Bristol-Myers Squibb Company (NYSE: BMY) today announced the
Phase 3 CheckMate -498 trial evaluating Opdivo (nivolumab) plus
radiation versus temozolomide plus radiation in patients with newly
diagnosed O6-methylguanine-DNA methyltransferase
(MGMT)-unmethylated glioblastoma multiforme (GBM) did not meet its
primary endpoint of overall survival (OS) at final analysis. The
safety profile of Opdivo was consistent with previously reported
studies in solid tumors. The Company will complete a full
evaluation of the data from CheckMate -498 and work with
investigators on the future presentation and publication of the
results.
“While we are disappointed the CheckMate -498 trial did not meet
its primary endpoint, GBM is a notoriously aggressive cancer,” said
Fouad Namouni, M.D., head, oncology development, Bristol-Myers
Squibb. “We are grateful to all those who participated in this
trial and remain committed to researching the potential of
immunotherapy to address the important unmet medical need of
patients who suffer from this devastating disease.”
Opdivo is also being studied in patients with newly diagnosed
MGMT-methylated GBM in the Phase 3 CheckMate -548 (NCT02667587)
study, in which Opdivo is added to the current standard of care,
radiation plus temozolomide.
About CheckMate -498
CheckMate -498 (NCT02617589) is a Phase 3 randomized,
multi-center study evaluating Opdivo and radiation versus
temozolomide and radiation in patients with newly diagnosed
MGMT-unmethylated GBM. After surgery, patients in the experimental
arm received Opdivo every two weeks concurrent with radiation,
followed by maintenance with Opdivo every four weeks until disease
progression or unacceptable toxicity. The primary endpoint of the
trial was OS. Secondary endpoints included progression-free
survival, and OS rate at two years.
About Glioblastoma
Multiforme
Glioblastoma multiforme (GBM) is the most common and most
aggressive type of primary malignant tumor of the central nervous
system. Globally, an estimated 300,000 patients develop, and
241,000 patients die from, brain or central nervous system cancer
each year. Standard treatment for patients with newly diagnosed GBM
can include surgery followed by radiation and chemotherapy, but
treatment options are limited. The last investigational medicine to
improve survival for patients with newly diagnosed GBM was approved
by the U.S. Food and Drug Administration in 2005. The five year
survival rate of patients with GBM is less than five percent.
MGMT methylation status is the most commonly used biomarker in
GBM and, studies suggest, may be predictive of the likelihood of
patients with GBM to respond to alkylating chemotherapy such as
temozolomide. Patients with MGMT-unmethylated GBM are generally
known to have a worse prognosis than patients with MGMT-methylated
GBM.
Bristol-Myers Squibb: Advancing
Oncology Research
At Bristol-Myers Squibb, patients are at the center of
everything we do. The focus of our research is to increase quality,
long-term survival for patients and make cure a possibility.
Through a unique multidisciplinary approach powered by
translational science, we harness our deep scientific experience in
oncology and Immuno-Oncology (I-O) research to identify novel
treatments tailored to individual patient needs. Our researchers
are developing a diverse, purposefully built pipeline designed to
target different immune system pathways and address the complex and
specific interactions between the tumor, its microenvironment and
the immune system. We source innovation internally, and in
collaboration with academia, government, advocacy groups and
biotechnology companies, to help make the promise of
transformational medicines, like I-O, a reality for patients.
About Opdivo
Opdivo is a programmed death-1 (PD-1) immune checkpoint
inhibitor that is designed to uniquely harness the body’s own
immune system to help restore anti-tumor immune response. By
harnessing the body’s own immune system to fight
cancer, Opdivo has become an important treatment option
across multiple cancers.
Opdivo’s leading global development program is based on
Bristol-Myers Squibb’s scientific expertise in the field of
Immuno-Oncology, and includes a broad range of clinical trials
across all phases, including Phase 3, in a variety of tumor types.
To date, the Opdivo clinical development program has
enrolled more than 25,000 patients. The Opdivo trials
have contributed to gaining a deeper understanding of the potential
role of biomarkers in patient care, particularly regarding how
patients may benefit from Opdivo across the continuum of
PD-L1 expression.
