Significantly longer progression-free survival and higher
objective response rates with Opdivo and Yervoy combination
and Opdivo monotherapy versus Yervoy alone, with a minimum of
18-month follow-up, from CheckMate -067
In CheckMate -067, median duration of response had not been
reached with the combination regimen, and was 22.3 months for
Opdivo monotherapy and 14.4 months for Yervoy alone
With longer follow-up, the Opdivo and Yervoy
combination regimen had a consistent safety profile with previously
reported studies of the combination
Bristol-Myers Squibb Company (NYSE:BMY) announced today results
from two trials evaluating the Opdivo and Yervoy combination
regimen in advanced melanoma. In the pivotal Phase 3 trial,
CheckMate -067 trial, at a minimum follow-up of 18 months, the
Opdivo and Yervoy combination demonstrated continued clinical
benefit with a 58% reduction in the risk of disease progression
versus Yervoy monotherapy (HR=0.42 [99.5% CI: 0.31-0.57;
p<0.0001]), while Opdivo monotherapy demonstrated a 45% risk
reduction versus Yervoy alone (HR=0.55 [99.5% CI: 0.43-0.76;
p<0.0001]). Durable responses were also observed with the
combination regimen in a subgroup of patients who discontinued
therapy due to treatment-related adverse events (n=35) and appeared
consistent with the overall randomized patient population (n=95),
based on a post-hoc analysis from the Phase 2 study, CheckMate
-069. Among this subgroup of patients, the objective response rate
was 66%, and 20% achieved a complete response, with a minimum
follow-up of two years. At two years, the median duration of
response was not reached and 74% remain in response. The safety
profile of the Opdivo and Yervoy combination regimen in both
CheckMate -067 and -069 was consistent with previously reported
studies of the combination, and most treatment-related adverse
events were managed using established algorithms.
“The data from CheckMate -067 provide new insights on the
long-term durability of the progression-free survival benefit seen
with the nivolumab and ipilimumab combination regimen in advanced
melanoma relative to ipilimumab monotherapy,” said Jedd D. Wolchok,
M.D., Ph.D., Chief, Melanoma and Immunotherapeutics Service,
at Memorial Sloan Kettering Cancer Center. “In addition, in a
post-hoc analysis from CheckMate -069, we observed that even for
patients who discontinue treatment with the combination regimen due
to toxicity, efficacy outcomes appeared consistent with that seen
in the overall study population. These data are encouraging and
provide additional important information about the efficacy and
safety of the combination regimen in these patients.”
The CheckMate -067 data will be presented at the 52nd Annual
Meeting of the American Society of Clinical Oncology (ASCO) in an
oral abstract session on Monday, June 6, from 2:39 PM – 2:51 PM CDT
(Abstract #9505). The CheckMate -069 data were presented in a
poster discussion session on Saturday, June 4 (Abstract #9518).
Vicki Goodman, M.D., Development Lead, Melanoma and
Genitourinary Cancers, Bristol-Myers Squibb, commented, “With the
CheckMate -067 and -069 data presented at ASCO, we observe, with
longer follow-up, the durability of progression-free survival and
response for the Opdivo and Yervoy combination regimen in advanced
melanoma. These findings further validate our research strategy to
study the combination of Immuno-Oncology agents, and we remain
committed to building on this research and evaluating more ways to
improve long-term survival and patient outcomes in advanced
cancers.”
About CheckMate -067
CheckMate -067 is a Phase 3, double-blind, randomized study that
evaluated the Opdivo and Yervoy combination regimen or Opdivo
monotherapy versus Yervoy monotherapy 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 and Yervoy
combination regimen (Opdivo 1 mg/kg plus Yervoy 3 mg/kg every 3
weeks administered intravenously for 4 doses followed by Opdivo 3
mg/kg every 2 weeks thereafter; n=314), Opdivo monotherapy (Opdivo
3 mg/kg every 2 weeks administered intravenously; n=316) or Yervoy
monotherapy (Yervoy 3 mg/kg every 3 weeks administered
intravenously for 4 doses followed by placebo every 2 weeks;
n=315). Patients were treated until progression or unacceptable
toxic effects. Co-primary endpoints were progression-free survival
(PFS) and overall survival (OS); secondary endpoints included PFS
and objective response rate (ORR), as well as safety and
tolerability. The study is ongoing in its evaluation for OS.
