Opdivo + Yervoy Regimen now indicated for
unresectable or metastatic melanoma patients, regardless of BRAF
mutational status, based on accelerated approval1
Demonstrated significantly superior
progression-free survival vs. Yervoy alone in CheckMate -067
with the first and only FDA-approved combination of immune
checkpoint inhibitors1,2
FDA also expands use of Opdivo as
single-agent to include previously untreated BRAF mutation-positive
advanced melanoma patients, based on accelerated
approval1
With this seventh approval for Opdivo
in just over a year, and the fourth for late-stage melanoma, more
patients fighting cancer now have access to Immuno-Oncology
treatment options1
Bristol-Myers Squibb Company (NYSE:BMY) today announced that the
U.S. Food and Drug Administration (FDA) has approved Opdivo
(nivolumab) in combination with Yervoy (ipilimumab) for
the treatment of patients with BRAF V600 wild-type and BRAF V600
mutation-positive unresectable or metastatic melanoma.1 This
indication is approved under accelerated approval based on
progression-free survival (PFS).1 Continued approval for this
indication may be contingent upon verification and description of
clinical benefit in confirmatory trials.1 This approval expands the
original indication for the Opdivo + Yervoy Regimen for the
treatment of patients with BRAF V600 wild-type unresectable or
metastatic melanoma to include patients, regardless of BRAF
mutational status, based on data from the Phase 3 CheckMate -067
trial, in which PFS and overall survival (OS) were co-primary
endpoints.1,2
Opdivo is associated with immune-mediated: pneumonitis,
colitis, hepatitis, endocrinopathies, nephritis and renal
dysfunction, rash, encephalitis, other adverse reactions; infusion
reactions; and embryofetal toxicity.1 Please see the Important
Safety Information section below, including Boxed WARNING
for Yervoy regarding immune-mediated adverse
reactions.
“For nearly a decade, our researchers have worked tirelessly to
find treatment options that could improve outcomes for patients
with late-stage melanoma, a particularly aggressive cancer, and we
are incredibly proud of today’s approval to expand the use of the
Opdivo + Yervoy Regimen to include patients with BRAF
mutation-positive unresectable or metastatic melanoma. CheckMate
-067 is the first Phase 3 study to observe the efficacy and safety
of both Opdivo as a single-agent as well as in combination with
Yervoy versus Yervoy alone,” said Chris Boerner, Head of U.S.
Commercial, Bristol-Myers Squibb. “To make this treatment option
available to more patients is truly a milestone in the fight
against this deadly disease.”
The FDA also expanded the use of Opdivo as a single-agent to
include previously untreated BRAF mutation-positive advanced
melanoma patients.1 The use of Opdivo as a single-agent in patients
with BRAF V600 mutation-positive unresectable or metastatic
melanoma is approved under accelerated approval based on
progression-free survival.1 Continued approval for this indication
may be contingent upon verification and description of clinical
benefit in confirmatory trials.1 Opdivo was approved by the FDA in
November 2015, for use in previously untreated patients with BRAF
V600 wild-type unresectable or metastatic melanoma.1
“Patients with metastatic melanoma historically have a very
challenging disease. Recent advances in our understanding of the
immune response to cancer has yielded therapies which provide
meaningful responses and hope. The combination of two
Immuno-Oncology treatments, nivolumab and ipilimumab, has been
shown to provide these patients with a much needed improvement in
progression-free survival and response rates,” said Jedd D.
Wolchok, MD, PhD, Chief, Melanoma and Immunotherapeutics Service,
Department of Medicine and Ludwig Center at Memorial Sloan
Kettering Cancer Center. “This expanded approval for the nivolumab
and ipilimumab regimen provides more advanced melanoma patients
with an Immuno-Oncology combination treatment, and the potential
for improved outcomes.”
