FDA Grants BAVENCIO(R) (avelumab) Approval for a Common Type of Advanced Bladder Cancer

PR68500

DARMSTADT, Germany, and NEW YORK, May 10, 2017 /PRNewswire=KYODO JBN/ --

- Second approval for BAVENCIO in less than two months    

- Advanced urothelial carcinoma is an aggressive disease with a high rate of

recurrence    

Merck and Pfizer Inc. (NYSE: PFE) today announced that the US Food and Drug

Administration (FDA) has approved BAVENCIO(R) (avelumab) Injection for the

treatment of patients with locally advanced or metastatic urothelial carcinoma

(UC) who have disease progression during or following platinum-containing

chemotherapy therapy, or who have disease progression within 12 months of

neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

BAVENCIO was previously granted accelerated approval from the FDA for the

treatment of adults and pediatric patients 12 years and older with metastatic

Merkel cell carcinoma (MCC). These indications are approved under accelerated

approval based on tumor response and duration of response. Continued approval

for these indications may be contingent upon verification and description of

clinical benefit in confirmatory trials.[1] BAVENCIO will be co-commercialized

by EMD Serono, the biopharmaceutical business of Merck in the US and Canada,

and Pfizer.

"This approval for BAVENCIO in patients with locally advanced or metastatic

urothelial carcinoma exemplifies our unwavering commitment to finding new

treatments for the most challenging cancers," said Luciano Rossetti, M.D.,

Executive Vice President, Global Head of Research & Development at biopharma

business of Merck. "Coming just a few weeks after the approval for metastatic

Merkel cell carcinoma, we continue to demonstrate our ability to accelerate

access to innovative medicines for patients in need."

"This approval builds on the ongoing clinical development program for BAVENCIO

in urothelial carcinoma and reinforces our commitment to providing new

medicines to patients with difficult-to-treat cancers," said Liz Barrett,

Global President, Pfizer Oncology. "By drawing on the strength of the alliance,

as well as Pfizer's deep experience in genitourinary cancers, we believe

BAVENCIO will be an important treatment option, and we hope it will help to

improve outcomes for these patients."

Bladder cancer makes up approximately 90% of urothelial carcinomas and is the

sixth most common cancer in the US.[2],[3] When the disease has metastasized,

the five-year survival rate is approximately 5%.[4] Despite advances in the

treatment of locally advanced or metastatic urothelial carcinoma, the prognosis

for patients remains poor and more treatment options are needed.[2]

"Once urothelial carcinoma progresses after treatment with chemotherapy, the

five-year survival rate is alarmingly low," said Dr. Andrea Apolo, National

Cancer Institute, Bethesda, MD. "Until recently, there had been limited

innovation in urothelial carcinoma, and this approval gives us another

treatment to help battle this aggressive disease."

The efficacy and safety of BAVENCIO was demonstrated in the urothelial

carcinoma cohorts (N=242) of the JAVELIN Solid Tumor trial, a Phase I,

open-label, single-arm, multicenter study of BAVENCIO in the treatment of

various solid tumors. The urothelial carcinoma cohorts enrolled patients with

locally advanced or metastatic urothelial carcinoma with disease progression on

or after platinum-containing chemotherapy or who had disease progression within

12 months of treatment with a platinum-containing neoadjuvant or adjuvant

chemotherapy regimen. These data will be presented at an upcoming medical

congress.

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. The most common adverse reactions (reported in at

least 20% of patients) in patients with locally advanced or metastatic

urothelial carcinoma were fatigue (41%), infusion-related reaction (30%),

musculoskeletal pain (25%), nausea (24%), decreased appetite/hypophagia (21%)

and urinary tract infection (21%).[1] For more information, please see

Important Safety Information for BAVENCIO below.

BAVENCIO is designed to potentially engage both the adaptive and innate immune

systems. By binding to PD-L1, BAVENCIO is thought to prevent tumor cells from

using PD-L1 for protection against white blood cells, such as T cells, exposing

them to anti-tumor responses.[1] BAVENCIO has also been shown to induce

antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro.[1]

The alliance is committed to providing industry-leading patient access and

reimbursement support through its CoverOne(TM) program in the United States.

This program provides a spectrum of patient access and reimbursement support

services intended to help patients receive appropriate access to BAVENCIO in

the United States.

