Yervoy is the first and only Immuno-Oncology
agent to receive approval in the European Union in this patient
population
Bristol-Myers Squibb Company (NYSE:BMY) announced today that the
European Commission (EC) has expanded the indication of Yervoy
(ipilimumab) to include treatment of advanced (unresectable or
metastatic) melanoma in pediatric patients 12 years of age and
older. The EC approval marks Bristol-Myers Squibb’s first pediatric
indication for an Immuno-Oncology medicine in the European Union
(EU) and allows for the marketing of Yervoy for this indication in
all 28 Member States of the EU.
“The expanded EU indication of Yervoy for pediatric patients
with unresectable or metastatic melanoma is an outcome of
Bristol-Myers Squibb’s unyielding commitment to advancing
treatments for patients with unmet clinical needs,” said Fouad
Namouni, M.D., head of development, Oncology, Bristol-Myers Squibb.
“With this approval, we’re able to provide an alternative to young
patients whose treatment options have traditionally been
limited.”
Yervoy has been evaluated in pediatric and adolescent
patient populations across two clinical trials: a dose-finding
study in 33 patients aged two to 21 years with relapsed or
refractory solid tumors; and an open-label, single-arm trial in 12
adolescents (ages ranging from 12 to 16 years) with previously
treated or untreated, unresectable Stage III or IV malignant
melanoma.
“While pediatric melanoma is rare, more effective therapeutic
approaches are needed for this patient population,” said Peter
Mohr, M.D., chief physician for the Department of Dermatology at
Elbe Klinikum Buxtehude and head of Skin Cancer Center Buxtehude.
“This approval of Yervoy in the EU expands physicians’ options for
pediatric patients with advanced melanoma to include an
Immuno-Oncology treatment.”
The U.S. Food and Drug Administration (FDA) approved Yervoy to
treat pediatric patients 12 years and older with unresectable or
metastatic melanoma in July 2017.
About the Yervoy Studies in
Pediatric Patients
In the dose-finding trial in patients with relapsed or
refractory solid tumors, the median patient age was 13 years,
and 20 of the patients were 12 years of age or
older. Yervoy was administered at doses of 1, 3, 5 and 10
mg/kg intravenously over 90 minutes every three weeks for four
doses and then every 12 weeks thereafter until progression or
treatment discontinuation.
In the open-label, single-arm trial in previously treated or
untreated, unresectable Stage III or IV malignant melanoma,
patients received Yervoy 3 mg/kg (four patients) or 10
mg/kg (eight patients) intravenously over 90 minutes every three
weeks for four doses. Of the 12 patients 12 years of age and older
with melanoma treated with Yervoy across both studies,
two patients experienced objective responses, including one partial
response that was sustained for more than one year.
The use of Yervoy in this age group is also supported
by evidence from adequate and well-controlled studies
of Yervoy in adults and population pharmacokinetic data
demonstrating that the exposure at a dose of 3 mg/kg in the
pediatric and adult populations is comparable. In addition, the
tumor biology and the course of advanced melanoma is sufficiently
similar in adults and pediatric patients 12 years and older to
allow extrapolation of data from adults to pediatric patients.
The approved dose for Yervoy in pediatric patients
with unresectable or metastatic melanoma is 3 mg/kg, administered
intravenously over 90 minutes every three weeks for a total of four
doses.
About Yervoy
Yervoy is a recombinant, human monoclonal antibody that
binds to the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4).
CTLA-4 is a negative regulator of T-cell
activity. Yervoy binds to CTLA-4 and blocks the
interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of
CTLA-4 has been shown to augment T-cell activation and
proliferation, including the activation and proliferation of tumor
infiltrating T-effector cells. Inhibition of CTLA-4 signaling can
also reduce T-regulatory cell function, which may contribute to a
general increase in T-cell responsiveness, including the anti-tumor
immune response. On March 25, 2011, the U.S. Food and Drug
Administration (FDA) approved Yervoy 3 mg/kg monotherapy
for patients with unresectable or metastatic
melanoma. Yervoy is approved for unresectable or
metastatic melanoma in more than 50 countries. There is a broad,
ongoing development program in place for Yervoy spanning
multiple tumor types.
