (NSCLC) were
neutropenia (5% vs 40%); leukopenia (4% vs 27%); thrombocytopenia (2% vs
0%); anemia (4% vs 4%); fatigue (5% vs 5%); nausea (3% vs 2%); anorexia
(2% vs 3%); vomiting (2% vs 1%); increased ALT (2% vs 0%); increased AST
(1% vs 0%); and stomatitis/pharyngitis (1% vs 1%).

Common adverse reactions (all grades) with ALIMTA as a single agent
versus docetaxel, respectively, were fatigue (34% vs 36%); nausea (31%
vs 17%); anorexia (22% vs 24%); anemia (19% vs 22%); vomiting (16% vs
12%); stomatitis/pharyngitis (15% vs 17%); rash (14% vs 6%); diarrhea
(13% vs 24%); leukopenia (12% vs 34%); thrombocytopenia (8% vs 1%);
increased ALT (8% vs 1%); increased AST (7% vs 1%); constipation (6% vs
4%); fever (8% vs 8%); pruritus (7% vs 2%); alopecia (6% vs 38%); and
neutropenia (11% vs 45%).

For safety and dosing guidelines, see complete Warnings and
Precautions, Adverse Reactions, and Dosage and Administration sections
in the accompanying full Prescribing Information.

PM_HCP_ISI_NSCLCall_17OCT2012

IMPORTANT SAFETY INFORMATION FOR CYRAMZA

WARNING: HEMORRHAGE
CYRAMZA increased the risk of
hemorrhage, including severe and sometimes fatal hemorrhagic events.
Permanently discontinue CYRAMZA in patients who experience severe
bleeding.

Warnings and Precautions

Hemorrhage

• CYRAMZA increased the risk of hemorrhage and gastrointestinal
  hemorrhage including severe and sometimes fatal hemorrhagic events. In
  Study 1, which evaluated CYRAMZA as a single agent in advanced gastric
  cancer, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6%
  for placebo. In Study 2, which evaluated CYRAMZA plus paclitaxel in
  advanced gastric cancer, the incidence of severe bleeding was 4.3% for
  CYRAMZA plus paclitaxel and 2.4% for placebo plus paclitaxel. Patients
  with gastric cancer receiving nonsteroidal anti-inflammatory drugs
  (NSAIDs) were excluded from enrollment in Studies 1 and 2; therefore,
  the risk of gastric hemorrhage in CYRAMZA-treated patients with
  gastric tumors receiving NSAIDs is unknown. In Study 3, which
  evaluated CYRAMZA plus docetaxel in metastatic non-small cell lung
  cancer (NSCLC), the incidence of severe bleeding was 2.4% for CYRAMZA
  plus docetaxel and 2.3% for placebo plus docetaxel. Patients with
  NSCLC receiving therapeutic anticoagulation or chronic therapy with
  NSAIDs or other antiplatelet therapy other than once-daily aspirin or
  with radiographic evidence of major airway or blood vessel invasion or
  intratumor cavitation were excluded from Study 3; therefore, the risk
  of pulmonary hemorrhage in these groups of patients is unknown.
  Permanently discontinue CYRAMZA in patients who experience severe
  bleeding.

Arterial Thromboembolic Events

• Serious, sometimes fatal, arterial thromboembolic events (ATEs)
  including myocardial infarction, cardiac arrest, cerebrovascular
  accident, and cerebral ischemia occurred in clinical trials including
  1.7% of 236 patients who received CYRAMZA as a single agent for
  gastric cancer in Study 1. Permanently discontinue CYRAMZA in patients
  who experience a severe ATE.

