Bristol-Myers
Squibb Company (NYSE:BMY) today announced results from a pooled
analysis of survival data for 12 studies (n=1,861) in patients with
metastatic or locally advanced or unresectable melanoma who were treated
with Yervoy® (ipilimumab) at different doses and regimens. A
plateau in the survival curve begins at approximately three years, with
follow-up of up to ten years in some patients. Approximately 22% of
patients were alive at three years. The data will be presented at the
2013 European Cancer Congress on September 28 at 1:00 p.m. CEST and were
highlighted at a Congress press briefing (Abstract # 24LBA, “Pooled
analysis of long-term survival data from Phase 2 and Phase 3 trials of
ipilimumab in metastatic or locally advanced, unresectable melanoma”).
Safety data were not included in this analysis. However, safety data
from these individual studies have been reported. Overall, the types of
adverse events (AEs) attributed to Yervoy are generally mechanism
(immune)-based. Yervoy can result in severe and fatal immune-related
adverse reactions due to T-cell activation and proliferation. In these
clinical trials, adverse events associated with Yervoy were managed with
protocol-specific guidelines, including the administration of systemic
corticosteroids, dose interruption/discontinuation and/or other
immunosuppressants.
“This pooled analysis reinforces the long-term survival data seen in the
individual studies and provides additional insight into the overall
survival of metastatic melanoma patients treated with Yervoy,” said Brian
Daniels, senior vice president, Global Development and Medical
Affairs. “The durability and consistency of long-term survival observed
in this analysis is encouraging as we continue to advance the research
and development of our immuno-oncology portfolio.”
“In this analysis, approximately 26% of treatment-naïve and 20% of
previously-treated patients were alive at three years after being
treated with an ipilimumab regimen,” said F. Stephen Hodi, M.D.,
Department of Medicine, Harvard Medical School, Dana-Farber Cancer
Institute. “This pooled analysis is encouraging, particularly when
considering that metastatic melanoma is one of the most aggressive forms
of cancer and historically, average survival was just six to nine
months.”
About The Analysis
This pooled analysis was conducted to provide a more precise estimate of
the long-term survival effect of Yervoy in patients with metastatic
melanoma. It is comprised of patient-level data from 12 prospective and
retrospective studies, including two Phase 3 trials (n=790), eight Phase
2 trials (n=821), and two retrospective, observational studies (n=250),
which have been or will be reported on as individual studies. Three
studies included overall survival follow-up in some patients for up to
ten years.
The analysis included both previously-treated (n=1,257) and previously
untreated patients (n=604) who received Yervoy at different doses and
regimens. The majority of patients received Yervoy 3 mg/kg (n=965) or 10
mg/kg (n=706). Yervoy was given every 3 weeks for 4 doses, and most
studies included the option to receive either Yervoy retreatment or
Yervoy maintenance therapy for eligible patients.
About Yervoy
Yervoy, which is a recombinant, human monoclonal antibody, blocks the
cytotoxic T- lymphocyte-associated antigen-4 (CTLA-4). CTLA-4 is a
negative regulator of T-cell activation. 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.
The mechanism of action of Yervoy’s effect in patients with melanoma is
indirect, possibly through T-cell mediated anti-tumor immune responses.
On March 25, 2011, the FDA approved Yervoy 3 mg/kg monotherapy for
patients with unresectable or metastatic melanoma. Yervoy is now
approved in more than 40 countries.
YERVOY® (ipilimumab) INDICATION & IMPORTANT
SAFETY INFORMATION
YERVOY (ipilimumab) is indicated for the treatment of unresectable or
metastatic melanoma.
Important Safety Information
WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS
YERVOY can result in severe and fatal immune-mediated adverse
reactions due to T-cell activation and proliferation. 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) 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
Withhold dose for any moderate immune-mediated adverse reactions or for
symptomatic endocrinopathy until return to baseline, improvement to mild
severity, or complete resolution, and patient is receiving <7.5 mg
prednisone or equivalent per day.
