Approval recommended for first-line
treatment of advanced melanoma patients with tumor cell PD-L1
expression < 1%
Recommendation based on results from the
Phase 2/3 RELATIVITY-047 trial, in which the fixed-dose combination
of the PD-1 inhibitor nivolumab and novel LAG-3-blocking antibody
relatlimab more than doubled median progression-free survival
compared to nivolumab monotherapy
If approved, it would be the first LAG-3
blocking antibody combination in Europe
Bristol Myers Squibb (NYSE: BMY) today announced that the
Committee for Medicinal Products for Human Use (CHMP) of the
European Medicines Agency (EMA) has recommended approval of the
fixed-dose combination of nivolumab and relatlimab for the
first-line treatment of advanced (unresectable or metastatic)
melanoma in adults and adolescents 12 years of age and older with
tumor cell PD-L1 expression < 1%. The European Commission (EC),
which has the authority to approve medicines for the European Union
(EU), will now review the CHMP opinion.
“We are very proud of the role we have played in progressing the
treatment of advanced melanoma over the years. As part of our
mission to deliver new medicines for patients, we have continued to
develop new dual immunotherapy combinations,” said Paul Basciano,
development lead, relatlimab, Bristol Myers Squibb. “This positive
CHMP opinion marks the first step toward the potential approval of
the first LAG-3 blocking antibody combination – and the third
distinct checkpoint inhibitor for BMS – for advanced melanoma
patients in the EU.”
The positive opinion is based upon efficacy and safety results
from the Phase 2/3 RELATIVITY-047 trial. The trial showed that
treatment with the fixed-dose combination of nivolumab and
relatlimab more than doubled the median progression-free survival
(PFS), including in patients with tumor cell PD-L1 expression <
1%, when compared to nivolumab monotherapy – an established
standard of care. The proposed indication for the EU is based upon
an exploratory analysis of the data in patients with tumor cell
PD-L1 expression < 1%. No new safety events were identified with
the combination when compared to nivolumab monotherapy.
On March 18, 2022, the U.S. Food and Drug Administration (FDA)
approved the fixed-dose combination of nivolumab and relatlimab as
Opdualag™ (nivolumab and relatlimab-rmbw) for the treatment of
adult and pediatric patients 12 years of age or older with
unresectable or metastatic melanoma. Please see important safety
information from the U.S. prescribing information below.
Bristol Myers Squibb thanks the patients and investigators
involved in the RELATIVITY-047 trial.
About RELATIVITY-047
RELATIVITY-047 is a global, randomized, double-blind Phase 2/3
study evaluating the fixed-dose combination of nivolumab and
relatlimab versus nivolumab alone in patients with previously
untreated metastatic or unresectable melanoma. Patients were
enrolled regardless of tumor cell PD-L1 expression. The trial
excluded patients with active autoimmune disease, medical
conditions requiring systemic treatment with moderate or high dose
corticosteroids or immunosuppressive medications, uveal melanoma,
and active or untreated brain or leptomeningeal metastases. The
primary endpoint of the trial is progression-free survival (PFS)
determined by Blinded Independent Central Review (BICR) using
Response Evaluation Criteria in Solid Tumors (RECIST v1.1) in the
all-comer population. The secondary endpoints are overall survival
(OS) and objective response rate (ORR) in the all-comer population.
A total of 714 patients were randomized 1:1 to receive a fixed-dose
combination of nivolumab (480 mg) and relatlimab (160 mg) or
nivolumab (480 mg) by intravenous infusion every four weeks until
disease progression, unacceptable toxicity or withdrawal of
consent.
About LAG-3
Lymphocyte-activation gene 3 (LAG-3) is a cell-surface molecule
expressed on effector T cells and regulatory T cells (Tregs) and
functions to control T-cell response, activation and growth.
Preclinical studies indicate that inhibition of LAG-3 may restore
effector function of exhausted T cells and potentially promote an
anti-tumor response. Early research demonstrates that targeting
LAG-3 in combination with other potentially complementary immune
checkpoints may be a key strategy to more effectively potentiate
anti-tumor immune activity.
Bristol Myers Squibb is evaluating relatlimab, its
LAG-3-blocking antibody, in clinical trials in combination with
other agents in a variety of tumor types.
About 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 other organs. The incidence of melanoma has been
increasing steadily for the last 30 years. In the United States,
106,110 new diagnoses of melanoma and about 7,180 related deaths
are estimated for 2021. Globally, the World Health Organization
estimates that by 2035, melanoma incidence will reach 424,102, with
94,308 related deaths. Melanoma can be mostly treatable when caught
in its very early stages; however, survival rates can decrease as
the disease progresses.
Bristol Myers Squibb: Creating a Better
Future for People with Cancer
Bristol Myers Squibb is inspired by a single vision —
transforming patients’ lives through science. The goal of the
company’s cancer research is to deliver medicines that offer each
patient a better, healthier life and to make cure a possibility.
Building on a legacy across a broad range of cancers that have
changed survival expectations for many, Bristol Myers Squibb
researchers are exploring new frontiers in personalized medicine,
and through innovative digital platforms, are turning data into
insights that sharpen their focus. Deep scientific expertise,
cutting-edge capabilities and discovery platforms enable the
company to look at cancer from every angle. Cancer can have a
relentless grasp on many parts of a patient’s life, and Bristol
Myers Squibb is committed to taking actions to address all aspects
of care, from diagnosis to survivorship. Because as a leader in
cancer care, Bristol Myers Squibb is working to empower all people
with cancer to have a better future.