Indications and Important Safety Information for
YERVOY® (ipilimumab)
Indications
YERVOY® (ipilimumab) is indicated for the treatment of
unresectable or metastatic melanoma in adults and pediatric
patients (12 years and older).
YERVOY® (ipilimumab) is indicated for the adjuvant treatment of
patients with cutaneous melanoma with pathologic involvement of
regional lymph nodes of more than 1 mm who have undergone complete
resection, including total lymphadenectomy.
Important Safety Information
WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS
YERVOY (ipilimumab) can result in severe and fatal
immune-mediated adverse reactions. These immune-mediated reactions
may involve any organ system; however, the most common severe
immune-mediated adverse reactions are enterocolitis, hepatitis,
dermatitis (including toxic epidermal necrolysis), neuropathy, and
endocrinopathy. The majority of these immune-mediated reactions
initially manifested during treatment; however, a minority occurred
weeks to months after discontinuation of YERVOY.
Assess patients for signs and symptoms of enterocolitis,
dermatitis, neuropathy, and endocrinopathy and evaluate clinical
chemistries including liver function tests (LFTs),
adrenocorticotropic hormone (ACTH) level, and thyroid function
tests, at baseline and before each dose.
Permanently discontinue YERVOY and initiate systemic
high-dose corticosteroid therapy for severe immune-mediated
reactions.
Recommended Dose Modifications
Endocrine: Withhold YERVOY for symptomatic endocrinopathy.
Resume YERVOY in patients with complete or partial resolution of
adverse reactions (Grade 0-1) and who are receiving <7.5 mg
prednisone or equivalent per day. Permanently discontinue YERVOY
for symptomatic reactions lasting 6 weeks or longer or an inability
to reduce corticosteroid dose to 7.5 mg prednisone or equivalent
per day.
Ophthalmologic: Permanently discontinue YERVOY for Grade 2-4
reactions not improving to Grade 1 within 2 weeks while receiving
topical therapy or requiring systemic treatment.
All Other Organ Systems: Withhold YERVOY for Grade 2 adverse
reactions. Resume YERVOY in patients with complete or partial
resolution of adverse reactions (Grade 0-1) and who are receiving
<7.5 mg prednisone or equivalent per day. Permanently
discontinue YERVOY for Grade 2 reactions lasting 6 weeks or longer,
an inability to reduce corticosteroid dose to 7.5 mg prednisone or
equivalent per day, and Grade 3 or 4 adverse reactions.
Immune-mediated Enterocolitis
Immune-mediated enterocolitis, including fatal cases, can occur
with YERVOY. Monitor patients for signs and symptoms of
enterocolitis (such as diarrhea, abdominal pain, mucus or blood in
stool, with or without fever) and of bowel perforation (such as
peritoneal signs and ileus). In symptomatic patients, rule out
infectious etiologies and consider endoscopic evaluation for
persistent or severe symptoms. Withhold YERVOY for moderate
enterocolitis; administer anti-diarrheal treatment and, if
persistent for >1 week, initiate systemic corticosteroids (0.5
mg/kg/day prednisone or equivalent). Permanently discontinue YERVOY
in patients with severe enterocolitis and initiate systemic
corticosteroids (1-2 mg/kg/day of prednisone or equivalent). Upon
improvement to ≤Grade 1, initiate corticosteroid taper and continue
over at least 1 month. In clinical trials, rapid corticosteroid
tapering resulted in recurrence or worsening symptoms of
enterocolitis in some patients. Consider adding anti-TNF or other
immunosuppressant agents for management of immune-mediated
enterocolitis unresponsive to systemic corticosteroids within 3-5
days or recurring after symptom improvement. In patients receiving
YERVOY 3 mg/kg in Trial 1, severe, life-threatening, or fatal
(diarrhea of ≥7 stools above baseline, fever, ileus, peritoneal
signs; Grade 3-5) immune-mediated enterocolitis occurred in 34
YERVOY-treated patients (7%) and moderate (diarrhea with up to 6
stools above baseline, abdominal pain, mucus or blood in stool;
Grade 2) enterocolitis occurred in 28 YERVOY-treated patients (5%).
