Pivotal Phase III Data for BAVENCIO® (avelumab) Plus INLYTA® (axitinib) in Advanced Renal Cell Carcinoma Published in the New England Journal of Medicine

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Darmstadt, Germany and New York (ots/PRNewswire) -

- JAVELIN Renal 101 shows significant improvement in progression-free
survival with a hazard ratio of 0.69 in patients regardless of
PD-L1 expression
- US FDA has granted Priority Review to BAVENCIO plus INLYTA for
patients with advanced renal cell carcinoma
- Data at 2019 Genitourinary Cancers Symposium reinforce consistency
of PFS and ORR benefits across broad population of patients with
advanced RCC, including all prognostic risk groups, and show
increased time to progression on next-line therapy

Merck and Pfizer Inc. (NYSE: PFE) today announced the publication
of results from an interim analysis of the pivotal JAVELIN Renal 101
trial online in the New England Journal of Medicine.1 The combination
of BAVENCIO® (avelumab) and INLYTA® (axitinib)* significantly
extended median progression-free survival (PFS) by more than five
months compared with SUTENT® (sunitinib) as a first-line treatment
for patients with advanced renal cell carcinoma (RCC), irrespective
of PD-L1 expression (HR: 0.69 [95% CI: 0.56-0.84]; BAVENCIO+INLYTA:
13.8 months [95% CI: 11.1-NE]; SUTENT: 8.4 months [95% CI: 6.9-11.1];
p<0.001). Further, the objective response rate (ORR) was doubled with
BAVENCIO+INLYTA versus SUTENT in this population (51.4% [95% CI:
46.6-56.1] vs. 25.7% [95% CI: 21.7-30.0]). The study is continuing
for the other primary endpoint of overall survival (OS).

"There is a significant need for patients with advanced RCC to
prolong the time until the disease worsens beyond what tyrosine
kinase inhibitors alone offer," said Robert J. Motzer, M.D., Jack and
Dorothy Byrne Chair in Clinical Oncology, Memorial Sloan Kettering
Cancer Center, New York, US, and principal investigator for JAVELIN
Renal 101. "The magnitude and consistency of PFS and response rates
seen thus far across populations in the JAVELIN Renal 101 study
suggest that many different types of patients, including those with a
favorable prognosis, could potentially derive benefit from this
particular combination."

Additional data presented today at the 2019 Genitourinary Cancers
Symposium reinforce the consistency of the PFS and ORR results across
patient subgroups, including patients with favorable, intermediate
and poor prognoses as well as those with PD-L1-positive or negative
tumors. In subgroup analyses, approximately two-thirds of patients
with favorable risk (66% of patients using the Memorial Sloan
Kettering Cancer Center risk model and 68% with the International
Metastatic Renal Cell Carcinoma Database Consortium risk model)
achieved a complete or partial response with BAVENCIO+INLYTA. Median
PFS for these patients is not yet estimable. BAVENCIO+INLYTA also
extended median PFS2, defined as the time from randomization to
disease progression on next-line therapy (HR: 0.56 [95% CI:
0.42-0.74]; NE [95% CI: 19.9-NE] vs. 18.4 months [95% CI: 15.7-23.6])
and increased median duration of response by more than four months
(95% CI: 2.9-5.1) in the overall population.

"In this study, the combination of avelumab plus axitinib not only
prolonged the initial response in treated patients compared to
sunitinib, but for patients who went on to subsequent therapy,
reduced the risk of disease progression or death on the next
treatment," said Toni K. Choueiri, M.D., Director of the Lank Center
for Genitourinary Oncology at Dana-Farber, Boston, US, senior and
co-corresponding author of JAVELIN Renal 101, and presenter.
"Together with the progression-free survival results and objective
response rates, these findings show the potential of this combination
regimen to be an important new treatment option for patients with
advanced RCC."

