FDA Grants Breakthrough Therapy Designation for Avelumab in Combination with INLYTA® in Advanced Renal Cell Carcinoma

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

- Second Breakthrough Therapy Designation for avelumab in
hard-to-treat cancer
- Renal cell carcinoma, the most common form of kidney cancer, has
a poor prognosis in advanced stage[1],[2]
- Javelin Renal clinical development program is ongoing, including
Phase III first-line study

Merck and Pfizer Inc. (NYSE: PFE) today announced that the US Food
and Drug Administration (FDA) has granted Breakthrough Therapy
Designation for avelumab in combination with INLYTA® (axitinib)* for
treatment-naïve patients with advanced renal cell carcinoma (RCC).
Breakthrough Therapy Designation is designed to accelerate the
development and review of potential medicines for serious conditions,
and preliminary clinical evidence indicates that the therapy may
demonstrate a substantial improvement over currently available
therapies on one or more clinically significant endpoints. This is
the second Breakthrough Therapy Designation granted to avelumab.

"A combination approach with an immunotherapy, whose activity may
complement existing agents such as INLYTA, has the potential to
improve outcomes for patients with advanced renal cancer - a disease
where the five-year survival rate remains low," said Chris Boshoff,
M.D., Ph.D., Senior Vice President and Head of Immuno-Oncology, Early
Development and Translational Oncology, Pfizer Global Product
Development. "Pfizer's expertise in developing treatments for
advanced RCC is a distinct advantage in tackling this tumor type, and
we look forward to the completion of our Phase III study combining
avelumab with INLYTA, which we're expecting at the end of next year."

"This announcement reinforces the need for innovative first-line
treatments for advanced RCC and our promise to advancing care for
these patients," said Luciano Rossetti, M.D., Global Head of Research
& Development at the Biopharma business of Merck. "The second
Breakthrough Therapy Designation by the FDA in another hard-to-treat
cancer underlines our focus on challenging tumor types."

RCC is the most common form of kidney cancer, with an estimated
57,500 new cases diagnosed in the US in 2017.[1],[3] This disease is
serious and life-threatening, and approximately 20-30% of patients
are first diagnosed at an advanced or metastatic stage.[4]

The Breakthrough Therapy Designation is based on the preliminary
evaluation of clinical data from JAVELIN Renal 100, a global Phase Ib
study assessing the safety and efficacy of avelumab in combination
with INLYTA for the treatment of treatment-naïve patients with
advanced RCC. Updated results from this Phase Ib study were presented
at the 2017 American Society of Clinical Oncology (ASCO) Annual
Meeting. The FDA previously granted avelumab Breakthrough Therapy
Designation for the treatment of patients with metastatic Merkel cell
carcinoma (mMCC) whose disease has progressed after at least one
previous chemotherapy regimen.

The clinical development program for avelumab, known as JAVELIN,
involves at least 30 clinical programs and over 7,000 patients
evaluated across more than 15 different tumor types. This includes
JAVELIN Renal 101, a randomized, Phase III, open-label, multicenter
trial investigating avelumab in combination with INLYTA versus
sunitinib as a first-line treatment option for advanced RCC, which
recently completed recruitment. In addition to RCC, cancer studies in
the JAVELIN program include non-small cell lung cancer, breast
cancer, head and neck cancer, Hodgkin's lymphoma, melanoma,
mesothelioma, MCC, ovarian cancer, gastric/gastroesophageal junction
cancer, and urothelial carcinoma (UC).

*Avelumab is under clinical investigation for advanced renal cell
carcinoma and has not been demonstrated to be safe and effective for
this indication. There is no guarantee that avelumab will be approved
for advanced renal cell carcinoma by any health authority worldwide.
INLYTA is under clinical investigation for this use in combination
with avelumab. In the US, INLYTA is approved as monotherapy for the
treatment of advanced RCC after failure of one prior systemic
therapy.

About the FDA Designation

Breakthrough Therapy Designation is designed to expedite the
development and review of drugs which are intended to treat a serious
condition, and preliminary clinical evidence indicates that the drug
may demonstrate substantial improvement over available therapy on a
clinically significant endpoint(s). The FDA's granting of the
Breakthrough Therapy Designation for metastatic RCC does not alter
the standard regulatory requirement to establish the safety and
effectiveness of a drug through adequate and well-controlled studies
to support approval.

About Renal Cell Carcinoma (RCC)

RCC is the most common form of kidney cancer, accounting for about
2-3% of all cancers in adults.[1],[5] The most common type of RCC is
clear cell carcinoma, accounting for approximately 70% of all
cases.[3] In 2012, there were approximately 304,000 new cases of RCC
diagnosed worldwide, with an estimated 57,500 cases in the US alone
in 2017.[3],[4],[6] Incidence varies substantially worldwide with
generally higher rates seen in Eastern Asia, North America and
Central/Eastern Europe.[7] The five-year overall survival rate for
patients with distant metastatic RCC is approximately 12%.[2]

About JAVELIN Renal 100

JAVELIN Renal 100 is a Phase Ib, open-label, multicenter,
multiple-dose study investigating avelumab in combination with
INLYTA® (axitinib), a tyrosine kinase inhibitor from Pfizer, for the
treatment of treatment-naïve patients with advanced RCC. The study
enrolled 55 patients from participating sites in the US, United
Kingdom and Japan.

About Avelumab

Avelumab is a human anti-programmed death ligand-1 (PD-L1)
antibody. Avelumab 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, avelumab has been shown to
release the suppression of the T cell-mediated antitumor immune
response in preclinical models.[8]-[10] Avelumab has also been shown
to induce NK cell-mediated direct tumor cell lysis via
antibody-dependent cell-mediated cytotoxicity (ADCC) in
vitro.[10]-[12] In November 2014, Merck and Pfizer announced a
strategic alliance to co-develop and co-commercialize avelumab.

Approved Indications in the US

The FDA granted accelerated approval for avelumab (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 (UC) 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.

Selected 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 metastatic UC 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 U.S., INLYTA is approved 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 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 (>=20%) 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 (>=10%) 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 (>=20%) 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 for INLYTA,
visit http://www.pfizer.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 avelumab, an anti-PD-L1 antibody
initially discovered and developed by Merck. The immuno-oncology
alliance is jointly developing and commercializing avelumab and
advancing Pfizer's PD-1 antibody. The alliance is focused on
developing high-priority international clinical programs to
investigate avelumab, 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. Around 50,000 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 2016, Merck
generated sales of EUR 15.0 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.

About Pfizer: Working together for a healthier world®

At Pfizer, we apply science and our global resources to bring
therapies to people that extend and significantly improve their
lives. We strive to set the standard for quality, safety and value in
the discovery, development and manufacture of health care products.
Our global portfolio includes medicines and vaccines as well as many
of the world's best-known consumer health care products. Every day,
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Pfizer Disclosure Notice

The information contained in this release is as of December 21,
2017. 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 indication for avelumab in
combination with INLYTA (axitinib) for the treatment of 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;
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 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 may be
submitted for the Potential Indication or 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, 2016, 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.

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