BAVENCIO(R) (avelumab) Plus INLYTA(R) (axitinib) Significantly Improved Progression-Free Survival in Previously Untreated Patients with Advanced Renal Cell Carcinoma in Phase III Study

PR75136

DARMSTADT, Germany and NEW YORK, Sept. 11, 2018 /PRNewswire=KYODO JBN/ --

      Not intended for US, Canada and UK-based media

    - First positive Phase III immunotherapy trial in combination with a

tyrosine kinase inhibitor (TKI) in any tumor type

    - Results significant in both PDL1+ and all-comer populations

    - Alliance plans to pursue a regulatory submission in the US and

discussions with other health authorities based on interim results for

progression-free survival

    - Trial will continue for the other primary endpoint of overall survival;

detailed results to be submitted for presentation at an upcoming medical

congress

    Merck and Pfizer Inc. (NYSE: PFE) today announced positive top-line results

from the pivotal Phase III JAVELIN Renal 101 study evaluating BAVENCIO(R)

(avelumab)* in combination with INLYTA(R) (axitinib)*, compared with SUTENT(R)

(sunitinib) as initial therapy for patients with advanced renal cell carcinoma

(RCC). As part of a planned interim analysis, an independent Data Monitoring

Committee confirmed that the trial showed a statistically significant

improvement in progression-free survival (PFS) by central review for patients

treated with the combination whose tumors had programmed death

ligand-1‒positive (PD-L1+) expression greater than 1% (primary

objective), as well as in the entire study population regardless of PD-L1 tumor

expression (secondary objective). According to the statistical analysis plan,

if PFS was statistically significant in the PD-L1+ subgroup, then PFS in the

entire study population was to be analyzed for statistical significance.

JAVELIN Renal 101 will continue as planned to the final analysis for the other

primary endpoint of overall survival (OS). No new safety signals were observed,

and adverse events for BAVENCIO, INLYTA and SUTENT in this trial were

consistent with the known safety profiles for all three medicines. The alliance

intends to pursue a regulatory submission in the US based on these interim

results, and these results will be discussed with global health authorities. A

detailed analysis will also be submitted for presentation at an upcoming

medical congress.

    "JAVELIN Renal 101 is the first positive Phase III study combining an

immune checkpoint blocker with a TKI, supporting the potential of BAVENCIO and

INLYTA as a new cancer treatment approach for patients with advanced RCC," said

Chris Boshoff, M.D., Ph.D.,  Senior Vice President and Head of Immuno-Oncology,

Early Development and Translational Oncology, Pfizer Global Product

Development. "These positive results reinforce Pfizer's long-standing heritage

in advancing standards of care for people with RCC, and we look forward to

discussing these data in greater detail with health authorities."

    In December 2017, the US Food and Drug Administration (FDA) granted

Breakthrough Therapy Designation for BAVENCIO in combination with INLYTA for

treatment-naïve patients with advanced RCC. Despite available therapies, the

outlook for patients with advanced RCC remains poor.[1] Approximately 20% to

30% of patients are first diagnosed at the metastatic stage.[2] The five-year

survival rate for patients with metastatic RCC is approximately 12%.[1]

    "We are encouraged by these data which illustrate the impact of BAVENCIO in

combination with INLYTA as a potential first-line treatment for people with

advanced RCC, a serious and life-threatening cancer," said Luciano Rossetti,

M.D., Executive Vice President, Global Head of Research & Development at the

Biopharma business of Merck. "They also support our firm belief in the promise

of combining BAVENCIO with currently approved therapies and novel agents, a

strong focus of the overall JAVELIN clinical development program."

    JAVELIN Renal 101 is a global Phase III, multicenter, randomized (1:1)

study investigating the efficacy and safety of BAVENCIO in combination with

INLYTA as a first-line treatment option compared with SUTENT monotherapy in 886

patients with advanced RCC across all risk groups. The primary objectives are

to demonstrate that BAVENCIO in combination with INLYTA is superior to SUTENT

monotherapy in prolonging PFS or OS in patients with PD-L1+ tumors. BAVENCIO

was administered at 10 mg/kg IV every two weeks in combination with INLYTA at 5

mg orally twice daily; SUTENT was administered at 50 mg orally once daily, four

weeks on/two weeks off.