In July 2014, Opdivo was the first PD-1 immune
checkpoint inhibitor to receive regulatory approval anywhere in the
world. Opdivo is currently approved in more than 65
countries, including the United States, the European Union, Japan
and China. In October 2015, the Company’s Opdivo and Yervoy
combination regimen was the first Immuno-Oncology combination to
receive regulatory approval for the treatment of metastatic
melanoma and is currently approved in more than 50 countries,
including the United States and the European Union.
U.S. FDA-APPROVED INDICATIONS FOR
OPDIVO®
OPDIVO® (nivolumab) as a single agent is indicated for the
treatment of patients with unresectable or metastatic melanoma.
OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab),
is indicated for the treatment of patients with unresectable or
metastatic melanoma.
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 metastatic small cell lung cancer (SCLC) with progression
after platinum-based chemotherapy and at least one other line of
therapy. This indication is approved under accelerated approval
based on overall response rate and duration of
response. Continued approval for this indication may be
contingent upon verification and description of clinical benefit in
confirmatory trials.
OPDIVO® (nivolumab) is indicated for the treatment of patients
with advanced renal cell carcinoma (RCC) who have received prior
anti-angiogenic therapy.
OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab),
is indicated for the treatment of patients with intermediate or
poor risk, previously untreated advanced renal cell carcinoma
(RCC).
OPDIVO® (nivolumab) is indicated for the treatment of adult
patients with classical Hodgkin lymphoma (cHL) that has relapsed or
progressed after autologous hematopoietic stem cell transplantation
(HSCT) and brentuximab vedotin or after 3 or more lines of systemic
therapy that includes autologous HSCT. 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.
OPDIVO® (nivolumab) is indicated for the treatment of patients
with recurrent or metastatic squamous cell carcinoma of the head
and neck (SCCHN) with disease progression on or after
platinum-based therapy.
OPDIVO® (nivolumab) is indicated for the treatment of patients
with locally advanced or metastatic urothelial carcinoma who have
disease progression during or following platinum-containing
chemotherapy or have disease progression within 12 months of
neoadjuvant or adjuvant treatment with platinum-containing
chemotherapy. This indication is approved under accelerated
approval based on tumor response rate and duration of response.
Continued approval for this indication may be contingent upon
verification and description of clinical benefit in confirmatory
trials.
OPDIVO® (nivolumab), as a single agent, is indicated for the
treatment of adult and pediatric (12 years and older) patients with
microsatellite instability-high (MSI-H) or mismatch repair
deficient (dMMR) metastatic colorectal cancer (CRC) that has
progressed following treatment with a fluoropyrimidine,
oxaliplatin, and irinotecan. This indication is approved under
accelerated approval based on overall response rate and duration of
response. 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 adults and pediatric patients 12
years and older with microsatellite instability-high (MSI-H) or
mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC)
that has progressed following treatment with a fluoropyrimidine,
oxaliplatin, and irinotecan. This indication is approved under
accelerated approval based on overall response rate and duration of
response. Continued approval for this indication may be contingent
upon verification and description of clinical benefit in
confirmatory trials.
OPDIVO® (nivolumab) is indicated for the treatment of patients
with hepatocellular carcinoma (HCC) who have been previously
treated with sorafenib. This indication is approved under
accelerated approval based on tumor response rate and durability of
response. 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 adjuvant treatment of
patients with melanoma with involvement of lymph nodes or
metastatic disease who have undergone complete resection.
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
OPDIVO can cause immune-mediated pneumonitis. Fatal cases have
been reported. Monitor patients for signs with radiographic imaging
and for symptoms of pneumonitis. Administer corticosteroids for
Grade 2 or more severe pneumonitis. Permanently discontinue for
Grade 3 or 4 and withhold until resolution for Grade 2. In
patients receiving OPDIVO monotherapy, fatal cases of
immune-mediated pneumonitis have occurred. Immune-mediated
pneumonitis occurred in 3.1% (61/1994) of patients. In
patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg,
immune-mediated pneumonitis occurred in 6% (25/407) of
patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY
1 mg/kg, immune-mediated pneumonitis occurred in 4.4% (24/547) of
patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg
with YERVOY 1 mg/kg, immune-mediated pneumonitis occurred in 1.7%
(2/119) of patients.
