Bristol-Myers Squibb Company (NYSE: BMY) today announced
five-year follow-up results from the Phase 3 CheckMate -025 study,
which continue to demonstrate that treatment with Opdivo
(nivolumab) delivers superior overall survival (OS) and objective
response rates (ORR) in patients with previously treated advanced
or metastatic renal cell carcinoma (RCC) compared to those treated
with everolimus. The data will be presented on Saturday, February
15 at the American Society of Clinical Oncology 2020 Genitourinary
Cancers Symposium in San Francisco.
With an extended minimum follow-up of 64 months, patients
treated with Opdivo continue to demonstrate OS benefit with 26% of
patients alive compared to 18% of patients treated with everolimus.
Additionally, the percentage of patients experiencing an objective
response was 23% for Opdivo versus 4% for everolimus and the median
duration of response (mDOR) for Opdivo was also maintained longer
than for everolimus (18.2 months vs. 14 months, respectively). The
overall safety profile was consistent with that observed in
previously reported analyses from CheckMate -025 in patients with
RCC. No new safety signals or drug-related deaths occurred with
extended follow-up.
“Five-year survival results from the CheckMate -025 study, along
with the ongoing response rates observed in the trial, highlight
the potential for long-term survival and efficacy of nivolumab
monotherapy for patients with previously-treated advanced RCC,”
said lead investigator Robert J. Motzer, MD, Kidney Cancer Section
Head, Memorial Sloan Kettering Cancer Center. “These data represent
the longest follow-up for a PD-1 immune checkpoint inhibitor in
this setting and underscore the potential increased survival rates
nivolumab can deliver for patients with advanced RCC who have
received prior antiangiogenic therapy.”
“The updated CheckMate -025 results support why Opdivo
monotherapy became a standard of care for previously treated RCC
patients worldwide and offer additional evidence that treatment
with Opdivo has the potential to help patients live longer,” said
Brian Lamon, Ph.D., development lead, genitourinary cancers,
Bristol-Myers Squibb. “This study represents exciting progress in
our mission to improve survival outcomes for all patients.”
About CheckMate -025
CheckMate -025 is an open-label, randomized Phase 3 study of
Opdivo versus everolimus in patients with previously treated
advanced renal cell carcinoma (RCC) after prior anti-angiogenic
therapy. Patients (n=803) received either Opdivo (n=406) 3 mg/kg
intravenously (IV) every two weeks or everolimus (n=397) 10 mg
orally once daily until disease progression or unacceptable
toxicity. The primary endpoint of the study was overall survival
(OS). Secondary endpoints included objective response rate (ORR),
progression-free survival (PFS), quality of life (QoL) and
safety.
With a minimum of five years of follow-up, the incidence and
type of treatment-related adverse events (AEs) were consistent with
the primary analysis. Treatment-related grade 3/4 AEs were
experienced by 21% of patients in the Opdivo group and 37% in the
everolimus group.
About Renal Cell
Carcinoma
Renal cell carcinoma (RCC) is the most common type of kidney
cancer in adults, accounting for more than 140,000 deaths worldwide
each year. RCC is approximately twice as common in men as in women,
with the highest rates of the disease in North America and Europe.
Globally, the five-year survival rate for those diagnosed with
metastatic, or advanced, kidney cancer is 12.1%.
Bristol-Myers Squibb: Advancing
Oncology Research
At Bristol-Myers Squibb, patients are at the center of
everything we do. The focus of our research is to increase quality,
long-term survival for patients and make cure a possibility.
Through a unique multidisciplinary approach powered by
translational science, we harness our deep scientific experience in
oncology and Immuno-Oncology (I-O) research to identify novel
treatments tailored to individual patient needs. Our researchers
are developing a diverse, purposefully built pipeline designed to
target different immune system pathways and address the complex and
specific interactions between the tumor, its microenvironment and
the immune system. We source innovation internally, and in
collaboration with academia, government, advocacy groups and
biotechnology companies, to help make the promise of
transformational medicines, like I-O, a reality for patients.
About Opdivo
Opdivo is a programmed death-1 (PD-1) immune checkpoint
inhibitor that is designed to uniquely harness the body’s own
immune system to help restore anti-tumor immune response. By
harnessing the body’s own immune system to fight cancer, Opdivo has
become an important treatment option across multiple cancers.
