CheckMate -743 is the first and only Phase 3
trial in which first-line immunotherapy treatment improved survival
in patients with malignant pleural mesothelioma
With these positive results, Opdivo plus
Yervoy has now shown clinical benefit in six different tumor types,
including durable, superior overall survival vs. chemotherapy in
two thoracic cancers
Bristol Myers Squibb (NYSE: BMY) today announced that
Opdivo® (nivolumab) plus Yervoy® (ipilimumab)
demonstrated a significant improvement in overall survival (OS) in
patients with previously untreated, unresectable malignant pleural
mesothelioma (MPM) in the Phase 3 CheckMate -743 clinical trial.
With a minimum follow-up of 22 months, treatment with Opdivo plus
Yervoy reduced the risk of death by 26%, demonstrating a median OS
of 18.1 months vs. 14.1 months for platinum-based standard of care
chemotherapy (Hazard Ratio [HR]: 0.74 [96.6% Confidence Interval
[CI]: 0.60, 0.91]; p=0.002). At two years, 41% of patients treated
with the Opdivo plus Yervoy combination were alive, compared to 27%
of patients treated with chemotherapy.
The safety profile of Opdivo plus Yervoy was consistent with
previously reported studies, and no new safety signals were
observed.
These data will be presented at the 2020 World Conference on
Lung Cancer Virtual Presidential Symposium hosted by the
International Association for the Study of Lung Cancer on August 8,
2020, 7:00 a.m. EDT (Abstract #3).
“An aggressive cancer with a five-year survival rate of less
than 10 percent, malignant pleural mesothelioma has shown
resistance to many clinical treatments,” said Paul Baas, M.D.,
Ph.D., Department of Thoracic Oncology, Netherlands Cancer
Institute and the University of Leiden. “Now, for the first time,
we have evidence that a dual immunotherapy combination showed a
superior, sustained overall survival benefit compared to
chemotherapy in the first-line treatment of all types of malignant
pleural mesothelioma. The CheckMate -743 data support the potential
for nivolumab plus ipilimumab to become a new standard of
care.”
Histology is a well-established prognostic factor in
mesothelioma, with non-epithelioid patients generally experiencing
poorer outcomes. In CheckMate -743, Opdivo plus Yervoy showed
improvements in survival across both non-epithelioid and
epithelioid MPM, with a larger magnitude of benefit observed in the
non-epithelioid subgroup. With the dual immunotherapy combination,
median OS was 18.7 months for epithelioid patients and 18.1 months
for non-epithelioid patients, compared to 16.5 months and 8.8
months, respectively, with chemotherapy (epithelioid subgroup HR:
0.86 [95% CI: 0.69, 1.08]; and non-epithelioid subgroup HR: 0.46
[95% CI: 0.31, 0.68]).
“These data in malignant pleural mesothelioma follow on the
established long-term efficacy of Opdivo plus Yervoy in patients
with non-small cell lung cancer and further demonstrate the
combination’s potential to change survival expectations in thoracic
cancers,” said Sabine Maier, Vice President, Oncology Clinical
Development, Bristol Myers Squibb. “For more than 15 years, no new
systemic treatment options that can extend survival have been
approved for patients with malignant pleural mesothelioma. We look
forward to discussions with global health authorities over the
coming months about the positive results from CheckMate -743.”
Opdivo plus Yervoy is a unique combination of two immune
checkpoint inhibitors that features a potentially synergistic
mechanism of action, targeting two different checkpoints (PD-1 and
CTLA-4) to help destroy tumor cells: Yervoy helps activate and
proliferate T cells, while Opdivo helps existing T cells discover
the tumor. Some of the T cells stimulated by Yervoy can become
memory T cells, which may allow for a long-term immune
response.
About CheckMate -743
CheckMate -743 is an open-label, multi-center, randomized Phase
3 trial evaluating Opdivo plus Yervoy compared to chemotherapy
(pemetrexed and cisplatin or carboplatin) in patients with
previously untreated malignant pleural mesothelioma (n=605). In the
trial, 303 patients received Opdivo at 3 mg/kg every two weeks and
Yervoy at 1 mg/kg every six weeks for up to 24 months or until
disease progression or unacceptable toxicity; 302 patients received
cisplatin 75 mg/m2 or carboplatin AUC 5 plus pemetrexed 500 mg/m2
in 21 day cycles for six cycles or until disease progression or
unacceptable toxicity. The primary endpoint of the trial was OS in
all randomized patients. Key secondary endpoints included objective
response rate (ORR), disease control rate (DCR) and
progression-free survival (PFS). Exploratory endpoints included
safety, pharmacokinetics, immunogenicity and patient reported
outcomes.
