CHMP Adopts Positive Opinion for BAVENCIO® (avelumab) Plus Axitinib for First-Line Treatment of Patients with Advanced Renal Cell Carcinoma

Not intended for US, Canada and UK-based media

- Opinion based on Phase III data showing combination lowered risk of
disease progression or death by 31% and improved objective response
rate compared with sunitinib1
- Decision by the European Commission anticipated in fourth quarter
of 2019

Darmstadt, Germany and New York, Us (ots/PRNewswire) - Merck and
Pfizer Inc. (NYSE: PFE) today announced that the Committee for
Medicinal Products for Human Use (CHMP) of the European Medicines
Agency (EMA) adopted a positive opinion recommending approval of
BAVENCIO® (avelumab) in combination with axitinib for the first-line
treatment of adult patients with advanced renal cell carcinoma (RCC).
The opinion was based on positive findings from the Phase III JAVELIN
Renal 101 study, which demonstrated a significant extension in median
progression-free survival (PFS) and a clinically meaningful
improvement in objective response rate (ORR) for the combination
across all prognostic risk groups compared with sunitinib.1 The CHMP
positive opinion will be reviewed by the European Commission (EC),
with a decision anticipated in the fourth quarter of this year. Merck
and Pfizer have a global strategic alliance to jointly develop and
commercialize BAVENCIO.

"Today's positive CHMP opinion is a significant step toward
potentially transforming the treatment landscape and bringing much
needed options to people living with advanced renal cell carcinoma in
Europe. We believe that the combination of BAVENCIO plus axitinib has
the potential to help address a significant need for patients with
advanced renal cell carcinoma for first-line treatments with a
benefit across all prognostic risk groups, and we look forward to a
decision from the European Commission," said Luciano Rossetti, M.D.,
Executive Vice President, Head of Global Research & Development at
the Biopharma business of Merck.

In 2018, an estimated 136,500 new cases of kidney cancer were
diagnosed in Europe, and approximately 54,700 people died from the
disease.2 RCC is the most common form of kidney cancer, accounting
for about 3% of all cancers in adults.2 Approximately 20% to 30% of
patients are first diagnosed with RCC at the advanced stage, and 30%
of patients treated for an earlier stage go on to develop
metastases.3,4 About half of patients living with advanced RCC do not
go on to receive additional treatment after first-line therapy,5,6
for reasons that may include poor performance status or adverse
events from their initial treatment.5,7,8 The five-year survival rate
for patients with metastatic RCC is approximately 12%.9

"Kidney cancer represents a significant burden in Europe, where
incidence rates are among the highest in the world," said Chris
Boshoff, M.D., Ph.D., Chief Development Officer, Oncology, Pfizer
Global Product Development. "Pfizer has been a leader in the
development of kidney cancer treatments for more than a decade, and
it is a privilege to continue our efforts to bring a new treatment
option to this community."

The U.S. Food and Drug Administration (FDA) approved BAVENCIO in
combination with axitinib for the first-line treatment of patients
with advanced RCC in May 2019.10 A supplemental application for
BAVENCIO in combination with axitinib in unresectable or metastatic
RCC was submitted in Japan in January 2019.

About the JAVELIN Renal 101 Study

The Phase III JAVELIN Renal 101 study is a randomized,
multicenter, open-label study of BAVENCIO in combination with
axitinib in 886 patients with untreated advanced or metastatic RCC.
The major efficacy outcome measures were PFS as assessed by a Blinded
Independent Central Review (BICR) using RECIST v1.1 and overall
survival (OS) in the first-line treatment of patients with advanced
RCC who have PD-L1-positive tumors (PD-L1 expression level >=1%). If
PFS was statistically significant in patients with PD-L1-positive
tumors, it was then tested in all patients irrespective of PD-L1
expression. PFS based on BICR assessment per RECIST v1.1 and OS
irrespective of PD-L1 expression, objective response, time to
response (TTR), duration of response (DOR) and safety are included as
secondary endpoints. The study is continuing for OS.

About the JAVELIN Clinical Development Program

The clinical development program for avelumab, known as JAVELIN,
involves at least 30 clinical programs and more than 10,000 patients
evaluated across more than 15 different tumor types. In addition to
RCC, these tumor types include gastric/gastro-esophageal junction
cancer, head and neck cancer, Merkel cell carcinoma, non-small cell
lung cancer and urothelial carcinoma.