In Checkmate 205 and 039, pneumonitis, including interstitial
lung disease, occurred in 6.0% (16/266) of patients receiving
OPDIVO. Immune-mediated pneumonitis occurred in 4.9% (13/266) of
patients receiving OPDIVO: Grade 3 (n=1) and Grade 2 (n=12).
Immune-Mediated Colitis
OPDIVO can cause immune-mediated colitis. Monitor patients for
signs and symptoms of colitis. Administer corticosteroids for Grade
2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO
monotherapy for Grade 2 or 3 and permanently discontinue for Grade
4 or recurrent colitis upon re-initiation of OPDIVO. When
administered with YERVOY, withhold OPDIVO and YERVOY for Grade 2
and permanently discontinue for Grade 3 or 4 or recurrent
colitis. In patients receiving OPDIVO monotherapy,
immune-mediated colitis occurred in 2.9% (58/1994) of
patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3
mg/kg, immune-mediated colitis occurred in 26% (107/407) of
patients including three fatal cases. In RCC patients
receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated
colitis occurred in 10% (52/547) of patients. In MSI-H/dMMR
mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg,
immune-mediated colitis occurred in 7% (8/119) 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
OPDIVO can cause immune-mediated hepatitis. Monitor patients for
abnormal liver tests prior to and periodically during treatment.
Administer corticosteroids for Grade 2 or greater transaminase
elevations. For patients without HCC, withhold OPDIVO for
Grade 2 and permanently discontinue OPDIVO for Grade 3 or
4. For patients with HCC, withhold OPDIVO and administer
corticosteroids if AST/ALT is within normal limits at baseline and
increases to >3 and up to 5 times the upper limit of normal
(ULN), if AST/ALT is >1 and up to 3 times ULN at baseline and
increases to >5 and up to 10 times the ULN, and if AST/ALT is
>3 and up to 5 times ULN at baseline and increases to >8 and
up to 10 times the ULN. Permanently discontinue OPDIVO and
administer corticosteroids if AST or ALT increases to >10 times
the ULN or total bilirubin increases >3 times the ULN. In
patients receiving OPDIVO monotherapy, immune-mediated hepatitis
occurred in 1.8% (35/1994) of patients. In patients receiving
OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated hepatitis
occurred in 13% (51/407) of patients. In RCC patients
receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated
hepatitis occurred in 7% (38/547) of patients. In MSI-H/dMMR
mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg,
immune-mediated hepatitis occurred in 8% (10/119) of patients.
In Checkmate 040, immune-mediated hepatitis requiring systemic
corticosteroids occurred in 5% (8/154) of patients receiving
OPDIVO.
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 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
OPDIVO can cause immune-mediated hypophysitis, immune-mediated
adrenal insufficiency, autoimmune thyroid disorders, and Type 1
diabetes mellitus. Monitor patients for signs and symptoms of
hypophysitis, signs and symptoms of adrenal insufficiency, thyroid
function prior to and periodically during treatment, and
hyperglycemia. Administer hormone replacement as clinically
indicated and 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. Withhold OPDIVO for Grade 3 and permanently
discontinue for Grade 4 hyperglycemia.