At a minimum follow-up of 18 months, the Opdivo and Yervoy
combination 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: 0.31-0.57;
p<0.0001]), while Opdivo monotherapy demonstrated a 45% risk
reduction versus Yervoy monotherapy (HR=0.55 [99.5% CI: 0.43-0.76;
p<0.0001]). At a minimum follow-up of 18 months, the median PFS
for the combination regimen was 11.5 months (95% CI: 8.9-16.7) and
6.9 months (95% CI: 4.3-9.5) for Opdivo monotherapy versus 2.9
months (95% CI: 2.8-3.4) for Yervoy monotherapy. At 18 months, the
PFS rate was 46% for the combination regimen (HR=0.42 [99.5% CI:
0.31-0.57; p<0.00001]), 39% for Opdivo monotherapy (HR=0.55
[99.5% CI: 0.43-0.76; p<0.00001]), and 14% for Yervoy.
The Opdivo and Yervoy combination regimen and Opdivo monotherapy
also demonstrated a higher 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 combination 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.
The median duration of response had not been reached for those
patients treated with the Opdivo and Yervoy combination regimen,
and was 22.3 months for Opdivo monotherapy and 14.4 months for
Yervoy alone. In the study, a change in tumor burden was seen with
the Opdivo and Yervoy combination regimen and Opdivo monotherapy,
with a median decrease of 51.9% and 34.5%, respectively, and 5.9%
increase for Yervoy alone.
As part of a pre-planned, descriptive analysis of data from
CheckMate -067, a greater improvement in PFS for the combination of
Opdivo with Yervoy, relative to Opdivo monotherapy, was only
observed in patients with low tumor PD-L1 expression. Overall
response rates were higher for the combination of Opdivo and Yervoy
relative to Opdivo monotherapy, regardless of tumor PD-L1
expression levels. In addition, efficacy of the Opdivo and Yervoy
combination regimen and Opdivo monotherapy was observed, regardless
of BRAF mutational status.
With longer follow-up, the safety of the Opdivo and Yervoy
combination regimen in CheckMate -067 was consistent with
previously reported studies of the combination regimen and most
treatment-related select adverse events (AEs) were managed with
immune-modulating medications. Grade 3-4 treatment-related AEs
were reported more frequently with the combination regimen (56.5%),
relative to the Opdivo monotherapy (19.8%) versus Yervoy alone
(27%). Treatment-related AEs of any grade led to discontinuation in
38.7% of patients treated with the combination regimen, 10.5% for
patients treated with Opdivo monotherapy, and 15.4% of patients
treated with Yervoy alone. No treatment-related deaths
occurred in the Opdivo and Yervoy combination regimen arm. The
most common treatment-related select AEs of any grade with the
combination regimen versus Yervoy alone included increased ALT
(17.9% vs. 3.9%), increased AST (15.7% vs. 3.9%), diarrhea (45.4 %
vs. 33.8%), colitis (11.5% vs. 11.3%), rash (28.4% vs. 21.2%),
pruritus (35.1% vs. 36.3%), hypothyroidism (16% vs. 4.5%),
hyperthyroidism (10.2% vs. 1%), elevated creatinine (4.2% vs.
1.6%), and pneumonitis (6.7% vs. 1.6%).
About CheckMate -069
CheckMate -069 is a Phase 2, double-blind, randomized study that
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.
Based on a post-hoc analysis at a minimum follow-up of two
years, OS and response rates in patients who discontinued treatment
with the Opdivo and Yervoy combination regimen due to
treatment-related adverse events (AEs, n=35) appeared consistent
with the overall population. The two-year OS rate in patients who
discontinued treatment with the Opdivo and Yervoy combination
regimen due to AEs was 71%. In the original exploratory analysis of
the overall study population, the OS rate was 64% at two years for
the Opdivo and Yervoy combination regimen and 54% for Yervoy alone
(HR=0.74 [95% CI: 0.43-1.26]).
For the overall patient population and the subgroup of patients
who discontinued the Opdivo and Yervoy combination regimen due
to AEs, the median PFS has still not been reached. In addition,
based on the post-hoc analysis, the PFS rate at two years for those
patients who discontinued the Opdivo and Yervoy combination
regimen due to treatment-related AEs was 52% (95% CI: NR; 7.03-NR).
The PFS rate observed in the original exploratory analysis at two
years was 51% (95% CI: NR; 7.36-NR) in all patients treated with
the combination regimen and 12% with Yervoy alone.
