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
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Bristol-Myers Squibb Forward-Looking Statement
This press release contains "forward-looking statements" as that term
is defined in the Private Securities Litigation Reform Act of 1995
regarding the research, development and commercialization of
pharmaceutical products. Such forward-looking statements are based on
current expectations and involve inherent risks and uncertainties,
including factors that could delay, divert or change any of them, and
could cause actual outcomes and results to differ materially from
current expectations. No forward-looking statement can be guaranteed.
Forward-looking statements in this press release should be evaluated
together with the many uncertainties that affect Bristol-Myers Squibb's
business, particularly those identified in the cautionary factors
discussion in Bristol-Myers Squibb's Annual Report on Form 10-K for the
year ended December 31, 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.
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