In patients receiving OPDIVO monotherapy, hypophysitis occurred
in 0.6% (12/1994) of patients. In patients receiving OPDIVO 1
mg/kg with YERVOY 3 mg/kg, hypophysitis occurred in 9% (36/407) of
patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY
1 mg/kg, hypophysitis occurred in 4.6% (25/547) of
patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg
with YERVOY 1 mg/kg, immune-mediated hypophysitis occurred in 3.4%
(4/119) of patients. In patients receiving OPDIVO monotherapy,
adrenal insufficiency occurred in 1% (20/1994) of patients. In
patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, adrenal
insufficiency occurred in 5% (21/407) of patients. In RCC
patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, adrenal
insufficiency occurred in 7% (41/547) of patients. In
MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1
mg/kg, adrenal insufficiency occurred in 5.9% (7/119) of
patients. In patients receiving OPDIVO monotherapy,
hypothyroidism or thyroiditis resulting in hypothyroidism occurred
in 9% (171/1994) of patients. Hyperthyroidism occurred in 2.7%
(54/1994) of patients receiving OPDIVO monotherapy. In
patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg,
hypothyroidism or thyroiditis resulting in hypothyroidism occurred
in 22% (89/407) of patients. Hyperthyroidism occurred in 8%
(34/407) of patients receiving this dose of OPDIVO with
YERVOY. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1
mg/kg, hypothyroidism or thyroiditis resulting in hypothyroidism
occurred in 22% (119/547) of patients. Hyperthyroidism occurred in
12% (66/547) of patients receiving this dose of OPDIVO with
YERVOY. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg
with YERVOY 1 mg/kg, hypothyroidism or thyroiditis resulting in
hypothyroidism occurred in 15% (18/119) of patients.
Hyperthyroidism occurred in 12% (14/119) of patients. In
patients receiving OPDIVO monotherapy, diabetes occurred in 0.9%
(17/1994) of patients. In patients receiving OPDIVO 1 mg/kg
with YERVOY 3 mg/kg, diabetes occurred in 1.5% (6/407) of
patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY
1 mg/kg, diabetes occurred in 2.7% (15/547) of patients.
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. Six of the 9
patients were hospitalized for severe endocrinopathies.
Immune-Mediated Nephritis and Renal Dysfunction
OPDIVO can cause immune-mediated nephritis. Monitor patients for
elevated serum creatinine prior to and periodically during
treatment. Administer corticosteroids for Grades 2-4 increased
serum creatinine. Withhold OPDIVO for Grade 2 or 3 and permanently
discontinue for Grade 4 increased serum creatinine. In
patients receiving OPDIVO monotherapy, immune-mediated nephritis
and renal dysfunction occurred in 1.2% (23/1994) of
patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3
mg/kg, immune-mediated nephritis and renal dysfunction occurred in
2.2% (9/407) of patients. In RCC patients receiving OPDIVO 3
mg/kg with YERVOY 1 mg/kg, immune-mediated nephritis and renal
dysfunction occurred in 4.6% (25/547) of patients. In
MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1
mg/kg, immune-mediated nephritis and renal dysfunction occurred in
1.7% (2/119) of patients.
Immune-Mediated Skin Adverse Reactions and
Dermatitis
OPDIVO can cause immune-mediated rash, including Stevens-Johnson
syndrome (SJS) and toxic epidermal necrolysis (TEN), some cases
with fatal outcome. Administer corticosteroids for Grade 3 or 4
rash. Withhold for Grade 3 and permanently discontinue for Grade 4
rash. For symptoms or signs of SJS or TEN, withhold OPDIVO and
refer the patient for specialized care for assessment and
treatment; if confirmed, permanently discontinue. In patients
receiving OPDIVO monotherapy, immune-mediated rash occurred in 9%
(171/1994) of patients. In patients receiving OPDIVO 1 mg/kg
with YERVOY 3 mg/kg, immune-mediated rash occurred in 22.6%
(92/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg
with YERVOY 1 mg/kg, immune-mediated rash occurred in 16.6%
(91/547) of patients. In MSI-H/dMMR mCRC patients receiving
OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated rash occurred
in 14% (17/119) of patients.
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 Encephalitis
OPDIVO can cause immune-mediated encephalitis. Evaluation of
patients with neurologic symptoms may include, but not be limited
to, consultation with a neurologist, brain MRI, and lumbar
puncture. 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 patients receiving OPDIVO
monotherapy, encephalitis occurred in 0.2% (3/1994) of patients.