Objective response rates among patients who discontinued the
Opdivo and Yervoy combination regimen was 66% (95% CI: 48-81), and
20% achieved a complete response. The ORR observed in the original
exploratory analysis was 59% (95% CI: 48-69), and 22% achieved a
complete response. Median duration of response was not reached in
either group, with ongoing responses seen in 80% of the overall
patient population, and in 74% patients who discontinued the
combination regimen due to AEs. In addition, exploratory results
showed a median reduction of 69% in tumor burden in those patients
who discontinued the Opdivo and Yervoy combination
regimen.
The rates of overall treatment-related adverse events (AEs)
leading to discontinuation remained consistent with previously
reported results from CheckMate -069. The most common
treatment-related select AEs of any grade for patients treated with
the Opdivo and Yervoy combination regimen were rash (43%), pruritus
(40%), diarrhea (45%), colitis (18%), increased ALT (26%),
increased AST (28%), hypothyroidism (17%), hypophysitis (13%),
pneumonitis (10%), and increased creatinine (2%).
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 mostly curable when treated
in its early stages. However, in its late stages, the average
five-year survival rate is 15% - 20%.
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 of 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 51 countries including the
United States, Japan, and in the European Union.
U.S. FDA APPROVED INDICATIONS FOR
OPDIVO®
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.
OPDIVO® (nivolumab) is indicated for the treatment of patients
with classical Hodgkin lymphoma (cHL) that has relapsed or
progressed after autologous hematopoietic stem cell transplantation
(HSCT) and post- transplantation brentuximab vedotin. This
indication is approved under accelerated approval based on overall
response rate. Continued approval for this indication may be
contingent upon verification and description of clinical benefit in
confirmatory trials.
Please refer to the end of the Important Safety Information for
a brief description of the patient populations studied in the
Checkmate trials.
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). In Checkmate 205 and 039, pneumonitis,
including interstitial lung disease, occurred in 4.9% (13/263) of
patients receiving OPDIVO. Immune-mediated pneumonitis occurred in
3.4% (9/263) of patients receiving OPDIVO: Grade 3 (n=1) and Grade
2 (n=8).
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 Checkmate 205 and 039,
diarrhea or colitis occurred in 30% (80/263) of patients receiving
OPDIVO. Immune-mediated diarrhea (Grade 3) occurred in 1.1% (3/263)
of patients.
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 Checkmate 205 and 039,
hepatitis occurred in 11% (30/263) of patients receiving OPDIVO.
Immune-mediated hepatitis occurred in 3.4% (9/263): Grade 3 (n=7)
and Grade 2 (n=2).
In a separate Phase 3 study of YERVOY 3 mg/kg, severe,
life-threatening, or fatal hepatotoxicity (AST or ALT elevations
>5x the ULN or total bilirubin elevations >3x the ULN; Grade
3-5) occurred in 8 (2%) patients, with fatal hepatic failure in
0.2% and hospitalization in 0.4%.
Immune-Mediated Dermatitis
In a separate Phase 3 study of YERVOY 3 mg/kg, severe,
life-threatening, or fatal immune-mediated dermatitis (eg,
Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash
complicated by full thickness dermal ulceration, or necrotic,
bullous, or hemorrhagic manifestations; Grade 3-5) occurred in 13
(2.5%) patients. 1 (0.2%) patient died as a result of toxic
epidermal necrolysis. 1 additional patient required hospitalization
for severe dermatitis.
Immune-Mediated Neuropathies
In a separate Phase 3 study of YERVOY 3 mg/kg, 1 case of fatal
Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral
motor neuropathy were reported.
Immune-Mediated Endocrinopathies
Hypophysitis, adrenal insufficiency, thyroid disorders, and type
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 205 and 039, adrenal
insufficiency (Grade 2) occurred in 0.4% (1/263) of patients
receiving OPDIVO. 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 205 and 039, hypothyroidism/thyroiditis
occurred in 12% (32/263) of patients receiving OPDIVO: Grade 2
(n=18) and Grade 1: (n=14). Hyperthyroidism occurred in 1.5%
(4/263) of patients receiving OPDIVO: Grade 2: (n=3) and Grade 1
(n=1). 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 Checkmate 205 and 039, diabetes mellitus
occurred in 0.8% (2/263) of patients receiving OPDIVO: Grade 3
(n=1) 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). In Checkmate 205 and 039, nephritis and
renal dysfunction occurred in 4.9% (13/263) of patients treated
with OPDIVO. This included one reported case (0.3%) of Grade 3
autoimmune nephritis.