    *The combination of BAVENCIO and INLYTA is under clinical investigation for

advanced RCC, and there is no guarantee this combination will be approved for

advanced RCC by any health authority worldwide. In the US, INLYTA is approved

as monotherapy for the treatment of advanced RCC after failure of one prior

systemic therapy. INLYTA is also approved by the European Medicines Agency

(EMA) for use in the EU in adult patients with advanced RCC after failure of

prior treatment with SUTENT or a cytokine.

    About the JAVELIN Clinical Development Program

    The clinical development program for BAVENCIO, known as JAVELIN, involves

at least 30 clinical programs, eight Phase III trials and more than 8,600

patients evaluated across more than 15 different tumor types. In addition to

RCC, these tumor types include breast, gastric/gastro-esophageal junction, head

and neck, Hodgkin's lymphoma, melanoma, mesothelioma, Merkel cell carcinoma,

non-small cell lung cancer, ovarian and urothelial carcinoma.

    About Renal Cell Carcinoma

    RCC is the most common form of kidney cancer, accounting for about 2% to 3%

of all cancers in adults.[3],[4] The most common type of RCC is clear cell

carcinoma, accounting for approximately 70% of all cases.[3] In 2012, there

were approximately 338,000 new cases of RCC diagnosed worldwide, with an

estimated 63,340 cases expected in the US alone in 2018.[3],[5] Incidence

varies substantially worldwide, with generally higher rates seen in North

America and Central/Eastern Europe.[5]

    About BAVENCIO(R)(avelumab)

    BAVENCIO is a human anti-programmed death ligand-1 (PD-L1) antibody.

BAVENCIO has been shown in preclinical models to engage both the adaptive and

innate immune functions. By blocking the interaction of PD-L1 with PD-1

receptors, BAVENCIO has been shown to release the suppression of the T

cell-mediated antitumor immune response in preclinical models.[6] -[8] BAVENCIO

has also been shown to induce NK cell-mediated direct tumor cell lysis via

antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro.[8]-[10] In

November 2014, Merck and Pfizer announced a strategic alliance to co-develop

and co-commercialize BAVENCIO.

    Approved Indications

    The FDA granted accelerated approval for BAVENCIO for the treatment of (i)

adults and pediatric patients 12 years and older with metastatic Merkel cell

carcinoma (mMCC) and (ii)  patients with locally advanced or metastatic

urothelial carcinoma (mUC) who have disease progression during or following

platinum-containing chemotherapy, or have disease progression within 12 months

of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

These indications are approved under accelerated approval based on tumor

response rate and duration of response. Continued approval for these

indications may be contingent upon verification and description of clinical

benefit in confirmatory trials.

    BAVENCIO is also approved by the European Medicines Agency (EMA) for use in

the EU as a monotherapy for the treatment of adult patients with mMCC.

    Important Safety Information from the US FDA Approved Label

    The warnings and precautions for BAVENCIO include immune-mediated adverse

reactions (such as pneumonitis, hepatitis, colitis, endocrinopathies, nephritis

and renal dysfunction, and other adverse reactions), infusion-related reactions

and embryo-fetal toxicity.

    Common adverse reactions (reported in at least 20% of patients) in patients

treated with BAVENCIO for mMCC and patients with locally advanced or mUC

include fatigue, musculoskeletal pain, diarrhea, nausea, infusion-related

reaction, peripheral edema, decreased appetite/hypophagia, urinary tract

infection and rash.

    About INLYTA(R) (axitinib)

    INLYTA is an oral therapy that is designed to inhibit tyrosine kinases,

including vascular endothelial growth factor (VEGF) receptors 1, 2 and 3; these

receptors can influence tumor growth, vascular angiogenesis and progression of

cancer (the spread of tumors). In the US, INLYTA is approved for the treatment

of advanced renal cell carcinoma (RCC) after failure of one prior systemic

therapy. INLYTA is also approved by the European Medicines Agency (EMA) for use

in the EU in adult patients with advanced RCC after failure of prior treatment

with sunitinib or a cytokine.