OPDUALAG U.S. INDICATION
Opdualag™ (nivolumab and relatlimab-rmbw) is indicated for the
treatment of adult and pediatric patients 12 years of age or older
with unresectable or metastatic melanoma.
OPDUALAG IMPORTANT SAFETY
INFORMATION
Severe and Fatal Immune-Mediated Adverse Reactions
Immune-mediated adverse reactions (IMARs) listed herein may not
include all possible severe and fatal immune-mediated adverse
reactions.
IMARs which may be severe or fatal, can occur in any organ
system or tissue. IMARs can occur at any time after starting
treatment with a LAG-3 and PD-1/PD-L1 blocking antibodies. While
IMARs usually manifest during treatment, they can also occur after
discontinuation of Opdualag. Early identification and management of
IMARs are essential to ensure safe use. Monitor patients closely
for symptoms and signs that may be clinical manifestations of
underlying IMARs. Evaluate clinical chemistries including liver
enzymes, creatinine, and thyroid function at baseline and
periodically during treatment. In cases of suspected IMARs,
initiate appropriate workup to exclude alternative etiologies,
including infection. Institute medical management promptly,
including specialty consultation as appropriate.
Withhold or permanently discontinue Opdualag depending on
severity (please see section 2 Dosage and Administration in the
accompanying Full Prescribing Information). In general, if Opdualag
requires interruption or discontinuation, administer systemic
corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent)
until improvement to Grade 1 or less. Upon improvement to Grade 1
or less, initiate corticosteroid taper and continue to taper over
at least 1 month. Consider administration of other systemic
immunosuppressants in patients whose IMARs are not controlled with
corticosteroid therapy. Toxicity management guidelines for adverse
reactions that do not necessarily require systemic steroids (e.g.,
endocrinopathies and dermatologic reactions) are discussed
below.
Immune-Mediated Pneumonitis
Opdualag can cause immune-mediated pneumonitis, which may be
fatal. In patients treated with other PD-1/PD-L1 blocking
antibodies, the incidence of pneumonitis is higher in patients who
have received prior thoracic radiation. Immune-mediated pneumonitis
occurred in 3.7% (13/355) of patients receiving Opdualag, including
Grade 3 (0.6%), and Grade 2 (2.3%) adverse reactions. Pneumonitis
led to permanent discontinuation of Opdualag in 0.8% and
withholding of Opdualag in 1.4% of patients.
Immune-Mediated Colitis
Opdualag can cause immune-mediated colitis, defined as requiring
use of corticosteroids and no clear alternate etiology. A common
symptom included in the definition of colitis was diarrhea.
Cytomegalovirus 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.
Immune-mediated diarrhea or colitis occurred in 7% (24/355) of
patients receiving Opdualag, including Grade 3 (1.1%) and Grade 2
(4.5%) adverse reactions. Colitis led to permanent discontinuation
of Opdualag in 2% and withholding of Opdualag in 2.8% of
patients.
Immune-Mediated Hepatitis
Opdualag can cause immune-mediated hepatitis, defined as
requiring the use of corticosteroids and no clear alternate
etiology.
Immune-mediated hepatitis occurred in 6% (20/355) of patients
receiving Opdualag, including Grade 4 (0.6%), Grade 3 (3.4%), and
Grade 2 (1.4%) adverse reactions. Hepatitis led to permanent
discontinuation of Opdualag in 1.7% and withholding of Opdualag in
2.3% of patients.
Immune-Mediated
Endocrinopathies
Opdualag can cause primary or secondary adrenal insufficiency,
hypophysitis, thyroid disorders, and Type 1 diabetes mellitus,
which can be present with diabetic ketoacidosis. Withhold or
permanently discontinue Opdualag depending on severity (please see
section 2 Dosage and Administration in the accompanying Full
Prescribing Information).
For Grade 2 or higher adrenal insufficiency, initiate
symptomatic treatment, including hormone replacement as clinically
indicated. In patients receiving Opdualag, adrenal insufficiency
occurred in 4.2% (15/355) of patients receiving Opdualag, including
Grade 3 (1.4%) and Grade 2 (2.5%) adverse reactions. Adrenal
insufficiency led to permanent discontinuation of Opdualag in 1.1%
and withholding of Opdualag in 0.8% of patients.
Hypophysitis can present with acute symptoms associated with
mass effect such as headache, photophobia, or visual field defects.
Hypophysitis can cause hypopituitarism; initiate hormone
replacement as clinically indicated. Hypophysitis occurred in 2.5%
(9/355) of patients receiving Opdualag, including Grade 3 (0.3%)
and Grade 2 (1.4%) adverse reactions. Hypophysitis led to permanent
discontinuation of Opdualag in 0.3% and withholding of Opdualag in
0.6% of patients.
Thyroiditis can present with or without endocrinopathy.
Hypothyroidism can follow hyperthyroidism; initiate hormone
replacement or medical management as clinically indicated.
Thyroiditis occurred in 2.8% (10/355) of patients receiving
Opdualag, including Grade 2 (1.1%) adverse reactions. Thyroiditis
did not lead to permanent discontinuation of Opdualag. Thyroiditis
led to withholding of Opdualag in 0.3% of patients. Hyperthyroidism
occurred in 6% (22/355) of patients receiving Opdualag, including
Grade 2 (1.4%) adverse reactions. Hyperthyroidism did not lead to
permanent discontinuation of Opdualag. Hyperthyroidism led to
withholding of Opdualag in 0.3% of patients. Hypothyroidism
occurred in 17% (59/355) of patients receiving Opdualag, including
Grade 2 (11%) adverse reactions. Hypothyroidism led to the
permanent discontinuation of Opdualag in 0.3% and withholding of
Opdualag in 2.5% of patients.
