First and only PD-1 immune checkpoint
inhibitor approved as a single agent for first-line use in advanced
BRAF wild-type melanoma
Approval based on Phase 3 trial, CheckMate
-066, which demonstrated superior overall survival vs. dacarbazine
in first-line treatment of patients with BRAF wild-type advanced
melanoma
Marks the sixth FDA approval for
Opdivo in the past 12 months
Bristol-Myers Squibb Company (NYSE:BMY) today announced
that the U.S. Food and Drug Administration (FDA) has approved
Opdivo (nivolumab) injection, for intravenous use, as a single
agent for the treatment of patients with BRAF V600 wild-type (WT)
unresectable or metastatic melanoma. The approval is based on data
from the Phase 3 trial, CheckMate -066, which evaluated overall
survival as the primary endpoint in treatment-naïve patients with
BRAF WT unresectable or metastatic melanoma compared to
chemotherapy (dacarbazine).
“Our focused approach to Immuno-Oncology research is to deliver
treatment options that have the potential to improve long-term
survival outcomes for patients,” said Michael Giordano, M.D.,
senior vice president, head of Oncology Development, Bristol-Myers
Squibb. “Opdivo has become a critical part of the treatment
landscape for advanced melanoma patients and their physicians, both
as a monotherapy and in combination, and we are committed to
exploring opportunities for this treatment across stages of disease
and lines of therapy.”
Opdivo is associated with immune-mediated: pneumonitis, colitis,
hepatitis, endocrinopathies, nephritis and renal dysfunction, rash,
encephalitis, other adverse reactions; infusion reactions; and
embryofetal toxicity. Please see additional Important Safety
Information section below.
“Advanced melanoma continues to be one of the deadliest and most
challenging cancers to treat, and ongoing research in
Immuno-Oncology from clinical trials like CheckMate -066 shows the
potential to provide improved overall survival for newly diagnosed
patients with BRAF wild-type metastatic melanoma,” said Jeffrey S.
Weber, M.D., PhD, deputy director of the Laura and Isaac Perlmutter
Cancer Center at the NYU Langone Medical Center. “This important
news means that we now have another new option to offer patients
with BRAF wild-type metastatic melanoma.”
A supplemental Biologics License Application for Opdivo in BRAF
V600 mutation positive unresectable or metastatic melanoma, which
was filed subsequent to data from CheckMate -066, is still under
review with the FDA.
Opdivo Demonstrated Efficacy in
Newly Diagnosed BRAF Wild-Type Advanced Melanoma
CheckMate -066 is a Phase 3, randomized, double-blind study of
treatment-naïve patients with unresectable or metastatic BRAF WT
melanoma. Patients were randomized to receive Opdivo (intravenously
3 mg/kg q2w; n=210) or dacarbazine (intravenously 1000 mg/m2 q3w;
n=208). The primary efficacy endpoint of the trial was overall
survival (OS), and secondary endpoints were progression-free
survival (PFS) and objective response rate (ORR).
In the trial, Opdivo demonstrated superior OS versus
chemotherapy in the first-line setting. Results were based on the
interim analysis conducted on 47% of the total planned events for
OS (50 for the Opdivo arm; 96 for the dacarbazine arm). The median
OS was not reached for Opdivo and was 10.8 months (95% CI:
9.3-12.1) in the dacarbazine arm (HR=0.42; 95% CI: 0.30-0.60;
p<0.0001). Median PFS more than doubled with Opdivo (5.1 months
[95% CI: 3.5-10.8] vs. 2.2 months [95% CI: 2.1-2.4] for patients
treated with dacarbazine [HR=0.43; 95% CI: 0.34-0.56;
p<0.0001]). ORR with Opdivo was 34% (4% complete response rate,
30% partial response rate [95% CI: 28-41]) compared to 9% with
dacarbazine (1% complete response rate, 8% partial response rate
[95% CI: 5-13]). At the time of analysis, 88% (63/72) of
Opdivo-treated patients had ongoing responses, which included 43
patients with ongoing responses of six months or longer.
