Opdivo + Yervoy Regimen now approved for
unresectable or metastatic melanoma patients, regardless of BRAF
mutational status
Approval of the Regimen marks a novel
combination treatment for advanced melanoma patients, demonstrating
the potential of targeting distinct and complementary immune
pathways
With this fifth EU approval for
Opdivo, in three distinct tumor types, more patients fighting
cancer have access to Immuno-Oncology treatment options in
Europe
Bristol-Myers Squibb Company (NYSE:BMY) announced today that the
European Commission (EC) has approved Opdivo in combination with
Yervoy for the treatment of advanced (unresectable or metastatic)
melanoma in adults, representing the first and only approved
combination of two Immuno-Oncology agents in the European Union
(EU). This approval allows for the marketing of the Opdivo + Yervoy
Regimen in all 28 Member States of the EU. Approval was based on
CheckMate -067, the first Phase 3, double-blind, randomized study,
in which the Opdivo + Yervoy Regimen and Opdivo monotherapy
demonstrated superior progression-free survival (PFS) and objective
response rates (ORR) in patients with advanced melanoma, regardless
of BRAF mutational status, versus Yervoy alone. The safety profile
was consistent with previously reported studies evaluating the
Opdivo + Yervoy Regimen, and most treatment-related adverse events
were managed using established algorithms.
Dr. James Larkin, from The Royal Marsden and lead author on
CheckMate - 067, the trial that led to this approval, commented,
“Historically, advanced melanoma has been a very difficult-to-treat
disease. Now, with this approval, patients in Europe will have a
treatment option combining two Immuno-Oncology therapies, Opdivo
and Yervoy, which in a Phase 3 randomized trial has shown its
ability to deliver superior efficacy versus Yervoy monotherapy in
progression-free survival and response. This is truly good news for
healthcare providers and the patients they treat, as it represents
an important new treatment option with the potential for improved
outcomes.”
In study CheckMate -067, the Opdivo + Yervoy Regimen
demonstrated a 58% reduction in the risk of disease progression
versus Yervoy monotherapy in previously untreated
patients with advanced melanoma (HR=0.42 [99.5% CI: 0.32-0.56;
p<0.0001]), while Opdivo monotherapy demonstrated a 45% risk
reduction versus Yervoy monotherapy (HR=0.55 [99.5% CI:
0.42-0.73; p<0.0001]). The median PFS for the Opdivo + Yervoy
Regimen was 11.5 months (95% CI: 8.9-22.18) and 6.9 months (95% CI:
4.3-9.5) for Opdivo monotherapy versus 2.89 months (95% CI:
2.8-3.4) for Yervoy monotherapy, at a minimum follow-up of 18
months. The Opdivo + Yervoy Regimen and Opdivo monotherapy also
demonstrated a higher ORR (ORR: 58% and 44%, p<0.0001,
respectively) versus Yervoy monotherapy (19%). Median duration of
response was not reached for the Opdivo + Yervoy Regimen and was
22.3 months for Opdivo monotherapy, versus 14.4 months for Yervoy
alone.
Based on a pre-planned, descriptive analysis of data from
CheckMate -067, the EC adopted the Committee for Medicinal Products
for Human Use (CHMP) recommendation to add an informative statement
to the broad indication that relative to Opdivo monotherapy, an
increase in PFS for the combination of Opdivo with Yervoy is
established only in patients with low tumor PD-L1 expression. In
the study, overall response rates were higher for the combination
of Opdivo and Yervoy relative to Opdivo monotherapy across tumor
PD-L1 expression levels.
The approval was also based on supportive data from the Phase 2
study, CheckMate -069, in which the Opdivo + Yervoy Regimen
demonstrated an ORR, the primary endpoint, of 61% (95% CI:
48.9-72.4) in patients with BRAF wild-type advanced melanoma,
versus 11% (95% CI: 3-25.4) ORR in the Yervoy monotherapy arm, with
a minimum follow-up of 11 months. The estimated 12- and 18-month
overall survival (OS) rates were 79% (95% CI: 67, 87) and 73% (95%
CI: 61, 82), respectively, for the Opdivo + Yervoy Regimen, and 62%
(95% CI: 44, 75) and 56% (95% CI: 39, 70), respectively, for Yervoy
monotherapy. The OS data are based on an exploratory, pre-planned
analysis of patients with BRAF wild-type advanced melanoma.
