DARMSTADT, Germany and
NEW YORK, March 19, 2019 /PRNewswire/ --
Not intended for UK-based media
Merck KGaA, Darmstadt, Germany,
which operates its biopharmaceutical business as EMD Serono in the
US and Canada, and Pfizer Inc.
(NYSE: PFE) today announced the discontinuation of the ongoing
Phase III JAVELIN Ovarian PARP 100 study evaluating the efficacy
and safety of avelumab in combination with chemotherapy followed by
maintenance therapy of avelumab in combination with talazoparib,* a
poly (ADP-ribose) polymerase (PARP) inhibitor, versus an active
comparator in treatment-naïve patients with locally advanced or
metastatic ovarian cancer (Stage III or Stage IV). The alliance has
notified health authorities and trial investigators of the decision
to discontinue the trial.
The decision was based on several emerging factors since
the trial's initiation, including the previously announced interim
results from JAVELIN Ovarian PARP 100. The alliance determined that
the degree of benefit observed with avelumab in frontline ovarian
cancer in that study does not support continuation of the JAVELIN
Ovarian PARP 100 trial in an unselected patient population and
emphasizes the need to better understand the role of immunotherapy
in ovarian cancer. Additional factors include the rapidly changing
treatment landscape and the approval of a PARP inhibitor in
the frontline maintenance setting. The decision to discontinue
the JAVELIN Ovarian PARP 100 trial was not made for safety
reasons.
The alliance between Merck KGaA, Darmstadt, Germany, and Pfizer was the first to test an
immunotherapy in this indication, given the significant unmet need
in the treatment of ovarian cancer. Four out of five women with
ovarian cancer are diagnosed with disease that has spread to the
lymph nodes or to distant organs.1 Most women with
advanced ovarian cancer ultimately die within five years due to
refractory, resistant or recurrent disease.2,3
JAVELIN Ovarian PARP 100 (B9991030) is an open-label,
international, multi-center, randomized study designed to evaluate
the efficacy and safety of avelumab in combination with
chemotherapy followed by maintenance therapy of avelumab in
combination with talazoparib versus an active comparator in
treatment-naïve patients with locally advanced or metastatic
ovarian cancer (Stage III or Stage IV). The primary endpoint is
progression-free survival (PFS) as determined based on blinded
independent central review (BICR) assessment per RECIST v1.1.
The decision to discontinue the JAVELIN Ovarian PARP 100 trial
does not impact the currently approved indications for avelumab or
the remainder of the ongoing JAVELIN clinical development program.
The program involves at least 30 clinical programs and more than
9,000 patients evaluated across more than 15 different tumor types,
including breast, gastric/gastro-esophageal junction, and head and
neck cancers, Merkel cell carcinoma, non-small cell lung cancer,
and urothelial carcinoma.
*Avelumab and talazoparib are under clinical investigation for
the treatment of advanced ovarian cancer and have not been
demonstrated to be safe and effective for this use.
About Avelumab (BAVENCIO®)
Avelumab (BAVENCIO®) 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.4-6
Avelumab has also been shown to induce NK cell-mediated direct
tumor cell lysis via antibody-dependent cell-mediated cytotoxicity
(ADCC) in vitro.6-8 In November 2014, Merck KGaA, Darmstadt,
Germany, and Pfizer announced a
strategic alliance to co-develop and co-commercialize avelumab.
Approved Indications in the US
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 (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.
Avelumab 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 BAVENCIO® US
FDA-Approved Label
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 reinitiation 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 antihyperglycemics or
insulin in patients with severe or life-threatening (Grade ≥ 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-Barré 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, ≥
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%).
Please see full US Prescribing Information and Medication Guide
available at http://www.BAVENCIO.com.
Indication for talazoparib (TALZENNA®) from the US
Prescribing Information
TALZENNA is a poly (ADP-ribose) polymerase (PARP) inhibitor
indicated for the treatment of adult patients with deleterious or
suspected deleterious germline breast cancer susceptibility gene
(BRCA)-mutated (gBRCAm) human epidermal growth factor
receptor 2 (HER2)-negative locally advanced or metastatic breast
cancer. Select patients for therapy based on an FDA-approved
companion diagnostic for TALZENNA.
