First and only PD-1 checkpoint inhibitor to
demonstrate two-year overall survival data in a Phase 3 trial,
CheckMate -066, with nearly 60% of patients still alive at two
years
Longest follow-up for the Opdivo +
Yervoy Regimen from Study 004 shows three-year overall survival
rate of 68% across Phase 1 dosing cohorts
Bristol-Myers Squibb Company (NYSE:BMY) today announced new
long-term data of Opdivo in treatment-naïve BRAF wild-type advanced
melanoma from CheckMate -066. In the trial, Opdivo continued to
demonstrate superior overall survival versus dacarbazine with 57.7%
of patients alive at two years compared to 26.7% of patients
treated with dacarbazine. The safety profile of Opdivo was
consistent with prior studies. The two-year survival and safety
data from CheckMate -066 represent the longest follow-up from a
randomized study of any PD-1 immune checkpoint inhibitor in the
first-line setting of advanced melanoma. These data will be
presented as a late-breaking presentation at the Society for
Melanoma Research (SMR) 2015 International Congress in San
Francisco, CA from November 18 to 21.
Bristol-Myers Squibb is also presenting updated data from
various Phase 1 cohorts of Study 004 evaluating the Opdivo + Yervoy
Regimen in patients with unresectable or metastatic melanoma,
including up to three-year overall survival. The Phase 1b Study 004
is a dose-finding study on which the proof of concept for Opdivo +
Yervoy Regimen approval was based.
“The long-term survival data for our Immuno-Oncology agent,
Opdivo, as a single agent and in combination with Yervoy presented
at SMR shows our continued commitment to improve outcomes for
patients with advanced melanoma,” said Michael Giordano, M.D.,
senior vice president, head of Oncology Development, Bristol-Myers
Squibb. “The Opdivo + Yervoy Regimen has shown compelling potential
for providing improved duration of response and long-term survival
for some patients, and, as single agents, Opdivo and Yervoy
continue to play a critical role as core components of the
treatment continuum for advanced melanoma in appropriate
patients.”
The global incidence of melanoma has been increasing over the
past three decades, and despite recent advances in treatment,
patients with advanced or metastatic disease often have a poor
prognosis. Currently, five-year survival rates for advanced
melanoma are between 5% and 19%.
Opdivo Associated with a
Doubling of Overall Survival in CheckMate -066
CheckMate -066 is a Phase 3, randomized study which evaluated
Opdivo as a single agent (n=210) versus dacarbazine (n=208) in
patients with previously untreated, BRAF wild-type unresectable or
metastatic melanoma. The primary endpoint of the trial was overall
survival (OS). Secondary endpoints included progression-free
survival (PFS) and objective response rate (ORR).
In the trial, patients administered Opdivo demonstrated
increased OS compared to dacarbazine. With a minimum follow-up of
15.1 months, Opdivo continued to demonstrate significantly improved
OS with the median OS not reached (NR) (95% CI: 23.1, NR) versus
11.2 months with dacarbazine (95% CI: 9.6, 13.0) (hazard ratio
[HR]=0.43; 95% CI: 0.33, 0.57; p<0.001). Overall survival rates
were 70.7% and 57.7% for Opdivo and 46.3% and 26.7% for dacarbazine
at 12 and 24 months, respectively. Subsequent treatment was used in
72.1% of patients in the dacarbazine arm, with 27 (13%) patients
receiving Opdivo as the subsequent therapy. ORR and PFS also
continued to be significantly greater with Opdivo. Objective
response rate was 42.9% for Opdivo with 11% of patients achieving a
complete response, compared to a 14.4% ORR for dacarbazine with 1%
of patients achieving a complete response. Of 90 responders, 81%
experienced ongoing responses with Opdivo. Median PFS was 5.4
months for Opdivo versus 2.2 months for dacarbazine (HR=0.42; 95%
CI: 0.32, 0.53; p<0.0001). At one and two years, PFS was 44.3%
and 39.2% for those patients administered Opdivo, respectively.
The safety profile of Opdivo in CheckMate -066 was consistent
with prior studies and continued to be acceptable at two years.
Incidences of treatment-related adverse events (AE) of any grade
were similar between treatment arms, with Grade 3-4 AEs occurring
in 13% and 17% of patients. Treatment-related select AEs reported
in ≥10% of patients treated with Opdivo included pruritus (22%),
diarrhea (18%) and rash (18%). Treatment-related AEs led to
discontinuation in 6% of patients treated with Opdivo.
