Opdivo and Yervoy combination regimen showed
two-year overall survival rate of 69% in an exploratory analysis of
patients with BRAF wild-type advanced melanoma in CheckMate -069;
with 22% of patients achieving a complete response
Safety profile of the combination regimen
from CheckMate -069 was consistent with previously reported studies
and adverse events were managed using established safety
algorithms
Data from study CA209-003, also to be
presented, showed a five-year overall survival rate of 34% with
Opdivo monotherapy in heavily pretreated advanced melanoma
patients
Bristol-Myers Squibb Company (NYSE:BMY) announced today first
time presentation of overall survival data from CheckMate -069, a
Phase 2 trial and the first randomized study to evaluate the Opdivo
and Yervoy combination regimen in patients with previously
untreated advanced melanoma. In the trial, the Opdivo and Yervoy
combination regimen demonstrated a two-year overall survival (OS)
rate of 69% compared to 53% for Yervoy alone (HR=0.58 [95% CI:
0.31-1.08]) in patients with BRAF wild-type advanced melanoma.
Overall survival was an exploratory endpoint in this trial. The
safety profile of the Opdivo and Yervoy combination regimen in this
study was consistent with previously reported studies. These data
will be presented today as an oral presentation at the American
Association for Cancer Research (AACR) 2016 Annual Meeting during
the Immuno-Oncology Clinical Trials I Plenary Session from 2:15 –
4:00 P.M. CT in New Orleans, Louisiana (Late-Breaking and Clinical
Trial Abstract #CT002).
Bristol-Myers Squibb is also presenting extended follow-up data,
including five-year OS rates, from the Phase 1 dose escalation
study, CA209-003, evaluating Opdivo monotherapy in heavily
pretreated advanced melanoma patients. These data represent the
longest survival follow-up of patients who received an anti-PD-1
therapy in a clinical trial. At five years, patients who received
Opdivo showed an OS rate of 34%, with an evident plateau in
survival at approximately four years. The safety profile of Opdivo
in study -003 was similar to previously reported studies, with no
new safety signals identified. These data were featured during the
Congress’ official press program today at 12:30 P.M. CT, and will
be presented as an oral presentation during the Immuno-Oncology
Clinical Trials I Plenary Session from 2:15 – 4:00 P.M. CT
(Late-Breaking and Clinical Trial Abstract #CT001).
“The data from CheckMate -069 and study -003 showed durable
responses for some patients with advanced melanoma using new
Immuno-Oncology approaches. These data contribute to our growing
understanding of this aggressive cancer and are promising news
for advanced melanoma patients. In particular, we are seeing
further data that evaluate the potential survival benefit of the
nivolumab and ipilimumab combination,” said F. Stephen Hodi, M.D.,
director of the Melanoma Center at Dana-Farber Cancer Institute and
associate professor of medicine at Harvard Medical School.
Melanoma continues to be the most aggressive and deadliest form
of skin cancer, with an increase in global incidence rates over the
last 30 years. Despite advances in treatment, patients with
advanced stages of the disease have lower survival rates, with a
five-year survival of 15% - 20% for Stage IV disease.
Jean Viallet, M.D., Global Clinical Research Lead, Oncology,
Bristol-Myers Squibb, commented, “We are encouraged to see that the
Opdivo and Yervoy combination showed improvement in overall
survival versus Yervoy alone based on two-year follow-up from
CheckMate -069, the registrational study of the combination
regimen. These data further validate our scientific rationale for
studying the combination of these Immuno-Oncology agents.
Additionally, study -003 shows five-year overall survival with
Opdivo monotherapy in heavily pretreated advanced melanoma
patients. These data provide important information about the
possible role of Opdivo as a single agent in improving long-term
survival for these patients.”