Emmanuel Blin, senior vice president, Head of Commercialization,
Policy and Operations, Bristol-Myers Squibb, commented, “Today’s
approval of the Opdivo + Yervoy Regimen for advanced melanoma
patients supports our goal of developing innovative treatment
approaches that have the potential to improve patient outcomes. The
Opdivo + Yervoy Regimen is the first and only approved
Immuno-Oncology combination, and only Regimen to deliver superior
efficacy compared to Yervoy, and we are thrilled to make this novel
combination treatment available to patients with advanced melanoma
in Europe.”
Approval Based on Superior Efficacy
Demonstrated Versus Yervoy In Pivotal Phase 3 Study
CheckMate -067 is a Phase 3, double-blind, randomized study that
evaluated the Opdivo + Yervoy Regimen or Opdivo monotherapy versus
Yervoy alone in patients with previously untreated advanced
melanoma, including both BRAF V600 mutation positive or BRAF
wild-type advanced melanoma. A total of 945 patients 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). Randomization was stratified by PD-L1 expression (≥5% vs.
<5%), BRAF status, and M stage per the American Joint Committee
on Cancer (AJCC) staging system. Patients were treated until
progression or unacceptable toxicity. The co-primary endpoints were
progression-free survival (PFS) and overall survival (OS); the
study is ongoing and patients continue to be followed for OS.
Objective response rate (ORR) and the duration of response were
also assessed.
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) versus Yervoy monotherapy. At a minimum
follow-up of 18 months, the Opdivo + Yervoy Regimen demonstrated a
58% reduction in the risk of disease progression
versus Yervoy monotherapy in previously untreated
patients with advanced melanoma (HR=0.42 [99.5% CI: 0.32-0.56;
p<0.0001]), while Opdivo monotherapy demonstrated a 45% risk
reduction versus Yervoy monotherapy (HR=0.55 [99.5% CI:
0.42-0.73; p<0.0001]). The median PFS for the Opdivo + Yervoy
Regimen was 11.5 months (95% CI: 8.9-22.18) and 6.9 months (95% CI:
4.3-9.5) for Opdivo monotherapy versus 2.89 months (95% CI:
2.8-3.4) for Yervoy monotherapy, at a minimum follow-up of 18
months.
The Opdivo + Yervoy Regimen and Opdivo monotherapy also
demonstrated a higher ORR (ORR: 58% and 44%, p<0.0001,
respectively) versus Yervoy monotherapy (19%). There were 38 (12%)
complete responses and 143 (46%) partial responses seen in patients
treated with the Opdivo + Yervoy Regimen, and 31 (10%) complete
responses and 107 (34%) partial responses seen in patients treated
with Opdivo monotherapy, versus 7 (2%) complete responses and 53
(17%) partial responses seen in patients treated with Yervoy alone.
Median duration of response was not reached (0+ - 24+ months) for
the Opdivo + Yervoy Regimen and was 22.3 months (0+ - 23+) for
Opdivo monotherapy, versus 14.4 months (1.4 - 22.3+) for Yervoy
alone.
CheckMate -069 is a Phase 2, double-blind, randomized study
evaluating the Opdivo + Yervoy Regimen versus Yervoy monotherapy in
142 patients with previously untreated unresectable or metastatic
melanoma. The trial included patients with BRAF V600 mutation
positive and BRAF wild-type advanced melanoma, and randomization
was stratified by BRAF mutation status. The primary endpoint was
ORR in patients with BRAF wild-type tumors. Secondary endpoints
included PFS in patients with BRAF wild-type tumors, ORR in
patients with BRAF V600 mutation positive tumors and safety.