Monitor patients for hyperglycemia or other signs and symptoms
of diabetes; initiate treatment with insulin as clinically
indicated. Diabetes occurred in 0.3% (1/355) of patients receiving
Opdualag, a Grade 3 (0.3%) adverse reaction, and no cases of
diabetic ketoacidosis. Diabetes did not lead to the permanent
discontinuation or withholding of Opdualag in any patient.
Immune-Mediated Nephritis with Renal
Dysfunction
Opdualag can cause immune-mediated nephritis, which is defined
as requiring use of steroids and no clear etiology. In patients
receiving Opdualag, immune-mediated nephritis and renal dysfunction
occurred in 2% (7/355) of patients, including Grade 3 (1.1%) and
Grade 2 (0.8%) adverse reactions. Immune-mediated nephritis and
renal dysfunction led to permanent discontinuation of Opdualag in
0.8% and withholding of Opdualag in 0.6% of patients.
Withhold or permanently discontinue Opdualag depending on
severity (please see section 2 Dosage and Administration in the
accompanying Full Prescribing Information).
Immune-Mediated Dermatologic Adverse
Reactions
Opdualag can cause immune-mediated rash or dermatitis, defined
as requiring use of steroids and no clear alternate etiology.
Exfoliative dermatitis, including Stevens-Johnson syndrome, toxic
epidermal necrolysis, and Drug Rash with eosinophilia and systemic
symptoms has occurred with PD-1/L-1 blocking antibodies. Topical
emollients and/or topical corticosteroids may be adequate to treat
mild to moderate non-exfoliative rashes.
Withhold or permanently discontinue Opdualag depending on
severity (please see section 2 Dosage and Administration in the
accompanying Full Prescribing Information).
Immune-mediated rash occurred in 9% (33/355) of patients,
including Grade 3 (0.6%) and Grade 2 (3.4%) adverse reactions.
Immune-mediated rash did not lead to permanent discontinuation of
Opdualag. Immune-mediated rash led to withholding of Opdualag in
1.4% of patients.
Immune-Mediated Myocarditis
Opdualag can cause immune-mediated myocarditis, which is defined
as requiring use of steroids and no clear alternate etiology. The
diagnosis of immune-mediated myocarditis requires a high index of
suspicion. Patients with cardiac or cardio-pulmonary symptoms
should be assessed for potential myocarditis. If myocarditis is
suspected, withhold dose, promptly initiate high dose steroids
(prednisone or methylprednisolone 1 to 2 mg/kg/day) and promptly
arrange cardiology consultation with diagnostic workup. If
clinically confirmed, permanently discontinue Opdualag for Grade
2-4 myocarditis.
Myocarditis occurred in 1.7% (6/355) of patients receiving
Opdualag, including Grade 3 (0.6%), and Grade 2 (1.1%) adverse
reactions. Myocarditis led to permanent discontinuation of Opdualag
in 1.7% of patients.
Other Immune-Mediated Adverse
Reactions
The following clinically significant IMARs occurred at an
incidence of <1% (unless otherwise noted) in patients who
received Opdualag or were reported with the use of other PD-1/PD-L1
blocking antibodies. Severe or fatal cases have been reported for
some of these adverse reactions: Cardiac/Vascular: pericarditis,
vasculitis; Nervous System: meningitis, encephalitis, myelitis and
demyelination, myasthenic syndrome/myasthenia gravis (including
exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune
neuropathy; Ocular: uveitis, iritis, and other ocular inflammatory
toxicities can occur. Some cases can be associated with retinal
detachment. Various grades of visual impairment, including
blindness, can occur. If uveitis occurs in combination with other
IMARs, consider a Vogt-Koyanagi-Harada–like syndrome, as this may
require treatment with systemic steroids to reduce the risk of
permanent vision loss; Gastrointestinal: pancreatitis including
increases in serum amylase and lipase levels, gastritis,
duodenitis; Musculoskeletal and Connective Tissue:
myositis/polymyositis, rhabdomyolysis (and associated sequelae
including renal failure), arthritis, polymyalgia rheumatica;
Endocrine: hypoparathyroidism; Other (Hematologic/Immune):
hemolytic anemia, aplastic anemia, hemophagocytic
lymphohistiocytosis, systemic inflammatory response syndrome,
histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis),
sarcoidosis, immune thrombocytopenic purpura, solid organ
transplant rejection.
Infusion-Related Reactions
Opdualag can cause severe infusion-related reactions.
Discontinue Opdualag in patients with severe or life-threatening
infusion-related reactions. Interrupt or slow the rate of infusion
in patients with mild to moderate infusion-related reactions. In
patients who received Opdualag as a 60-minute intravenous infusion,
infusion-related reactions occurred in 7% (23/355) of patients.
Complications of Allogeneic Hematopoietic Stem Cell
Transplantation (HSCT)
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/PD-L1 receptor blocking
antibody. Transplant-related complications include hyperacute
graft-versus-host disease (GVHD), acute GVHD, chronic GVHD, hepatic
veno-occlusive disease after reduced intensity conditioning, and
steroid-requiring febrile syndrome (without an identified
infectious cause). These complications may occur despite
intervening therapy between PD-1/PD-L1 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/PD-L1 receptor blocking antibody
prior to or after an allogeneic HSCT.
