First company to demonstrate the potential of an immune checkpoint
inhibitor in the adjuvant treatment for these patients
Bristol-Myers
Squibb Company (NYSE:BMY) today announced that the U.S. Food and
Drug Administration (FDA) has approved Yervoy (ipilimumab) 10
mg/kg 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.
This approval is based on clinical data from a pivotal Phase 3 trial,
CA184-029 (EORTC 18071), which demonstrated Yervoy 10 mg/kg
significantly improved recurrence-free survival (RFS) vs. placebo in
this setting, with a 25 percent reduction in the risk of recurrence or
death. The median RFS was 26 months (95% CI: 19, 39) for Yervoy vs.
17 months (95% CI: 13, 22) for placebo (hazard ratio [HR]=0.75; 95% CI:
0.64, 0.90; p<0.002). Yervoy is the first and only
FDA-approved immune checkpoint inhibitor in the adjuvant treatment for
fully resected Stage III melanoma (lymph node >1 mm).
Resectable, Stage III melanoma represents 5 percent, or approximately
3,100 cases, of all new melanoma cases diagnosed annually. This stage of
melanoma can be aggressive, with a 60 percent risk of recurrence after
surgery. Despite the risk of disease recurrence among Stage III melanoma
patients following resection, there are limited treatment options
available to help reduce the risk of recurrence after surgery.
“The science of Immuno-Oncology is rapidly advancing, and we are proud
to be the first to demonstrate the potential of an immune checkpoint
inhibitor in the adjuvant setting, an earlier stage of the disease,
where patients urgently need new medicines,” said Michael Giordano,
M.D., senior vice president, head of Development, Oncology,
Bristol-Myers Squibb. “The approval of Yervoy for the treatment
of adjuvant melanoma underscores our scientific leadership in
Immuno-Oncology, with a commitment to further developing our I-O agents
– Yervoy and Opdivo – across multiple tumor types and at
many stages of disease.”
Yervoy is associated with a Boxed Warning and can result in
severe to 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. Please see below for additional Important Safety
Information, including Boxed WARNING regarding immune-mediated adverse
reactions.
This Phase 3 trial, CA184-029 (EORTC 18071), is a cooperative group
study initiated in 2008 by the European Organization for Research and
Treatment of Cancer (EORTC) evaluating the 10 mg/kg dose in the adjuvant
setting. With the goal of advancing treatment options for the adjuvant
treatment of melanoma, Bristol-Myers Squibb is working with the Eastern
Cooperative Oncology Group (ECOG) and is conducting an ongoing study to
investigate other dosing options for Yervoy in the adjuvant
setting.
“Today’s approval is an important step in our commitment to bring our
Immuno-Oncology pipeline to earlier lines of cancer treatment and to
make new options available quickly while we continue to build upon our
scientific understanding and develop even better solutions,” continued
Giordano. “Bristol-Myers Squibb has broad development programs in the
adjuvant setting across multiple tumors, including the ongoing studies
of Opdivo and of Yervoy in adjuvant melanoma.”
To help ensure patient access to Yervoy in the adjuvant setting
at the 10 mg/kg dose, Bristol-Myers Squibb is offering a new patient
assistance program – the Adjuvant Patient Program for Melanoma. Through
this program, eligible patients who have been prescribed Yervoy
10 mg/kg for the adjuvant treatment of fully resected Stage III melanoma
(lymph node >1 mm), whether insured or uninsured, may receive Yervoy
10 mg/kg free of charge for the duration of treatment, which may be up
to three years. More information about the program is available from BMS
Access Support by calling 1-800-861-0048 or by visiting www.bmsaccesssupport.com.