Across all YERVOY-treated patients (n=511), 5 (1%) developed
intestinal perforation, 4 (0.8%) died as a result of complications,
and 26 (5%) were hospitalized for severe enterocolitis. Infliximab
was administered to 5 (8%) of the 62 patients with moderate,
severe, or life-threatening immune-mediated enterocolitis following
inadequate response to corticosteroids. In patients receiving
YERVOY 10 mg/kg in Trial 2, Grade 3-5 immune-mediated enterocolitis
occurred in 76 patients (16%) and Grade 2 enterocolitis occurred in
68 patients (14%). Seven (1.5%) developed intestinal perforation
and 3 patients (0.6%) died as a result of complications.
Immune-mediated Hepatitis
Immune-mediated hepatitis, including fatal cases, can occur with
YERVOY. Monitor LFTs (hepatic transaminase and bilirubin levels)
and assess patients for signs and symptoms of hepatotoxicity before
each dose of YERVOY. In patients with hepatotoxicity, rule out
infectious or malignant causes and increase frequency of LFT
monitoring until resolution. Withhold YERVOY in patients with Grade
2 hepatotoxicity. Permanently discontinue YERVOY in patients with
Grade 3-4 hepatotoxicity and administer systemic corticosteroids
(1-2 mg/kg/day of prednisone or equivalent). When LFTs show
sustained improvement or return to baseline, initiate
corticosteroid tapering and continue over 1 month. Across the
clinical development program for YERVOY, mycophenolate treatment
has been administered in patients with persistent severe hepatitis
despite high-dose corticosteroids. In patients receiving YERVOY 3
mg/kg in Trial 1, severe, life-threatening, or fatal hepatotoxicity
(AST or ALT elevations >5× the ULN or total bilirubin elevations
>3× the ULN; Grade 3-5) occurred in 8 YERVOY- treated patients
(2%), with fatal hepatic failure in 0.2% and hospitalization in
0.4%. An additional 13 patients (2.5%) experienced moderate
hepatotoxicity manifested by LFT abnormalities (AST or ALT
elevations >2.5× but ≤5× the ULN or total bilirubin elevation
>1.5× but ≤3× the ULN; Grade 2). In a dose-finding trial, Grade
3 increases in transaminases with or without concomitant increases
in total bilirubin occurred in 6 of 10 patients who received
concurrent YERVOY (3 mg/kg) and vemurafenib (960 mg BID or 720 mg
BID). In patients receiving YERVOY 10 mg/kg in Trial 2, Grade 3-4
immune- mediated hepatitis occurred in 51 patients (11%) and
moderate Grade 2 immune-mediated hepatitis occurred in 22 patients
(5%). Liver biopsy performed in 6 patients with Grade 3-4 hepatitis
showed evidence of toxic or autoimmune hepatitis.
Immune-mediated Dermatitis
Immune-mediated dermatitis, including fatal cases, can occur
with YERVOY. Monitor patients for signs and symptoms of dermatitis
such as rash and pruritus. Unless an alternate etiology has been
identified, signs or symptoms of dermatitis should be considered
immune-mediated. Treat mild to moderate dermatitis (e.g., localized
rash and pruritus) symptomatically; administer topical or systemic
corticosteroids if there is no improvement within 1 week. Withhold
YERVOY in patients with moderate to severe signs and symptoms.