Embryo-Fetal Toxicity
Based on its mechanism of action and data from animal studies,
Opdualag 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 Opdualag for at least 5 months
after the last dose of Opdualag.
Lactation
There are no data on the presence of Opdualag in human milk, the
effects on the breastfed child, or the effect on milk production.
Because nivolumab and relatlimab may be excreted in human milk and
because of the potential for serious adverse reactions in a
breastfed child, advise patients not to breastfeed during treatment
with Opdualag and for at least 5 months after the last dose.
Serious Adverse Reactions
In Relativity-047, fatal adverse reaction occurred in 3 (0.8%)
patients who were treated with Opdualag; these included
hemophagocytic lymphohistiocytosis, acute edema of the lung, and
pneumonitis. Serious adverse reactions occurred in 36% of patients
treated with Opdualag. The most frequent serious adverse reactions
reported in ≥1% of patients treated with Opdualag were adrenal
insufficiency (1.4%), anemia (1.4%), colitis (1.4%), pneumonia
(1.4%), acute myocardial infarction (1.1%), back pain (1.1%),
diarrhea (1.1%), myocarditis (1.1%), and pneumonitis (1.1%).
Common Adverse Reactions and Laboratory Abnormalities
The most common adverse reactions reported in ≥20% of the
patients treated with Opdualag were musculoskeletal pain (45%),
fatigue (39%), rash (28%), pruritus (25%), and diarrhea (24%).
The most common laboratory abnormalities that occurred in ≥20%
of patients treated with Opdualag were decreased hemoglobin (37%),
decreased lymphocytes (32%), increased AST (30%), increased ALT
(26%), and decreased sodium (24%).
Please see U.S. Full Prescribing Information for OPDUALAG.
OPDIVO U.S. INDICATIONS
OPDIVO® (nivolumab), as a single agent, is indicated for the
treatment of adult patients with unresectable or metastatic
melanoma.
OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab),
is indicated for the treatment of adult patients with unresectable
or metastatic melanoma.
OPDIVO® (nivolumab) is indicated for the adjuvant treatment of
adult patients with melanoma with involvement of lymph nodes or
metastatic disease who have undergone complete resection.
OPDIVO® (nivolumab), in combination with platinum-doublet
chemotherapy, is indicated as neoadjuvant treatment of adult
patients with resectable (tumors ≥4 cm or node positive) non-small
cell lung cancer (NSCLC).
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) is indicated for the treatment of adult
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), in combination with YERVOY® (ipilimumab),
is indicated for the first-line treatment of adult patients with
unresectable malignant pleural mesothelioma (MPM).
OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab),
is indicated for the first-line treatment of adult patients with
intermediate or poor risk advanced renal cell carcinoma (RCC).
OPDIVO® (nivolumab), in combination with cabozantinib, is
indicated for the first-line treatment of adult patients with
advanced renal cell carcinoma (RCC).
OPDIVO® (nivolumab) is indicated for the treatment of adult
patients with advanced renal cell carcinoma (RCC) who have received
prior anti-angiogenic therapy.
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 adult
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 adult
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.
OPDIVO® (nivolumab), as a single agent, is indicated for the
adjuvant treatment of adult patients with urothelial carcinoma (UC)
who are at high risk of recurrence after undergoing radical
resection of UC.
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), in combination with YERVOY® (ipilimumab),
is indicated for the treatment of adult 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.
OPDIVO® (nivolumab) is indicated for the treatment of adult
patients with unresectable advanced, recurrent or metastatic
esophageal squamous cell carcinoma (ESCC) after prior
fluoropyrimidine- and platinum-based chemotherapy.
OPDIVO® (nivolumab) is indicated for the adjuvant treatment of
completely resected esophageal or gastroesophageal junction cancer
with residual pathologic disease in adult patients who have
received neoadjuvant chemoradiotherapy (CRT).
OPDIVO® (nivolumab), in combination with fluoropyrimidine- and
platinum-containing chemotherapy, is indicated for the first-line
treatment of adult patients with unresectable advanced or
metastatic esophageal squamous cell carcinoma (ESCC).
OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab),
is indicated for the first-line treatment of adult patients with
unresectable advanced or metastatic esophageal squamous cell
carcinoma (ESCC).
OPDIVO® (nivolumab), in combination with fluoropyrimidine- and
platinum- containing chemotherapy, is indicated for the treatment
of adult patients with advanced or metastatic gastric cancer,
gastroesophageal junction cancer, and esophageal
adenocarcinoma.
IMPORTANT SAFETY
INFORMATION
Severe and Fatal Immune-Mediated Adverse Reactions
Immune-mediated adverse reactions listed herein may not include
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 after discontinuation of OPDIVO or YERVOY. Early
identification and management are essential to ensure safe use of
OPDIVO and 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 periodically during treatment with OPDIVO
and before each dose of YERVOY. In cases of suspected
immune-mediated adverse reactions, initiate appropriate workup to
exclude alternative etiologies, including infection. Institute
medical management promptly, including specialty consultation as
appropriate.