About CheckMate -069
CheckMate -069 is a Phase 2, double-blind, randomized study
which evaluated 142 patients with previously untreated unresectable
or metastatic melanoma who received either the Opdivo and Yervoy
combination regimen (n=95) or Yervoy alone (n=47). The trial
included patients with BRAF wild-type and BRAF V600
mutation-positive melanoma, and randomization was stratified by
BRAF mutation status. The primary endpoint was objective response
rate (ORR) in patients with BRAF wild-type tumors. Secondary
endpoints included progression-free survival (PFS) in patients with
BRAF wild-type tumors, ORR in patients with BRAF V600 mutation
positive tumors, and safety. Overall survival (OS) was an
exploratory endpoint.
In the trial, the combination of Opdivo and Yervoy demonstrated
a clinically meaningful improvement in survival at two years with
an OS rate of 69% compared to 53% for Yervoy alone in patients with
BRAF wild-type advanced melanoma (HR=0.58 [95% CI: 0.31-1.08]),
with a minimum follow-up of 24 months. Similar results were
observed in the overall study population, with an OS rate of 64% at
two years for the Opdivo and Yervoy combination regimen compared to
54% for Yervoy alone (HR=0.74 [95% CI: 0.43-1.26]). Per the study
protocol, patients who did not respond to treatment or experienced
disease progression after treatment received subsequent therapies,
including 55% of patients in the Yervoy monotherapy arm who crossed
over to receive Opdivo monotherapy. A change in tumor burden was
seen with the Opdivo and Yervoy combination regimen, with a median
change of 70% decrease in tumor burden compared to a 5% increase
for Yervoy alone.
At two years of follow-up, median duration of response was not
reached in both arms, with ongoing responses seen in 80% of
responders. Progression-free survival at two years was
significantly longer with the Opdivo and Yervoy combination regimen
(n=72) compared to Yervoy alone (n=37). In patients with BRAF
wild-type advanced melanoma, median PFS has not been reached
(8.6-NR) compared to 4.4 months (2.8-5.3) for Yervoy alone (HR=0.35
[95% CI: 0.21-0.59; p<0.0001]), with a two-year PFS rate of 54%
with the Opdivo and Yervoy combination regimen vs. 11% for Yervoy
alone. In all randomized patients, median PFS has also not been
reached (7.36-NR) in patients treated with the Opdivo and Yervoy
combination regimen vs. 3.0 months (2.7-5.1) for patients treated
with Yervoy alone, with a two-year PFS rate of 51% vs. 12%,
respectively. Similar efficacy was seen regardless of PD-L1
expression at 5% across endpoints with the Opdivo and Yervoy
combination regimen.
As reported last year at AACR, and with a minimum follow-up of
11 months, the Opdivo and Yervoy combination regimen demonstrated
improved ORR in both BRAF wild-type and BRAF V600 mutation-positive
advanced melanoma compared to Yervoy alone. In patients with BRAF
wild-type advanced melanoma, ORR in the combination regimen arm was
61% with 22% of patients achieving a complete response and 39%
achieving a partial response, compared to 11% ORR in the Yervoy
monotherapy arm with 0% of patients achieving a complete response
and 11% of patients achieving a partial response. In all randomized
patients, ORR in the combination regimen arm was 59% with 22% of
patients achieving a complete response and 37% of patients
achieving a partial response, compared to 11% in the Yervoy
monotherapy arm with 0% of patients achieving a complete response
and 11% of patients achieving a partial response.
The safety profile of the combination of Opdivo and Yervoy in
this updated analysis of CheckMate -069 was consistent with
previously reported studies and most treatment-related select
adverse events (AEs) were treated with immune-modulating
medications. The majority (>85%) of treatment-related select AEs
were managed when immune-modulating medications were utilized,
except for endocrinopathies. Grade 3-4 treatment-related AEs were
reported more frequently with the combination regimen (54%) than
with Yervoy alone (20%). Treatment-related AEs of any grade led to
discontinuation in 37% of patients treated with the combination
regimen and 9% of patients treated with Yervoy alone. Three
treatment-related deaths occurred in the Opdivo and Yervoy
combination regimen arm, which were previously-reported. The most
common treatment-related select AEs of any grade with the
combination regimen vs. Yervoy alone included rash (43% vs. 30%),
pruritus (40% vs. 33%), diarrhea (45% vs. 35%), colitis (18% vs.