Last year, the CheckMate -066 trial was stopped early following
a recommendation by the independent Data Monitoring Committee based
on their analysis which showed evidence of superior OS in patients
receiving Opdivo compared to the control arm. As a result, patients
in the trial were unblinded and patients who had received
dacarbazine were allowed to receive Opdivo. Dacarbazine was
selected as the comparator in this study because, at the time the
study protocol was designed, it represented the standard of care in
many regions outside of the U.S. where Yervoy had not yet been
approved for first-line use.
In the trial, serious adverse reactions occurred in 36% of
patients receiving Opdivo. Grade 3 and 4 adverse reactions occurred
in 41% of patients receiving Opdivo. The most frequent Grade 3 and
4 adverse reactions reported in ≥2% of patients receiving Opdivo
were gamma-glutamyltransferase increase (3.9%) and diarrhea (3.4%).
Adverse reactions led to permanent discontinuation of Opdivo in 7%
of patients and dose interruption in 26% of patients. The most
common adverse reactions in CheckMate -066 (>20%) reported with Opdivo versus dacarbazine
were fatigue (49% vs. 39%), musculoskeletal pain (32% vs. 25%),
rash (28% vs. 12%), and pruritus (23% vs. 12%).
About Advanced Melanoma
Melanoma is a form of skin cancer characterized by the
uncontrolled growth of pigment-producing cells (melanocytes)
located in the skin. Metastatic melanoma is the deadliest form of
the disease, and occurs when cancer spreads beyond the surface of
the skin to the other organs, such as the lymph nodes, lungs, brain
or other areas of the body. The incidence of melanoma has been
increasing for at least 30 years. In the U.S., more than 73,000
cases of melanoma will be diagnosed this year and nearly 10,000
people are expected to die from the disease. Melanoma is mostly
curable when treated in its early stages. However, in its late
stages, the average survival rate has historically been just six
months with a one-year survival rate of 25.5%, making it one of the
most aggressive forms of cancer.
Leading Immuno-Oncology Development in
Melanoma
Bristol-Myers Squibb is a pioneer in the 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.
Opdivo is a programmed death-1 (PD-1) immune checkpoint
inhibitor, and works by targeting the immune system through the
PD-1 immune checkpoint pathway.
Bristol-Myers Squibb has a broad, global development program to
study Opdivo in multiple tumor types consisting of more than 50
trials – as a monotherapy or in combination with other therapies –
in which more than 8,000 patients have been enrolled worldwide.
About Bristol-Myers Squibb’s Patient
Support Programs for Opdivo
Bristol-Myers Squibb remains committed to helping patients
through treatment with Opdivo. For support and assistance,
patients and physicians may call 1-855-OPDIVO-1. This number offers
one-stop access to a range of support services for patients and
healthcare professionals alike.
About Bristol-Myers Squibb’s Access
Support
Bristol-Myers Squibb is committed to helping patients
access Opdivo and offers BMS Access Support® to support
patients and providers in gaining access. BMS Access Support®, the
Bristol-Myers Squibb Reimbursement Services program, is designed to
support access to BMS medicines and expedite time to therapy
through reimbursement support including Benefit Investigations,
Prior Authorization Facilitation, Appeals Assistance, and
assistance for patient out-of-pocket costs. BMS Access Support
assists patients and providers throughout the treatment journey –
whether it is at initial diagnosis or in support of transition from
a clinical trial. More information about our reimbursement support
services can be obtained by calling 1-800-861-0048 or by
visiting www.bmsaccesssupport.com. For healthcare providers
seeking Opdivo specific reimbursement information, please
visit the BMS Access Support Product section by
visiting www.bmsaccesssupportopdivo.com.
INDICATIONS and IMPORTANT SAFETY
INFORMATION for OPDIVO (nivolumab)
INDICATIONS
OPDIVO® (nivolumab) as a single agent is indicated for the
treatment of patients with BRAF V600 wild-type unresectable or
metastatic melanoma.