Withhold or permanently discontinue OPDIVO and YERVOY depending
on severity (please see section 2 Dosage and Administration in the
accompanying Full Prescribing Information). In general, if OPDIVO
or YERVOY interruption or discontinuation is required, administer
systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or
equivalent) until improvement to Grade 1 or less. Upon improvement
to Grade 1 or less, initiate corticosteroid taper and continue to
taper over at least 1 month. Consider administration of other
systemic immunosuppressants in patients whose immune-mediated
adverse reactions are not controlled with corticosteroid therapy.
Toxicity management guidelines for adverse reactions that do not
necessarily require systemic steroids (e.g., endocrinopathies and
dermatologic reactions) are discussed below.
Immune-Mediated Pneumonitis
OPDIVO and YERVOY can cause immune-mediated pneumonitis. The
incidence of pneumonitis is higher in patients who have received
prior thoracic radiation. In patients receiving OPDIVO monotherapy,
immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients,
including Grade 4 (<0.1%), Grade 3 (0.9%), and Grade 2 (2.1%).
In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3
weeks, immune-mediated pneumonitis occurred in 7% (31/456) of
patients, including Grade 4 (0.2%), Grade 3 (2.0%), and Grade 2
(4.4%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg
every 3 weeks, immune-mediated pneumonitis occurred in 3.9%
(26/666) of patients, including Grade 3 (1.4%) and Grade 2 (2.6%).
In NSCLC patients receiving OPDIVO 3 mg/kg every 2 weeks with
YERVOY 1 mg/kg every 6 weeks, immune-mediated pneumonitis occurred
in 9% (50/576) of patients, including Grade 4 (0.5%), Grade 3
(3.5%), and Grade 2 (4.0%). Four patients (0.7%) died due to
pneumonitis.
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, including Grade 3 (n=1) and Grade 2
(n=12).
Immune-Mediated Colitis
OPDIVO and YERVOY can cause immune-mediated colitis, which may
be fatal. A common symptom included in the definition of colitis
was diarrhea. 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. In
patients receiving OPDIVO monotherapy, immune-mediated colitis
occurred in 2.9% (58/1994) of patients, including Grade 3 (1.7%)
and Grade 2 (1%). Inpatients receiving OPDIVO 1 mg/kg with YERVOY 3
mg/kg every 3 weeks, immune-mediated colitis occurred in 25%
(115/456) of patients, including Grade 4 (0.4%), Grade 3 (14%) and
Grade 2 (8%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1
mg/kg every 3 weeks, immune-mediated colitis occurred in 9%
(60/666) of patients, including Grade 3 (4.4%) and Grade 2
(3.7%).
Immune-Mediated Hepatitis and
Hepatotoxicity
OPDIVO and YERVOY can cause immune-mediated hepatitis. In
patients receiving OPDIVO monotherapy, immune-mediated hepatitis
occurred in 1.8% (35/1994) of patients, including Grade 4 (0.2%),
Grade 3(1.3%), and Grade 2 (0.4%). In patients receiving OPDIVO 1
mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated hepatitis
occurred in 15% (70/456) of patients, including Grade 4 (2.4%),
Grade 3 (11%), and Grade 2(1.8%). In patients receiving OPDIVO 3
mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated hepatitis
occurred in 7% (48/666) of patients, including Grade 4 (1.2%),
Grade 3 (4.9%), and Grade 2 (0.4%).
OPDIVO in combination with cabozantinib can cause hepatic
toxicity with higher frequencies of Grade 3 and 4ALT and AST
elevations compared to OPDIVO alone. Consider more frequent
monitoring of liver enzymes as compared to when the drugs are
administered as single agents. In patients receiving OPDIVO and
cabozantinib, Grades 3 and 4 increased ALT or AST were seen in 11%
of patients.
Immune-Mediated
Endocrinopathies
OPDIVO and YERVOY can cause primary or secondary adrenal
insufficiency, immune-mediated hypophysitis, immune-mediated
thyroid disorders, and Type 1 diabetes mellitus, which can present
with diabetic ketoacidosis. Withhold OPDIVO and YERVOY depending on
severity (please see section 2 Dosage and Administration in the
accompanying Full Prescribing Information). For Grade 2 or higher
adrenal insufficiency, initiate symptomatic treatment, including
hormone replacement as clinically indicated. Hypophysitis can
present with acute symptoms associated with mass effect such as
headache, photophobia, or visual field defects. Hypophysitis can
cause hypopituitarism; initiate hormone replacement as clinically
indicated. Thyroiditis can present with or without endocrinopathy.
Hypothyroidism can follow hyperthyroidism; initiate hormone
replacement or medical management as clinically indicated. Monitor
patients for hyperglycemia or other signs and symptoms of diabetes;
initiate treatment with insulin as clinically indicated.
In patients receiving OPDIVO monotherapy, adrenal insufficiency
occurred in 1% (20/1994), including Grade 3(0.4%) and Grade 2
(0.6%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg
every 3 weeks, adrenalin sufficiency occurred in 8% (35/456),
including Grade 4 (0.2%), Grade 3 (2.4%), and Grade 2 (4.2%). In
patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3
weeks, adrenal insufficiency occurred in 7% (48/666) of patients,
including Grade 4 (0.3%), Grade 3 (2.5%), and Grade 2 (4.1%). In
patients receiving OPDIVO and cabozantinib, adrenal insufficiency
occurred in 4.7% (15/320) of patients, including Grade 3 (2.2%) and
Grade 2 (1.9%).