7%), hypothyroidism (17% vs. 13%), hypophysitis (13% vs. 7%),
increased ALT (26% vs. 9%), increased AST (28% vs. 9%), pneumonitis
(10% vs. 2%), and increased creatinine (2% vs. 0%).
About Study CA209-003
CA209-003, or study -003, is a Phase 1b, open-label,
multicenter, multidose, dose-escalation study of Opdivo in patients
with select advanced or recurrent malignancies, including
previously treated melanoma. In this study, Yervoy-naïve patients
who had received one to five prior systemic therapies for advanced
melanoma (n=107) were treated with Opdivo (0.1, 0.3, 1, 3 or 10
mg/kg) every two weeks for <96 weeks. Patients were followed for
overall survival (OS), progression-free survival (PFS), long-term
safety, and response duration after discontinuing treatment.
At five years, the OS rate for patients treated with Opdivo was
34% (95% CI: 25-43), with a median OS of 17.3 months (95% CI:
12.5-37.8), with a minimum follow-up of 45 months. In patients
treated with Opdivo 3 mg/kg, median OS was 20.3 months (95% CI:
7.2-NR), with an OS rate of 35% at five years. At the last
timepoint for tumor assessment, PFS rates at 30 months were 26% for
patients who received Opdivo at 3 mg/kg, and 19% for all patients
receiving Opdivo at any dose. Objective response rate (ORR) for
Opdivo 3 mg/kg was 41% with a median duration of response lasting
22 months (9-27+), and the ORR was 32% for all doses with a median
duration of response lasting 23 months (4-32). Of responding
patients, 44% showed a response at first tumor assessment (8
weeks), and responses are ongoing in 41% of responders (14/34).
The safety profile of Opdivo in study -003 was similar to
previously reported studies, with no new safety signals identified.
The most common treatment-related adverse events (AEs) of any grade
in patients treated with Opdivo 3 mg/kg were fatigue (47.1%),
pruritus (17.6%), dermatitis acneiform (17.6%), nausea (17.6%),
lymphopenia (17.6%), infusion-related reactions (17.6%), rash
(11.8%) and diarrhea (11.8%). Adverse reactions leading to
discontinuation occurred in 5.9% of patients treated with Opdivo 3
mg/kg.
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 choice alongside surgery, radiation, chemotherapy
and targeted therapies 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. Our ongoing Immuno-Oncology
clinical program is looking at broad patient populations, across
multiple solid tumors and hematologic malignancies, and lines of
therapy and histologies, with the intent of powering our trials for
overall survival and other important measures like durability of
response. 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.
We are also investigating other immune system pathways in the
treatment of cancer including CTLA-4, CD-137, KIR, SLAMF7, PD-1,
GITR, CSF1R, IDO, and LAG-3. These pathways may lead to potential
new treatment options – in combination or monotherapy – to help
patients fight different types of cancers.
Our collaboration with academia, as well as small and large
biotech companies, to research the potential Immuno-Oncology and
non-Immuno-Oncology combinations, helps achieve our goal of
providing new treatment options in clinical practice.
At Bristol-Myers Squibb, we are committed to changing survival
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 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%).
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 www.BMS.com or
follow us on LinkedIn, Twitter, and YouTube.
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. Among other risks, there can be no guarantee
that Opdivo as a single agent or in combination with Yervoy will
receive regulatory approval for additional indications in advanced
melanoma. 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.
View source
version on businesswire.com: http://www.businesswire.com/news/home/20160417005056/en/
Media:Audrey Abernathy, 609-419-5375, Cell:
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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