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
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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.
Bristol-Myers Squibb Media: Audrey Abernathy, 919-605-4521 audrey.abernathy@bms.com or Investor: Tim Power, 609-252-7509 timothy.power@bms.com orBill Szablewski, 609-252-5894 william.szablewski@bms.com