In patients receiving OPDIVO monotherapy, hypophysitis occurred
in 0.6% (12/1994) of patients, including Grade 3 (0.2%) and Grade 2
(0.3%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg
every 3 weeks, hypophysitis occurred in 9% (42/456), including
Grade 3 (2.4%) and Grade 2 (6%). In patients receiving OPDIVO3
mg/kg with YERVOY 1 mg/kg every 3 weeks, hypophysitis occurred in
4.4% (29/666) of patients, including Grade 4 (0.3%), Grade 3
(2.4%), and Grade 2 (0.9%).
In patients receiving OPDIVO monotherapy, thyroiditis occurred
in 0.6% (12/1994) of patients, including Grade 2 (0.2%). In
patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3
weeks, thyroiditis occurred in 2.7% (22/666) of patients, including
Grade 3 (4.5%) and Grade 2 (2.2%).
In patients receiving OPDIVO monotherapy, hyperthyroidism
occurred in 2.7% (54/1994) of patients, including Grade 3
(<0.1%) and Grade 2 (1.2%). In patients receiving OPDIVO 1 mg/kg
with YERVOY 3 mg/kg every 3weeks, hyperthyroidism occurred in 9%
(42/456) of patients, including Grade 3 (0.9%) and Grade 2 (4.2%).
Inpatients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3
weeks, hyperthyroidism occurred in 12% (80/666) of patients,
including Grade 3 (0.6%) and Grade 2 (4.5%).
In patients receiving OPDIVO monotherapy, hypothyroidism
occurred in 8% (163/1994) of patients, including Grade 3 (0.2%) and
Grade 2 (4.8%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3
mg/kg every 3 weeks, hypothyroidism occurred in 20% (91/456) of
patients, including Grade 3 (0.4%) and Grade 2 (11%). Inpatients
receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks,
hypothyroidism occurred in 18% (122/666) of patients, including
Grade 3 (0.6%) and Grade 2 (11%).
In patients receiving OPDIVO monotherapy, diabetes occurred in
0.9% (17/1994) of patients, including Grade 3(0.4%) and Grade 2
(0.3%), and 2 cases of diabetic ketoacidosis. In patients receiving
OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, diabetes occurred
in 2.7% (15/666) of patients, including Grade 4 (0.6%), Grade 3
(0.3%), and Grade 2 (0.9%).
Immune-Mediated Nephritis with Renal
Dysfunction
OPDIVO and YERVOY can cause immune-mediated nephritis. In
patients receiving OPDIVO monotherapy, immune-mediated nephritis
and renal dysfunction occurred in 1.2% (23/1994) of patients,
including Grade 4(<0.1%), Grade 3 (0.5%), and Grade 2 (0.6%). In
patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3
weeks, immune-mediated nephritis with renal dysfunction occurred in
4.1% (27/666) of patients, including Grade 4 (0.6%), Grade 3
(1.1%), and Grade 2 (2.2%).
Immune-Mediated Dermatologic Adverse
Reactions
OPDIVO can cause immune-mediated rash or dermatitis. Exfoliative
dermatitis, including Stevens-Johnson syndrome (SJS), toxic
epidermal necrolysis (TEN), and drug rash with eosinophilia and
systemic symptoms (DRESS) has occurred with PD-1/PD-L1 blocking
antibodies. Topical emollients and/or topical corticosteroids maybe
adequate to treat mild to moderate nonexfoliative rashes.
YERVOY can cause immune-mediated rash or dermatitis, including
bullous and exfoliative dermatitis, SJS, TEN, and DRESS. Topical
emollients and/or topical corticosteroids may be adequate to treat
mild to moderate non-bullous/exfoliative rashes.
Withhold or permanently discontinue OPDIVO and YERVOY depending
on severity (please see section 2 Dosage and Administration in the
accompanying Full Prescribing Information).
In patients receiving OPDIVO monotherapy, immune-mediated rash
occurred in 9% (171/1994) of patients, including Grade 3 (1.1%) and
Grade 2 (2.2%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3
mg/kg every 3 weeks, immune-mediated rash occurred in 28% (127/456)
of patients, including Grade 3 (4.8%) and Grade 2 (10%). In
patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3
weeks, immune-mediated rash occurred in 16% (108/666) of patients,
including Grade 3 (3.5%) and Grade 2 (4.2%).
Other Immune-Mediated Adverse
Reactions
The following clinically significant immune-mediated adverse
reactions occurred at an incidence of <1% (unless otherwise
noted) in patients who received OPDIVO monotherapy or OPDIVO in
combination with YERVOY or were reported with the use of other
PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been
reported for some of these adverse reactions: cardiac/vascular:
myocarditis, pericarditis, vasculitis; nervous system: meningitis,
encephalitis, myelitis and demyelination, myasthenic
syndrome/myasthenia gravis (including exacerbation), Guillain-Barré
syndrome, nerve paresis, autoimmune neuropathy; ocular: uveitis,
iritis, and other ocular inflammatory toxicities can occur;
gastrointestinal: pancreatitis to include increases in serum
amylase and lipase levels, gastritis, duodenitis; musculoskeletal
and connective tissue: myositis/polymyositis, rhabdomyolysis, and
associated sequelae including renal failure, arthritis, polymyalgia
rheumatica; endocrine: hypoparathyroidism; other
(hematologic/immune): hemolytic anemia, aplastic anemia,
hemophagocytic lymphohistiocytosis (HLH),systemic inflammatory
response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi
lymphadenitis),sarcoidosis, immune thrombocytopenic purpura, solid
organ transplant rejection.