Permanently discontinue YERVOY for any of the following:
-
Persistent moderate adverse reactions or inability to reduce
corticosteroid dose to 7.5 mg prednisone or equivalent per day
-
Failure to complete full treatment course within 16 weeks from
administration of first dose
-
Severe or life-threatening adverse reactions, including any of the
following:
-
Colitis with abdominal pain, fever, ileus, or peritoneal signs;
increase in stool frequency (≥7 over baseline), stool
incontinence, need for intravenous hydration for >24 hours,
gastrointestinal hemorrhage, and gastrointestinal perforation
-
AST or ALT >5 × the upper limit of normal (ULN) or total bilirubin
>3 × the ULN
-
Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash
complicated by full-thickness dermal ulceration or necrotic,
bullous, or hemorrhagic manifestations
-
Severe motor or sensory neuropathy, Guillain-Barré syndrome, or
myasthenia gravis
-
Severe immune-mediated reactions involving any organ system
-
Immune-mediated ocular disease which is unresponsive to topical
immunosuppressive therapy
Immune-mediated Enterocolitis:
-
In the pivotal Phase 3 study in YERVOY (ipilimumab)-treated patients,
severe, life-threatening, or fatal (diarrhea of ≥7 stools above
baseline, fever, ileus, peritoneal signs; Grade 3-5) immune-mediated
enterocolitis occurred in 34 (7%) and moderate (diarrhea with up to 6
stools above baseline, abdominal pain, mucus or blood in stool; Grade
2) enterocolitis occurred in 28 (5%) patients
-
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 of 62 (8%) patients with moderate,
severe, or life-threatening immune-mediated enterocolitis following
inadequate response to corticosteroids
-
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
-
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
-
Withhold YERVOY (ipilimumab) for moderate enterocolitis; administer
anti-diarrheal treatment and, if persistent for >1 week, initiate
systemic corticosteroids (0.5 mg/kg/day prednisone or equivalent)
Immune-mediated Hepatitis:
-
In the pivotal Phase 3 study in YERVOY-treated patients, severe,
life-threatening, or fatal hepatotoxicity (AST or ALT elevations >5x
the ULN or total bilirubin elevations >3x the ULN; Grade 3–5) occurred
in 8 (2%) patients, with fatal hepatic failure in 0.2% and
hospitalization in 0.4%
-
13 (2.5%) additional YERVOY-treated patients experienced moderate
hepatotoxicity manifested by LFT abnormalities (AST or ALT elevations
>2.5x but ≤5x the ULN or total bilirubin elevation >1.5x but ≤3x the
ULN; Grade 2)
-
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
-
Permanently discontinue YERVOY in patients with Grade 3-5
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
-
Withhold YERVOY in patients with Grade 2 hepatotoxicity
Immune-mediated Dermatitis:
-
In the pivotal Phase 3 study in YERVOY-treated patients, 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 (2.5%)
patients
-
1 (0.2%) patient died as a result of toxic epidermal necrolysis
-
1 additional patient required hospitalization for severe dermatitis
-
There were 63 (12%) YERVOY-treated patients with moderate (Grade 2)
dermatitis
-
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
-
Permanently discontinue YERVOY (ipilimumab) 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. Withhold YERVOY in
patients with moderate to severe signs and symptoms
-
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
Immune-mediated Neuropathies:
-
In the pivotal Phase 3 study in YERVOY-treated patients, 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
-
Monitor for symptoms of motor or sensory neuropathy such as unilateral
or bilateral weakness, sensory alterations, or paresthesia.
Permanently discontinue YERVOY in patients with severe neuropathy
(interfering with daily activities) such as Guillain-Barré–like
syndromes
-
Institute medical intervention as appropriate for management of severe
neuropathy. Consider initiation of systemic corticosteroids (1-2
mg/kg/day of prednisone or equivalent) for severe neuropathies.
Withhold YERVOY in patients with moderate neuropathy (not interfering
with daily activities)
Immune-mediated Endocrinopathies:
-
In the pivotal Phase 3 study in YERVOY- treated patients, 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 (1.8%) patients
-
All 9 patients had hypopituitarism, and some had additional
concomitant endocrinopathies such as adrenal insufficiency,
hypogonadism, and hypothyroidism
-
6 of the 9 patients were hospitalized for severe endocrinopathies
-
Moderate endocrinopathy (requiring hormone replacement or medical
intervention; Grade 2) occurred in 12 (2.3%) YERVOY
(ipilimumab)-treated patients and consisted of hypothyroidism, adrenal
insufficiency, hypopituitarism, and 1 case each of hyperthyroidism and
Cushing’s syndrome
-
Median time to onset of moderate to severe immune-mediated
endocrinopathy was 11 weeks and ranged up to 19.3 weeks after the
initiation of 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 thyroid function tests and clinical chemistries 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. Initiate systemic
corticosteroids (1-2 mg/kg/day of prednisone or equivalent) and
initiate appropriate hormone replacement therapy. Long-term hormone
replacement therapy may be necessary
Other Immune-mediated Adverse Reactions, Including Ocular
Manifestations:
-
In the pivotal Phase 3 study in YERVOY-treated patients, clinically
significant immune-mediated adverse reactions seen in <1% were:
nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis, and
hemolytic anemia
-
Across the clinical development program for YERVOY, likely
immune-mediated adverse reactions also reported with <1% incidence
were: myocarditis, angiopathy, temporal arteritis, vasculitis,
polymyalgia rheumatica, conjunctivitis, blepharitis, episcleritis,
scleritis, leukocytoclastic vasculitis, erythema multiforme,
psoriasis, pancreatitis, arthritis, autoimmune thyroiditis,
sarcoidosis, neurosensory hypoacusis, autoimmune central neuropathy
(encephalitis), myositis, polymyositis, and ocular myositis
-
Permanently discontinue YERVOY (ipilimumab) 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
Pregnancy & Nursing:
-
YERVOY is classified as pregnancy category C. There are no adequate
and well-controlled studies of YERVOY in pregnant women. Use YERVOY
during pregnancy only if the potential benefit justifies the potential
risk to the fetus
-
Human IgG1 is known to cross the placental barrier and YERVOY is an
IgG1; therefore, YERVOY has the potential to be transmitted from the
mother to the developing fetus
-
It is not known whether YERVOY is secreted in human milk. Because many
drugs are secreted in human milk and because of the potential for
serious adverse reactions in nursing infants from YERVOY, a decision
should be made whether to discontinue nursing or to discontinue YERVOY
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%)
Please see Full Prescribing Information, including Boxed WARNING
regarding immune-mediated adverse reactions available at www.bms.com.
YERVOY is a registered trademark of Bristol-Myers Squibb Company.
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 www.bms.com,
or follow us on Twitter at http://twitter.com/bmsnews.
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. 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, 2012, 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.
Copyright Business Wire 2013