Expanded Approval Based on Efficacy
Demonstrated in a Phase 3 Trial
CheckMate -067 is a Phase 3, double-blind, randomized study that
evaluated the Opdivo + Yervoy Regimen
or Opdivo monotherapy vs. Yervoy monotherapy in
patients with previously untreated advanced melanoma.1, 2 The
trial evaluated previously untreated patients, including both BRAF
V600 mutant and wild-type advanced melanoma, and enrolled 945
patients who were randomized to receive the Opdivo +
Yervoy Regimen (Opdivo 1 mg/kg plus Yervoy 3 mg/kg every
3 weeks for 4 doses followed by Opdivo 3 mg/kg every 2 weeks
thereafter; n=314), Opdivo monotherapy (Opdivo 3 mg/kg every 2
weeks; n=316) or Yervoy monotherapy (Yervoy 3 mg/kg every
3 weeks for 4 doses followed by placebo every 2 weeks; n=315).1
Patients were treated until progression or unacceptable toxic
effects.1 The median duration of exposure was 2.8 months (range: 1
day to 18.8 months) for patients in the Opdivo + Yervoy Regimen arm
with a median of four doses (range: 1 to 39 for Opdivo; 1 to 4 for
Yervoy), and 6.6 months (range: 1 day to 17.3 months) duration for
the Opdivo monotherapy arm with a median of 15 doses (range: 1 to
38).1,2 The co-primary endpoints were PFS and OS; the study is
ongoing and patients continue to be followed for OS.2
Results from the trial demonstrated a statistically significant
improvement in PFS in patients with advanced melanoma treated with
the Opdivo + Yervoy Regimen (p<0.0001) and with Opdivo as a
single-agent (p<0.0001) vs. Yervoy monotherapy.1 Median PFS was
11.5 months (95% CI: 8.9-16.7) for the Opdivo +
Yervoy Regimen and 6.9 months (95% CI: 4.3-9.5)
for Opdivo monotherapy, vs. 2.9 months (95% CI: 2.8-3.4)
for Yervoy monotherapy.1 The Opdivo + Yervoy Regimen
demonstrated a 58% reduction in the risk of disease progression
vs. Yervoy (HR: 0.42; 95% CI: 0.34-0.51; p<0.0001),
while Opdivo monotherapy demonstrated a 43% risk reduction
vs. Yervoy monotherapy (HR: 0.57; 95% CI: 0.47-0.69;
p<0.0001).1
In addition, the Opdivo + Yervoy Regimen
and Opdivo monotherapy demonstrated higher confirmed
objective response rates (ORR; 50% and 40%; p<0.0001,
respectively) vs. Yervoy monotherapy (14%).1 The
percentage of patients with a complete response was 8.9%, 8.5% and
1.9%, favoring the Regimen and Opdivo monotherapy over
Yervoy monotherapy.1 Partial responses were seen in 41% of
patients treated with the Opdivo + Yervoy Regimen, 31% of patients
treated with Opdivo monotherapy, and 12% of patients treated with
Yervoy monotherapy. The Opdivo + Yervoy Regimen delivered durable
responses, with three of four (76%) patients experiencing an
ongoing response of at least six months (range: 1.2+ to 15.8+).1 Of
patients in the Opdivo monotherapy and Yervoy monotherapy arms, 74%
and 63% experienced an ongoing response of at least six months,
respectively (ranges: 1.3+ to 14.6+; 1.0+ to 13.8+).1
“The melanoma community is excited to see the ongoing
developments in research from the pharmaceutical industry,
including Bristol-Myers Squibb, who made the first approved
combination of two Immuno-Oncology treatments available to more
patients fighting this disease,” said Tim Turnham, Executive
Director, Melanoma Research Foundation. “Today’s expanded approvals
continue to bring new treatment options to patients, and
demonstrate the ongoing impact of Immuno-Oncology research.”