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: nervous
system: autoimmune neuropathy (2%), myasthenic syndrome/myasthenia
gravis, motor dysfunction; cardiovascular: angiopathy, temporal
arteritis; ocular: blepharitis, episcleritis, orbital myositis,
scleritis; gastrointestinal: pancreatitis (1.3%);
other(hematologic/immune):conjunctivitis, cytopenias (2.5%),
eosinophilia (2.1%), erythema multiforme, hypersensitivity
vasculitis, neurosensory hypoacusis, psoriasis.
Some ocular IMAR cases can be associated with retinal
detachment. Various grades of visual impairment, including
blindness, can occur. 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, as this may require treatment
with systemic corticosteroids to reduce the risk of permanent
vision loss.
Infusion-Related Reactions
OPDIVO and YERVOY can cause severe infusion-related reactions.
Discontinue OPDIVO and YERVOY in patients with severe (Grade 3) or
life-threatening (Grade 4) infusion-related reactions. Interrupt or
slow the rate of infusion in patients with mild (Grade 1) or
moderate (Grade 2) infusion-related 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
48hours 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 every
3 weeks, infusion-related reactions occurred in 8% (4/49) of
patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1
mg/kg every 3 weeks, 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 every 3 weeks, infusion-related
reactions occurred in 4.2% (5/119) of patients. In MPM patients
receiving OPDIVO 3 mg/kg every 2 weeks with YERVOY 1 mg/kg every 6
weeks, infusion-related reactions occurred in 12% (37/300) 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 OPDIVO 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 OPDIVO or YERVOY and allogeneic
HSCT.
Follow patients closely for evidence of transplant-related
complications and intervene promptly. Consider the benefit versus
risks of treatment with OPDIVO and YERVOY prior to or after an
allogeneic HSCT.
Embryo-Fetal Toxicity
Based on its mechanism of action and findings from animal
studies, OPDIVO and YERVOY can cause fetal harm when administered
to a pregnant woman. The effects of YERVOY are likely to be greater
during the second and third trimesters of pregnancy. Advise
pregnant women of the potential risk to a fetus. Advise females of
reproductive potential to use effective contraception during
treatment with OPDIVO and 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 randomized 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 orPD-L1 blocking antibody in
combination with a thalidomide analogue plus dexamethasone is not
recommended outside of controlled clinical trials.
Lactation
There are no data on the presence of OPDIVO or YERVOY in human
milk, the effects on the breastfed child, or the effects on milk
production. Because of the potential for serious adverse reactions
in breastfed children, advise women not to breastfeed during
treatment and for 5 months after the last 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-glutamyl transferase 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 238, serious adverse
reactions occurred in 18% of patients receiving OPDIVO (n=452).
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. In Checkmate 816, serious adverse
reactions occurred in 30% of patients (n=176) who were treated with
OPDIVO in combination with platinum-doublet chemotherapy. Serious
adverse reactions in >2% included pneumonia and vomiting. No
fatal adverse reactions occurred in patients who received OPDIVO in
combination with platinum-doublet chemotherapy. 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 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 057, fatal
adverse reactions occurred; these included events of infection (7
patients, including one case of Pneumocystis jirovecii
pneumonia),pulmonary embolism (4 patients), and limbic encephalitis
(1 patient). In Checkmate 743, serious adverse reactions occurred
in 54% of patients receiving OPDIVO plus YERVOY. The most frequent
serious adverse reactions reported in ≥2% of patients were
pneumonia, pyrexia, diarrhea, pneumonitis, pleural effusion,
dyspnea, acute kidney injury, infusion-related reaction,
musculoskeletal pain, and pulmonary embolism. Fatal adverse
reactions occurred in 4 (1.3%) patients and included pneumonitis,
acute heart failure, sepsis, and encephalitis. In Checkmate 214,
serious adverse reactions occurred in 59% of patients receiving
OPDIVO plus YERVOY(n=547). 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 9ER, serious
adverse reactions occurred in 48% of patients receiving OPDIVO and
cabozantinib(n=320). The most frequent serious adverse reactions
reported in ≥2% of patients were diarrhea, pneumonia, pneumonitis,
pulmonary embolism, urinary tract infection, and hyponatremia.
Fatal intestinal perforations occurred in 3 (0.9%) patients. 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 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 274, serious adverse reactions occurred
in 30% of patients receiving OPDIVO (n=351). The most frequent
serious adverse reaction reported in ≥2% of patients receiving
OPDIVO was urinary tract infection. Fatal adverse reactions
occurred in 1% of patients; these included events of pneumonitis
(0.6%). In Checkmate 142 in MSI-H/dMMR mCRC patients receiving
OPDIVO with YERVOY (n=119), 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. In Attraction-3, serious adverse reactions occurred in
38% of patients receiving OPDIVO (n=209). Serious adverse reactions
reported in ≥2% of patients who received OPDIVO were pneumonia,
esophageal fistula, interstitial lung disease, and pyrexia. The
following fatal adverse reactions occurred in patients who received
OPDIVO: interstitial lung disease or pneumonitis (1.4%), pneumonia
(1.0%), septic shock (0.5%), esophageal fistula (0.5%),
gastrointestinal hemorrhage (0.5%), pulmonary embolism (0.5%), and
sudden death (0.5%). In Checkmate 577, serious adverse reactions
occurred in 33% of patients receiving OPDIVO (n=532). A serious
adverse reaction reported in ≥2% of patients who received OPDIVO
was pneumonitis. A fatal reaction of myocardial infarction occurred
in one patient who received OPDIVO. In Checkmate 648, serious
adverse reactions occurred in 62% of patients receiving OPDIVO in
combination with chemotherapy (n=310). The most frequent serious
adverse reactions reported in ≥2% of patients who received OPDIVO
with chemotherapy were pneumonia (11%), dysphagia (7%), esophageal
stenosis (2.9%), acute kidney injury (2.9%), and pyrexia (2.3%).