Fatal limbic encephalitis occurred in one patient after 7.2 months
of exposure despite discontinuation of OPDIVO and administration of
corticosteroids. Encephalitis occurred in one patient
receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg (0.2%) after
1.7 months of exposure. Encephalitis occurred in one RCC
patient receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg (0.2%) after
approximately 4 months of exposure. Encephalitis occurred in
one MSI-H/dMMR mCRC patient (0.8%) receiving OPDIVO 3 mg/kg with
YERVOY 1 mg/kg after 15 days of exposure.
Other Immune-Mediated Adverse Reactions
Based on the severity of the adverse reaction, permanently
discontinue or withhold OPDIVO, administer high-dose
corticosteroids, and, if appropriate, initiate hormone-replacement
therapy. Across clinical trials of OPDIVO monotherapy or in
combination with YERVOY, the following clinically significant
immune-mediated adverse reactions, some with fatal outcome,
occurred in <1.0% of patients receiving OPDIVO: myocarditis,
rhabdomyolysis, myositis, uveitis, iritis, pancreatitis, facial and
abducens nerve paresis, demyelination, polymyalgia rheumatica,
autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism,
systemic inflammatory response syndrome, gastritis, duodenitis,
sarcoidosis, histiocytic necrotizing lymphadenitis (Kikuchi
lymphadenitis), motor dysfunction, vasculitis, aplastic anemia,
pericarditis, and myasthenic syndrome.
If uveitis occurs in combination with other immune-mediated
adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome,
which has been observed in patients receiving OPDIVO and may
require treatment with systemic steroids to reduce the risk of
permanent vision loss.
Infusion Reactions
OPDIVO can cause severe infusion reactions, which have been
reported in <1.0% of patients in clinical trials. 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 patients receiving OPDIVO monotherapy as a
60-minute infusion, infusion-related reactions occurred
in 6.4% (127/1994) of patients. In a separate study in which
patients received OPDIVO monotherapy as a 60-minute infusion or a
30-minute infusion, infusion-related reactions occurred in 2.2%
(8/368) and 2.7% (10/369) of patients, respectively. Additionally,
0.5% (2/368) and 1.4% (5/369) of patients, respectively,
experienced adverse reactions within 48 hours of infusion that led
to dose delay, permanent discontinuation or withholding of
OPDIVO. In patients receiving OPDIVO 1 mg/kg with YERVOY 3
mg/kg every 3 weeks, infusion-related reactions occurred
in 2.5% (10/407) of patients. In RCC patients
receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, infusion-related
reactions occurred in 5.1% (28/547) of patients. In MSI-H/dMMR
mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg,
infusion-related reactions occurred in 4.2% (5/119) of
patients.
Complications of Allogeneic Hematopoietic Stem Cell
Transplantation
Fatal and other serious complications can occur in patients who
receive allogeneic hematopoietic stem cell transplantation (HSCT)
before or after being treated with a PD-1 receptor blocking
antibody. Transplant-related complications include hyperacute
graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic
veno-occlusive disease (VOD) after reduced intensity conditioning,
and steroid-requiring febrile syndrome (without an identified
infectious cause). These complications may occur despite
intervening therapy between PD-1 blockade and allogeneic HSCT.
Follow patients closely for evidence of transplant-related
complications and intervene promptly. Consider the benefit versus
risks of treatment with a PD-1 receptor blocking antibody prior to
or after an allogeneic HSCT.
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.
Increased Mortality in Patients with Multiple Myeloma when
OPDIVO is Added to a Thalidomide Analogue and Dexamethasone
In clinical trials in patients with multiple myeloma, the
addition of OPDIVO to a thalidomide analogue plus dexamethasone
resulted in increased mortality. Treatment of patients with
multiple myeloma with a PD-1 or PD-L1 blocking antibody in
combination with a thalidomide analogue plus dexamethasone is not
recommended outside of controlled clinical trials.
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 breastfeeding during treatment with YERVOY and
for 3 months following the final dose.