Hypertension

• An increased incidence of severe hypertension occurred in patients
  receiving CYRAMZA as a single agent (8%) as compared to placebo (3%),
  in patients receiving CYRAMZA plus paclitaxel (15%) as compared to
  placebo plus paclitaxel (3%), and in patients receiving CYRAMZA plus
  docetaxel (6%) as compared to placebo plus docetaxel (2%). Control
  hypertension prior to initiating treatment with CYRAMZA. Monitor blood
  pressure every 2 weeks or more frequently as indicated during
  treatment. Temporarily suspend CYRAMZA for severe hypertension until
  medically controlled. Permanently discontinue CYRAMZA if medically
  significant hypertension cannot be controlled with antihypertensive
  therapy or in patients with hypertensive crisis or hypertensive
  encephalopathy.

Infusion-Related Reactions

• Prior to the institution of premedication recommendations across
  clinical trials of CYRAMZA, infusion-related reactions (IRRs) occurred
  in 6 out of 37 patients (16%), including 2 severe events. The majority
  of IRRs across trials occurred during or following a first or second
  CYRAMZA infusion. Symptoms of IRRs included rigors/tremors, back
  pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea,
  wheezing, hypoxia, and paresthesia. In severe cases, symptoms included
  bronchospasm, supraventricular tachycardia, and hypotension. Monitor
  patients during the infusion for signs and symptoms of IRRs in a
  setting with available resuscitation equipment. Immediately and
  permanently discontinue CYRAMZA for Grade 3 or 4 IRRs.

Gastrointestinal Perforations

• CYRAMZA is an antiangiogenic therapy that can increase the risk of
  gastrointestinal perforation, a potentially fatal event. Four of 570
  patients (0.7%) who received CYRAMZA as a single agent in advanced
  gastric cancer clinical trials experienced gastrointestinal
  perforation. In Study 2, the incidence of gastrointestinal perforation
  was 1.2% for CYRAMZA plus paclitaxel as compared to 0.3% for placebo
  plus paclitaxel. In Study 3, the incidence of gastrointestinal
  perforation was 1% for CYRAMZA plus docetaxel as compared to 0.3% for
  placebo plus docetaxel. Permanently discontinue CYRAMZA in patients
  who experience a gastrointestinal perforation.

Impaired Wound Healing

• CYRAMZA has not been studied in patients with serious or nonhealing
  wounds. CYRAMZA is an antiangiogenic therapy with the potential to
  adversely affect wound healing. Withhold CYRAMZA prior to surgery.
  Resume CYRAMZA following the surgical intervention based on clinical
  judgment of adequate wound healing. If a patient develops wound
  healing complications during therapy, discontinue CYRAMZA until the
  wound is fully healed.

Clinical Deterioration in Child-Pugh B or C Cirrhosis

• Clinical deterioration, manifested by new onset or worsening
  encephalopathy, ascites, or hepatorenal syndrome, was reported in
  patients with Child-Pugh B or C cirrhosis who received single-agent
  CYRAMZA. Use CYRAMZA in patients with Child-Pugh B or C cirrhosis only
  if the potential benefits of treatment are judged to outweigh the
  risks of clinical deterioration.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

• RPLS has been reported at a rate of <0.1% in clinical studies with
  CYRAMZA. Confirm the diagnosis of RPLS with MRI and discontinue
  CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve
  within days, although some patients with RPLS can experience ongoing
  neurologic sequelae or death.

Most Common Adverse Reactions—Single Agent

• The most commonly reported adverse reactions (all grades; Grade 3/4)
  occurring in ≥5% of patients receiving CYRAMZA and ≥2% higher than
  placebo in Study 1 were hypertension (16% vs 8%; 8% vs 3%), diarrhea
  (14% vs 9%; 1% vs 2%), headache (9% vs 3%; 0% vs 0%), and hyponatremia
  (6% vs 2%; 3% vs 1%).
• The most common serious adverse events with CYRAMZA in Study 1 were
  anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell
  transfusions were given to 11% of CYRAMZA-treated patients vs 8.7% of
  patients who received placebo.
• Clinically relevant adverse reactions reported in ≥1% and <5% of
  CYRAMZA-treated patients vs placebo in Study 1 were: neutropenia (4.7%
  vs 0.9%), epistaxis (4.7% vs 0.9%), rash (4.2% vs 1.7%), intestinal
  obstruction (2.1% vs 0%), and arterial thromboembolic events (1.7% vs
  0%).
• Across clinical trials of CYRAMZA administered as a single agent,
  clinically relevant adverse reactions (including Grade ≥3) reported in
  CYRAMZA-treated patients included proteinuria, gastrointestinal
  perforation, and infusion-related reactions. In Study 1, according to
  laboratory assessment, 8% of CYRAMZA-treated patients developed
  proteinuria vs 3% of placebo-treated patients. Two patients
  discontinued CYRAMZA due to proteinuria. The rate of gastrointestinal
  perforation in Study 1 was 0.8% and the rate of infusion-related
  reactions was 0.4%.