Important Safety Information from the TALZENNA US Prescribing
Information
Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML)
have been reported in patients who received TALZENNA. Overall,
MDS/AML have been reported in 2 out of 584 (0.3%) solid tumor
patients treated with TALZENNA in clinical studies.
Myelosuppression consisting of anemia,
leukopenia/neutropenia, and/or thrombocytopenia have been reported
in patients treated with TALZENNA. Grade ≥3 anemia, neutropenia,
and thrombocytopenia were reported, respectively, in 39%, 21%, and
15% of patients receiving TALZENNA. Discontinuation due to anemia,
neutropenia, and thrombocytopenia occurred, respectively, in 0.7%,
0.3%, and 0.3% of patients.
Monitor complete blood counts for cytopenia at baseline
and monthly thereafter. Do not start TALZENNA until patients have
adequately recovered from hematological toxicity caused by previous
therapy. If hematological toxicity occurs, dose modifications
(dosing interruption with or without dose reduction) are
recommended. With respect to MDS/AML, for prolonged
hematological toxicities, interrupt TALZENNA and monitor blood
counts weekly until recovery. If the levels have not recovered
after 4 weeks, refer the patient to a hematologist for further
investigations. If MDS/AML is confirmed, discontinue TALZENNA.
TALZENNA can cause fetal harm when administered to
pregnant women. Advise women of reproductive potential to use
effective contraception during treatment and for at least 7 months
following the last dose. A pregnancy test is recommended for
females of reproductive potential prior to initiating TALZENNA
treatment. Advise male patients with female partners of
reproductive potential or who are pregnant to use effective
contraception during treatment with TALZENNA and for at least
4 months after receiving the last dose. Based on animal
studies, TALZENNA may impair fertility in males of reproductive
potential. Advise women not to breastfeed while taking TALZENNA and
for at least 1 month after receiving the last dose because of the
potential for serious adverse reactions in nursing infants.
The most common adverse reactions (≥20%) of any
grade for TALZENNA vs chemotherapy were fatigue (62% vs 50%),
anemia (53% vs 18%), nausea (49% vs 47%), neutropenia (35% vs 43%),
headache (33% vs 22%), thrombocytopenia (27% vs 7%), vomiting (25%
vs 23%), alopecia (25% vs 28%), diarrhea (22% vs 26%), and
decreased appetite (21% vs 22%).
The most frequently reported Grade ≥3 adverse reactions
(≥5%) for TALZENNA vs chemotherapy were anemia (39% vs
5%), neutropenia (21% vs 36%), and thrombocytopenia (15% vs
2%).
The most common lab abnormalities (≥25%) for
TALZENNA vs chemotherapy were decreases in hemoglobin (90% vs 77%),
leukocytes (84% vs 73%), lymphocytes (76% vs 53%), neutrophils (68%
vs 70%), platelets (55% vs 29%), and calcium (28% vs 16%) and
increases in glucose (54% vs 51%), aspartate aminotransferase (37%
vs 48%), alkaline phosphatase (36% vs 34%), and alanine
aminotransferase (33% vs 37%).
Coadministration with P-gp inhibitors or BCRP
inhibitors may increase TALZENNA exposure. If
coadministering with the P-gp inhibitors amiodarone, carvedilol,
clarithromycin, itraconazole, or verapamil is unavoidable, reduce
the TALZENNA dose to 0.75 mg once daily. When the P-gp inhibitor is
discontinued, increase the TALZENNA dose (after 3–5 half-lives of
the P-gp inhibitor) to the dose used prior to the initiation of the
P-gp inhibitor. When co-administering TALZENNA with other known
P-gp inhibitors or BCRP inhibitors, monitor patients for potential
increased adverse reactions.
For patients with moderate renal impairment, the
recommended dose of TALZENNA is 0.75 mg once daily. No dose
adjustment is required for patients with mild renal impairment.
TALZENNA has not been studied in patients with severe renal
impairment or in patients requiring hemodialysis.