Serious Adverse Reactions
In Checkmate 037, serious adverse reactions occurred in 41% of
patients receiving OPDIVO (n=268). 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 (n=206). 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 067, serious adverse reactions (74%
and 44%), adverse reactions leading to permanent discontinuation
(47% and 18%) or to dosing delays (58% and 36%), and Grade 3 or 4
adverse reactions (72% and 51%) all occurred more frequently in the
OPDIVO plus YERVOY arm (n=313) relative to the OPDIVO arm (n=313).
The most frequent (≥10%) serious adverse reactions in the OPDIVO
plus YERVOY arm and the OPDIVO arm, respectively, were diarrhea
(13% and 2.2%), colitis (10% and 1.9%), and pyrexia (10% and
1.0%). In Checkmate 017 and 057, serious adverse reactions
occurred in 46% of patients receiving OPDIVO (n=418). The most
frequent serious adverse reactions reported in ≥2% of patients
receiving OPDIVO were pneumonia, pulmonary embolism, dyspnea,
pyrexia, pleural effusion, pneumonitis, and respiratory
failure. In Checkmate 032, serious adverse reactions occurred
in 45% of patients receiving OPDIVO (n=245). The most frequent
serious adverse reactions reported in at least 2% of patients
receiving OPDIVO were pneumonia, dyspnea, pneumonitis, pleural
effusions, and dehydration. In Checkmate 025, serious adverse
reactions occurred in 47% of patients receiving OPDIVO (n=406). The
most frequent serious adverse reactions reported in ≥2% of patients
were acute kidney injury, pleural effusion, pneumonia, diarrhea,
and hypercalcemia. In Checkmate 214, serious adverse reactions
occurred in 59% of patients receiving OPDIVO plus YERVOY and in 43%
of patients receiving sunitinib. The most frequent serious adverse
reactions reported in ≥2% of patients were diarrhea, pyrexia,
pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea,
adrenal insufficiency, and colitis; in patients treated with
sunitinib, they were pneumonia, pleural effusion, and
dyspnea. In Checkmate 205 and 039, adverse reactions leading
to discontinuation occurred in 7% and dose delays due to adverse
reactions occurred in 34% of patients (n=266). Serious adverse
reactions occurred in 26% of patients. The most frequent serious
adverse reactions reported in ≥1% of patients were pneumonia,
infusion-related reaction, pyrexia, colitis or diarrhea, pleural
effusion, pneumonitis, and rash. Eleven patients died from causes
other than disease progression: 3 from adverse reactions within 30
days of the last OPDIVO dose, 2 from infection 8 to 9 months after
completing OPDIVO, and 6 from complications of allogeneic
HSCT. In Checkmate 141, serious adverse reactions occurred in
49% of patients receiving OPDIVO (n=236). The most frequent serious
adverse reactions reported in ≥2% of patients receiving OPDIVO were
pneumonia, dyspnea, respiratory failure, respiratory tract
infection, and sepsis. In Checkmate 275, serious adverse
reactions occurred in 54% of patients receiving OPDIVO (n=270). The
most frequent serious adverse reactions reported in ≥2% of patients
receiving OPDIVO were urinary tract infection, sepsis, diarrhea,
small intestine obstruction, and general physical health
deterioration. In Checkmate 142 in MSI-H/dMMR mCRC patients
receiving OPDIVO with YERVOY, serious adverse reactions occurred in
47% of patients. The most frequent serious adverse reactions
reported in ≥2% of patients were colitis/diarrhea, hepatic events,
abdominal pain, acute kidney injury, pyrexia, and
dehydration. In Checkmate 040, serious adverse reactions
occurred in 49% of patients (n=154). The most frequent serious
adverse reactions reported in ≥2% of patients were pyrexia,
ascites, back pain, general physical health deterioration,
abdominal pain, and pneumonia. In Checkmate 238, Grade 3 or 4
adverse reactions occurred in 25% of OPDIVO-treated patients
(n=452). The most frequent Grade 3 and 4 adverse reactions reported
in ≥2% of OPDIVO-treated patients were diarrhea and increased
lipase and amylase. Serious adverse reactions occurred in 18% of
OPDIVO-treated patients.