    INLYTA Important Safety Information

    Hypertension including hypertensive crisis has been observed. Blood

pressure should be well controlled prior to initiating INLYTA. Monitor for

hypertension and treat as needed. For persistent hypertension, despite use of

antihypertensive medications, reduce the dose. Discontinue INLYTA if

hypertension is severe and persistent despite use of antihypertensive therapy

and dose reduction of INLYTA, and discontinuation should be considered if there

is evidence of hypertensive crisis.

    Arterial and venous thrombotic events have been observed and can be fatal.

Use with caution in patients who are at increased risk or who have a history of

these events.

    Hemorrhagic events, including fatal events, have been reported. INLYTA has

not been studied in patients with evidence of untreated brain metastasis or

recent active gastrointestinal bleeding and should not be used in those

patients. If any bleeding requires medical intervention, temporarily interrupt

the INLYTA dose.

    Cardiac failure has been observed and can be fatal. Monitor for signs or

symptoms of cardiac failure throughout treatment with INLYTA. Management of

cardiac failure may require permanent discontinuation of INLYTA.

    Gastrointestinal perforation and fistula, including death, have occurred.

Use with caution in patients at risk for gastrointestinal perforation or

fistula. Monitor for symptoms of gastrointestinal perforation or fistula

periodically throughout treatment.

    Hypothyroidism requiring thyroid hormone replacement has been reported.

Monitor thyroid function before initiation of, and periodically throughout,

treatment.

    No formal studies of the effect of INLYTA on wound healing have been

conducted. Stop INLYTA at least 24 hours prior to scheduled surgery.

    Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been observed.

If signs or symptoms occur, permanently discontinue treatment.

    Monitor for proteinuria before initiation of, and periodically throughout,

treatment. For moderate to severe proteinuria, reduce the dose or temporarily

interrupt treatment.

    Liver enzyme elevation has been observed during treatment with INLYTA.

Monitor ALT, AST, and bilirubin before initiation of, and periodically

throughout, treatment.

    For patients with moderate hepatic impairment, the starting dose should be

decreased. INLYTA has not been studied in patients with severe hepatic

impairment.

    Women of childbearing potential should be advised of potential hazard to

the fetus and to avoid becoming pregnant while receiving INLYTA.

    Avoid strong CYP3A4/5 inhibitors. If unavoidable, reduce the dose.

Grapefruit or grapefruit juice may also increase INLYTA plasma concentrations

and should be avoided.

    Avoid strong CYP3A4/5 inducers and, if possible, avoid moderate CYP3A4/5

inducers.

    The most common (greater than or equal to20%) adverse events (AEs)

occurring in patients receiving INLYTA (all grades, vs sorafenib) were diarrhea

(55% vs 53%), hypertension (40% vs 29%), fatigue (39% vs 32%), decreased

appetite (34% vs 29%), nausea (32% vs 22%), dysphonia (31% vs 14%), hand-foot

syndrome (27% vs 51%), weight decreased (25% vs 21%), vomiting (24% vs 17%),

asthenia (21% vs 14%), and constipation (20% vs 20%).

    The most common (greater than or equal to10%) grade 3/4 AEs occurring in

patients receiving INLYTA (vs sorafenib) were hypertension (16% vs 11%),

diarrhea (11% vs 7%), and fatigue (11% vs 5%).

    The most common (greater than or equal to20%) lab abnormalities occurring

in patients receiving INLYTA (all grades, vs sorafenib) included increased

creatinine (55% vs 41%), decreased bicarbonate (44% vs 43%), hypocalcemia (39%

vs 59%), decreased hemoglobin (35% vs 52%), decreased lymphocytes (absolute)

(33% vs 36%), increased ALP (30% vs 34%), hyperglycemia (28% vs 23%), increased

lipase (27% vs 46%), increased amylase (25% vs 33%), increased ALT (22% vs

22%), and increased AST (20% vs 25%).

    For more information and full Prescribing Information, visit

http://www.INLYTA.com [https://www.inlyta.com ].