About Malignant Pleural
Mesothelioma
Malignant pleural mesothelioma is a rare but aggressive form of
cancer that forms in the lining of the lungs. It is most frequently
caused by exposure to asbestos. Diagnosis is often delayed, with
the majority of patients presenting with advanced or metastatic
disease. Prognosis is generally poor: in previously untreated
patients with advanced or metastatic malignant pleural
mesothelioma, median survival is less than one year and the
five-year survival rate is approximately 10%.
Bristol Myers Squibb: Advancing Cancer
Research
At Bristol Myers Squibb, patients are at the center of
everything we do. The goal of our cancer research is to increase
patients’ quality of life, long-term survival and make cure a
possibility. We harness our deep scientific experience,
cutting-edge technologies and discovery platforms to discover,
develop and deliver novel treatments for patients.
Building upon our transformative work and legacy in hematology
and Immuno-Oncology that has changed survival expectations for many
cancers, our researchers are advancing a deep and diverse pipeline
across multiple modalities. In the field of immune cell therapy,
this includes registrational CAR T cell agents for numerous
diseases, and a growing early-stage pipeline that expands cell and
gene therapy targets, and technologies. We are developing cancer
treatments directed at key biological pathways using our protein
homeostasis platform, a research capability that has been the basis
of our approved therapies for multiple myeloma and several
promising compounds in early- to mid-stage development. Our
scientists are targeting different immune system pathways to
address interactions between tumors, the microenvironment and the
immune system to further expand upon the progress we have made and
help more patients respond to treatment. Combining these approaches
is key to delivering potential new options for the treatment of
cancer and addressing the growing issue of resistance to
immunotherapy. We source innovation internally, and in
collaboration with academia, government, advocacy groups and
biotechnology companies, to help make the promise of
transformational medicines 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 treated more
than 35,000 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.
About Yervoy
Yervoy is a recombinant, human monoclonal antibody that binds to
the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4). CTLA-4 is
a negative regulator of T-cell activity. Yervoy binds to CTLA-4 and
blocks the interaction of CTLA-4 with its ligands, CD80/CD86.
Blockade of CTLA-4 has been shown to augment T-cell activation and
proliferation, including the activation and proliferation of tumor
infiltrating T-effector cells. Inhibition of CTLA-4 signaling can
also reduce T-regulatory cell function, which may contribute to a
general increase in T-cell responsiveness, including the anti-tumor
immune response. On March 25, 2011, the U.S. Food and Drug
Administration (FDA) approved Yervoy 3 mg/kg monotherapy for
patients with unresectable or metastatic melanoma. Yervoy is
approved for unresectable or metastatic melanoma in more than 50
countries. There is a broad, ongoing development program in place
for Yervoy spanning multiple tumor types.
Indications
OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab),
is indicated for the treatment of patients with unresectable or
metastatic melanoma.
OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab),
is indicated for the first-line treatment of adult patients with
metastatic non-small cell lung cancer (NSCLC) whose tumors express
PD-L1 (≥1%) as determined by an FDA-approved test, with no EGFR or
ALK genomic tumor aberrations.
OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab)
and 2 cycles of platinum-doublet chemotherapy, is indicated for the
first-line treatment of adult patients with metastatic or recurrent
non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic
tumor aberrations.
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), 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), in combination with YERVOY® (ipilimumab),
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
overall response rate and duration of response. Continued approval
for this indication may be contingent upon verification and
description of clinical benefit in the confirmatory trials.
Important Safety
Information
Severe and Fatal Immune-Mediated Adverse Reactions
Immune-mediated adverse reactions listed herein may not be
inclusive of all possible severe and fatal immune-mediated adverse
reactions.
Immune-mediated adverse reactions, which may be severe or fatal,
can occur in any organ system or tissue. While immune-mediated
adverse reactions usually manifest during treatment, they can also
occur at any time after starting or discontinuing YERVOY. Early
identification and management are essential to ensure safe use of
YERVOY. Monitor for signs and symptoms that may be clinical
manifestations of underlying immune-mediated adverse reactions.