CA184-029 (EORTC 18071) is a Phase 3 Trial
The randomized, double-blind Phase 3 trial, CA184-029 (EORTC 18071),
demonstrated that Yervoy 10 mg/kg (n=475) significantly improved
RFS vs. placebo (n=476) in patients with resected Stage IIIa (lymph node
>1 mm), IIIb and IIIc (with no in-transit metastases) histologically
confirmed cutaneous melanoma. The median RFS was 26 months (95% CI: 19,
39) for Yervoy vs. 17 months (95% CI: 13, 22) for placebo
(HR=0.75; 95% CI: 0.64, 0.90; p<0.002). In the trial, patients were
randomized to receive Yervoy 10 mg/kg (n=475) or placebo (n=476)
as an intravenous infusion every 3 weeks for 4 doses, followed by Yervoy
10 mg/kg or placebo every 12 weeks from Week 24 to Week 156 (3
years), or until documented disease recurrence or unacceptable toxicity. Yervoy
was studied across a broad range of patient characteristics,
including patients with Stage IIIa with lymph node >1 mm (20%), IIIb
(44%) or IIIc with no in-transit metastases (36%); 42% had ulcerated
primary lesions and 58% had macroscopic lymph node involvement. The
primary endpoint was RFS, defined as the time between the date of
randomization and the date of first recurrence or death, as assessed by
the Independent Review Committee.
In patients who received Yervoy 10 mg/kg (n=471), severe to
fatal immune-mediated adverse reactions were reported, and included
enterocolitis (16%), hepatitis (11%), endocrinopathy (8%),
hypopituitarism (7%), dermatitis (4%), neuropathy (1.7%),
hyperthyroidism (0.6%), meningitis (0.4%), primary hypothyroidism
(0.2%), myocarditis (0.2%), pericarditis (0.2%), pneumonitis (0.2%), and
uveitis (0.2%). The most common adverse reactions 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%). Yervoy was
discontinued for adverse reactions in 52% of patients.
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 FDA approved Yervoy 3 mg/kg
monotherapy for patients with unresectable or metastatic melanoma. Yervoy is
approved in more than 40 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.
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.
Permanently discontinue YERVOY and initiate systemic high-dose
corticosteroid therapy for severe immune-mediated reactions.
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.
Recommended Dose Modifications
Endocrine: Withhold YERVOY for systemic 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. 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.
Embyro-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%), pruritis (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, including Boxed WARNING
regarding immune-mediated adverse reactions.
Indications and Important Safety Information for OPDIVO® (nivolumab)
Indications
OPDIVO® (nivolumab) is indicated for the treatment of unresectable or
metastatic melanoma as a single agent in patients with disease
progression following ipilimumab and, if BRAF V600 mutation positive, a
BRAF inhibitor and in combination with ipilimumab in patients with BRAF
V600 wild-type melanloma.
These indications are approved under accelerated approval based on tumor
response rate and durability of response. Continued approval for these
indications may be contingent upon verification and description of
clinical benefit in the confirmatory trials.
OPDIVO® (nivolumab) is indicated for the treatment of
patients with metastatic non-small cell lung cancer (NSCLC) with
progression on or after platinum-based chemotherapy. Patients with EGFR
or ALK genomic tumor aberrations should have disease progression on
FDA-approved therapy for these aberrations prior to receiving OPDIVO.
IMPORTANT SAFETY INFORMATION
WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS
YERVOY 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.
Immune-Mediated Pneumonitis
Immune-mediated pneumonitis or interstitial lung disease, including
fatal cases, occurred with OPDIVO treatment. Across the clinical trial
experience with solid tumors, fatal immune-mediated pneumonitis occurred
in 0.5% (5/978) of patients receiving OPDIVO as a single agent. Monitor
patients for signs with radiographic imaging and symptoms of
pneumonitis. Administer corticosteroids for Grade 2 or greater
pneumonitis. Permanently discontinue for Grade 3 or 4 and withhold until
resolution for Grade 2. In Checkmate 037, pneumonitis, including
interstitial lung disease, occurred in 3.4% (9/268) of patients
receiving OPDIVO and none of the 102 patients receiving chemotherapy.
Immune-mediated pneumonitis occurred in 2.2% (6/268) of patients
receiving OPDIVO; Grade 3 (n=1) and Grade 2 (n=5). In Checkmate 057,
immune-mediated pneumonitis, including interstitial lung disease,
occurred in 3.4% (10/287) of patients receiving OPDIVO as a single
agent: Grade 3 (n=5), Grade 2 (n=2), and Grade 1 (n=3). Across the
clinical trial experience in 188 patients with melanoma who received
OPDIVO in combination with YERVOY, in Checkmate 069 (n=94) and an
additional dose-finding study (n=94), fatal immune-mediated pneumonitis
occurred in 0.5% (1/188) of patients. In Checkmate 069, there were six
additional patients who died without resolution of abnormal respiratory
findings. In Checkmate 069, pneumonitis, including interstitial lung
disease, occurred in 10% (9/94) of patients receiving OPDIVO in
combination with YERVOY and 2.2% (1/46) of patients receiving YERVOY.