    SUTENT Important Safety Information

    Boxed Warning/Hepatotoxicity has been observed in clinical trials and

postmarketing experience. Hepatotoxicity may be severe, and in some cases

fatal. Monitor hepatic function and interrupt, reduce, or discontinue dosing as

recommended. Fatal liver failure has been observed. Monitor liver function

tests before initiation of treatment, during each cycle of treatment, and as

clinically indicated. Interrupt SUTENT for Grade 3 or 4 drug-related hepatic

adverse reactions and discontinue if there is no resolution. Do not restart

SUTENT if patients subsequently experience severe changes in liver function

tests or have signs and symptoms of liver failure.

    Cardiovascular events, including myocardial ischemia, myocardial

infarction, left ventricular ejection fraction declines to below the lower

limit of normal and cardiac failure including death have occurred. Monitor

patients for signs and symptoms of congestive heart failure. Discontinue SUTENT

for clinical manifestations of congestive heart failure. In patients without

cardiac risk factors, a baseline evaluation of ejection fraction should be

considered. Baseline and periodic evaluations of left ventricular ejection

fraction should also be considered while these patients are receiving SUTENT.

    SUTENT can cause QT Prolongation in a dose-dependent manner, which may lead

to an increased risk for ventricular arrhythmias including Torsades de Pointes,

which has been seen in <0.1% of patients. Monitor patients that are at a higher

risk for developing QT interval prolongation, including those with a history of

QT interval prolongation, patients who are taking antiarrhythmics, or patients

with relevant pre-existing cardiac disease, bradycardia, or electrolyte

disturbances. Consider monitoring of electrocardiograms and electrolytes.

Concomitant treatment with strong CYP3A4 inhibitors may increase sunitinib

plasma concentrations and dose reduction of SUTENT should be considered.

    Hypertension may occur. Monitor blood pressure and treat as needed with

standard antihypertensive therapy. In cases of severe hypertension, temporary

suspension of SUTENT is recommended until hypertension is controlled.

    Hemorrhagic events, including tumor-related hemorrhage, and viscus

perforation (both with fatal events) have occurred. These events may occur

suddenly, and in the case of pulmonary tumors, may present as severe and

life-threatening hemoptysis or pulmonary hemorrhage. Perform serial complete

blood counts (CBCs) and physical examinations.

    Cases of tumor lysis syndrome (TLS) (some fatal) have been reported.

Patients generally at risk of TLS are those with high tumor burden prior to

treatment. Monitor these patients closely and treat as clinically indicated.

    Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic

purpura and hemolytic uremic syndrome, sometimes leading to renal failure or a

fatal outcome, has been reported in patients who received SUTENT as monotherapy

and in combination with bevacizumab. Discontinue SUTENT in patients developing

TMA. Reversal of the effects of TMA has been observed after treatment was

discontinued.

    Proteinuria and nephrotic syndrome have been reported. Some of these cases

have resulted in renal failure and fatal outcomes. Monitor patients for the

development or worsening of proteinuria. Perform baseline and periodic

urinalysis during treatment, with follow-up measurement of 24-hour urine

protein as clinically indicated. Interrupt treatment for 24-hour urine protein

greater than or equal to3 grams. Discontinue for repeat episodes of protein

greater than or equal to3 grams despite dose reductions or nephrotic syndrome.

    Dermatologic toxicities: Severe cutaneous reactions have been reported,

including cases of necrotizing fasciitis, erythema multiforme (EM),

Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), some of

which were fatal. If signs or symptoms of EM,  SJS, or TEN are present,

discontinue SUTENT treatment. If a diagnosis of SJS or TEN is suspected,

treatment must not be restarted.

    Necrotizing fasciitis, including fatal cases, has been reported, including

of the perineum and secondary to fistula formation. Discontinue SUTENT in

patients who develop necrotizing fasciitis.

    Thyroid dysfunction may occur. Monitor thyroid function in patients with

signs and/or symptoms suggestive of thyroid dysfunction, including

hypothyroidism, hyperthyroidism, and thyroiditis, and treat per standard

medical practice.

    Hypoglycemia may occur. SUTENT can result in symptomatic hypoglycemia,

which may lead to a loss of consciousness or require hospitalization.

Reductions in blood glucose levels may be worse in patients with diabetes.

Check blood glucose levels regularly during and after discontinuation of

treatment with SUTENT. Assess if antidiabetic drug dosage needs to be adjusted

to minimize the risk of hypoglycemia.