Evaluate clinical chemistries including liver enzymes, creatinine,
adrenocorticotropic hormone (ACTH) level, and thyroid function at
baseline and before each dose. Institute medical management
promptly, including specialty consultation as appropriate.
Withhold or permanently discontinue YERVOY depending on
severity. In general, if YERVOY requires interruption or
discontinuation, administer systemic corticosteroid therapy (1 to 2
mg/kg/day prednisone or equivalent) until improvement to Grade 1 or
less followed by corticosteroid taper for at least 1 month.
Consider administration of other systemic immunosuppressants in
patients whose immune-mediated adverse reaction is not controlled
with corticosteroid therapy. Institute hormone replacement therapy
for endocrinopathies as warranted.
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 melanoma patients receiving OPDIVO 1
mg/kg with YERVOY 3 mg/kg, immune-mediated pneumonitis occurred in
6% (25/407) of patients. In HCC patients receiving OPDIVO 1 mg/kg
with YERVOY 3 mg/kg, immune-mediated pneumonitis occurred in 10%
(5/49) 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 NSCLC patients receiving OPDIVO 3
mg/kg with YERVOY 1 mg/kg, immune-mediated pneumonitis occurred in
9% (50/576) of patients, including Grade 4 (0.5%), Grade 3 (3.5%),
and Grade 2 (4.0%) immune-mediated pneumonitis. Four patients
(0.7%) died due to pneumonitis. The incidence and severity of
immune-mediated pneumonitis in patients with NSCLC treated with
OPDIVO 360 mg every 3 weeks in combination with YERVOY 1 mg/kg
every 6 weeks and 2 cycles of platinum-doublet chemotherapy were
comparable to treatment with OPDIVO in combination with YERVOY
only.
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 melanoma 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 HCC patients receiving OPDIVO 1 mg/kg with YERVOY 3
mg/kg, immune-mediated colitis occurred in 10% (5/49) of patients.
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 trial of YERVOY 3 mg/kg, immune-mediated
diarrhea/colitis occurred in 12% (62/511) of patients, including
Grade 3-5 (7%).
Cytomegalovirus (CMV) infection/reactivation has been reported
in patients with corticosteroid-refractory immune-mediated colitis.
In cases of corticosteroid-refractory colitis, consider repeating
infectious workup to exclude alternative etiologies. Addition of an
alternative immunosuppressive agent to the corticosteroid therapy,
or replacement of the corticosteroid therapy, should be considered
in corticosteroid-refractory immune-mediated colitis if other
causes are excluded.
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 melanoma patients receiving OPDIVO 1 mg/kg with
YERVOY 3 mg/kg, immune-mediated hepatitis occurred in 13% (51/407)
of patients. In HCC patients receiving OPDIVO 1 mg/kg with YERVOY 3
mg/kg, immune-mediated hepatitis occurred in 20% (10/49) 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 a separate Phase 3 trial of YERVOY 3 mg/kg, immune-mediated
hepatitis occurred in 4.1% (21/511) of patients, including Grade
3-5 (1.6%).
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. Withhold for Grades 2, 3, or 4 endocrinopathies if
not clinically stable. 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 melanoma patients receiving
OPDIVO 1 mg/kg with YERVOY 3 mg/kg, hypophysitis occurred in 9%
(36/407) of patients. In HCC patients receiving OPDIVO 1 mg/kg with
YERVOY 3 mg/kg, hypophysitis occurred in 4% (2/49) 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 melanoma patients
receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, adrenal insufficiency
occurred in 5% (21/407) of patients. In HCC patients receiving
OPDIVO 1 mg/kg with YERVOY 3 mg/kg, adrenal insufficiency occurred
in 18% (9/49) 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 melanoma
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
HCC patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg,
hypothyroidism or thyroiditis resulting in hypothyroidism occurred
in 22% (11/49) of patients. Hyperthyroidism occurred in 10% (5/49)
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 melanoma
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 trial of YERVOY 3 mg/kg, severe to
life-threatening endocrinopathies 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 melanoma
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 and Dermatologic Adverse
Reactions
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 melanoma patients receiving OPDIVO 1
mg/kg with YERVOY 3 mg/kg, immune-mediated rash occurred in 22.6%
(92/407) of patients. In HCC patients receiving OPDIVO 1 mg/kg with
YERVOY 3 mg/kg, immune-mediated rash occurred in 35% (17/49) of
patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1
mg/kg, immune-mediated rash occurred in 16% (90/547) 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.