About BAVENCIO® (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.11-13 BAVENCIO has also been shown to
induce NK cell-mediated direct tumor cell lysis via
antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro.13-15
In November 2014, Merck and Pfizer announced a strategic alliance to
co-develop and co-commercialize BAVENCIO.

BAVENCIO Approved Indications

In September 2017, the European Commission granted conditional
marketing authorization for BAVENCIO® (avelumab) as a monotherapy for
the treatment of adult patients with metastatic Merkel cell carcinoma
(MCC). BAVENCIO is currently approved for patients with MCC in more
than 45 countries globally, with the majority of these approvals in a
broad indication that is not limited to a specific line of
treatment.16

In the US, BAVENCIO in combination with axitinib is indicated for
the first-line treatment of patients with advanced renal cell
carcinoma (RCC). Additionally, the US 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.10

Avelumab Important Safety Information from the US FDA-Approved
Label

The warnings and precautions for avelumab (BAVENCIO®) include
immune-mediated adverse reactions (such as pneumonitis and hepatitis,
colitis, endocrinopathies, nephritis and renal dysfunction and other
adverse reactions), infusion-related reactions, hepatotoxicity, major
adverse cardiovascular events (MACE), and embryo-fetal toxicity.

The most common adverse reactions (all grades, >= 20%) in patients
with metastatic Merkel cell carcinoma (MCC) were fatigue (50%),
musculoskeletal pain (32%), diarrhea (23%), nausea (22%),
infusion-related reaction (22%), rash (22%), decreased appetite
(20%), and peripheral edema (20%).

Selected treatment-emergent laboratory abnormalities (all grades,
>= 20%) in patients with metastatic MCC were lymphopenia (49%),
anemia (35%), increased aspartate aminotransferase (34%),
thrombocytopenia (27%), and increased alanine aminotransferase (20%).

The most common adverse reactions (all grades, >= 20%) in patients
with locally advanced or metastatic urothelial carcinoma (UC) were
fatigue (41%), infusion-related reaction (30%), musculoskeletal pain
(25%), nausea (24%), decreased appetite/hypophagia (21%), and urinary
tract infection (21%).

Selected laboratory abnormalities (Grades 3-4, >= 3%) in patients
with locally advanced or metastatic UC were hyponatremia (16%),
increased gamma-glutamyltransferase (12%), lymphopenia (11%),
hyperglycemia (9%), increased alkaline phosphatase (7%), anemia (6%),
increased lipase (6%), hyperkalemia (3%), and increased aspartate
aminotransferase (3%).

Fatal adverse reactions in patients occurred in 1.8% of patients
with advanced renal cell carcinoma (RCC) receiving BAVENCIO in
combination with axitinib. These included sudden cardiac death
(1.2%), stroke (0.2%), myocarditis (0.2%), and necrotizing
pancreatitis (0.2%).

The most common adverse reactions (all grades, >=20%) in patients
with advanced RCC receiving BAVENCIO in combination with axitinib (vs
sunitinib) were diarrhea (62% vs 48%), fatigue (53% vs 54%),
hypertension (50% vs 36%), musculoskeletal pain (40% vs 33%), nausea
(34% vs 39%), mucositis (34% vs 35%), palmar-plantar
erythrodysesthesia (33% vs 34%), dysphonia (31% vs 3.2%), decreased
appetite (26% vs 29%), hypothyroidism (25% vs 14%), rash (25% vs
16%), hepatotoxicity (24% vs 18%), cough (23% vs 19%), dyspnea (23%
vs 16%), abdominal pain (22% vs 19%), and headache (21% vs 16%).

Selected laboratory abnormalities (all grades, >=20%) worsening
from baseline in patients with advanced RCC receiving BAVENCIO in
combination with axitinib (vs sunitinib) were blood triglycerides
increased (71% vs 48%), blood creatinine increased (62% vs 68%),
blood cholesterol increased (57% vs 22%), alanine aminotransferase
increased (ALT) (50% vs 46%), aspartate aminotransferase increased
(AST) (47% vs 57%), blood sodium decreased (38% vs 37%), lipase
increased (37% vs 25%), blood potassium increased (35% vs 28%),
platelet count decreased (27% vs 80%), blood bilirubin increased (21%
vs 23%), and hemoglobin decreased (21% vs 65%).