In CheckMate -067, serious adverse reactions (73% and 37%),
adverse reactions leading to discontinuation (43% and 14%), or to
dosing delays (55% and 28%), and Grade 3 or 4 adverse reactions
(72% and 44%) all occurred more frequently in the Opdivo + Yervoy
arm relative to the Opdivo arm.1 No overall differences in safety
or efficacy were reported between elderly and younger patients.1
The most common adverse reactions leading to discontinuation of the
Opdivo + Yervoy Regimen relative to Opdivo as a single-agent
were diarrhea (8% and 1.9%), colitis (8% and 0.6%), increased ALT
(4.8% and 1.3%), increased AST (4.5% and. 0.6%), and pneumonitis
(1.9% and 0.3%).1 The most frequent (≥10%) serious adverse
reactions in the Opdivo + Yervoy arm and the Opdivo arm,
respectively, were diarrhea (13% and 2.6%), colitis (10% and 1.6%)
and pyrexia (10% and 0.6%).1 The most common adverse reactions
(≥20%) reported in patients receiving the Opdivo + Yervoy
Regimen relative to Opdivo as a single-agent were fatigue (59% and
53%), rash (53% and 40%), diarrhea (52% and 31%), and nausea (40%
and 28%).1 Pyrexia (37%), vomiting (28%) and dyspnea (20%) were
also reported in ≥20% of patients receiving the Opdivo +
Yervoy Regimen.1
About
the Opdivo + Yervoy Regimen
The scientific rationale for targeting the immune system via
dual immune checkpoint inhibition in cancer has formed the basis of
a novel approach to the treatment of metastatic melanoma.2
Cancer cells may exploit “regulatory” pathways, such as
checkpoint pathways, to hide from the immune system and shield the
tumor from immune attack.2 Opdivo and Yervoy are
immune checkpoint inhibitors that target separate, distinct and
complementary checkpoint pathways (PD-1 and CTLA-4).1 The
mechanism of action involves dual immune checkpoint inhibition
resulting in increased anti-tumor
activity.1 Yervoy blockade of CTLA-4 has been shown to
augment T-cell activation and
proliferation, while Opdivo restores the active
T-cell response directed at the tumor.1,3 This may affect healthy
cells and result in immune-mediated adverse reactions, which can be
severe and potentially fatal.1
Bristol-Myers Squibb has a broad, global development program to
study the combination
of Opdivo and Yervoy consisting of more than 14
trials in which more than 2,000 patients have been enrolled
worldwide through September 2015.
About Opdivo
Cancer cells may exploit “regulatory” pathways, such as
checkpoint pathways, to hide from the immune system and shield the
tumor from immune attack.3 Opdivo’s broad global development
program is based on Bristol-Myers Squibb’s understanding of the
biology behind Immuno-Oncology. This scientific expertise serves as
the basis for the Opdivo development program, which includes a
broad range of Phase 3 clinical trials across a variety of tumor
types. To date, the Opdivo clinical development program has
enrolled more than 18,000 patients.
Opdivo was the first PD-1 immune checkpoint inhibitor to receive
regulatory approval anywhere in the world in July 2014, and
currently has regulatory approval in 46 countries including the
United States, Japan, and in the European Union.
About Metastatic
Melanoma
Melanoma is a form of skin cancer characterized by the
uncontrolled growth of pigment-producing cells (melanocytes)
located in the skin.3 Metastatic melanoma is the deadliest
form of the disease, and occurs when cancer spreads beyond the
surface of the skin to other organs.3 The incidence of
melanoma has been increasing for at least 30
years.3 Approximately 73,870 melanoma cases were estimated to
be diagnosed in the U.S. in 2015.3 Melanoma is mostly curable
when treated in its early stages.3 However, in its late
stages, 5-year and 10-year survival rates in the U.S. average
15-20% and 10-15%, respectively.3
About Bristol-Myers Squibb’s Patient
Support Programs
Bristol-Myers Squibb remains committed to helping patients
through treatment with our medicines. 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
the Opdivo + Yervoy Regimen 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 specific reimbursement information,
please visit the BMS Access Support Product section by
visiting www.bmsaccesssupportopdivo.com.
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 BRAF V600 mutation-positive unresectable
or metastatic melanoma. This indication is approved under
accelerated approval based on progression-free survival. Continued
approval for this indication may be contingent upon demonstration
of clinical benefit in confirmatory trials.
OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab),
is indicated for the treatment of patients with unresectable or
metastatic melanoma. This indication is approved under accelerated
approval based on progression-free survival. Continued approval for
this indication may be contingent upon demonstration of clinical
benefit in 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.
OPDIVO® (nivolumab) is indicated for the treatment of
patients with advanced renal cell carcinoma (RCC) who have received
prior anti-angiogenic therapy.
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, 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 069 and 067,
immune-mediated pneumonitis occurred in 6% (25/407) of patients
receiving OPDIVO with YERVOY: Fatal (n=1), Grade 3 (n=6), Grade 2
(n=17), and Grade 1 (n=1). In Checkmate 037, 066, and 067,
immune-mediated pneumonitis occurred in 1.8% (14/787) of patients
receiving OPDIVO: Grade 3 (n=2) and Grade 2 (n=12). 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 025, pneumonitis,
including interstitial lung disease, occurred in 5% (21/406) of
patients receiving OPDIVO and 18% (73/397) of patients receiving
everolimus. Immune-mediated pneumonitis occurred in 4.4% (18/406)
of patients receiving OPDIVO: Grade 4 (n=1), Grade 3 (n=4), Grade 2
(n=12), and Grade 1 (n=1).