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). In
Checkmate 205 and 039, rash occurred in 22% (58/263) of patients
receiving OPDIVO. Immune-mediated rash occurred in 7% (18/263) of
patients on OPDIVO: Grade 3 (n=4), Grade 2 (n=3), and Grade 1
(n=11).
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. In
Checkmate 205 and 039, encephalitis occurred in 0.8% (2/263) of
patients after allogeneic HSCT after 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, iritis, 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. In Checkmate 205 and 039, hypersensitivity/infusion-
related reactions occurred in 16% (42/263) of patients receiving
OPDIVO: Grade 3 (n=2), Grade 2 (n=24), and Grade 1 (n=16).
Complications of Allogeneic HSCT after OPDIVO
Complications, including fatal events, occurred in patients who
received allogeneic HSCT after OPDIVO. Outcomes were evaluated in
17 patients from Checkmate 205 and 039, who underwent allogeneic
HSCT after discontinuing OPDIVO (15 with reduced-intensity
conditioning, 2 with myeloablative conditioning). Thirty-five
percent (6/17) of patients died from complications of allogeneic
HSCT after OPDIVO. Five deaths occurred in the setting of severe or
refractory GVHD. Grade 3 or higher acute GVHD was reported in 29%
(5/17) of patients. Hyperacute GVHD was reported in 20% (n=2) of
patients. A steroid-requiring febrile syndrome, without an
identified infectious cause, was reported in 35% (n=6) of patients.
Two cases of encephalitis were reported: Grade 3 (n=1) lymphocytic
encephalitis without an identified infectious cause, and Grade 3
(n=1) suspected viral encephalitis. Hepatic veno-occlusive disease
(VOD) occurred in one patient, who received reduced-intensity
conditioned allogeneic SCT and died of GVHD and multi-organ
failure. Other cases of hepatic VOD after reduced-intensity
conditioned allogeneic HSCT have also been reported in patients
with lymphoma who received a PD-1 receptor blocking antibody before
transplantation. Cases of fatal hyperacute GVHD have also been
reported. These complications may occur despite intervening therapy
between PD-1 blockade and allogeneic HSCT.
Follow patients closely for early evidence of transplant-related
complications such as hyperacute GVHD, severe (Grade 3 to 4) acute
GVHD, steroid-requiring febrile syndrome, hepatic VOD, and other
immune- mediated adverse reactions, and intervene promptly.
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. In
Checkmate 205 and 039, among all patients (safety population
[n=263]), adverse reactions leading to discontinuation (4.2%) or to
dosing delays (23%) occurred. The most frequent serious adverse
reactions reported in ≥1% of patients were infusion-related
reaction, pneumonia, pleural effusion, pyrexia, rash and
pneumonitis. Ten patients died from causes other than disease
progression, including 6 who died from complications of allogeneic
HSCT. Serious adverse reactions occurred in 21% of patients in the
safety population (n=263) and 27% of patients in the subset of
patients evaluated for efficacy (efficacy population [n=95]).
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 Checkmate 205 and 039, among all patients (safety
population [n=263]) and the subset of patients in the efficacy
population (n=95), respectively, the most common adverse reactions
(reported in at least 20%) were fatigue (32% and 43%), upper
respiratory tract infection (28% and 48%), pyrexia (24% and 35%),
diarrhea (23% and 30%), and cough (22% and 35%). In the subset of
patients in the efficacy population (n=95), the most common adverse
reactions also included rash (31%), musculoskeletal pain (27%),
pruritus (25%), nausea (23%), arthralgia (21%), and peripheral
neuropathy (21%).
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%).
CHECKMATE Trials and Patient
Populations
Checkmate 069 and 067 - advanced melanoma alone or in
combination with YERVOY; Checkmate 037 and 066 - advanced
melanoma; Checkmate 057 – non-squamous non-small cell lung
cancer (NSCLC); Checkmate 025 - renal cell carcinoma;
Checkmate 205/039 - classical Hodgkin lymphoma
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.
View source
version on businesswire.com: http://www.businesswire.com/news/home/20160606005377/en/
Media:Bristol-Myers Squibb CompanyAudrey 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
Bristol Myers Squibb (NYSE:BMY)
Historical Stock Chart
From Mar 2024 to Apr 2024
Bristol Myers Squibb (NYSE:BMY)
Historical Stock Chart
From Apr 2023 to Apr 2024