Opdivo’s leading global development program is based on
Bristol-Myers Squibb’s scientific expertise in the field of
Immuno-Oncology, and includes a broad range of clinical trials
across all phases, including Phase 3, in a variety of tumor types.
To date, the Opdivo clinical development program has 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.
U.S. FDA-APPROVED INDICATIONS FOR
OPDIVO®
OPDIVO® (nivolumab) as a single agent is indicated for the
treatment of patients with unresectable or metastatic melanoma.
OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab),
is indicated for the treatment of patients with unresectable or
metastatic melanoma.
OPDIVO® (nivolumab) is indicated for the treatment of patients
with metastatic non-small cell lung cancer (NSCLC) with progression
on or after platinum-based chemotherapy. Patients with EGFR or ALK
genomic tumor aberrations should have disease progression on
FDA-approved therapy for these aberrations prior to receiving
OPDIVO.
OPDIVO® (nivolumab) is indicated for the treatment of patients
with metastatic small cell lung cancer (SCLC) with progression
after platinum-based chemotherapy and at least one other line of
therapy. This indication is approved under accelerated approval
based on overall response rate and duration of response. Continued
approval for this indication may be contingent upon verification
and description of clinical benefit in confirmatory trials.
OPDIVO® (nivolumab) is indicated for the treatment of patients
with advanced renal cell carcinoma (RCC) who have received prior
anti-angiogenic therapy.
OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab),
is indicated for the treatment of patients with intermediate or
poor risk, previously untreated advanced renal cell carcinoma
(RCC).
OPDIVO® (nivolumab) is indicated for the treatment of adult
patients with classical Hodgkin lymphoma (cHL) that has relapsed or
progressed after autologous hematopoietic stem cell transplantation
(HSCT) and brentuximab vedotin or after 3 or more lines of systemic
therapy that includes autologous HSCT. This indication is approved
under accelerated approval based on overall response rate.
Continued approval for this indication may be contingent upon
verification and description of clinical benefit in confirmatory
trials.
OPDIVO® (nivolumab) is indicated for the treatment of patients
with recurrent or metastatic squamous cell carcinoma of the head
and neck (SCCHN) with disease progression on or after
platinum-based therapy.
OPDIVO® (nivolumab) is indicated for the treatment of patients
with locally advanced or metastatic urothelial carcinoma who have
disease progression during or following platinum-containing
chemotherapy or have disease progression within 12 months of
neoadjuvant or adjuvant treatment with platinum-containing
chemotherapy. This indication is approved under accelerated
approval based on tumor response rate and duration of response.
Continued approval for this indication may be contingent upon
verification and description of clinical benefit in confirmatory
trials.
OPDIVO® (nivolumab), as a single agent, is indicated for the
treatment of adult and pediatric (12 years and older) patients with
microsatellite instability-high (MSI-H) or mismatch repair
deficient (dMMR) metastatic colorectal cancer (CRC) that has
progressed following treatment with a fluoropyrimidine,
oxaliplatin, and irinotecan. This indication is approved under
accelerated approval based on overall response rate and duration of
response. Continued approval for this indication may be contingent
upon verification and description of clinical benefit in
confirmatory trials.
OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab),
is indicated for the treatment of adults and pediatric patients 12
years and older with microsatellite instability-high (MSI-H) or
mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC)
that has progressed following treatment with a fluoropyrimidine,
oxaliplatin, and irinotecan. This indication is approved under
accelerated approval based on overall response rate and duration of
response. Continued approval for this indication may be contingent
upon verification and description of clinical benefit in
confirmatory trials.
OPDIVO® (nivolumab) is indicated for the treatment of patients
with hepatocellular carcinoma (HCC) who have been previously
treated with sorafenib. This indication is approved under
accelerated approval based on tumor response rate and durability of
response. Continued approval for this indication may be contingent
upon verification and description of clinical benefit in the
confirmatory trials.
OPDIVO® (nivolumab) is indicated for the adjuvant treatment of
patients with melanoma with involvement of lymph nodes or
metastatic disease who have undergone complete resection.
IMPORTANT SAFETY
INFORMATION
WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS
YERVOY can result in severe and fatal immune-mediated adverse
reactions. These immune-mediated reactions may involve any organ
system; however, the most common severe immune-mediated adverse
reactions are enterocolitis, hepatitis, dermatitis (including toxic
epidermal necrolysis), neuropathy, and endocrinopathy. The majority
of these immune-mediated reactions initially manifested during
treatment; however, a minority occurred weeks to months after
discontinuation of YERVOY.