About Urothelial Carcinoma Cohorts in JAVELIN Solid Tumor Trial   

The efficacy and safety of BAVENCIO was demonstrated in the urothelial

carcinoma cohorts of the JAVELIN Solid Tumor trial, a Phase I, open-label,

single-arm, multicenter study that included 242 patients with locally advanced

or metastatic urothelial carcinoma with disease progression on or after

platinum-containing chemotherapy or who had disease progression within 12

months of treatment with a platinum-containing neoadjuvant or adjuvant

chemotherapy regimen who were treated with BAVENCIO.

Patients with active or a history of central nervous system metastasis; other

malignancies within the last five years; an organ transplant; conditions

requiring therapeutic immune suppression; or active infection with HIV,

hepatitis B or C were excluded. Patients with autoimmune disease, other than

type 1 diabetes, vitiligo, psoriasis, or thyroid disease that did not require

immunosuppressive treatment, were excluded. Patients were included regardless

of their PD-L1 status. Patients received BAVENCIO at a dose of 10 mg/kg

intravenously over 60 minutes every two weeks until disease progression or

unacceptable toxicity. Tumor response assessments were performed every six

weeks, as assessed by an Independent Endpoint Review Committee (IERC) using

Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Efficacy outcome

measures included confirmed overall response rate (ORR) and duration of

response (DOR). Efficacy measures were evaluated in patients who were followed

for a minimum of both 13 weeks and 6 months at the time of data cut-off.

Out of the total 226 patients evaluable for efficacy, 44% had non-bladder

urothelial carcinoma, including 23% of patients with upper tract disease; 83%

of patients had visceral metastases; 34% of patients had liver metastases. Nine

patients (4%) had disease progression following prior platinum-containing

neoadjuvant or adjuvant therapy only. Forty-seven percent of patients only

received prior cisplatin-based regimens, 32% received only prior

carboplatin-based regimens, and 20% received both cisplatin and

carboplatin-based regimens.

The international clinical development program for avelumab, known as JAVELIN,

involves more than 30 clinical programs, including nine Phase III trials, and

more than 5,200 patients across more than 15 tumor types.  

In December 2015, Merck and Pfizer announced the initiation of a Phase III

multicenter, multinational, randomized, open-label, parallel-arm study (JAVELIN

Bladder 100) of BAVENCIO plus best supportive care versus best supportive care

alone as a maintenance treatment in patients with locally advanced or

metastatic urothelial carcinoma whose disease did not progress after completion

of first-line platinum-containing chemotherapy. This trial is currently

enrolling patients.

IMPORTANT SAFETY INFORMATION and INDICATIONS   

BAVENCIO can cause immune-mediated pneumonitis, including fatal cases. Monitor

patients for signs and symptoms of pneumonitis and evaluate suspected cases

with radiographic imaging. Administer corticosteroids for Grade 2 or greater

pneumonitis. Withhold BAVENCIO for moderate (Grade 2) and permanently

discontinue for severe (Grade 3), life-threatening (Grade 4), or recurrent

moderate (Grade 2) pneumonitis. Pneumonitis occurred in 1.2% (21/1738) of

patients, including one (0.1%) patient with Grade 5, one (0.1%) with Grade 4,

and five (0.3%) with Grade 3.

BAVENCIO can cause immune-mediated hepatitis, including fatal cases. Monitor

patients for abnormal liver tests prior to and periodically during treatment.

Administer corticosteroids for Grade 2 or greater hepatitis. Withhold BAVENCIO

for moderate (Grade 2) immune-mediated hepatitis until resolution and

permanently discontinue for severe (Grade 3) or life-threatening (Grade 4)

immune-mediated hepatitis. Immune-mediated hepatitis was reported in 0.9%

(16/1738) of patients, including two (0.1%) patients with Grade 5 and 11 (0.6%)

with Grade 3.

BAVENCIO can cause immune-mediated colitis. Monitor patients for signs and

symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis.

Withhold BAVENCIO until resolution for moderate or severe (Grade 2 or 3)

colitis and permanently discontinue for life-threatening (Grade 4) or recurrent

(Grade 3) colitis upon re-initiation of BAVENCIO. Immune-mediated colitis

occurred in 1.5% (26/1738) of patients, including seven (0.4%) with Grade 3.

BAVENCIO can cause immune-mediated endocrinopathies, including adrenal

insufficiency, thyroid disorders, and type 1 diabetes mellitus.