Most Common Adverse Reactions—Combination With Paclitaxel

• The most commonly reported adverse reactions (all grades; Grade 3/4)
  occurring in ≥5% of patients receiving CYRAMZA plus paclitaxel and ≥2%
  higher than placebo plus paclitaxel in Study 2 were fatigue/asthenia
  (57% vs 44%; 12% vs 6%), neutropenia (54% vs 31%; 41% vs 19%),
  diarrhea (32% vs 23%; 4% vs 2%), epistaxis (31% vs 7%; 0% vs 0%),
  hypertension (25% vs 6%; 15% vs 3%), peripheral edema (25% vs 14%; 2%
  vs 1%), stomatitis (20% vs 7%; 1% vs 1%), proteinuria (17% vs 6%; 1%
  vs 0%), thrombocytopenia (13% vs 6%; 2% vs 2%), hypoalbuminemia (11%
  vs 5%; 1% vs 1%), and gastrointestinal hemorrhage events (10% vs 6%;
  4% vs 2%).
• The most common serious adverse events with CYRAMZA plus paclitaxel in
  Study 2 were neutropenia (3.7%) and febrile neutropenia (2.4%); 19% of
  patients treated with CYRAMZA plus paclitaxel received granulocyte
  colony-stimulating factors.
• Adverse reactions resulting in discontinuation of any component of the
  CYRAMZA plus paclitaxel combination in 2% or more patients in Study 2
  were neutropenia (4%) and thrombocytopenia (3%).
• Clinically relevant adverse reactions reported in ≥1% and <5% of the
  CYRAMZA plus paclitaxel-treated patients in Study 2 were sepsis (3.1%
  for CYRAMZA plus paclitaxel vs 1.8% for placebo plus paclitaxel) and
  gastrointestinal perforations (1.2% for CYRAMZA plus paclitaxel vs
  0.3% for placebo plus paclitaxel).

Most Common Adverse Reactions—Combination With Docetaxel

• The most commonly reported adverse reactions (all grades; Grade 3/4)
  occurring in ≥5% of patients receiving CYRAMZA plus docetaxel and ≥2%
  higher than placebo plus docetaxel in Study 3 were neutropenia (55% vs
  46%; 49% vs 40%), fatigue/asthenia (55% vs 50%; 14% vs 11%),
  stomatitis/mucosal inflammation (37% vs 19%; 7% vs 2%), epistaxis (19%
  vs 7%; <1% vs <1%), febrile neutropenia (16% vs 10%; 16% vs 10%),
  peripheral edema (16% vs 9%; 0% vs <1%), thrombocytopenia (13% vs 5%;
  3% vs <1%), lacrimation increased (13% vs 5%; <1% vs 0%), and hypertension
  (11% vs 5%; 6% vs 2%).
• The most common serious adverse events with CYRAMZA plus docetaxel in
  Study 3 were febrile neutropenia (14%), pneumonia (6%), and
  neutropenia (5%). The use of granulocyte colony-stimulating factors
  was 42% in CYRAMZA plus docetaxel-treated patients versus 37% in
  patients who received placebo plus docetaxel.
• Treatment discontinuation due to adverse reactions occurred more
  frequently in CYRAMZA plus docetaxel-treated patients (9%) than in
  placebo plus docetaxel-treated patients (5%). The most common adverse
  events leading to treatment discontinuation of CYRAMZA in Study 3 were
  infusion-related reaction (0.5%) and epistaxis (0.3%).
• Clinically relevant adverse reactions reported in ≥1% and <5% of
  CYRAMZA plus docetaxel-treated patients in Study 3 were hyponatremia
  (4.8% CYRAMZA plus docetaxel versus 2.4% for placebo plus docetaxel)
  and proteinuria (3.3% CYRAMZA plus docetaxel versus 0.8% placebo plus
  docetaxel).