Permanently discontinue YERVOY in patients with severe,
life-threatening, or fatal immune-mediated dermatitis (Grade 3-5).
Administer systemic corticosteroids (1-2 mg/kg/day of prednisone or
equivalent). When dermatitis is controlled, corticosteroid tapering
should occur over a period of at least 1 month. In patients
receiving YERVOY 3 mg/kg in Trial 1, severe, life-threatening, or
fatal immune-mediated dermatitis (e.g., Stevens-Johnson syndrome,
toxic epidermal necrolysis, or rash complicated by full thickness
dermal ulceration, or necrotic, bullous, or hemorrhagic
manifestations; Grade 3-5) occurred in 13 YERVOY-treated patients
(2.5%); 1 patient (0.2%) died as a result of toxic epidermal
necrolysis and 1 additional patient required hospitalization for
severe dermatitis. There were 63 patients (12%) with moderate
(Grade 2) dermatitis. In patients receiving YERVOY 10 mg/kg in
Trial 2, Grade 3-4 immune-mediated dermatitis occurred in 19
patients (4%). There were 99 patients (21%) with moderate Grade 2
dermatitis.
Immune-mediated Neuropathies
Immune-mediated neuropathies, including fatal cases, can occur
with YERVOY. Monitor for symptoms of motor or sensory neuropathy
such as unilateral or bilateral weakness, sensory alterations, or
paresthesia. Withhold YERVOY in patients with moderate neuropathy
(not interfering with daily activities). Permanently discontinue
YERVOY in patients with severe neuropathy (interfering with daily
activities), such as Guillain-Barre-like syndromes. Institute
medical intervention as appropriate for management for severe
neuropathy. Consider initiation of systemic corticosteroids (1-2
mg/kg/day of prednisone or equivalent) for severe neuropathies. In
patients receiving YERVOY 3 mg/kg in Trial 1, 1 case of fatal
Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral
motor neuropathy were reported. Across the clinical development
program of YERVOY, myasthenia gravis and additional cases of
Guillain-Barré syndrome have been reported. In patients receiving
YERVOY 10 mg/kg in Trial 2, Grade 3-5 immune-mediated neuropathy
occurred in 8 patients (2%); the sole fatality was due to
complications of Guillain-Barré syndrome. Moderate Grade 2
immune-mediated neuropathy occurred in 1 patient (0.2%).
Immune-mediated Endocrinopathies
Immune-mediated endocrinopathies, including life-threatening
cases, can occur with YERVOY. Monitor patients for clinical signs
and symptoms of hypophysitis, adrenal insufficiency (including
adrenal crisis), and hyper- or hypothyroidism. Patients may present
with fatigue, headache, mental status changes, abdominal pain,
unusual bowel habits, and hypotension, or nonspecific symptoms
which may resemble other causes such as brain metastasis or
underlying disease. Unless an alternate etiology has been
identified, signs or symptoms should be considered immune-mediated.