Axitinib Important Safety Information from the US FDA-Approved
Label

In the study of advanced RCC after failure of one prior systemic
therapy, the warnings and precautions for axitinib include
hypertension, including hypertensive crisis, arterial and venous
thrombotic events, hemorrhagic events, cardiac failure,
gastrointestinal perforation and fistula, hypothyroidism, wound
healing complications, reversible posterior leukoencephalopathy
syndrome (RPLS), proteinuria, liver enzyme elevation, hepatic
impairment and fetal harm during pregnancy.

Common adverse events (reported in at least 20% of patients) in
patients receiving axitinib were diarrhea, hypertension, fatigue,
decreased appetite, nausea, dysphonia, hand-foot syndrome, weight
decreased, vomiting, asthenia and constipation.

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, an anti-PD-L1 antibody
initially discovered and developed by Merck. The immuno-oncology
alliance is jointly developing and commercializing BAVENCIO. 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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holds the global rights to the Merck name and brand. The only
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Pfizer Disclosure Notice

The information contained in this release is as of September 20,
2019. 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 in the European
Union for BAVENCIO in combination with axitinib for the treatment of
patients with advanced renal cell carcinoma, the alliance between
Merck and Pfizer involving BAVENCIO 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 and axitinib; the
uncertainties inherent in research and development, including the
ability to meet anticipated clinical endpoints, commencement and/or
completion dates for our clinical trials, regulatory submission
dates, regulatory approval dates and/or launch dates, as well as the
possibility of unfavorable new clinical data and further 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 assessments by regulatory authorities;
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 combination with axitinib
in any other jurisdictions or in any jurisdictions for any other
potential indications for BAVENCIO or combination therapies; whether
and when the pending applications in the European Union and Japan for
BAVENCIO in combination with axitinib may be approved and whether and
when regulatory authorities in any jurisdictions where any other
applications are pending or may be submitted for BAVENCIO or
combination therapies, including BAVENCIO in combination with
axitinib may approve any such applications, which will depend on
myriad factors, including making a determination as to whether the
product's benefits outweigh its known risks and determination of the
product's efficacy, and, if approved, whether they will be
commercially successful; decisions by regulatory authorities
impacting labeling, manufacturing processes, safety and/or other
matters that could affect the availability or commercial potential of
BAVENCIO or combination therapies, including BAVENCIO in combination
with axitinib; 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, 2018, 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 www.sec.gov and www.pfizer.com.

References

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carcinoma. Eur Urol. 2011;60:615-621.
4. Klatte T, Rossi SH, Stewart GD. Prognostic factors and prognostic
models for renal cell carcinoma: a literature review. World J
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6. Motzer R, et al. Nivolumab plus Ipilimumab versus Sunitinib in
Advanced Renal-Cell Carcinoma. The New England Journal of
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7. Eichelberg C, Vervenne WL, De Santis M, et al. SWITCH: A
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the treatment of metastatic renal cell cancer. Eur Urol.
2015;68;837-847.
8. Motzer RJ, Barrios CH, Kim TM, et al. Phase II randomized trial
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in patients with metastatic renal cell carcinoma. J Clin Oncol.
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anti-tumor activity of antibodies targeting the PD-1/PD-L1 axis.
Cancer Cell. 2015;28(3):285-295.
13. Boyerinas B, Jochems C, Fantini M, et al. Antibody-dependent
cellular cytotoxicity activity of a novel anti-PD-L1 antibody
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14. Kohrt HE, Houot R, Marabelle A, et al. Combination strategies to
enhance antitumor ADCC. Immunotherapy. 2012;4(5):511-527.
15. Hamilton G, Rath B. Avelumab: combining immune checkpoint
inhibition and antibody-dependent cytotoxicity. Expert Opin Biol
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16. BAVENCIO® (avelumab) EU SmPC. Available from:
http://www.ema.europa.eu/ema/. Accessed September 2019.

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