Drug Interactions

• No pharmacokinetic (PK) interactions were observed between ramucirumab
  (CYRAMZA) and paclitaxel or between ramucirumab (CYRAMZA) and
  docetaxel.

Use in Specific Populations

• Pregnancy Category C: Based on its mechanism of action, CYRAMZA may
  cause fetal harm. Advise females of reproductive potential to avoid
  getting pregnant, including use of adequate contraception, while
  receiving CYRAMZA and for at least 3 months after the last dose of
  CYRAMZA. Animal models link angiogenesis, VEGF and VEGF Receptor 2 to
  critical aspects of female reproduction, embryofetal development, and
  postnatal development. There are no adequate or well-controlled
  studies of ramucirumab in pregnant women. If this drug is used during
  pregnancy, or if the patient becomes pregnant while taking this drug,
  apprise the patient of the potential hazard to a fetus.
• Nursing Mothers: It is recommended to discontinue nursing or
  discontinue CYRAMZA due to the potential risks to the nursing infant.
• Females of Reproductive Potential: Advise females of reproductive
  potential that CYRAMZA may impair fertility.

Please see full Prescribing
Information for CYRAMZA, including Boxed Warning for
hemorrhage.

RB-P HCP ISI 16DEC2014

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 and other areas of breakthrough science 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.

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.

About Lilly Oncology

For more than fifty years, Lilly has been dedicated to delivering
life-changing medicines and support to people living with cancer and
those who care for them. Lilly is determined to build on this heritage
and continue making life better for all those affected by cancer around
the world. To learn more about Lilly’s commitment to people with cancer,
please visit www.LillyOncology.com.

About Eli Lilly and Company

Lilly is a global healthcare leader that unites caring with discovery to
make life better for people around the world. We were founded more than
a century ago by a man committed to creating high-quality medicines that
meet real needs, and today we remain true to that mission in all our
work. Across the globe, Lilly employees work to discover and bring
life-changing medicines to those who need them, improve the
understanding and management of disease, and give back to communities
through philanthropy and volunteerism. To learn more about Lilly, please
visit us at www.lilly.com
and newsroom.lilly.com/social-channels.

C-LLY

RB93109 12/2014 © Lilly USA, LLC 2014. ALL RIGHTS RESERVED.
CYRAMZA^®
is a registered trademark of Eli Lilly and Company.

Merck 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).

Lilly Forward-Looking Statement

This press release contains “forward-looking statements” (as that
term is defined in the United States Private Securities Litigation
Reform Act of 1995) regarding the research collaboration between Merck
and Lilly. This press release reflects Lilly’s current beliefs.
However, there are substantial risks and uncertainties in the process of
drug research, development, and commercialization. Among other risks,
there can be no guarantee that this investigational combination regimen
will receive regulatory approval, or, if approved, that it will achieve
intended benefits or become a commercially successful product. For
further discussion of these and other risks and uncertainties that could
cause actual results to differ materially from Lilly’s expectations,
please see the company’s latest Forms 10-K and 10-Q filed with the U.S.
Securities and Exchange Commission. Except as required by law, Lilly
undertakes no duty to update forward-looking statements.

P-LLY

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Merck
Media:
Pamela Eisele, 267-305-3558
Claire Mulhearn, 908-236-1118
or
Investors:
Justin Holko, 908-740-1879
or
Lilly
Eli Lilly and Company
Keri McGrath, 317-277-3768
Communications Manager
mcgrath_happeks@lilly.com