Monitor clinical chemistries, adrenocorticotropic hormone (ACTH)
level, and thyroid function tests at the start of treatment, before
each dose, and as clinically indicated based on symptoms. In a
limited number of patients, hypophysitis was diagnosed by imaging
studies through enlargement of the pituitary gland. Withhold YERVOY
in symptomatic patients and consider referral to an
endocrinologist. Initiate systemic corticosteroids (1-2 mg/kg/day
of prednisone or equivalent) and initiate appropriate hormone
replacement therapy. In patients receiving YERVOY 3 mg/kg in Trial
1, severe to life-threatening immune-mediated endocrinopathies
(requiring hospitalization, urgent medical intervention, or
interfering with activities of daily living; Grade 3-4) occurred in
9 YERVOY-treated patients (1.8%). All 9 patients had
hypopituitarism, and some had additional concomitant
endocrinopathies such as adrenal insufficiency, hypogonadism, and
hypothyroidism. Six of the 9 patients were hospitalized for severe
endocrinopathies. Moderate endocrinopathy (requiring hormone
replacement or medical intervention; Grade 2) occurred in 12
patients (2.3%) and consisted of hypothyroidism, adrenal
insufficiency, hypopituitarism, and 1 case each of hyperthyroidism
and Cushing's syndrome. The median time to onset of moderate to
severe immune-mediated endocrinopathy was 2.5 months and ranged up
to 4.4 months after the initiation of YERVOY. In patients receiving
YERVOY 10 mg/kg in Trial 2, Grade 3-4 immune-mediated
endocrinopathies occurred in 39 patients (8%) and Grade 2
immune-mediated endocrinopathies occurred in 93 patients (20%). Of
the 39 patients with Grade 3-4 immune-mediated endocrinopathies, 35
patients had hypopituitarism (associated with 1 or more secondary
endocrinopathies, e.g., adrenal insufficiency, hypogonadism, and
hypothyroidism), 3 patients had hyperthyroidism, and 1 had primary
hypothyroidism. The median time to onset of Grade 3-4
immune-mediated endocrinopathy was 2.2 months (range: 2 days-8
months). Twenty-seven (69.2%) of the 39 patients were hospitalized
for immune-mediated endocrinopathies. Of the 93 patients with Grade
2 immune-mediated endocrinopathy, 74 had primary hypopituitarism
(associated with 1 or more secondary endocrinopathy, e.g., adrenal
insufficiency, hypogonadism, and hypothyroidism), 9 had primary
hypothyroidism, 3 had hyperthyroidism, 3 had thyroiditis with hypo-
or hyperthyroidism, 2 had hypogonadism, 1 had both hyperthyroidism
and hypopituitarism, and 1 subject developed Graves’
ophthalmopathy. The median time to onset of Grade 2 immune-mediated
endocrinopathy was 2.1 months (range: 9 days-19.3 months).
Other Immune-mediated Adverse Reactions, Including Ocular
Manifestations
Permanently discontinue YERVOY for clinically significant or
severe immune-mediated adverse reactions. Initiate systemic
corticosteroids (1-2 mg/kg/day of prednisone or equivalent) for
severe immune-mediated adverse reactions. Administer corticosteroid
eye drops for uveitis, iritis, or episcleritis. Permanently
discontinue YERVOY for immune-mediated ocular disease unresponsive
to local immunosuppressive therapy. If uveitis occurs in
combination with other immune-mediated adverse reactions, consider
a Vogt-Koyanagi-Harada-like syndrome, which has been observed in
patients receiving YERVOY and may require treatment with systemic
steroids to reduce the risk of permanent vision loss. In Trial 1,
the following clinically significant immune-mediated adverse
reactions were seen in <1% of YERVOY-treated patients:
nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis,
and hemolytic anemia. In Trial 2, the following clinically
significant immune- mediated adverse reactions were seen in <1%
of YERVOY-treated patients unless specified: eosinophilia (2.1%),
pancreatitis (1.3%), meningitis, pneumonitis, sarcoidosis,
pericarditis, uveitis and fatal myocarditis. Across 21 dose-ranging
trials administering YERVOY at doses of 0.1 to 20 mg/kg (n=2478),
the following likely immune-mediated adverse reactions were also
reported with <1% incidence: angiopathy, temporal arteritis,
vasculitis, polymyalgia rheumatica, conjunctivitis, blepharitis,
episcleritis, scleritis, iritis, leukocytoclastic vasculitis,
erythema multiforme, psoriasis, arthritis, autoimmune thyroiditis,
neurosensory hypoacusis, autoimmune central neuropathy
(encephalitis), myositis, polymyositis, ocular myositis, hemolytic
anemia, and nephritis.
Embryo-fetal Toxicity
Based on its mechanism of action, YERVOY can cause fetal harm
when administered to a pregnant woman. The effects of YERVOY are
likely to be greater during the second and third trimesters of
pregnancy. Advise pregnant women of the potential risk to a fetus.