Monitor patients for signs and symptoms of adrenal insufficiency during and

after treatment, and administer corticosteroids as appropriate. Withhold

BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) adrenal

insufficiency. Adrenal insufficiency was reported in 0.5% (8/1738) of patients,

including one (0.1%) with Grade 3.

Thyroid disorders can occur at any time during treatment. Monitor patients for

changes in thyroid function at the start of treatment, periodically during

treatment, and as indicated based on clinical evaluation. Manage hypothyroidism

with hormone replacement therapy and hyperthyroidism with medical management.

Withhold BAVENCIO for severe (Grade 3) or life- threatening (Grade 4) thyroid

disorders. Thyroid disorders including hypothyroidism, hyperthyroidism, and

thyroiditis were reported in 6% (98/1738) of patients, including three (0.2%)

with Grade 3.

Type 1 diabetes mellitus including diabetic ketoacidosis: Monitor patients for

hyperglycemia or other signs and symptoms of diabetes. Withhold BAVENCIO and

administer anti-hyperglycemics or insulin in patients with severe or

life-threatening (Grade ＞or = 3) hyperglycemia, and resume treatment when

metabolic control is achieved. Type 1 diabetes mellitus without an alternative

etiology occurred in 0.1% (2/1738) of patients, including two cases of Grade 3

hyperglycemia.

BAVENCIO can cause immune-mediated nephritis and renal dysfunction. Monitor

patients for elevated serum creatinine prior to and periodically during

treatment. Administer corticosteroids for Grade 2 or greater nephritis.

Withhold BAVENCIO for moderate (Grade 2) or severe (Grade 3) nephritis until

resolution to Grade 1 or lower. Permanently discontinue BAVENCIO for

life-threatening (Grade 4) nephritis. Immune-mediated nephritis occurred in

0.1% (1/1738) of patients.

BAVENCIO can result in other severe and fatal immune-mediated adverse reactions

involving any organ system during treatment or after treatment discontinuation.

For suspected immune-mediated adverse reactions, evaluate to confirm or rule

out an immune-mediated adverse reaction and to exclude other causes. Depending

on the severity of the adverse reaction, withhold or permanently discontinue

BAVENCIO, administer high-dose corticosteroids, and initiate hormone

replacement therapy if appropriate. Resume BAVENCIO when the immune-mediated

adverse reaction remains at Grade 1 or lower following a corticosteroid taper.

Permanently discontinue BAVENCIO for any severe (Grade 3) immune-mediated

adverse reaction that recurs and for any life-threatening (Grade 4)

immune-mediated adverse reaction. The following clinically significant

immune-mediated adverse reactions occurred in less than 1% of 1738 patients

treated with BAVENCIO: myocarditis with fatal cases, myositis, psoriasis,

arthritis, exfoliative dermatitis, erythema multiforme, pemphigoid,

hypopituitarism, uveitis, Guillain-Barre syndrome, and systemic inflammatory

response.

BAVENCIO can cause severe (Grade 3) or life-threatening (Grade 4)

infusion-related reactions. Patients should be premedicated with an

antihistamine and acetaminophen prior to the first 4 infusions and for

subsequent doses based upon clinical judgment and presence/severity of prior

infusion reactions. Monitor patients for signs and symptoms of infusion-related

reactions, including pyrexia, chills, flushing, hypotension, dyspnea, wheezing,

back pain, abdominal pain, and urticaria. Interrupt or slow the rate of

infusion for mild (Grade 1) or moderate (Grade 2) infusion-related reactions.

Permanently discontinue BAVENCIO for severe (Grade 3) or life-threatening

(Grade 4) infusion-related reactions. Infusion-related reactions occurred in

25% (439/1738) of patients, including three (0.2%) patients with Grade 4 and

nine (0.5%) with Grade 3.

BAVENCIO can cause fetal harm when administered to a pregnant woman. Advise

patients of the potential risk to a fetus including the risk of fetal death.

Advise females of childbearing potential to use effective contraception during

treatment with BAVENCIO and for at least 1 month after the last dose of

BAVENCIO. It is not known whether BAVENCIO is excreted in human milk. Advise a

lactating woman not to breastfeed during treatment and for at least 1 month

after the last dose of BAVENCIO due to the potential for serious adverse

reactions in breastfed infants.