The Phase III JAVELIN Renal 101 study is evaluating the
combination of BAVENCIO+INLYTA compared with SUTENT in 886 patients
with previously untreated advanced RCC. BAVENCIO+INLYTA significantly
reduced the risk of disease progression or death by 39% in patients
with PD-L1-positive (>=1%) tumors, a primary endpoint (HR: 0.61 [95%
CI: 0.47-0.79], p<0.001; median PFS: 13.8 months [95% CI: 11.1-NE]
vs. 7.2 months [95% CI: 5.7-9.7]). In the overall population, which
was tested after achieving statistical significance for the primary
endpoint, the risk was reduced by 31%. The confirmed ORR in patients
with PD-L1-positive tumors was 55.2% (95% CI: 49.0-61.2) with
BAVENCIO+INLYTA vs. 25.5% (95% CI: 20.6-30.9) with SUTENT.

In the BAVENCIO+INLYTA arm, 20.8% of patients received subsequent
anticancer drug therapies, compared with 39.2% in the SUTENT arm. In
the SUTENT arm, about two-thirds (66.7%) of patients who received
subsequent anticancer therapy were known to have been treated with an
anti-PD-1/PD-L1 agent.

Adverse events of grade 3 or higher during treatment
(treatment-emergent adverse events [TEAEs]) occurred in 71.2% of
patients in the BAVENCIO+INLYTA arm and 71.5% in the SUTENT arm;
grade 3 or higher TEAEs that occurred in more than 5% of patients
receiving the combination were hypertension (25.6%), diarrhea (6.7%),
increased alanine aminotransferase level (6.0%) and hand-foot
syndrome (5.8%). In the combination arm, 9.0% of patients experienced
grade 3 or higher immune-related adverse events. Grade 5 events
occurred in three patients in the BAVENCIO+INLYTA arm (myocarditis,
necrotizing pancreatitis, sudden death; n=1 each); and in one patient
in the SUTENT arm (intestinal perforation). There were fewer
discontinuations due to adverse events that occurred during treatment
with BAVENCIO+INLYTA, compared with SUTENT (7.6% vs. 13.4%).

On February 11, 2019, the alliance announced that the US Food and
Drug Administration (FDA) accepted for Priority Review the
supplemental Biologics License Application (sBLA) for BAVENCIO in
combination with INLYTA for patients with advanced RCC. The
application has been given a target action date in June 2019. A
supplemental application for BAVENCIO+INLYTA in unresectable or
metastatic RCC was submitted in Japan on January 30, 2019. In
December 2017, the 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.2

*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 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 2019, an estimated 73,820 new cases of kidney cancer will be
diagnosed in the US, and approximately 14,770 people will die from
the disease.5 Approximately 20% to 30% of patients are first
diagnosed at the metastatic stage.6 The five-year survival rate for
patients with metastatic RCC is approximately 12%.2

About the JAVELIN Clinical Development Program

The clinical development program for avelumab, known as JAVELIN,
involves at least 30 clinical programs and more than 9,000 patients
evaluated across more than 15 different tumor types. In addition to
RCC, these tumor types include breast, gastric/gastro-esophageal
junction, and head and neck cancers, 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.7-9 BAVENCIO has also been shown to
induce NK cell-mediated direct tumor cell lysis via
antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro.9-11 In
November 2014, Merck and Pfizer announced a strategic alliance to
co-develop and co-commercialize BAVENCIO.

Approved Indications in the US

In the US, 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 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.

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® (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 from the US FDA-Approved Label

In the study of advanced RCC after failure of one prior systemic
therapy, the warnings and precautions for INLYTA 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 INLYTA were diarrhea, hypertension, fatigue,
decreased appetite, nausea, dysphonia, hand-foot syndrome, weight
decreased, vomiting, asthenia, and constipation.

For more information and full Prescribing Information, visit
www.INLYTA.com.

About SUTENT® (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 PDGFR?),
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 RCC; the
adjuvant treatment of adult patients at high risk of recurrent RCC
following nephrectomy; and the treatment of progressive,
well-differentiated pancreatic neuroendocrine tumors (pNET) in
patients with unresectable locally advanced or metastatic disease.

SUTENT Important Safety Information from the US FDA-Approved Label

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.