OPDIVO® (nivolumab) as a single agent is indicated for the
treatment of patients with unresectable or metastatic, BRAF V600
mutation-positive melanoma and disease progression following
ipilimumab and a BRAF inhibitor. This indication is approved under
accelerated approval based on tumor response rate and durability of
response. Continued approval for this indication may be contingent
upon verification and description of clinical benefit in the
confirmatory trials.
OPDIVO® (nivolumab), in combination with (ipilimumab), is
indicated for the treatment of patients with BRAF V600 wild-type,
unresectable or metastatic melanoma. This indication is approved
under accelerated approval based on tumor response rate and
durability of response. Continued approval for this indication 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 with OPDIVO. In addition, in Checkmate 069,
there were six patients who died without resolution of abnormal
respiratory findings. 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 066, immune-mediated pneumonitis occurred in
1.4% (3/206) of patients receiving OPDIVO and in none of the 205
patients receiving dacarbazine: Grade 2 (n=3). In Checkmate 057,
immune-mediated pneumonitis, including interstitial lung disease,
occurred in 3.4% (10/287) of patients: Grade 3 (n=5), Grade 2
(n=2), and Grade 1 (n=3). 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 066, diarrhea or
colitis occurred in 28% (58/206) of patients receiving OPDIVO and
25% (52/205) of patients receiving dacarbazine. Immune-mediated
colitis occurred in 4.9% (10/206) of patients receiving OPDIVO:
Grade 3 (n=5) and Grade 2 (n=5). In Checkmate 057, diarrhea or
colitis occurred in 17% (50/287) of patients receiving OPDIVO.
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 066, there was an increased incidence of liver
test abnormalities in the OPDIVO-treated group as compared to the
dacarbazine-treated group, with increases in ALT (25% vs. 19%), AST
(24% vs. 19%), alkaline phosphatase (21% vs. 14%), and total
bilirubin (13% vs. 6%). Immune-mediated hepatitis occurred in 0.9%
(2/206) of patients receiving OPDIVO: Grade 3 (n=1) 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, thyroid disorders, and type
I diabetes mellitus can occur with OPDIVO treatment. Monitor
patients for signs and symptoms of hypophysitis, signs and symptoms
of adrenal insufficiency during and after treatment, thyroid
function prior to and periodically during treatment, and
hyperglycemia. 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. Administer insulin for
type I diabetes. Withhold OPDIVO for Grade 3 and permanently
discontinue for Grade 4 hyperglycemia.
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). In Checkmate 037, 066, 057, <1% of
OPDIVO-treated patients developed adrenal insufficiency. 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 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 066, hypothyroidism occurred in 7% (14/206) of patients
receiving OPDIVO (Grade 3 (n=1)) and 0.9% (2/205) of patients
receiving dacarbazine. Hyperthyroidism occurred in 4.4% (9/206) of
patients receiving OPDIVO (Grade 3 (n=1)) and 0.9% (2/205) of
patients receiving dacarbazine. 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. Grade 1
or 2 hyperthyroidism occurred in 1.4% (4/287) of patients. 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 066, diabetes mellitus or diabetic ketoacidosis occurred
in 1.0% (2/206) of patients receiving OPDIVO and none of the 205
receiving dacarbazine; Grade 3 diabetic ketoacidosis (n=1) and
Grade 2 diabetes mellitus (n=1).
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 066, there was an increased
incidence of elevated creatinine in the OPDIVO-treated group as
compared to the dacarbazine-treated group (11% vs. 10%). Grade 3
immune-mediated renal dysfunction occurred in 0.5% (1/206) of
patients. In Checkmate 057, Grade 2 immune-mediated renal
dysfunction occurred in 0.3% (1/287) of patients receiving OPDIVO.
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 057, immune-mediated rash occurred in 6% (17/287) of
patients receiving OPDIVO 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, <1.0% of patients
were identified as having encephalitis. In Checkmate 057, fatal
limbic encephalitis occurred in one patient (0.3%) receiving
OPDIVO.