Assess patients for signs and symptoms of enterocolitis,
dermatitis, neuropathy, and endocrinopathy, and evaluate clinical
chemistries including liver function tests (LFTs),
adrenocorticotropic hormone (ACTH) level, and thyroid function
tests, at baseline and before each dose.
Permanently discontinue YERVOY and initiate systemic
high-dose corticosteroid therapy for severe immune-mediated
reactions.
Immune-Mediated Pneumonitis
OPDIVO can cause immune-mediated pneumonitis. Fatal cases have
been reported. Monitor patients for signs with radiographic imaging
and for symptoms of pneumonitis. Administer corticosteroids for
Grade 2 or more severe pneumonitis. Permanently discontinue for
Grade 3 or 4 and withhold until resolution for Grade 2. In patients
receiving OPDIVO monotherapy, fatal cases of immune-mediated
pneumonitis have occurred. Immune-mediated pneumonitis occurred in
3.1% (61/1994) of patients. In patients receiving OPDIVO 1 mg/kg
with YERVOY 3 mg/kg, immune-mediated pneumonitis occurred in 6%
(25/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with
YERVOY 1 mg/kg, immune-mediated pneumonitis occurred in 4.4%
(24/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO
3 mg/kg with YERVOY 1 mg/kg, immune-mediated pneumonitis occurred
in 1.7% (2/119) of patients.
In Checkmate 205 and 039, pneumonitis, including interstitial
lung disease, occurred in 6.0% (16/266) of patients receiving
OPDIVO. Immune-mediated pneumonitis occurred in 4.9% (13/266) of
patients receiving OPDIVO: Grade 3 (n=1) and Grade 2 (n=12).
Immune-Mediated Colitis
OPDIVO can cause immune-mediated colitis. Monitor patients for
signs and symptoms of colitis. Administer corticosteroids for Grade
2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO
monotherapy for Grade 2 or 3 and permanently discontinue for Grade
4 or recurrent colitis upon re-initiation of OPDIVO. When
administered with YERVOY, withhold OPDIVO and YERVOY for Grade 2
and permanently discontinue for Grade 3 or 4 or recurrent colitis.
In patients receiving OPDIVO monotherapy, immune-mediated colitis
occurred in 2.9% (58/1994) of patients. In patients receiving
OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated colitis
occurred in 26% (107/407) of patients including three fatal cases.
In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg,
immune-mediated colitis occurred in 10% (52/547) of patients. In
MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1
mg/kg, immune-mediated colitis occurred in 7% (8/119) of
patients.
In a separate Phase 3 study of YERVOY 3 mg/kg, severe,
life-threatening, or fatal (diarrhea of ≥7 stools above baseline,
fever, ileus, peritoneal signs; Grade 3-5) immune-mediated
enterocolitis occurred in 34 (7%) patients. Across all
YERVOY-treated patients in that study (n=511), 5 (1%) developed
intestinal perforation, 4 (0.8%) died as a result of complications,
and 26 (5%) were hospitalized for severe enterocolitis.
Immune-Mediated Hepatitis
OPDIVO can cause immune-mediated hepatitis. Monitor patients for
abnormal liver tests prior to and periodically during treatment.
Administer corticosteroids for Grade 2 or greater transaminase
elevations. For patients without HCC, withhold OPDIVO for Grade 2
and permanently discontinue OPDIVO for Grade 3 or 4. For patients
with HCC, withhold OPDIVO and administer corticosteroids if AST/ALT
is within normal limits at baseline and increases to >3 and up
to 5 times the upper limit of normal (ULN), if AST/ALT is >1 and
up to 3 times ULN at baseline and increases to >5 and up to 10
times the ULN, and if AST/ALT is >3 and up to 5 times ULN at
baseline and increases to >8 and up to 10 times the ULN.
Permanently discontinue OPDIVO and administer corticosteroids if
AST or ALT increases to >10 times the ULN or total bilirubin
increases >3 times the ULN. In patients receiving OPDIVO
monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994)
of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3
mg/kg, immune-mediated hepatitis occurred in 13% (51/407) of
patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1
mg/kg, immune-mediated hepatitis occurred in 7% (38/547) of
patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with
YERVOY 1 mg/kg, immune-mediated hepatitis occurred in 8% (10/119)
of patients.
In Checkmate 040, immune-mediated hepatitis requiring systemic
corticosteroids occurred in 5% (8/154) of patients receiving
OPDIVO.