Common Adverse Reactions
In Checkmate 037, the most common adverse reaction (≥20%)
reported with OPDIVO (n=268) was rash (21%). In Checkmate 066, the
most common adverse reactions (≥20%) reported with OPDIVO (n=206)
vs dacarbazine (n=205) were fatigue (49% vs 39%), musculoskeletal
pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%). In
Checkmate 067, the most common (≥20%) adverse reactions in the
OPDIVO plus YERVOY arm (n=313) were fatigue (62%), diarrhea (54%),
rash (53%), nausea (44%), pyrexia (40%), pruritus (39%),
musculoskeletal pain (32%), vomiting (31%), decreased appetite
(29%), cough (27%), headache (26%), dyspnea (24%), upper
respiratory tract infection (23%), arthralgia (21%), and increased
transaminases (25%). In Checkmate 067, the most common (≥20%)
adverse reactions in the OPDIVO arm (n=313) were fatigue (59%),
rash (40%), musculoskeletal pain (42%), diarrhea (36%), nausea
(30%), cough (28%), pruritus (27%), upper respiratory tract
infection (22%), decreased appetite (22%), headache (22%),
constipation (21%), arthralgia (21%), and vomiting (20%). In
Checkmate 017 and 057, the most common adverse reactions (≥20%) in
patients receiving OPDIVO (n=418) were fatigue, musculoskeletal
pain, cough, dyspnea, and decreased appetite. In Checkmate
032, the most common adverse reactions (≥20%) in patients receiving
OPDIVO (n=245) were fatigue (45%), decreased appetite (27%),
musculoskeletal pain (25%), dyspnea (22%), nausea (22%), diarrhea
(21%), constipation (20%), and cough (20%). In Checkmate 025,
the most common adverse reactions (≥20%) reported in patients
receiving OPDIVO (n=406) vs everolimus (n=397) were fatigue (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 214, the most common
adverse reactions (≥20%) reported in patients treated with OPDIVO
plus YERVOY (n=547) vs sunitinib (n=535) were fatigue (58% vs 69%),
rash (39% vs 25%), diarrhea (38% vs 58%), musculoskeletal pain (37%
vs 40%), pruritus (33% vs 11%), nausea (30% vs 43%), cough (28% vs
25%), pyrexia (25% vs 17%), arthralgia (23% vs 16%), decreased
appetite (21% vs 29%), dyspnea (20% vs 21%), and vomiting (20% vs
28%). In Checkmate 205 and 039, the most common adverse
reactions (≥20%) reported in patients receiving OPDIVO (n=266) were
upper respiratory tract infection (44%), fatigue (39%), cough
(36%), diarrhea (33%), pyrexia (29%), musculoskeletal pain (26%),
rash (24%), nausea (20%) and pruritus (20%). In Checkmate 141,
the most common adverse reactions (≥10%) in patients receiving
OPDIVO (n=236) were cough and dyspnea at a higher incidence than
investigator’s choice. In Checkmate 275, the most common
adverse reactions (≥20%) reported in patients receiving OPDIVO
(n=270) were fatigue (46%), musculoskeletal pain (30%), nausea
(22%), and decreased appetite (22%). In Checkmate 142 in
MSI-H/dMMR mCRC patients receiving OPDIVO as a single agent, the
most common adverse reactions (≥20%) were fatigue (54%), diarrhea
(43%), abdominal pain (34%), nausea (34%), vomiting (28%),
musculoskeletal pain (28%), cough (26%), pyrexia (24%), rash (23%),
constipation (20%), and upper respiratory tract infection
(20%). In Checkmate 142 in MSI-H/dMMR mCRC patients receiving
OPDIVO with YERVOY, the most common adverse reactions (≥20%) were
fatigue (49%), diarrhea (45%), pyrexia (36%), musculoskeletal pain
(36%), abdominal pain (30%), pruritus (28%), nausea (26%), rash
(25%), decreased appetite (20%), and vomiting (20%). In
Checkmate 040, the most common adverse reactions (≥20%) in patients
receiving OPDIVO (n=154) were fatigue (38%), musculoskeletal pain
(36%), abdominal pain (34%), pruritus (27%), diarrhea (27%), rash
(26%), cough (23%), and decreased appetite (22%). In Checkmate
238, the most common adverse reactions (≥20%) reported in
OPDIVO-treated patients (n=452) vs ipilimumab-treated patients
(n=453) were fatigue (57% vs 55%), diarrhea (37% vs 55%), rash (35%
vs 47%), musculoskeletal pain (32% vs 27%), pruritus (28% vs 37%),
headache (23% vs 31%), nausea (23% vs 28%), upper respiratory
infection (22% vs 15%), and abdominal pain (21% vs 23%). The most
common immune-mediated adverse reactions were rash (16%),
diarrhea/colitis (6%), and hepatitis (3%).