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. When administered with YERVOY, withhold OPDIVO
for Grade 2 and permanently discontinue for Grade 3 or 4 or
recurrent colitis upon restarting OPDIVO. In Checkmate 069 and 067,
diarrhea or colitis occurred in 56% (228/407) of patients receiving
OPDIVO with YERVOY. Immune-mediated colitis occurred in 26%
(107/407) of patients: Grade 4 (n=2), Grade 3 (n=60), Grade 2
(n=32), and Grade 1 (n=13). In Checkmate 037, 066, and 067,
diarrhea or colitis occurred in 31% (242/787) of patients receiving
OPDIVO. Immune-mediated colitis occurred in 4.1% (32/787) of
patients: Grade 3 (n=20), Grade 2 (n=10), and Grade 1 (n=2). 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 025, diarrhea or colitis occurred in 25%
(100/406) of patients receiving OPDIVO and 32% (126/397) of
patients receiving everolimus. Immune-mediated diarrhea or colitis
occurred in 3.2% (13/406) of patients receiving OPDIVO: Grade 3
(n=5), Grade 2 (n=7), and Grade 1 (n=1).
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 069 and 067, immune-mediated hepatitis occurred in 13%
(51/407) of patients receiving OPDIVO with YERVOY: Grade 4 (n=8),
Grade 3 (n=37), Grade 2 (n=5), and Grade 1 (n=1). In Checkmate 037,
066, and 067, immune-mediated hepatitis occurred in 2.3% (18/787)
of patients receiving OPDIVO: Grade 4 (n=3), Grade 3 (n=11), and
Grade 2 (n=4). In Checkmate 057, one patient (0.3%) developed
immune-mediated hepatitis. In Checkmate 025, there was an increased
incidence of liver test abnormalities compared to baseline in AST
(33% vs 39%), alkaline phosphatase (32% vs 32%), ALT (22% vs 31%),
and total bilirubin (9% vs 3.5%) in the OPDIVO and everolimus arms,
respectively. Immune-mediated hepatitis requiring systemic
immunosuppression occurred in 1.5% (6/406) of patients receiving
OPDIVO: Grade 3 (n=5) and Grade 2 (n=1).
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
1 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 1 diabetes. Withhold OPDIVO for Grade 3 and permanently
discontinue for Grade 4 hyperglycemia.
In Checkmate 069 and 067, hypophysitis occurred in 9% (36/407)
of patients receiving OPDIVO with YERVOY: Grade 3 (n=8), Grade 2
(n=25), and Grade 1 (n=3). In Checkmate 037, 066, and 067,
hypophysitis occurred in 0.9% (7/787) of patients receiving OPDIVO:
Grade 3 (n=2), Grade 2 (n=3), and Grade 1 (n=2). In Checkmate 025,
hypophysitis occurred in 0.5% (2/406) of patients receiving OPDIVO:
Grade 3 (n=1) and Grade 1 (n=1). In Checkmate 069 and 067, adrenal
insufficiency occurred in 5% (21/407) of patients receiving OPDIVO
with YERVOY: Grade 4 (n=1), Grade 3 (n=7), Grade 2 (n=11), and
Grade 1 (n=2). In Checkmate 037, 066, and 067, adrenal
insufficiency occurred in 1% (8/787) of patients receiving OPDIVO:
Grade 3 (n=2), Grade 2 (n=5), and Grade 1 (n=1). In Checkmate 057,
0.3% (1/287) of OPDIVO-treated patients developed adrenal
insufficiency. In Checkmate 025, adrenal insufficiency occurred in
2.0% (8/406) of patients receiving OPDIVO: Grade 3 (n=3), Grade 2
(n=4), and Grade 1 (n=1). In Checkmate 069 and 067, hypothyroidism
or thyroiditis occurred in 22% (89/407) of patients receiving
OPDIVO with YERVOY: Grade 3 (n=6), Grade 2 (n=47), and Grade 1
(n=36). Hyperthyroidism occurred in 8% (34/407) of patients: Grade
3 (n=4), Grade 2 (n=17), and Grade 1 (n=13). In Checkmate 037, 066,
and 067, hypothyroidism or thyroiditis occurred in 9% (73/787) of
patients receiving OPDIVO: Grade 3 (n=1), Grade 2 (n=37), Grade 1
(n=35). Hyperthyroidism occurred in 4.4% (35/787) of patients
receiving OPDIVO: Grade 3 (n=1), Grade 2 (n=12), and Grade 1
(n=22). In Checkmate 057, Grade 1 or 2 hypothyroidism, including
thyroiditis, occurred in 7% (20/287) and elevated thyroid
stimulating hormone occurred in 17% of patients receiving OPDIVO.