In a separate Phase 3 study of YERVOY 3 mg/kg, severe,
life-threatening, or fatal hepatotoxicity (AST or ALT elevations
>5x the ULN or total bilirubin elevations >3x the ULN; Grade
3-5) occurred in 8 (2%) patients, with fatal hepatic failure in
0.2% and hospitalization in 0.4%.
Immune-Mediated Neuropathies
In a separate Phase 3 study of YERVOY 3 mg/kg, 1 case of fatal
Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral
motor neuropathy were reported.
Immune-Mediated Endocrinopathies
OPDIVO can cause immune-mediated hypophysitis, immune-mediated
adrenal insufficiency, autoimmune thyroid disorders, and Type 1
diabetes mellitus. Monitor patients for signs and symptoms of
hypophysitis, signs and symptoms of adrenal insufficiency, thyroid
function prior to and periodically during treatment, and
hyperglycemia. Administer hormone replacement as clinically
indicated and corticosteroids for Grade 2 or greater hypophysitis.
Withhold for Grade 2 or 3 and permanently discontinue for Grade 4
hypophysitis. Administer corticosteroids for Grade 3 or 4 adrenal
insufficiency. Withhold for Grade 2 and permanently discontinue for
Grade 3 or 4 adrenal insufficiency. Administer hormone-replacement
therapy for hypothyroidism. Initiate medical management for control
of hyperthyroidism. Withhold OPDIVO for Grade 3 and permanently
discontinue for Grade 4 hyperglycemia.
In patients receiving OPDIVO monotherapy, hypophysitis occurred
in 0.6% (12/1994) of patients. In patients receiving OPDIVO 1 mg/kg
with YERVOY 3 mg/kg, hypophysitis occurred in 9% (36/407) of
patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1
mg/kg, hypophysitis occurred in 4.6% (25/547) of patients. In
MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1
mg/kg, immune-mediated hypophysitis occurred in 3.4% (4/119) of
patients. In patients receiving OPDIVO monotherapy, adrenal
insufficiency occurred in 1% (20/1994) of patients. In patients
receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, adrenal insufficiency
occurred in 5% (21/407) of patients. In RCC patients receiving
OPDIVO 3 mg/kg with YERVOY 1 mg/kg, adrenal insufficiency occurred
in 7% (41/547) of patients. In MSI-H/dMMR mCRC patients receiving
OPDIVO 3 mg/kg with YERVOY 1 mg/kg, adrenal insufficiency occurred
in 5.9% (7/119) of patients. In patients receiving OPDIVO
monotherapy, hypothyroidism or thyroiditis resulting in
hypothyroidism occurred in 9% (171/1994) of patients.
Hyperthyroidism occurred in 2.7% (54/1994) of patients receiving
OPDIVO monotherapy. In patients receiving OPDIVO 1 mg/kg with
YERVOY 3 mg/kg, hypothyroidism or thyroiditis resulting in
hypothyroidism occurred in 22% (89/407) of patients.
Hyperthyroidism occurred in 8% (34/407) of patients receiving this
dose of OPDIVO with YERVOY. In RCC patients receiving OPDIVO 3
mg/kg with YERVOY 1 mg/kg, hypothyroidism or thyroiditis resulting
in hypothyroidism occurred in 22% (119/547) of patients.
Hyperthyroidism occurred in 12% (66/547) of patients receiving this
dose of OPDIVO with YERVOY. In MSI-H/dMMR mCRC patients receiving
OPDIVO 3 mg/kg with YERVOY 1 mg/kg, hypothyroidism or thyroiditis
resulting in hypothyroidism occurred in 15% (18/119) of patients.
Hyperthyroidism occurred in 12% (14/119) of patients. In patients
receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994)
of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3
mg/kg, diabetes occurred in 1.5% (6/407) of patients. In RCC
patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, diabetes
occurred in 2.7% (15/547) of patients.
In a separate Phase 3 study of YERVOY 3 mg/kg, severe to
life-threatening immune-mediated endocrinopathies (requiring
hospitalization, urgent medical intervention, or interfering with
activities of daily living; Grade 3-4) occurred in 9 (1.8%)
patients. All 9 patients had hypopituitarism, and some had
additional concomitant endocrinopathies such as adrenal
insufficiency, hypogonadism, and hypothyroidism. Six of the 9
patients were hospitalized for severe endocrinopathies.