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 <1.0% of OPDIVO-treated patients:
uveitis, pancreatitis, facial and abducens nerve paresis,
demyelination, polymyalgia rheumatica, autoimmune neuropathy,
systemic inflammatory response syndrome, Guillain-Barre syndrome
and hypopituitarism. 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: motor dysfunction, vasculitis, and myasthenic syndrome.
Across clinical trials of OPDIVO in combination with YERVOY, the
following additional clinically significant, immune-mediated
adverse reactions were identified: sarcoidosis, duodenitis, and
gastritis.
Infusion Reactions
Severe infusion reactions have been reported in <1.0% of
patients in clinical trials of OPDIVO as a single agent.
Discontinue OPDIVO in patients with Grade 3 or 4 infusion
reactions. Interrupt or slow the rate of infusion in patients with
Grade 1 or 2. In Checkmate 057 and 066, Grade 2 infusion reactions
occurred in 1.0% (5/493) of patients receiving OPDIVO. In Checkmate
069, Grade 2 infusion reactions occurred in 3.2% (3/94) of patients
receiving OPDIVO in combination with YERVOY.
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 066,
serious adverse reactions occurred in 36% of patients receiving
OPDIVO. Grade 3 and 4 adverse reactions occurred in 41% of patients
receiving OPDIVO. The most frequent Grade 3 and 4 adverse reactions
reported in ≥2% of patients receiving OPDIVO were
gamma-glutamyltransferase increase (3.9%) and diarrhea (3.4%). In
Checkmate 057, serious adverse reactions occurred in 47% of
patients receiving OPDIVO. 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 066, the most
common adverse reactions (≥20%) reported with OPDIVO vs dacarbazine
were fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash
(28% vs 12%), and pruritus (23% vs 12%). In Checkmate 057, the most
common adverse reactions (≥20%) reported with OPDIVO 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.
Indication
YERVOY® (ipilimumab) is indicated for the treatment of
unresectable or metastatic melanoma.
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.
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).
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.
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.
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.
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.
Across 21 dose-ranging trials administering YERVOY at doses of 0.1
to 20 mg/kg (n=2478), the following likely immune-mediated adverse
reactions were also reported with <1% incidence: angiopathy,
temporal arteritis, vasculitis, polymyalgia rheumatica,
conjunctivitis, blepharitis, episcleritis, scleritis, iritis,
leukocytoclastic vasculitis, erythema multiforme, psoriasis,
arthritis, autoimmune thyroiditis, neurosensory hypoacusis,
autoimmune central neuropathy (encephalitis), myositis,
polymyositis, ocular myositis, hemolytic anemia, and nephritis.
Embryo-fetal Toxicity
Based on its mechanism of action, YERVOY can cause fetal harm
when administered to a pregnant woman. The effects of YERVOY are
likely to be greater during the second and third trimesters of
pregnancy. Advise pregnant women of the potential risk to a fetus.
Advise females of reproductive potential to use effective
contraception during treatment with a YERVOY-containing regimen and
for 3 months after the last dose of YERVOY.
Lactation
It is not known whether YERVOY is secreted in human milk. Advise
women to discontinue nursing during treatment with YERVOY and for 3
months following the final dose.
Common Adverse Reactions
The most common adverse reactions (≥5%) in patients who received
YERVOY at 3 mg/kg were fatigue (41%), diarrhea (32%), pruritus
(31%), rash (29%), and colitis (8%).
Please see U.S. Full Prescribing Information, including Boxed
WARNING regarding immune-mediated adverse reactions for YERVOY.
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.
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Bristol-Myers Squibb CompanyMedia:Jaisy Wagner Styles,
609-897-3958Cell:
610-291-5168jaisy.styles@bms.comorInvestors:Ranya Dajani,
609-252-5330ranya.dajani@bms.comorBill Szablewski,
609-252-5894william.szablewski@bms.com
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