Grade 1 or 2 hyperthyroidism occurred in 1.4% (4/287) of patients.
In Checkmate 025, thyroid disease occurred in 11% (43/406) of
patients receiving OPDIVO, including one Grade 3 event, and in 3.0%
(12/397) of patients receiving everolimus.
Hypothyroidism/thyroiditis occurred in 8% (33/406) of patients
receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=17), and Grade 1
(n=14). Hyperthyroidism occurred in 2.5% (10/406) of patients
receiving OPDIVO: Grade 2 (n=5) and Grade 1 (n=5). In Checkmate 069
and 067, diabetes mellitus or diabetic ketoacidosis occurred in
1.5% (6/407) of patients: Grade 4 (n=3), Grade 3 (n=1), Grade 2
(n=1), and Grade 1 (n=1). In Checkmate 037, 066, and 067, diabetes
mellitus or diabetic ketoacidosis occurred in 0.8% (6/787) of
patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=3), and Grade
1 (n=1). In Checkmate 025, hyperglycemic adverse events occurred in
9% (37/406) patients. Diabetes mellitus or diabetic ketoacidosis
occurred in 1.5% (6/406) of patients receiving OPDIVO: Grade 3
(n=3), Grade 2 (n=2), and Grade 1 (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 069 and 067, immune-mediated
nephritis and renal dysfunction occurred in 2.2% (9/407) of
patients: Grade 4 (n=4), Grade 3 (n=3), and Grade 2 (n=2). In
Checkmate 037, 066, and 067, nephritis and renal dysfunction of any
grade occurred in 5% (40/787) of patients receiving OPDIVO.
Immune-mediated nephritis and renal dysfunction occurred in 0.8%
(6/787) of patients: Grade 3 (n=4) and Grade 2 (n=2). In Checkmate
057, Grade 2 immune-mediated renal dysfunction occurred in 0.3%
(1/287) of patients receiving OPDIVO. In Checkmate 025, renal
injury occurred in 7% (27/406) of patients receiving OPDIVO and
3.0% (12/397) of patients receiving everolimus. Immune-mediated
nephritis and renal dysfunction occurred in 3.2% (13/406) of
patients receiving OPDIVO: Grade 5 (n=1), Grade 4 (n=1), Grade 3
(n=5), and Grade 2 (n=6).
Immune-Mediated Rash
Immune-mediated rash can occur with OPDIVO treatment. Severe
rash (including rare cases of fatal toxic epidermal necrolysis)
occurred in the clinical program of OPDIVO. Monitor patients for
rash. Administer corticosteroids for Grade 3 or 4 rash. Withhold
for Grade 3 and permanently discontinue for Grade 4. In Checkmate
069 and 067, immune-mediated rash occurred in 22.6% (92/407) of
patients receiving OPDIVO with YERVOY: Grade 3 (n=15), Grade 2
(n=31), and Grade 1 (n=46). In Checkmate 037, 066, and 067,
immune-mediated rash occurred in 9% (72/787) of patients receiving
OPDIVO: Grade 3 (n=7), Grade 2 (n=15), and Grade 1 (n=50). In
Checkmate 057, immune-mediated rash occurred in 6% (17/287) of
patients receiving OPDIVO including four Grade 3 cases. In
Checkmate 025, rash occurred in 28% (112/406) of patients receiving
OPDIVO and 36% (143/397) of patients receiving everolimus.