Immune-mediated pneumonitis occurred in 6% (6/94) of patients receiving
OPDIVO in combination with YERVOY: Grade 5 (n=1), Grade 3 (n=2) and
Grade 2 (n=3).
Immune-Mediated Colitis
Immune-mediated colitis can occur with OPDIVO treatment. Monitor
patients for signs and symptoms of colitis. Administer corticosteroids
for Grade 2 (of more than 5 days duration), 3, or 4 colitis. As a single
agent, withhold OPDIVO for Grade 2 or 3 and permanently discontinue for
Grade 4 or recurrent colitis upon restarting OPDIVO. In combination with
YERVOY, withhold OPDIVO for Grade 2 and permanently discontinue for
Grade 3 or 4 or recurrent colitis upon restarting OPDIVO. In Checkmate
037, diarrhea or colitis occurred in 21% (57/268) of patients receiving
OPDIVO and 18% (18/102) of patients receiving chemotherapy.
Immune-mediated colitis occurred in 2.2% (6/268) of patients receiving
OPDIVO; Grade 3 (n=5) and Grade 2 (n=1). In Checkmate 057, diarrhea or
colitis occurred in 17% (50/287) of patients receiving OPDIVO as a
single agent. Immune-mediated colitis occurred in 2.4% (7/287) of
patients: Grade 3 (n=3), Grade 2 (n=2), and Grade 1 (n=2). In Checkmate
069, diarrhea or colitis occurred in 57% (54/94) of patients receiving
OPDIVO in combination with YERVOY and 46% (21/46) of patients receiving
YERVOY. Immune-mediated colitis occurred in 33% (31/94) of patients
receiving OPDIVO in combination with YERVOY: Grade 4 (n=1), Grade 3
(n=16), Grade 2 (n=9), and Grade 1 (n=5).
In a separate Phase 3 study of YERVOY 3 mg/kg, 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%)
patients. Across all YERVOY-treated patients in that study (n=511), 5
(1%) developed intestinal perforation, 4 (0.8%) died as a result of
complications, and 26 (5%) were hospitalized for severe enterocolitis.
Immune-Mediated Hepatitis
Immune-mediated hepatitis can occur with OPDIVO treatment. Monitor
patients for abnormal liver tests prior to and periodically during
treatment. Administer corticosteroids for Grade 2 or greater
transaminase elevations. Withhold for Grade 2 and permanently
discontinue for Grade 3 or 4 immune-mediated hepatitis. In Checkmate
037, there was an increased incidence of liver test abnormalities in the
OPDIVO-treated group as compared to the chemotherapy-treated group, with
increases in AST (28% vs 12%), alkaline phosphatase (22% vs 13%), ALT
(16% vs 5%), and total bilirubin (9% vs 0). Immune-mediated hepatitis
occurred in 1.1% (3/268) of patients receiving OPDIVO; Grade 3 (n=2) and
Grade 2 (n=1). In Checkmate 057, one patient (0.3%) developed
immune-mediated hepatitis. In Checkmate 069, immune-mediated hepatitis
occurred in 15% (14/94) of patients receiving OPDIVO in combination with
YERVOY: Grade 4 (n=3), Grade 3 (n=9), and Grade 2 (n=2).
In a separate Phase 3 study of YERVOY 3 mg/kg, 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%.
Immune-Mediated Dermatitis
In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening,
or fatal immune-mediated dermatitis (eg, 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.
Immune-Mediated Neuropathies
In a separate Phase 3 study of YERVOY 3 mg/kg, 1 case of fatal
Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor
neuropathy were reported.
Immune-Mediated Endocrinopathies
Hypophysitis, adrenal insufficiency, and thyroid disorders can occur
with OPDIVO treatment. Monitor patients for signs and symptoms of
hypophysitis, signs and symptoms of adrenal insufficiency during and
after treatment, and thyroid function prior to and periodically during
treatment. Administer corticosteroids for Grade 2 or greater
hypophysitis. Withhold for Grade 2 or 3 and permanently discontinue for
Grade 4 hypophysitis. Administer corticosteroids for Grade 3 or 4
adrenal insufficiency. Withhold for Grade 2 and permanently discontinue
for Grade 3 or 4 adrenal insufficiency. Administer hormone replacement
therapy for hypothyroidism. Initiate medical management for control of
hyperthyroidism.