YERVOY can cause immune-mediated rash or dermatitis, including
bullous and exfoliative dermatitis, Stevens Johnson syndrome (SJS)
and toxic epidermal necrolysis (TEN). Topical emollients and/or
topical corticosteroids may be adequate to treat mild to moderate
non-bullous exfoliative rashes. Withhold YERVOY until specialist
assessment for Grade 2 and permanently discontinue for Grade 3 or 4
exfoliative or bullous dermatologic conditions.
In a separate Phase 3 trial of YERVOY 3 mg/kg, immune-mediated
rash occurred in 15% (76/511) of patients, including Grade 3-5
(2.5%).
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 melanoma 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. Dose modifications for YERVOY for adverse reactions that
require management different from these general guidelines are
summarized as follows. Withhold for Grade 2 and permanently
discontinue YERVOY for Grade 3 or 4 neurological toxicities.
Withhold for Grade 2 and permanently discontinue YERVOY for Grade 3
or 4 myocarditis. Permanently discontinue YERVOY for Grade 2, 3, or
4 ophthalmologic adverse reactions that do not improve to Grade 1
within 2 weeks while receiving topical therapy OR that require
systemic 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. In addition to the
immune-mediated adverse reactions listed above, across clinical
trials of YERVOY monotherapy or in combination with OPDIVO, the
following clinically significant immune-mediated adverse reactions,
some with fatal outcome, occurred in <1% of patients unless
otherwise specified: autoimmune neuropathy (2%), meningitis,
encephalitis, myelitis and demyelination, myasthenic
syndrome/myasthenia gravis, nerve paresis, angiopathy, temporal
arteritis, pancreatitis (1.3%), arthritis, polymyositis,
conjunctivitis, cytopenias (2.5%), eosinophilia (2.1%), erythema
multiforme, hypersensitivity vasculitis, neurosensory hypoacusis,
psoriasis, blepharitis, episcleritis, orbital myositis, and
scleritis. Some cases of ocular IMARs have been associated with
retinal detachment.
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 YERVOY and
may require treatment with systemic steroids to reduce the risk of
permanent vision loss.
Infusion-Related Reactions
OPDIVO can cause severe infusion-related reactions, which have
been reported in <1.0% of patients in clinical trials.
Discontinue OPDIVO in patients with Grade 3 or 4 infusion-related
reactions. Interrupt or slow the rate of infusion in patients with
Grade 1 or 2. Severe infusion-related reactions can also occur with
YERVOY. Discontinue YERVOY in patients with severe or
life-threatening infusion reactions and interrupt or slow the rate
of infusion in patients with mild or moderate infusion reactions.
In patients receiving OPDIVO monotherapy as a 60-minute
infusion, infusion-related reactions occurred in 6.4% (127/1994) of
patients. In a separate trial 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 melanoma
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 HCC patients receiving OPDIVO 1 mg/kg with YERVOY 3
mg/kg, infusion-related reactions occurred in 8% (4/49) 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.
In separate Phase 3 trials of YERVOY 3 mg/kg and 10 mg/kg,
infusion-related reactions occurred in 2.9% (28/982).
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 or YERVOY. 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 or CTLA-4 receptor 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 or YERVOY
prior to or after an allogeneic HSCT.
Embryo-Fetal Toxicity
Based on mechanism 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
OPDIVO or YERVOY and for at least 5 months after the last dose.
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 OPDIVO or YERVOY, advise women
not to breastfeed during treatment and for at least 5 months after
the last dose.
