FDA Grants Breakthrough Therapy Designation for Avelumab in Combination with INLYTA(R) in Advanced Renal Cell Carcinoma

PR71646

DARMSTADT, Germany and NEW YORK, Dec. 21, 2017 /PRNewswire=KYODO JBN/ --

- 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(R) (axitinib)* for treatment-naive 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(R) (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(R)) 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(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 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 (greater than or equal to 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 (greater than or equal to 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 (greater than 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

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

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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(R)

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

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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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