    Osteonecrosis of the jaw (ONJ) has been reported. Consider preventive

dentistry prior to treatment with SUTENT. If possible, avoid invasive dental

procedures, particularly in patients receiving intravenous bisphosphonate

therapy.

    Impaired wound healing has occurred with SUTENT. Temporary interruption of

therapy with SUTENT is recommended in patients undergoing major surgical

procedures. There is limited clinical experience regarding the timing of

reinitiation of therapy following major surgical intervention. Therefore, the

decision to resume SUTENT therapy following a major surgical intervention

should be based upon clinical judgment of recovery from surgery.

    Embryo fetal toxicity and reproductive potential

    Females - SUTENT can cause fetal harm when administered to pregnant women.

Advise pregnant women of the potential risk to a fetus. Advise females of

reproductive potential to use effective contraception during treatment with

SUTENT and for 4 weeks following the final dose.

    Males - Based on findings in animal reproduction studies, advise male

patients with female partners of reproductive potential to use effective

contraception during treatment with SUTENT and for 7 weeks after the last dose.

    Male and female infertility - based on findings in animals, male and female

fertility may be compromised by treatment with SUTENT

    Lactation: Because of the potential for serious adverse reactions in

breastfed infants from SUTENT, advise a lactating woman not to breastfeed

during treatment with SUTENT and for at least 4 weeks after the last dose.

    Venous thromboembolic events: In patients treated with SUTENT (N=7527) for

GIST, advanced RCC, adjuvant treatment of RCC and pNET, 3.5% of patients

experienced a venous thromboembolic event; 2.2% Grade 3-4.

    There have been (<1%) reports, some fatal, of subjects presenting with

seizures and radiological evidence of reversible posterior leukoencephalopathy

syndrome (RPLS). Patients with seizures and signs/symptoms consistent with

RPLS, such as hypertension, headache, decreased alertness, altered mental

functioning, and visual loss, including cortical blindness, should be

controlled with medical management including control of hypertension. Temporary

suspension of SUTENT is recommended; following resolution, treatment may be

resumed at the discretion of the treating healthcare provider.

    Pancreatic function: In a trial of patients receiving adjuvant treatment

for RCC, 1 patient (<1%) on SUTENT and none on placebo experienced pancreatitis.

    CYP3A4 inhibitors and inducers: Dose adjustments are recommended when

SUTENT is administered with CYP3A4 inhibitors or inducers. During treatment

with SUTENT, patients should not drink grapefruit juice, eat grapefruit, or

take St. John's Wort.

    Most common ARs & most common grade 3/4 ARs (adjuvant RCC): The most common

ARs reported in greater than or equal to20% of patients receiving SUTENT for

adjuvant treatment of RCC and more commonly than in patients given placebo (all

grades, vs placebo) were mucositis/stomatitis (61% vs 15%), diarrhea (57% vs

22%), fatigue/asthenia (57% vs 34%), hand-foot syndrome (50% vs 10%),

hypertension (39% vs 14%), altered taste (38% vs 6%) , nausea (34% vs 15%),

dyspepsia (27% vs 7%), abdominal pain (25% vs 9%), hypothyroidism/TSH increased

(24% vs 4%), rash (24% vs 12%), hair color changes (22% vs 2%). The most common

grade 3/4 ARs reported in greater than or equal to5% of patients receiving

SUTENT for adjuvant treatment of RCC and more commonly than in patients given

placebo (vs placebo) were hand-foot syndrome (16% vs <1%), fatigue/asthenia (8%

vs 2%), hypertension (8% vs 1%), and mucositis/stomatitis (6% vs 0%).

    Most common grade 3/4 lab abnormalities (adjuvant RCC): The most common

grade 3/4 lab abnormalities (occurring in greater than or equal to 2% of

patients receiving SUTENT) included neutropenia (13%), thrombocytopenia (5%),

leukopenia (3%), lymphopenia (3%), elevated alanine aminotransferase (2%),

elevated aspartate aminotransferase (2%), hyperglycemia (2%), and hyperkalemia

(2%).