Serious Adverse Reactions
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 227, serious adverse reactions occurred in 58% of
patients (n=576). The most frequent (≥2%) serious adverse reactions
were pneumonia, diarrhea/colitis, pneumonitis, hepatitis, pulmonary
embolism, adrenal insufficiency, and hypophysitis. Fatal adverse
reactions occurred in 1.7% of patients; these included events of
pneumonitis (4 patients), myocarditis, acute kidney injury, shock,
hyperglycemia, multi-system organ failure, and renal failure. In
Checkmate 9LA, serious adverse reactions occurred in 57% of
patients (n=358). The most frequent (>2%) serious adverse
reactions were pneumonia, diarrhea, febrile neutropenia, anemia,
acute kidney injury, musculoskeletal pain, dyspnea, pneumonitis,
and respiratory failure. Fatal adverse reactions occurred in 7 (2%)
patients, and included hepatic toxicity, acute renal failure,
sepsis, pneumonitis, diarrhea with hypokalemia, and massive
hemoptysis in the setting of thrombocytopenia. In Checkmate 214,
serious adverse reactions occurred in 59% of patients receiving
OPDIVO plus YERVOY. 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 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 59% of patients receiving OPDIVO with YERVOY (n=49). Serious
adverse reactions reported in ≥4% of patients were pyrexia,
diarrhea, anemia, increased AST, adrenal insufficiency, ascites,
esophageal varices hemorrhage, hyponatremia, increased blood
bilirubin, and pneumonitis.
Common Adverse Reactions
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 227, the most common (≥20%) adverse reactions were
fatigue (44%), rash (34%), decreased appetite (31%),
musculoskeletal pain (27%), diarrhea/colitis (26%), dyspnea (26%),
cough (23%), hepatitis (21%), nausea (21%), and pruritus (21%). In
Checkmate 9LA, the most common (>20%) adverse reactions were
fatigue (49%), musculoskeletal pain (39%), nausea (32%), diarrhea
(31%), rash (30%), decreased appetite (28%), constipation (21%),
and pruritus (21%). In Checkmate 214, the most common adverse
reactions (≥20%) reported in patients treated with OPDIVO plus
YERVOY (n=547) were fatigue (58%), rash (39%), diarrhea (38%),
musculoskeletal pain (37%), pruritus (33%), nausea (30%), cough
(28%), pyrexia (25%), arthralgia (23%), decreased appetite (21%),
dyspnea (20%), and vomiting (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 with YERVOY (n=49), were rash (53%),
pruritus (53%), musculoskeletal pain (41%), diarrhea (39%), cough
(37%), decreased appetite (35%), fatigue (27%), pyrexia (27%),
abdominal pain (22%), headache (22%), nausea (20%), dizziness
(20%), hypothyroidism (20%), and weight decreased (20%).
In a separate Phase 3 trial 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.
CheckMate Trials and Patient Populations
Checkmate 067–previously untreated metastatic melanoma, as a
single agent or in combination with YERVOY; Checkmate
227–previously untreated metastatic non-small cell lung cancer, in
combination with YERVOY; Checkmate 9LA–previously untreated
recurrent or metastatic non-small cell lung cancer in combination
with YERVOY and 2 cycles of platinum-doublet chemotherapy by
histology; Checkmate 214–previously untreated renal cell carcinoma,
in combination with YERVOY; Checkmate 142–MSI-H or dMMR metastatic
colorectal cancer, as a single agent or in combination with YERVOY;
Checkmate 040–hepatocellular carcinoma, as a single agent or in
combination with YERVOY
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, Facebook and
Instagram.
Celgene and Juno Therapeutics are wholly owned subsidiaries of
Bristol-Myers Squibb Company. In certain countries outside the
U.S., due to local laws, Celgene and Juno Therapeutics are referred
to as, Celgene, a Bristol Myers Squibb company and Juno
Therapeutics, a Bristol Myers Squibb company.
Cautionary Statement Regarding
Forward-Looking Statements
This press release contains “forward-looking statements” within
the meaning of the Private Securities Litigation Reform Act of 1995
regarding, among other things, 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, that
are difficult to predict, may be beyond our control and could cause
our future financial results, goals, plans and objectives to differ
materially from those expressed in, or implied by, the statements.
These risks, assumptions, uncertainties and other factors include,
among others, that future study results will be consistent with the
results to date, that Opdivo plus Yervoy may not receive regulatory
approval for the additional indication described in this release
and, if approved, whether such combination treatment for such
additional indication described in this release will be
commercially successful. No forward-looking statement can be
guaranteed. Forward-looking statements in this press release should
be evaluated together with the many risks and uncertainties that
affect Bristol Myers Squibb’s business and market, particularly
those identified in the cautionary statement and risk factors
discussion in Bristol Myers Squibb’s Annual Report on Form 10-K for
the year ended December 31, 2019, 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
applicable 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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