Immune-mediated rash, defined as a rash treated with systemic or
topical corticosteroids, occurred in 7% (30/406) of patients
receiving OPDIVO: Grade 3 (n=4), Grade 2 (n=7), 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. In
Checkmate 067, encephalitis was identified in one patient (0.2%)
receiving OPDIVO with YERVOY. 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. In < 1.0% of patients receiving OPDIVO, the following
clinically significant, immune-mediated adverse reactions occurred:
uveitis, pancreatitis, facial and abducens nerve paresis,
demyelination, polymyalgia rheumatica, autoimmune neuropathy,
Guillain-Barré syndrome, hypopituitarism, systemic inflammatory
response syndrome, gastritis, duodenitis, and sarcoidosis. Across
clinical trials of OPDIVO as a single agent administered at doses
of 3 mg/kg and 10 mg/kg, additional clinically significant,
immune-mediated adverse reactions were identified: motor
dysfunction, vasculitis, and myasthenic syndrome.
Infusion Reactions
Severe infusion reactions have been reported in <1.0% of
patients in clinical trials of OPDIVO. 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
069 and 067, infusion- related reactions occurred in 2.5% (10/407)
of patients receiving OPDIVO with YERVOY: Grade 2 (n=6) and Grade 1
(n=4). In Checkmate 037, 066, and 067, Grade 2 infusion related
reactions occurred in 2.7% (21/787) of patients receiving OPDIVO:
Grade 3 (n=2), Grade 2 (n=8), and Grade 1 (n=11). In Checkmate 057,
Grade 2 infusion reactions requiring corticosteroids occurred in
1.0% (3/287) of patients receiving OPDIVO. In Checkmate 025,
hypersensitivity/infusion-related reactions occurred in 6% (25/406)
of patients receiving OPDIVO and 1.0% (4/397) of patients receiving
everolimus.
Embryo-fetal 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 an 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 067, serious adverse reactions (73% and 37%),
adverse reactions leading to permanent discontinuation (43% and
14%) or to dosing delays (55% and 28%), and Grade 3 or 4 adverse
reactions (72% and 44%) all occurred more frequently in the OPDIVO
plus YERVOY arm relative to the OPDIVO arm. The most frequent
(≥10%) serious adverse reactions in the OPDIVO plus YERVOY arm and
the OPDIVO arm, respectively, were diarrhea (13% and 2.6%), colitis
(10% and 1.6%), and pyrexia (10% and 0.6%). 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 025, serious adverse reactions occurred in 47% of
patients receiving OPDIVO. The most frequent serious adverse
reactions reported in ≥2% of patients were acute kidney injury,
pleural effusion, pneumonia, diarrhea, and hypercalcemia.
Common Adverse Reactions
In Checkmate 067, the most common (≥20%) adverse reactions in
the OPDIVO plus YERVOY arm were fatigue (59%), rash (53%), diarrhea
(52%), nausea (40%), pyrexia (37%), vomiting (28%), and dyspnea
(20%). The most common (≥20%) adverse reactions in the OPDIVO arm
were fatigue (53%), rash (40%), diarrhea (31%), and nausea (28%).
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 025, the most common
adverse reactions (≥20%) reported in patients receiving OPDIVO vs
everolimus were asthenic conditions (56% vs 57%), cough (34% vs
38%), nausea (28% vs 29%), rash (28% vs 36%), dyspnea (27% vs 31%),
diarrhea (25% vs 32%), constipation (23% vs 18%), decreased
appetite (23% vs 30%), back pain (21% vs 16%), and arthralgia (20%
vs 14%).
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 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 our social channels:
- Twitter:
https://twitter.com/bmsnews
- LinkedIn:
https://www.linkedin.com/company/bristol-myers-squibb
- YouTube:
https://www.youtube.com/channel/UCjFf4oKibYrHae2NZ_GPS6g
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.
References
1. Opdivo Prescribing Information. Opdivo
U.S. Product Information. Last updated: January 23, 2016.
Princeton, NJ: Bristol-Myers Squibb Company.2. Larkin J,
Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and
ipilimumab or monotherapy in untreated melanoma. N Engl J Med.
2015;373(1):23-34.3. American Cancer Society. Melanoma Skin Cancer.
http://www.cancer.org/acs/groups/cid/documents/webcontent/003120-pdf.pdf.
Updated November 10, 2015. Accessed January 20, 2016.
View source
version on businesswire.com: http://www.businesswire.com/news/home/20160123005053/en/
Bristol-Myers Squibb CompanyMedia:Jaisy Wagner Styles,
609-897-3958Cell: 610-291-5168jaisy.styles@bms.comorInvestors:Ranya
Dajani, 609-252-5330ranya.dajani@bms.comBill Szablewski,
609-252-5894william.szablewski@bms.com
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