Additional warnings and precautions for SUTENT include
cardiovascular events, QT prolongation and Torsades de Pointes,
hypertension, hemorrhagic events, tumor lysis syndrome (TLS),
thrombotic microangiopathy (TMA), proteinuria, dermatologic
toxicities including erythema multiforme, Sevens-Johnson syndrome,
and toxic epidermal necrolysis, necrotizing fasciitis, thyroid
dysfunction, hypoglycemia, osteonecrosis of the jaw (ONJ), impaired
wound healing, embryo fetal toxicity and impaired reproductive
potential, potential harm during lactation, venous thromboembolic
events, reversible posterior leukoencephalopathy syndrome (RPLS), and
pancreatic function.

Common adverse reactions (reported in at least 20% of patients) in
patients receiving SUTENT for treatment-naïve metastatic RCC were
diarrhea, fatigue, nausea, anorexia, altered taste,
mucositis/stomatitis, pain in extremity/limb discomfort, vomiting,
bleeding, all sites, hypertension, dyspepsia, arthralgia, abdominal
pain, rash, hand-foot syndrome, back pain, cough, asthenia, dyspnea,
skin discoloration/yellow skin, peripheral edema, headache,
constipation, dry skin, fever, and hair color changes.

Common adverse reactions (reported in at least 20% of patients) in
patients receiving SUTENT for adjuvant treatment of RCC, GIST or pNET
- and more commonly than in patients given placebo - were
mucositis/stomatitis/oral syndromes, diarrhea, fatigue, asthenia,
hand-foot syndrome, hypertension, altered taste, nausea, dyspepsia,
abdominal pain, hypothyroidism/TSH increased, rash, hair color
changes, anorexia, skin discoloration, constipation, vomiting,
bleeding events, epistaxis, and dysgeusia.

For more information and full Prescribing Information, visit
www.SUTENT.com.

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
exceptions are the United States and Canada, where the business
sectors of Merck operate as EMD Serono in healthcare, MilliporeSigma
in life science, and EMD Performance Materials.

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At Pfizer, we apply science and our global resources to bring
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Pfizer Disclosure Notice

The information contained in this release is as of February 16,
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 for BAVENCIO in
combination with INLYTA (axitinib) for the treatment of patients with
advanced renal cell carcinoma, the alliance between Merck KGaA,
Darmstadt, Germany, 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; 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 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 INLYTA
for the potential new indication 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 U.S. and Japan for BAVENCIO in combination with INLYTA for the
potential new indication 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 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 and/or other
matters that could affect the availability or commercial potential of
BAVENCIO or combination therapies, including BAVENCIO in combination
with INLYTA for the potential new 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 www.sec.gov and www.pfizer.com.

References

1. Motzer R, Penkov K, Haanen J, et al. Avelumab plus axitinib
versus sunitinib for advanced renal-cell carcinoma. NEJM.
February 16, 2019.Published online ahead of print.
2. National Cancer Institute: SEER Stat Fact Sheets: Kidney and
renal pelvis. Available from:
http://seer.cancer.gov/statfacts/html/kidrp.html. Accessed
February 2019.
3. American Cancer Society. What is kidney cancer? Available from:
https://www.cancer.org/cancer/kidney-cancer/about.html. Accessed
February 2019.
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. American Cancer Society. Cancer facts and figures 2019. Available
at: https://www.cancer.org/content/dam/cancer-org/research/cancer
-facts-and-statistics/annual-cancer-facts-and-figures/2019/cancer
-facts-and-figures-2019.pdf. Accessed February 2019.
6. Ljungberg B, Campbell S and Cho H. The Epidemiology of Renal Cell
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7. Dolan DE, Gupta S. PD-1 pathway inhibitors: changing the
landscape of cancer immunotherapy. Cancer Control.
2014;21(3):231-237.
8. Dahan R, Sega E, Engelhardt J, Selby M, Korman AJ, Ravetch JV.
Fc?Rs modulate the anti-tumor activity of antibodies targeting
the PD-1/PD-L1 axis. Cancer Cell. 2015;28(3):285-295.
9. 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.
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11. Hamilton G, Rath B. Avelumab: combining immune checkpoint
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