    Most common ARs & most common grade 3/4 ARs (advanced RCC): The most common

ARs reported in greater than or equal to20% of patients receiving SUTENT for

treatment-naïve metastatic RCC (all grades, vs IFNalpha) were diarrhea (66% vs

21%), fatigue (62% vs 56%), nausea (58% vs 41%), anorexia (48% vs 42%), altered

taste (47% vs 15%), mucositis/stomatitis (47% vs 5%), pain in extremity/limb

discomfort (40% vs 30%), vomiting (39% vs 17%), bleeding, all sites (37% vs

10%), hypertension (34% vs 4%), dyspepsia (34% vs 4%), arthralgia (30% vs 19%),

abdominal pain (30% vs 12%), rash (29% vs 11%), hand-foot syndrome (29% vs 1%),

back pain (28% vs 14%), cough (27% vs 14%), asthenia (26% vs 22%), dyspnea (26%

vs 20%), skin discoloration/yellow skin (25% vs 0%), peripheral edema (24% vs

5%), headache (23% vs 19%), constipation (23% vs 14%), dry skin (23% vs 7%),

fever (22% vs 37%), and hair color changes (20% vs <1%). The most common grade

3/4 ARs reported in greater than or equal to5% of patients with RCC receiving

SUTENT (vs IFNalpha) were fatigue (15% vs 15%), hypertension (13% vs <1%),

asthenia (11% vs 6%), diarrhea (10% vs <1%), hand-foot syndrome (8% vs 0%),

dyspnea (6% vs 4%), nausea (6% vs 2%), back pain (5% vs 2%), pain in

extremity/limb discomfort (5% vs 2%), vomiting (5% vs 1%), and abdominal pain

(5% vs 1%).

    Most common grade 3/4 lab abnormalities (advanced RCC): The most common

grade 3/4 lab abnormalities (occurring in greater than or equal to5% of

patients with RCC receiving SUTENT vs IFNalpha) included lymphocytes (18% vs

26%), lipase (18% vs 8%), neutrophils (17% vs 9%), uric acid (14% vs 8%),

platelets (9% vs 1%), hemoglobin (8% vs 5%), sodium decreased (8% vs 4%),

leukocytes (8% vs 2%), glucose increased (6% vs 6%), phosphorus (6% vs 6%), and

amylase (6% vs 3%).

    Most common ARs & most common grade 3/4 ARs (imatinib-resistant or

-intolerant GIST): The most common ARs reported in greater than or equal to20%

of patients with GIST and more commonly with SUTENT than placebo (all grades,

vs placebo) were diarrhea (40% vs 27%), anorexia (33% vs 29%), skin

discoloration (30% vs 23%), mucositis/stomatitis (29% vs 18%), asthenia (22% vs

11%), altered taste (21% vs 12%), and constipation (20% vs 14%). The most

common grade 3/4 ARs reported in greater than or equal to4% of patients with

GIST receiving SUTENT (vs placebo) were asthenia (5% vs 3%), hand-foot syndrome

(4% vs 3%), diarrhea (4% vs 0%), and hypertension (4% vs0%).

    Most common grade 3/4 lab abnormalities (imatinib-resistant or - intolerant

GIST): The most common grade 3/4 lab abnormalities (occurring in greater than

or equal to5% of patients with GIST receiving SUTENT vs placebo) included

lipase (10% vs 7%), neutrophils (10% vs 0%), amylase (5% vs 3%), and platelets

(5% vs 0%).

    Most common ARs & most common grade 3/4 ARs (advanced pNET): The most

common ARs reported in greater than or equal to20% of patients with advanced

pNET and more commonly with SUTENT than placebo (all grades, vs placebo) were

diarrhea (59% vs 39%), stomatitis/oral syndromes (48% vs 18%), nausea (45% vs

29%), abdominal pain (39% vs 34%), vomiting (34% vs 31%), asthenia (34% vs

27%), fatigue (33% vs 27%), hair color changes (29% vs 1%), hypertension (27%

vs 5%), hand-foot syndrome (23% vs 2%), bleeding events (22% vs 10%), epistaxis

(21% vs 5%), and dysgeusia (21% vs 5%). The most common grade 3/4 ARs reported

in greater than or equal to5% of patients with advanced pNET receiving SUTENT

(vs placebo) were hypertension (10% vs 1%), hand-foot syndrome (6% vs 0%),

stomatitis/oral syndromes (6% vs 0%), abdominal pain (5% vs 10%), fatigue (5%

vs 9%), asthenia (5% vs 4%), and diarrhea (5% vs 2%).