Immune-Mediated Nephritis and Renal Dysfunction
OPDIVO can cause immune-mediated nephritis. Monitor patients for
elevated serum creatinine prior to and periodically during
treatment. Administer corticosteroids for Grades 2-4 increased
serum creatinine. Withhold OPDIVO for Grade 2 or 3 and permanently
discontinue for Grade 4 increased serum creatinine. In patients
receiving OPDIVO monotherapy, immune-mediated nephritis and renal
dysfunction occurred in 1.2% (23/1994) of patients. In patients
receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated
nephritis and renal dysfunction occurred in 2.2% (9/407) of
patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1
mg/kg, immune-mediated nephritis and renal dysfunction occurred in
4.6% (25/547) of patients. In MSI-H/dMMR mCRC patients receiving
OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated nephritis and
renal dysfunction occurred in 1.7% (2/119) of patients.
Immune-Mediated Skin Adverse Reactions and Dermatitis
OPDIVO can cause immune-mediated rash, including Stevens-Johnson
syndrome (SJS) and toxic epidermal necrolysis (TEN), some cases
with fatal outcome. Administer corticosteroids for Grade 3 or 4
rash. Withhold for Grade 3 and permanently discontinue for Grade 4
rash. For symptoms or signs of SJS or TEN, withhold OPDIVO and
refer the patient for specialized care for assessment and
treatment; if confirmed, permanently discontinue. In patients
receiving OPDIVO monotherapy, immune-mediated rash occurred in 9%
(171/1994) of patients. In patients receiving OPDIVO 1 mg/kg with
YERVOY 3 mg/kg, immune-mediated rash occurred in 22.6% (92/407) of
patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1
mg/kg, immune-mediated rash occurred in 16% (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.
In a separate Phase 3 study of YERVOY 3 mg/kg, severe,
life-threatening, or fatal immune-mediated dermatitis (eg,
Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash
complicated by full thickness dermal ulceration, or necrotic,
bullous, or hemorrhagic manifestations; Grade 3-5) occurred in 13
(2.5%) patients. 1 (0.2%) patient died as a result of toxic
epidermal necrolysis. 1 additional patient required hospitalization
for severe dermatitis.
Immune-Mediated Encephalitis
OPDIVO can cause immune-mediated encephalitis. Evaluation of
patients with neurologic symptoms may include, but not be limited
to, consultation with a neurologist, brain MRI, and lumbar
puncture. Withhold OPDIVO in patients with new-onset moderate to
severe neurologic signs or symptoms and evaluate to rule out other
causes. If other etiologies are ruled out, administer
corticosteroids and permanently discontinue OPDIVO for
immune-mediated encephalitis. In patients receiving OPDIVO
monotherapy, encephalitis occurred in 0.2% (3/1994) of patients.
Fatal limbic encephalitis occurred in one patient after 7.2 months
of exposure despite discontinuation of OPDIVO and administration of
corticosteroids. Encephalitis occurred in one patient receiving
OPDIVO 1 mg/kg with YERVOY 3 mg/kg (0.2%) after 1.7 months of
exposure. Encephalitis occurred in one RCC patient receiving OPDIVO
3 mg/kg with YERVOY 1 mg/kg (0.2%) after approximately 4 months of
exposure. Encephalitis occurred in one MSI-H/dMMR mCRC patient
(0.8%) receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg after 15 days
of exposure.
Other Immune-Mediated Adverse Reactions
Based on the severity of the adverse reaction, permanently
discontinue or withhold OPDIVO, administer high-dose
corticosteroids, and, if appropriate, initiate hormone-replacement
therapy. Across clinical trials of OPDIVO monotherapy or in
combination with YERVOY, the following clinically significant
immune-mediated adverse reactions, some with fatal outcome,
occurred in <1.0% of patients receiving OPDIVO: myocarditis,
rhabdomyolysis, myositis, uveitis, iritis, pancreatitis, facial and
abducens nerve paresis, demyelination, polymyalgia rheumatica,
autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism,
systemic inflammatory response syndrome, gastritis, duodenitis,
sarcoidosis, histiocytic necrotizing lymphadenitis (Kikuchi
lymphadenitis), motor dysfunction, vasculitis, aplastic anemia,
pericarditis, and myasthenic syndrome.
If uveitis occurs in combination with other immune-mediated
adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome,
which has been observed in patients receiving OPDIVO and may
require treatment with systemic steroids to reduce the risk of
permanent vision loss.