The most common adverse reactions (all grades, ＞ or = 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, ＞ or = 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, ＞ or = 20%) in patients with

locally advanced or metastatic urothelial cancer (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, ＞ or = 3%) in patients with

locally advanced or metastatic UC  were hyponatremia (16%),

gamma-glutamyltransferase increased (12%), lymphopenia (11%), hyperglycemia

(9%), increased alkaline phosphatase (7%), anemia (6%), increased lipase (6%),

hyperkalemia (3%), and increased aspartate aminotransferase (3%).

INDICATIONS   

BAVENCIO is indicated for the treatment of adults and pediatric patients 12

years and older with metastatic Merkel cell carcinoma (MCC).

BAVENCIO is indicated for the treatment of 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 and duration of response. Continued approval for these indications may

be contingent upon verification and description of clinical benefit in

confirmatory trials.

Avelumab has not yet been approved for any indication in any market outside of

the US. As announced on October 31, 2016, the European Medicines Agency (EMA)

has validated for review Merck's Marketing Authorization Application for

avelumab, for the proposed indication of metastatic Merkel cell carcinoma.  

About BAVENCIO(R) (avelumab)   

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

indicated in the US for the treatment of patients with locally advanced or

metastatic urothelial carcinoma who have disease progression during or

following platinum-containing chemotherapy or who have disease progression

within 12 months of neoadjuvant or adjuvant treatment with platinum-containing

chemotherapy, as well as for the treatment of adults and pediatric patients 12

years and older with metastatic Merkel cell carcinoma.[1] These indications are

approved under accelerated approval based on tumor response and duration of

response. Continued approval for these indications is contingent upon

verification and description of clinical benefit in confirmatory trials.

BAVENCIO is not approved for any indication in any market outside the US.

About Merck-Pfizer Alliance   

Immuno-oncology is a top priority for Merck and Pfizer Inc. 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 will jointly develop and

commercialize avelumab and advance 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 in combination regimens, and

is striving to find new ways to treat cancer.

About EMD Serono, Inc.    

EMD Serono is the biopharmaceutical business of Merck - a leading science and

technology company - in the US and Canada focused exclusively on specialty

care. For more than 40 years, the business has integrated cutting-edge science,

innovative products and industry-leading patient support and access programs.

EMD Serono has deep expertise in neurology, fertility and endocrinology, as

well as a robust pipeline of potential therapies in oncology, immuno-oncology

and immunology as R&D focus areas. Today, the business has 1,200 employees

around the country with commercial, clinical and research operations based in

the company's home state of Massachusetts.

http://www.emdserono.com

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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 Inc.: 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

and vaccines as well as many of the world's best-known consumer health care

products. Every day, Pfizer colleagues work across developed and emerging

markets to advance wellness, prevention, treatments and cures that challenge

the most feared diseases of our time. Consistent with our responsibility as one

of the world's premier innovative biopharmaceutical companies, we collaborate

with health care providers, governments and local communities to support and

expand access to reliable,  affordable health care around the world. For more

than 150 years, we have worked to make a difference for all who rely on us. We

routinely post information that may be important to investors on our website

at http://www.pfizer.com. In addition, to learn more, please visit us

on http://www.pfizer.com and follow us on Twitter at @Pfizer

[https://twitter.com/pfizer ] and @PfizerNews [https://twitter.com/pfizer_news

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Pfizer Disclosure Notice   

The information contained in this release is as of May 9, 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),

Merck-Pfizer's 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 and when drug applications may be filed in any other

jurisdictions for the Indication or in any jurisdictions for any other

potential indications for BAVENCIO, combination therapies or other product

candidates; whether and when any such applications (including the pending

application for BAVENCIO for metastatic Merkel cell carcinoma in the EU) may be

approved by regulatory authorities, 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; 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.

References   

BAVENCIO Prescribing Information. Rockland, MA: EMD Serono Inc.; 2017.

National Cancer Institute. Bladder Cancer Treatment (PDQ) - Health Professional

Version. Available at

https://www.cancer.gov/types/bladder/hp/bladder-treatment-pdq. Accessed May 9,

2017.

National Comprehensive Cancer Network. NCCN Guidelines Version 1.2017 Updates.

Bladder Cancer. Available from:

https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf.    Accessed

May 9, 2017.

National Cancer Institute. The Surveillance, Epidemiology, and End Results

(SEER): Cancer Stat Facts: Bladder Cancer. Available at:

https://seer.cancer.gov/statfacts/html/urinb.html. Accessed May 9, 2017.

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SOURCE: Merck and Pfizer