TALZENNA has not been studied in patients with moderate or
severe hepatic impairment. No dose adjustment is
required for patients with mild hepatic impairment.
Please see full US Prescribing Information available at
http://www.TALZENNA.com.
Alliance between Merck KGaA, Darmstadt, Germany, and Pfizer Inc., New York, US
Immuno-oncology is a top priority for Merck KGaA, Darmstadt,
Germany, and Pfizer. The global
strategic alliance between Merck KGaA, Darmstadt, Germany, 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 KGaA,
Darmstadt, Germany. 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.
All Merck KGaA, Darmstadt, Germany, press releases are distributed by
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About Merck KGaA, Darmstadt, Germany
Merck KGaA, Darmstadt, Germany,
a leading science and technology company, operates across
healthcare, life science and performance materials. Around 52,000
employees work to make a positive difference to millions of
people's lives every day by creating more joyful and sustainable
ways to live. From advancing gene editing technologies and
discovering unique ways to treat the most challenging diseases to
enabling the intelligence of devices – the company is everywhere.
In 2018, Merck KGaA, Darmstadt, Germany, generated sales of € 14.8 billion in
66 countries.
The company holds the global rights to the name and trademark
"Merck" internationally. The only exceptions are the United States and Canada, where the business sectors of Merck
KGaA, Darmstadt, Germany operate
as EMD Serono in healthcare, MilliporeSigma in life science, and
EMD Performance Materials. Since its founding 1668, scientific
exploration and responsible entrepreneurship have been key to the
company's technological and scientific advances. To this day, the
founding family remains the majority owner of the publicly listed
company.
Pfizer Inc.: 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, 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
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addition, to learn more, please visit us
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Pfizer Disclosure Notice
The information contained in this release is as of March 19, 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 avelumab
(BAVENCIO), the Merck KGaA, Darmstadt, Germany-Pfizer Alliance
involving avelumab, 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 avelumab; 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; 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 in any jurisdictions for any potential indications for
avelumab, combination therapies or talazoparib; whether and when
regulatory authorities in any jurisdictions where applications are
pending or may be submitted for avelumab, combination therapies or
talazoparib 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, safety, manufacturing processes and/or other
matters that could affect the availability or commercial potential
of avelumab, combination therapies or talazoparib; 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
1.SEER Cancer Stat Facts: Ovarian Cancer. National Cancer
Institute. Bethesda,
MD, https://seer.cancer.gov/statfacts/html/ovary.html.
Accessed March 2019.
2.Ledermann, JA, Raja FA, Fotopoulou C, et al. Newly diagnosed
and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice
Guidelines for diagnosis, treatment and follow-up. Ann
Oncol. 2013; 24 (Supplement 6): vi24–vi32,
doi:10.1093/annonc/mdt333.
3.Ozol, RJ. Challenges for chemotherapy in ovarian cancer.
Ann Oncol. 2006;17(5):v181-187.
4.Dolan DE, Gupta S. PD-1 pathway inhibitors: changing the
landscape of cancer immunotherapy. Cancer Control.
2014;21(3):231-237.
5.Dahan R, Sega E, Engelhardt J, et al. FcγRs modulate the
anti-tumor activity of antibodies targeting the PD-1/PD-L1 axis.
Cancer Cell. 2015;28(3):285-295.
6.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. 2015;3(10):1148-1157.
7.Kohrt HE, Houot R, Marabelle A, et al. Combination strategies
to enhance antitumor ADCC. Immunotherapy.
2012;4(5):511-527.
8.Hamilton G, Rath B. Avelumab: combining immune checkpoint
inhibition and antibody-dependent cytotoxicity. Expert Opin Biol
Ther. 2017;17(4):515-523.
Merck KGaA, Darmstadt, Germany
Media Relations: +49-6151-72-6328,
friederike.segeberg@emdgroup.com
Investor Relations: +49-6151-72-3321,
investor.relations@emdgroup.com
Pfizer
Media Relations: +1-212-733-6213, jessica.m.smith@pfizer.com
Investor Relations: +1-212-733-8160,
ryan.crowe@pfizer.com
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