Opdivo + Yervoy Regimen Shows
Improved Overall Survival Across Dosing Cohorts
Study 004 (CA209-004) is a Phase 1b, open-label, multicenter,
multidose, dose-finding study of Opdivo in combination with Yervoy
in patients with unresectable or metastatic melanoma. The trial
evaluated different dosing schedules for the Opdivo + Yervoy
Regimen, including Opdivo + Yervoy every three weeks for 12 weeks,
followed by Opdivo every three weeks for 12 weeks (Cohorts 1, 2,
2a, and 3) (n=53), or Opdivo 1 mg/kg and Yervoy 3 mg/kg every three
weeks for 12 weeks followed by Opdivo 3 mg/kg every two weeks
(Cohort 8) (n=41). Forty percent of patients in Cohorts 1-3 and 51%
of patients in Cohort 8 were previously treated.
For Cohorts 1-3, median duration of follow-up was 32.7 months
(range 2.5 to 61.4). At 36 months (three years), the OS rate was
68% for patients in Cohorts 1-3 treated with the combination of
Opdivo and Yervoy. Objective response rate was 42% with a 22.3
month median duration of response (95% CI: 12.09-NR). Complete
responses were seen in 21% of patients in Cohorts 1-3. Rates of
ongoing response were similar between Cohorts 1-3 and Cohort 8 (55%
and 56%, respectively). These data represent the longest follow-up
of the combination of Opdivo and Yervoy.
Patients included in Cohort 8 had poor prognostic factors at
baseline, including ECOG performance status, history of brain
metastases, prior systemic therapy and PD-L1 expression. At 18
months, 68% of patients were alive, with a median duration of
follow-up of 19.9 months (range 0.9 to 24.0). Objective response
rate was 44% with a median duration of response of 13.7 months (95%
CI: 5.59-NR). Complete responses were seen in 17% of patients. In
the study, high response rates and durable tumor response were
observed in patients with or without poor prognostic factors at
baseline.
The frequency of treatment-related AEs in the study were similar
between Cohorts 1-3 and Cohort 8, and was consistent with the Phase
2 and 3 trials for the combination therapy. Across all concurrent
cohorts, the incidence of treatment-related Grade 3-4 AEs was 56%
and the incidence of treatment-related AEs leading to
discontinuation was 27%.
About Opdivo
Bristol-Myers Squibb has a broad, global development program to
study Opdivo in multiple tumor types consisting of more than 50
trials – as monotherapy or in combination with other therapies – in
which more than 8,000 patients have been enrolled worldwide. Opdivo
is the first PD-1 immune checkpoint inhibitor to receive regulatory
approval anywhere in the world in July 2014, and currently has
regulatory approval in more than 37 countries including the United
States, Japan, and in the European Union.
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. Yervoy is now
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 melanoma.
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
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.
Immuno-Oncology at Bristol-Myers
Squibb
Surgery, radiation, cytotoxic or targeted therapies have
represented the mainstay of cancer treatment over the last several
decades, but long-term survival and a positive quality of life have
remained elusive for many patients with advanced disease.
To address this unmet medical need, Bristol-Myers Squibb is
leading research in an innovative field of cancer research and
treatment known as Immuno-Oncology, which involves agents whose
primary mechanism is to work directly with the body’s immune system
to fight cancer. The company is exploring a variety of compounds
and immunotherapeutic approaches for patients with different types
of cancer, including researching the potential of combining
Immuno-Oncology agents that target different pathways in the
treatment of cancer.
Bristol-Myers Squibb is committed to advancing the science of
Immuno-Oncology, with the goal of changing survival
expectations and the way patients live with cancer.
About the Bristol-Myers Squibb and Ono
Pharmaceutical Collaboration
In 2011, through a collaboration agreement with Ono
Pharmaceutical Co., Bristol-Myers Squibb expanded its territorial
rights to develop and commercialize Opdivo globally
except in Japan, South Korea and Taiwan, where Ono had retained all
rights to the compound at the time. On July 23, 2014, Bristol-Myers
Squibb and Ono Pharmaceutical further expanded the companies’
strategic collaboration agreement to jointly develop and
commercialize multiple immunotherapies – as single agents and
combination regimens – for patients with cancer in Japan, South
Korea and Taiwan.
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,
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.
View source
version on businesswire.com: http://www.businesswire.com/news/home/20151118006206/en/
Media:Carrie Fernandez,
215-859-2605carrie.fernandez@bms.comorInvestors:Ranya
Dajani, 609-252-5330ranya.dajani@bms.comorBill Szablewski,
609-252-5864william.szablewski@bms.com
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