Infusion Reactions
OPDIVO can cause severe infusion reactions, which have been
reported in <1.0% of patients in clinical trials. Discontinue
OPDIVO in patients with Grade 3 or 4 infusion reactions. Interrupt
or slow the rate of infusion in patients with Grade 1 or 2. In
patients receiving OPDIVO monotherapy as a 60-minute infusion,
infusion-related reactions occurred in 6.4% (127/1994) of patients.
In a separate study in which patients received OPDIVO monotherapy
as a 60-minute infusion or a 30-minute infusion, infusion-related
reactions occurred in 2.2% (8/368) and 2.7% (10/369) of patients,
respectively. Additionally, 0.5% (2/368) and 1.4% (5/369) of
patients, respectively, experienced adverse reactions within 48
hours of infusion that led to dose delay, permanent discontinuation
or withholding of OPDIVO. In patients receiving OPDIVO 1 mg/kg with
YERVOY 3 mg/kg every 3 weeks, infusion-related reactions occurred
in 2.5% (10/407) of patients. In RCC patients receiving OPDIVO 3
mg/kg with YERVOY 1 mg/kg, infusion-related reactions occurred in
5.1% (28/547) of patients. In MSI-H/dMMR mCRC patients receiving
OPDIVO 3 mg/kg with YERVOY 1 mg/kg, infusion-related reactions
occurred in 4.2% (5/119) of patients.
Complications of Allogeneic Hematopoietic Stem Cell
Transplantation
Fatal and other serious complications can occur in patients who
receive allogeneic hematopoietic stem cell transplantation (HSCT)
before or after being treated with a PD-1 receptor blocking
antibody. Transplant-related complications include hyperacute
graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic
veno-occlusive disease (VOD) after reduced intensity conditioning,
and steroid-requiring febrile syndrome (without an identified
infectious cause). These complications may occur despite
intervening therapy between PD-1 blockade and allogeneic HSCT.
Follow patients closely for evidence of transplant-related
complications and intervene promptly. Consider the benefit versus
risks of treatment with a PD-1 receptor blocking antibody prior to
or after an allogeneic HSCT.
Embryo-Fetal Toxicity
Based on their mechanisms of action, OPDIVO and YERVOY can cause
fetal harm when administered to a pregnant woman. Advise pregnant
women of the potential risk to a fetus. Advise females of
reproductive potential to use effective contraception during
treatment with an OPDIVO- or YERVOY- containing regimen and for at
least 5 months after the last dose of OPDIVO.
Increased Mortality in Patients with Multiple Myeloma when
OPDIVO is Added to a Thalidomide Analogue and Dexamethasone
In clinical trials in patients with multiple myeloma, the
addition of OPDIVO to a thalidomide analogue plus dexamethasone
resulted in increased mortality. Treatment of patients with
multiple myeloma with a PD-1 or PD-L1 blocking antibody in
combination with a thalidomide analogue plus dexamethasone is not
recommended outside of controlled clinical trials.
Lactation
It is not known whether OPDIVO or YERVOY is present in human
milk. Because many drugs, including antibodies, are excreted in
human milk and because of the potential for serious adverse
reactions in nursing infants from an OPDIVO-containing regimen,
advise women to discontinue breastfeeding during treatment. Advise
women to discontinue breastfeeding during treatment with YERVOY and
for 3 months following the final dose.
Serious Adverse Reactions
In Checkmate 037, serious adverse reactions occurred in 41% of
patients receiving OPDIVO (n=268). Grade 3 and 4 adverse reactions
occurred in 42% of patients receiving OPDIVO. The most frequent
Grade 3 and 4 adverse drug reactions reported in 2% to <5% of
patients receiving OPDIVO were abdominal pain, hyponatremia,
increased aspartate aminotransferase, and increased lipase. In
Checkmate 066, serious adverse reactions occurred in 36% of
patients receiving OPDIVO (n=206). Grade 3 and 4 adverse reactions
occurred in 41% of patients receiving OPDIVO. The most frequent
Grade 3 and 4 adverse reactions reported in ≥2% of patients
receiving OPDIVO were gamma-glutamyltransferase increase (3.9%) and
diarrhea (3.4%). In Checkmate 067, serious adverse reactions (74%
and 44%), adverse reactions leading to permanent discontinuation
(47% and 18%) or to dosing delays (58% and 36%), and Grade 3 or 4
adverse reactions (72% and 51%) all occurred more frequently in the
OPDIVO plus YERVOY arm (n=313) relative to the OPDIVO arm (n=313).