In Checkmate 069, hypophysitis occurred in 13% (12/94) of patients
receiving OPDIVO in combination with YERVOY: Grade 3 (n=2) and Grade 2
(n=10). Adrenal insufficiency occurred in 1% (n=555) of patients
receiving OPDIVO as a single agent. In Checkmate 069, adrenal
insufficiency occurred in 9% (8/94) of patients receiving OPDIVO in
combination with YERVOY: Grade 3 (n=3), Grade 2 (n=4), and Grade 1
(n=1). In Checkmate 069, hypothyroidism occurred in 19% (18/94) of
patients receiving OPDIVO in combination with YERVOY. All were Grade 1
or 2 in severity except for one patient who experienced Grade 3
autoimmune thyroiditis. Grade 1 hyperthyroidism occurred in 2.1% (2/94)
of patients receiving OPDIVO in combination with YERVOY. In Checkmate
037, Grade 1 or 2 hypothyroidism occurred in 8% (21/268) of patients
receiving OPDIVO and none of the 102 patients receiving chemotherapy.
Grade 1 or 2 hyperthyroidism occurred in 3% (8/268) of patients
receiving OPDIVO and 1% (1/102) of patients receiving chemotherapy. In
Checkmate 057, Grade 1 or 2 hypothyroidism, including thyroiditis,
occurred in 7% (20/287) and elevated TSH occurred in 17% of patients
receiving OPDIVO as a single agent. Grade 1 or 2 hyperthyroidism
occurred in 1.4% (4/287) of patients.
In a separate Phase 3 study of YERVOY 3 mg/kg, 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.
Immune-Mediated Nephritis and Renal Dysfunction
Immune-mediated nephritis can occur with OPDIVO treatment. Monitor
patients for elevated serum creatinine prior to and periodically during
treatment. For Grade 2 or 3 increased serum creatinine, withhold and
administer corticosteroids; if worsening or no improvement occurs,
permanently discontinue. Administer corticosteroids for Grade 4 serum
creatinine elevation and permanently discontinue. In Checkmate 037,
there was an increased incidence of elevated creatinine in the
OPDIVO-treated group as compared to the chemotherapy-treated group (13%
vs 9%). Grade 2 or 3 immune-mediated nephritis or renal dysfunction
occurred in 0.7% (2/268) of patients. In Checkmate 057, Grade 2
immune-mediated renal dysfunction occurred in 0.3% (1/287) of patients
receiving OPDIVO as a single agent. In Checkmate 069, Grade 2 or higher
immune-mediated nephritis or renal dysfunction occurred in 2.1% (2/94)
of patients. One patient died without resolution of renal dysfunction.
Immune-Mediated Rash
Immune-mediated rash can occur with OPDIVO treatment. Monitor patients
for rash. Administer corticosteroids for Grade 3 or 4 rash. Withhold for
Grade 3 and permanently discontinue for Grade 4. In Checkmate 037
(n=268), the incidence of rash was 21%; the incidence of Grade 3 or 4
rash was 0.4%. In Checkmate 057, immune-mediated rash occurred in 6%
(17/287) of patients receiving OPDIVO as a single agent including four
Grade 3 cases. In Checkmate 069, immune-mediated rash occurred in 37%
(35/94) of patients receiving OPDIVO in combination with YERVOY: Grade 3
(n=6), Grade 2 (n=10), and Grade 1 (n=19).
Immune-Mediated Encephalitis
Immune-mediated encephalitis can occur with OPDIVO treatment. Withhold
OPDIVO in patients with new-onset moderate to severe neurologic signs or
symptoms and evaluate to rule out other causes. If other etiologies are
ruled out, administer corticosteroids and permanently discontinue OPDIVO
for immune-mediated encephalitis. Across clinical trials of 8490
patients receiving OPDIVO as a single agent or in combination with
YERVOY, <1% of patients were identified as having encephalitis. In
Checkmate 057, fatal limbic encephalitis occurred in one patient (0.3%)
receiving OPDIVO as a single agent.