    Most common grade 3/4 lab abnormalities (advanced pNET): The most common

grade 3/4 lab abnormalities (occurring in greater than or equal to5% of

patients with advanced pNET receiving SUTENT vs placebo) included decreased

neutrophils (16% vs 0%), increased glucose (12% vs 18%), increased alkaline

phosphatase (10% vs 11%), decreased phosphorus (7% vs 5%),  decreased

lymphocytes (7% vs 4%), increased creatinine (5% vs 5%), increased lipase (5%

vs 4%), increased AST (5% vs 3%), and decreased platelets (5% vs 0%).

    Please see full Prescribing Information, including BOXED WARNING and

Medication Guide, for SUTENT(R) (sunitinib malate) at http://www.SUTENT.com.

[http://www.SUTENT.com ]

    About SUTENT(R) (sunitinib malate)

    Sunitinib is a small molecule that inhibits multiple receptor tyrosine

kinases, some of which are implicated in tumor growth, pathologic angiogenesis,

and metastatic progression of cancer. Sunitinib was evaluated for its

inhibitory activity against a variety of kinases (>80 kinases) and was

identified as an inhibitor of platelet-derived growth factor receptors

(PDGFRalpha and PDGFRbeta), vascular endothelial growth factor receptors

(VEGFR1, VEGFR2 and VEGFR3), stem cell factor receptor (KIT), Fms-like tyrosine

kinase-3 (FLT3), colony stimulating factor receptor Type 1 (CSF-1R), and the

glial cell-line derived neurotrophic factor receptor (RET).

    SUTENT is indicated in the US for the treatment of gastrointestinal stromal

tumor (GIST) after disease progression on or intolerance to imatinib mesylate;

the treatment of advanced renal cell carcinoma (RCC); the adjuvant treatment of

adult patients at high risk of recurrent RCC following nephrectomy; the

treatment of progressive, well-differentiated pancreatic neuroendocrine tumors

(pNET) in patients with unresectable locally advanced or metastatic disease.

    About Merck-Pfizer Alliance

    Immuno-oncology is a top priority for Merck and Pfizer. The global

strategic alliance between Merck and Pfizer enables the companies to benefit

from each other's strengths and capabilities and further explore the

therapeutic potential of BAVENCIO (avelumab), an anti-PD-L1 antibody initially

discovered and developed by Merck. The immuno-oncology alliance is jointly

developing and commercializing BAVENCIO and advancing Pfizer's PD-1 antibody.

The alliance is focused on developing high-priority international clinical

programs to investigate BAVENCIO, as a monotherapy, as well as combination

regimens, and is striving to find new ways to treat cancer.

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    About Merck

    Merck is a leading science and technology company in healthcare, life

science and performance materials. Almost 53,000 employees work to further

develop technologies that improve and enhance life - from biopharmaceutical

therapies to treat cancer or multiple sclerosis, cutting-edge systems for

scientific research and production, to liquid crystals for smartphones and LCD

televisions. In 2017, Merck generated sales of EUR 15.3 billion in 66 countries.

    Founded in 1668, Merck is the world's oldest pharmaceutical and chemical

company. The founding family remains the majority owner of the publicly listed

corporate group. Merck, Darmstadt, Germany holds the global rights to the

"Merck" name and brand except in the United States and Canada, where the

company operates as EMD Serono, MilliporeSigma and EMD Performance Materials.

Pfizer Inc.: Working together for a healthier world(R)

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    Pfizer Disclosure Notice

    The information contained in this release is as of September 11, 2018.

Pfizer assumes no obligation to update forward-looking statements contained in

this release as the result of new information or future events or developments.