The most frequent (≥10%) serious adverse reactions in the OPDIVO
plus YERVOY arm and the OPDIVO arm, respectively, were diarrhea
(13% and 2.2%), colitis (10% and 1.9%), and pyrexia (10% and 1.0%).
In Checkmate 017 and 057, serious adverse reactions occurred in 46%
of patients receiving OPDIVO (n=418). The most frequent serious
adverse reactions reported in ≥2% of patients receiving OPDIVO were
pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion,
pneumonitis, and respiratory failure. In Checkmate 032, serious
adverse reactions occurred in 45% of patients receiving OPDIVO
(n=245). The most frequent serious adverse reactions reported in at
least 2% of patients receiving OPDIVO were pneumonia, dyspnea,
pneumonitis, pleural effusions, and dehydration. In Checkmate 025,
serious adverse reactions occurred in 47% of patients receiving
OPDIVO (n=406). The most frequent serious adverse reactions
reported in ≥2% of patients were acute kidney injury, pleural
effusion, pneumonia, diarrhea, and hypercalcemia. In Checkmate 214,
serious adverse reactions occurred in 59% of patients receiving
OPDIVO plus YERVOY and in 43% of patients receiving sunitinib. The
most frequent serious adverse reactions reported in ≥2% of patients
were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute
kidney injury, dyspnea, adrenal insufficiency, and colitis; in
patients treated with sunitinib, they were pneumonia, pleural
effusion, and dyspnea. In Checkmate 205 and 039, adverse reactions
leading to discontinuation occurred in 7% and dose delays due to
adverse reactions occurred in 34% of patients (n=266). Serious
adverse reactions occurred in 26% of patients. The most frequent
serious adverse reactions reported in ≥1% of patients were
pneumonia, infusion-related reaction, pyrexia, colitis or diarrhea,
pleural effusion, pneumonitis, and rash. Eleven patients died from
causes other than disease progression: 3 from adverse reactions
within 30 days of the last OPDIVO dose, 2 from infection 8 to 9
months after completing OPDIVO, and 6 from complications of
allogeneic HSCT. In Checkmate 141, serious adverse reactions
occurred in 49% of patients receiving OPDIVO (n=236). The most
frequent serious adverse reactions reported in ≥2% of patients
receiving OPDIVO were pneumonia, dyspnea, respiratory failure,
respiratory tract infection, and sepsis. In Checkmate 275, serious
adverse reactions occurred in 54% of patients receiving OPDIVO
(n=270). The most frequent serious adverse reactions reported in
≥2% of patients receiving OPDIVO were urinary tract infection,
sepsis, diarrhea, small intestine obstruction, and general physical
health deterioration. In Checkmate 142 in MSI-H/dMMR mCRC patients
receiving OPDIVO with YERVOY, serious adverse reactions occurred in
47% of patients. The most frequent serious adverse reactions
reported in ≥2% of patients were colitis/diarrhea, hepatic events,
abdominal pain, acute kidney injury, pyrexia, and dehydration. In
Checkmate 040, serious adverse reactions occurred in 49% of
patients (n=154). The most frequent serious adverse reactions
reported in ≥2% of patients were pyrexia, ascites, back pain,
general physical health deterioration, abdominal pain, and
pneumonia. In Checkmate 238, Grade 3 or 4 adverse reactions
occurred in 25% of OPDIVO-treated patients (n=452). The most
frequent Grade 3 and 4 adverse reactions reported in ≥2% of
OPDIVO-treated patients were diarrhea and increased lipase and
amylase. Serious adverse reactions occurred in 18% of
OPDIVO-treated patients.