Fatal adverse reactions occurred in 5 (1.6%) patients who received
OPDIVO in combination with chemotherapy; these included
pneumonitis, pneumatosis intestinalis, pneumonia, and acute kidney
injury. In Checkmate 648, serious adverse reactions occurred in 69%
of patients receiving OPDIVO in combination with YERVOY (n=322).
The most frequent serious adverse reactions reported in ≥2% who
received OPDIVO in combination with YERVOY were pneumonia (10%),
pyrexia (4.3%), pneumonitis (4.0%), aspiration pneumonia (3.7%),
dysphagia (3.7%), hepatic function abnormal (2.8%), decreased
appetite (2.8%), adrenal insufficiency (2.5%), and dehydration
(2.5%). Fatal adverse reactions occurred in 5 (1.6%) patients who
received OPDIVO in combination with YERVOY; these included
pneumonitis, interstitial lung disease, pulmonary embolism, and
acute respiratory distress syndrome. In Checkmate 649, serious
adverse reactions occurred in 52% of patients treated with OPDIVO
in combination with chemotherapy (n=782). The most frequent serious
adverse reactions reported in ≥2% of patients treated with OPDIVO
in combination with chemotherapy were vomiting (3.7%), pneumonia
(3.6%), anemia (3.6%), pyrexia (2.8%), diarrhea (2.7%), febrile
neutropenia (2.6%), and pneumonitis (2.4%). Fatal adverse reactions
occurred in 16 (2.0%) patients who were treated with OPDIVO in
combination with chemotherapy; these included pneumonitis (4
patients), febrile neutropenia (2 patients), stroke (2 patients),
gastrointestinal toxicity, intestinal mucositis, septic shock,
pneumonia, infection, gastrointestinal bleeding, mesenteric vessel
thrombosis, and disseminated intravascular coagulation.
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%), Musculo
skeletal 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 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 Checkmate 816, the most common (>20%) adverse
reactions in the OPDIVO plus chemotherapy arm (n=176) were nausea
(38%), constipation (34%), fatigue (26%), decreased appetite (20%),
and rash (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 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 743, the most common adverse reactions
(≥20%) in patients receiving OPDIVO plus YERVOY were fatigue (43%),
musculoskeletal pain (38%), rash (34%), diarrhea (32%), dyspnea
(27%), nausea (24%),decreased appetite (24%), cough (23%), 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 9ER, the most common adverse
reactions (≥20%) in patients receiving OPDIVO and cabozantinib
(n=320) were diarrhea (64%),fatigue (51%), hepatotoxicity (44%),
palmar-plantar erythrodysaesthesia syndrome (40%), stomatitis
(37%), rash (36%), hypertension (36%), hypothyroidism (34%),
musculoskeletal pain (33%), decreased appetite (28%),nausea (27%),
dysgeusia (24%), abdominal pain (22%), cough (20%) and upper
respiratory tract infection (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 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 (14%) and dyspnea (14%) 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 274, the
most common adverse reactions (≥20%) reported in patients receiving
OPDIVO (n=351) were rash (36%), fatigue (36%), diarrhea (30%),
pruritus (30%), musculoskeletal pain (28%), and urinary tract
infection (22%). In Checkmate 142 in MSI-H/dMMR mCRC patients
receiving OPDIVO as a single agent (n=74), 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 (n=119), 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 Attraction-3, the most common adverse reactions
(≥20%) in OPDIVO-treated patients (n=209) were rash (22%) and
decreased appetite (21%). In Checkmate 577, the most common adverse
reactions (≥20%) in patients receiving OPDIVO (n=532) were fatigue
(34%), diarrhea (29%), nausea (23%), rash (21%), musculoskeletal
pain (21%), and cough (20%). In Checkmate 648, the most common
adverse reactions (≥20%) in patients treated with OPDIVO in
combination with chemotherapy (n=310) were nausea (65%), decreased
appetite (51%), fatigue (47%), constipation (44%), stomatitis
(44%), diarrhea (29%), and vomiting (23%). In Checkmate 648, the
most common adverse reactions reported in ≥20% of patients treated
with OPDIVO in combination with YERVOY were rash (31%), fatigue
(28%), pyrexia (23%), nausea (22%), diarrhea (22%), and
constipation (20%). In Checkmate 649, the most common adverse
reactions (≥20%) in patients treated with OPDIVO in combination
with chemotherapy(n=782) were peripheral neuropathy (53%), nausea
(48%), fatigue (44%), diarrhea (39%), vomiting (31%), decreased
appetite (29%), abdominal pain (27%), constipation (25%), and
musculoskeletal pain (20%).
Please see US Full Prescribing Information for OPDIVO and
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.
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 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 the CHMP opinion is not binding on the EMA/EC, that the
fixed-dose combination of nivolumab and relatlimab may not receive
regulatory approval for the indication described in this release in
the currently anticipated timeline or at all, any marketing
approvals, if granted, may have significant limitations on their
use, and, if approved, whether such combination treatment for such
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, 2021, 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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