Overall survival was an exploratory endpoint. Treatment was
continued until progression or unacceptable toxicity. In this
study, the Opdivo + Yervoy Regimen demonstrated a response rate of
61% (95% CI: 48.9-72.4) in patients with BRAF wild-type advanced
melanoma, versus 11% (95% CI: 3-25.4) ORR in the Yervoy monotherapy
arm, with a minimum follow-up of 11 months. The estimated 12- and
18-month OS rates were 79% (95% CI: 67, 87) and 73% (95% CI: 61,
82), respectively, for the Opdivo + Yervoy Regimen, and 62% (95%
CI: 44, 75) and 56% (95% CI: 39, 70), respectively, for Yervoy.
In a pooled dataset of the Opdivo + Yervoy Regimen, based on
three studies of the combination, the most frequent adverse
reactions (≥10%) were rash (51%), fatigue (43%), diarrhea (42%),
pruritus (35%), nausea (25%), pyrexia (19%), decreased appetite
(15%), hypothyroidism (15%), vomiting (14%), colitis (14%),
abdominal pain (13%), anthralgia (11%) and headache (11%). The
majority of adverse reactions were mild to moderate (Grade 1 or 2).
Among the patients treated with Opdivo in combination with Yervoy
in CheckMate -067, 151/313 (48%) had the first onset of
Grade 3 or 4 adverse reactions during the initial
combination phase. Among the 147 patients in this group who
continued treatment in the single-agent phase,
37 (25%) experienced at least one
Grade 3 or 4 adverse reaction during the
single-agent phase.
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. Melanoma is the ninth most common
cancer in Europe, with an estimated 100,000 new cases diagnosed
annually and more than 20,000 deaths.
Bristol-Myers Squibb &
Immuno-Oncology: Advancing Oncology Research
At Bristol-Myers Squibb, we have a vision for the future of
cancer care that is focused on Immuno-Oncology, now considered a
major treatment modality alongside surgery, radiation and
chemotherapy for certain types of cancer.
We have a comprehensive clinical portfolio of investigational
and approved Immuno-Oncology agents, many of which were discovered
and developed by our scientists. We pioneered the research leading
to the first regulatory approval for the combination of two
Immuno-Oncology agents, and continue to study the role of
combinations in cancer.
Our collaboration with academia, as well as small and large
biotech companies is responsible for researching the potential of
Immuno-Oncology and non-Immuno-Oncology combinations, with the goal
of providing new treatment options in clinical practice.
At Bristol-Myers Squibb, we are committed to changing
expectations in hard-to-treat cancers and the way patients live
with cancer.
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. Opdivo is a PD-1 immune checkpoint
inhibitor that binds to the checkpoint receptor PD-1 expressed on
activated T-cells, and blocks the binding of PD-L1 and PD-L2,
preventing the PD-1 pathway’s suppressive signaling on the immune
system, including the interference with an anti-tumor immune
response.
Opdivo’s broad global development program is based on
Bristol-Myers Squibb’s understanding of the biology behind
Immuno-Oncology. Our company is at the forefront of researching the
potential of Immuno-Oncology to extend survival in hard-to-treat
cancers. This scientific expertise serves as the basis for the
Opdivo development program, which includes a broad range of Phase 3
clinical trials evaluating overall survival as the primary endpoint
across a variety of tumor types. The Opdivo trials have also
contributed toward the clinical and scientific understanding of the
role of biomarkers and how patients may benefit from Opdivo across
the continuum of PD-L1 expression. 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 50 countries including the
United States, Japan, and in the European Union.
U.S. FDA APPROVED
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 verification
and description 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 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.
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%).
About the Bristol-Myers Squibb and Ono
Pharmaceutical Co., Ltd. Collaboration
In 2011, through a collaboration agreement with Ono
Pharmaceutical Co., Ltd (Ono) 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 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 us at BMS.com or
follow us on LinkedIn, Twitter, YouTube and Facebook.
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,
2015 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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version on businesswire.com: http://www.businesswire.com/news/home/20160511006116/en/
Bristol-Myers SquibbMedia:Audrey Abernathy,
609-419-5375cell:
919-605-4521audrey.abernathy@bms.comorInvestors:Ranya
Dajani, 609-252-5330ranya.dajani@bms.comorBill Szablewski,
609-252-5894william.szablewski@bms.com
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