Advise females of reproductive potential to use effective
contraception during treatment with a YERVOY-containing regimen and
for 3 months after the last dose of YERVOY.
Lactation
It is not known whether YERVOY is secreted in human milk. Advise
women to discontinue nursing during treatment with YERVOY and for 3
months following the final dose.
Common Adverse Reactions
The most common adverse reactions (≥5%) in patients who received
YERVOY at 3 mg/kg were fatigue (41%), diarrhea (32%), pruritus
(31%), rash (29%), and colitis (8%). The most common adverse
reactions (≥5%) in patients who received YERVOY at 10 mg/kg were
rash (50%), diarrhea (49%), fatigue (46%), pruritus (45%), headache
(33%), weight loss (32%), nausea (25%), pyrexia (18%), colitis
(16%), decreased appetite (14%), vomiting (13%), and insomnia
(10%).
Please see U.S. Full Prescribing Information for YERVOY,
including Boxed WARNING regarding immune-mediated adverse
reactions.
Bristol-Myers Squibb &
Immuno-Oncology: Advancing Oncology Research
At Bristol-Myers Squibb, patients are at the center of
everything we do. Our vision for the future of cancer care is
focused on researching and developing transformational
Immuno-Oncology (I-O) medicines for hard-to-treat cancers that
could potentially improve outcomes for these patients.
We are leading the scientific understanding of I-O through our
extensive portfolio of investigational compounds and approved
agents. Our differentiated clinical development program is studying
broad patient populations across more than 50 types of cancers with
14 clinical-stage molecules designed to target different immune
system pathways. Our deep expertise and innovative clinical trial
designs position us to advance the I-O/I-O, I-O/chemotherapy,
I-O/targeted therapies and I-O radiation therapies across multiple
tumors and potentially deliver the next wave of therapies with a
sense of urgency. We also continue to pioneer research that will
help facilitate a deeper understanding of the role of immune
biomarkers and how a patient’s tumor biology can be used as a guide
for treatment decisions throughout their journey.
We understand making the promise of I-O a reality for the many
patients who may benefit from these therapies requires not only
innovation on our part but also close collaboration with leading
experts in the field. Our partnerships with academia, government,
advocacy and biotech companies support our collective goal of
providing new treatment options to advance the standards of
clinical practice.
About Bristol-Myers
Squibb
Bristol-Myers Squibb is a global biopharmaceutical company whose
mission is to discover, develop and deliver innovative medicines
that help patients prevail over serious diseases. For more
information about Bristol-Myers Squibb, visit us at BMS.com or
follow us on LinkedIn, Twitter, YouTube and Facebook.
Bristol-Myers Squibb Forward-Looking Statement
This press release contains "forward-looking statements" as that
term is defined in the Private Securities Litigation Reform Act of
1995 regarding the research, development and commercialization of
pharmaceutical products. Such forward-looking statements are based
on current expectations and involve inherent risks and
uncertainties, including factors that could delay, divert or change
any of them, and could cause actual outcomes and results to differ
materially from current expectations. No forward-looking statement
can be guaranteed. Among other risks, there can be no guarantee
that Yervoy will receive regulatory approval for additional
indications. Forward-looking statements in this press release
should be evaluated together with the many uncertainties that
affect Bristol-Myers Squibb's business, particularly those
identified in the cautionary factors discussion in Bristol-Myers
Squibb's Annual Report on Form 10-K for the year ended December 31,
2016 in our Quarterly Reports on Form 10-Q and our Current Reports
on Form 8-K. Bristol-Myers Squibb undertakes no obligation to
publicly update any forward-looking statement, whether as a result
of new information, future events or otherwise.
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Bristol-Myers SquibbMedia:Audrey Abernathy,
919-605-4521audrey.abernathy@bms.comorInvestor:Tim Power,
609-252-7509timothy.power@bms.comorBill Szablewski,
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