Other Immune-Mediated Adverse Reactions
Based on the severity of adverse reaction, permanently discontinue or
withhold treatment, administer high-dose corticosteroids, and, if
appropriate, initiate hormone-replacement therapy. The following
clinically significant immune-mediated adverse reactions occurred in <2%
(n=555) of single-agent OPDIVO-treated patients: uveitis, pancreatitis,
abducens nerve paresis, demyelination, polymyalgia rheumatica, and
autoimmune neuropathy. Across clinical trials of OPDIVO administered as
a single agent at doses 3 mg/kg and 10 mg/kg, additional clinically
significant, immune-mediated adverse reactions were identified: facial
nerve paralysis, motor dysfunction, vasculitis, diabetic ketoacidosis,
and myasthenic syndrome. In Checkmate 069, the following additional
immune-mediated adverse reactions occurred in 1% of patients treated
with OPDIVO in combination with YERVOY: Guillain-Barré syndrome and
hypopituitarism. Across clinical trials of OPDIVO in combination with
YERVOY, the following additional clinically significant, immune-mediated
adverse reactions were identified: uveitis, sarcoidosis, duodenitis,
pancreatitis, and gastritis.
Infusion Reactions
Severe infusion reactions have been reported in <1% of patients in
clinical trials of OPDIVO as a single agent. In Checkmate 057, Grade 2
infusion reactions occurred in 1% (3/287) of patients receiving OPDIVO
as a single agent. In Checkmate 069, Grade 2 infusion reactions occurred
in 3% (3/94) of patients receiving OPDIVO in combination with YERVOY.
Discontinue OPDIVO in patients with severe or life-threatening infusion
reactions. Interrupt or slow the rate of infusion in patients with mild
or moderate infusion reactions.
Embryofetal Toxicity
Based on their mechanisms of action, OPDIVO and YERVOY can cause fetal
harm when administered to a pregnant woman. Advise pregnant women of the
potential risk to a fetus. Advise females of reproductive potential to
use effective contraception during treatment with an OPDIVO- or
YERVOY-containing regimen and for at least 5 months after the last dose
of OPDIVO.
Lactation
It is not known whether OPDIVO or YERVOY is present in human milk.
Because many drugs, including antibodies, are excreted in human milk and
because of the potential for serious adverse reactions in nursing
infants from OPDIVO-containing regimen, advise women to discontinue
breastfeeding during treatment. Advise women to discontinue nursing
during treatment with YERVOY and for 3 months following the final dose.
Serious Adverse Reactions
In Checkmate 037, serious adverse reactions occurred in 41% of patients
receiving OPDIVO. Grade 3 and 4 adverse reactions occurred in 42% of
patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse drug
reactions reported in 2% to <5% of patients receiving OPDIVO were
abdominal pain, hyponatremia, increased aspartate aminotransferase, and
increased lipase. In Checkmate 057, serious adverse reactions occurred
in 47% of patients receiving OPDIVO as a single agent. The most frequent
serious adverse reactions reported in ≥2% of patients were pneumonia,
pulmonary embolism, dyspnea, pleural effusion, and respiratory failure.
In Checkmate 069, serious adverse reactions occurred in 62% of patients
receiving OPDIVO; the most frequent serious adverse events with OPDIVO
in combination with YERVOY, as compared to YERVOY alone, were colitis
(17% vs 9%), diarrhea (9% vs 7%), pyrexia (6% vs 7%), and pneumonitis
(5% vs 0).
Common Adverse Reactions
In Checkmate 037, the most common adverse reaction (≥20%) reported with
OPDIVO was rash (21%). In Checkmate 057, the most common adverse
reactions (≥20%) reported with OPDIVO as a single agent were fatigue
(49%), musculoskeletal pain (36%), cough (30%), decreased appetite
(29%), and constipation (23%). In Checkmate 069, the most common adverse
reactions (≥20%) reported in patients receiving OPDIVO in combination
with YERVOY vs YERVOY alone were rash (67% vs 57%), pruritus (37% vs
26%), headache (24% vs 20%), vomiting (23% vs 15%), and colitis (22% vs
11%).
In a separate Phase 3 study of YERVOY 3 mg/kg, 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 U.S. Full Prescribing Information, including Boxed WARNING
regarding immune-mediated adverse reactions, for YERVOY.
Please
see U.S. Full Prescribing Information for OPDIVO.
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,
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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.
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, 2014 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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