In a separate Phase 3 study of YERVOY 3 mg/kg, the most common
adverse reactions (≥5%) in patients who received YERVOY at
3 mg/kg were fatigue (41%), diarrhea (32%), pruritus (31%),
rash (29%), and colitis (8%).
Please see U.S. Full Prescribing Information for OPDIVO
and YERVOY, including Boxed WARNING regarding
immune-mediated adverse reactions for YERVOY.
Checkmate Trials and Patient Populations
Checkmate 037–previously treated metastatic melanoma;
Checkmate 066–previously untreated metastatic melanoma;
Checkmate 067–previously untreated metastatic melanoma, as a
single agent or in combination with YERVOY; Checkmate
017–second-line treatment of metastatic squamous non-small cell
lung cancer; Checkmate 057–second-line treatment of
metastatic non-squamous non-small cell lung cancer; Checkmate
032–small cell lung cancer; Checkmate 025–previously
treated renal cell carcinoma; Checkmate 214–previously
untreated renal cell carcinoma, in combination with YERVOY;
Checkmate 205/039–classical Hodgkin lymphoma; Checkmate
141–recurrent or metastatic squamous cell carcinoma of the head
and neck; Checkmate 275–urothelial carcinoma; Checkmate
142–MSI-H or dMMR metastatic colorectal cancer, as a single
agent or in combination with YERVOY; Checkmate
040–hepatocellular carcinoma; Checkmate 238–adjuvant
treatment of melanoma.
About the Bristol-Myers Squibb and Ono
Pharmaceutical Collaboration
In 2011, through a collaboration agreement with Ono
Pharmaceutical Co., Bristol-Myers Squibb expanded its territorial
rights to develop and commercialize Opdivo globally, except in
Japan, South Korea and Taiwan, where Ono had retained all rights to
the compound at the time. On July 23, 2014, Ono and Bristol-Myers
Squibb 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" within
the meaning of the Private Securities Litigation Reform Act of 1995
regarding the research, development and commercialization of
pharmaceutical products. All statements that are not statements of
historical facts are, or may be deemed to be, forward-looking
statements. Such forward-looking statements are based on historical
performance and current expectations and projections about our
future financial results, goals, plans and objectives and involve
inherent risks, assumptions and uncertainties, including internal
or external factors that could delay, divert or change any of them
in the next several years, and could cause our future financial
results, goals, plans and objectives to differ materially from
those expressed in, or implied by, the statements. 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, 2018, as updated by our subsequent Quarterly
Reports on Form 10-Q, Current Reports on Form 8-K and other filings
with the Securities and Exchange Commission. The forward-looking
statements included in this document are made only as of the date
of this document and except as otherwise required by federal
securities law, Bristol-Myers Squibb undertakes no obligation to
publicly update or revise any forward-looking statement, whether as
a result of new information, future events, changed circumstances
or otherwise.
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Bristol-Myers Squibb CompanyMedia Inquiries:Kirby
Hosea609-302-4399kirby.hosea@bms.com
Investors:Tim Power609-252-7509timothy.power@bms.com
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