    This release contains forward-looking information about BAVENCIO

(avelumab), including a potential new indication for BAVENCIO in combination

with INLYTA (axitinib) for the treatment of patients with advanced renal cell

carcinoma (the "Potential Indication"), the Merck-Pfizer Alliance involving

anti-PD-L1 and anti-PD-1 therapies, and clinical development plans, including

their potential benefits, that involves substantial risks and uncertainties

that could cause actual results to differ materially from those expressed or

implied by such statements. Risks and uncertainties include, among other

things, uncertainties regarding the commercial success of BAVENCIO; the

uncertainties inherent in research and development, including the ability to

meet anticipated clinical study commencement and completion dates and

regulatory submission dates, as well as the possibility of unfavorable study

results, including unfavorable new clinical data and additional analyses of

existing clinical data and uncertainties regarding whether the other primary

endpoint of JAVELIN Renal 101 will be met; risks associated with interim data;

the risk that clinical trial data are subject to differing interpretations,

and, even when we view data as sufficient to support the safety and/or

effectiveness of a product candidate, regulatory authorities may not share our

views and may require additional data or may deny approval altogether; whether

regulatory authorities will be satisfied with the design of and results from

our clinical studies; whether and when any drug applications may be filed for

BAVENCIO in any jurisdictions for the Potential Indication or for any other

potential indications for BAVENCIO, combination therapies or other product

candidates; whether and when regulatory authorities in any jurisdictions where

applications are pending or may be submitted for BAVENCIO, combination

therapies or other product candidates may approve any such applications, which

will depend on the assessment by such regulatory authorities of the

benefit-risk profile suggested by the totality of the efficacy and safety

information submitted; decisions by regulatory authorities regarding labeling

and other matters that could affect the availability or commercial potential of

BAVENCIO, combination therapies or other product candidates, including the

Potential Indication and competitive developments.

    A further description of risks and uncertainties can be found in Pfizer's

Annual Report on Form 10-K for the fiscal year ended December 31, 2017, and in

its subsequent reports on Form 10-Q, including in the sections thereof

captioned "Risk Factors" and "Forward-Looking Information and Factors That May

Affect Future Results", as well as in its subsequent reports on Form 8-K, all

of which are filed with the U.S. Securities and Exchange Commission and

available at http://www.sec.gov and http://www.pfizer.com.

    References

    1) National Cancer Institute: SEER Stat Fact Sheets: Kidney and renal

pelvis. Available from: http://seer.cancer.gov/statfacts/html/kidrp.html.

Accessed July       2018.

    2) Ljungberg B, Campbell S and Cho H. The Epidemiology of Renal Cell

Carcinoma. Eur Urol. 2011;60:615-621.

    3) American Cancer Society. What is kidney cancer? Available from:

https://www.cancer.org/cancer/kidney-cancer/about.html. Accessed July 2018.

    4) Escudier B, Porta C, Schmidinger M et al Renal cell carcinoma: ESMO

clinical practice guidelines for diagnosis, treatment and follow-up. Annal

Oncol. 2014; 25(Suppl3):iii49-iii56.

    5) World Cancer Research Fund International: Kidney cancer statistics.

Available from:  

http://www.wcrf.org/int/cancer-facts-figures/data-specific-cancers/kidney-cancer-statistics.

Accessed July 2018.

    6) Dolan DE, Gupta S. PD-1 pathway inhibitors: changing the landscape of

cancer immunotherapy. Cancer Control. 2014;21(3):231-237.

    7) Dahan R, Sega E, Engelhardt J, Selby M, Korman AJ, Ravetch JV. FcgammaRs

modulate the anti-tumor activity of antibodies targeting the PD-1/PD-L1 axis.

Cancer Cell. 2015;28(3):285-295.

    8) Boyerinas B, Jochems C, Fantini M, et al. Antibody-dependent cellular

cytotoxicity activity of a novel anti-PD-L1 antibody avelumab (MSB0010718C) on

human tumor cells. Cancer Immunol Res. 2015;3(10):1148-1157.

    9) Kohrt HE, Houot R, Marabelle A, et al. Combination strategies to enhance

antitumor ADCC. Immunotherapy. 2012;4(5):511-527.

   10) Hamilton G, Rath B. Avelumab: combining immune checkpoint inhibition and

antibody-dependent cytotoxicity. Expert Opin Biol Ther. 2017;17(4):515-523.

    Merck

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Source:  Merck KGaA, Darmstadt, Germany