Common Adverse Reactions
In Checkmate 037, the most common adverse reaction (≥20%)
reported with OPDIVO (n=268) was rash (21%). In Checkmate 066, the
most common adverse reactions (≥20%) reported with OPDIVO (n=206)
vs dacarbazine (n=205) were fatigue (49% vs 39%), musculoskeletal
pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%). In
Checkmate 067, the most common (≥20%) adverse reactions in the
OPDIVO plus YERVOY arm (n=313) were fatigue (62%), diarrhea (54%),
rash (53%), nausea (44%), pyrexia (40%), pruritus (39%),
musculoskeletal pain (32%), vomiting (31%), decreased appetite
(29%), cough (27%), headache (26%), dyspnea (24%), upper
respiratory tract infection (23%), arthralgia (21%), and increased
transaminases (25%). In Checkmate 067, the most common (≥20%)
adverse reactions in the OPDIVO arm (n=313) were fatigue (59%),
rash (40%), musculoskeletal pain (42%), diarrhea (36%), nausea
(30%), cough (28%), pruritus (27%), upper respiratory tract
infection (22%), decreased appetite (22%), headache (22%),
constipation (21%), arthralgia (21%), and vomiting (20%). In
Checkmate 017 and 057, the most common adverse reactions (≥20%) in
patients receiving OPDIVO (n=418) were fatigue, musculoskeletal
pain, cough, dyspnea, and decreased appetite. In Checkmate 032, the
most common adverse reactions (≥20%) in patients receiving OPDIVO
(n=245) were fatigue (45%), decreased appetite (27%),
musculoskeletal pain (25%), dyspnea (22%), nausea (22%), diarrhea
(21%), constipation (20%), and cough (20%). In Checkmate 025, the
most common adverse reactions (≥20%) reported in patients receiving
OPDIVO (n=406) vs everolimus (n=397) were fatigue (56% vs 57%),
cough (34% vs 38%), nausea (28% vs 29%), rash (28% vs 36%), dyspnea
(27% vs 31%), diarrhea (25% vs 32%), constipation (23% vs 18%),
decreased appetite (23% vs 30%), back pain (21% vs 16%), and
arthralgia (20% vs 14%). In Checkmate 214, the most common adverse
reactions (≥20%) reported in patients treated with OPDIVO plus
YERVOY (n=547) vs sunitinib (n=535) were fatigue (58% vs 69%), rash
(39% vs 25%), diarrhea (38% vs 58%), musculoskeletal pain (37% vs
40%), pruritus (33% vs 11%), nausea (30% vs 43%), cough (28% vs
25%), pyrexia (25% vs 17%), arthralgia (23% vs 16%), decreased
appetite (21% vs 29%), dyspnea (20% vs 21%), and vomiting (20% vs
28%). In Checkmate 205 and 039, the most common adverse reactions
(≥20%) reported in patients receiving OPDIVO (n=266) were upper
respiratory tract infection (44%), fatigue (39%), cough (36%),
diarrhea (33%), pyrexia (29%), musculoskeletal pain (26%), rash
(24%), nausea (20%) and pruritus (20%). In Checkmate 141, the most
common adverse reactions (≥10%) in patients receiving OPDIVO
(n=236) were cough and dyspnea at a higher incidence than
investigator’s choice. In Checkmate 275, the most common adverse
reactions (≥20%) reported in patients receiving OPDIVO (n=270) were
fatigue (46%), musculoskeletal pain (30%), nausea (22%), and
decreased appetite (22%). In Checkmate 142 in MSI-H/dMMR mCRC
patients receiving OPDIVO as a single agent, the most common
adverse reactions (≥20%) were fatigue (54%), diarrhea (43%),
abdominal pain (34%), nausea (34%), vomiting (28%), musculoskeletal
pain (28%), cough (26%), pyrexia (24%), rash (23%), constipation
(20%), and upper respiratory tract infection (20%). In Checkmate
142 in MSI-H/dMMR mCRC patients receiving OPDIVO with YERVOY, the
most common adverse reactions (≥20%) were fatigue (49%), diarrhea
(45%), pyrexia (36%), musculoskeletal pain (36%), abdominal pain
(30%), pruritus (28%), nausea (26%), rash (25%), decreased appetite
(20%), and vomiting (20%). In Checkmate 040, the most common
adverse reactions (≥20%) in patients receiving OPDIVO (n=154) were
fatigue (38%), musculoskeletal pain (36%), abdominal pain (34%),
pruritus (27%), diarrhea (27%), rash (26%), cough (23%), and
decreased appetite (22%). In Checkmate 238, the most common adverse
reactions (≥20%) reported in OPDIVO-treated patients (n=452) vs
ipilimumab-treated patients (n=453) were fatigue (57% vs 55%),
diarrhea (37% vs 55%), rash (35% vs 47%), musculoskeletal pain (32%
vs 27%), pruritus (28% vs 37%), headache (23% vs 31%), nausea (23%
vs 28%), upper respiratory infection (22% vs 15%), and abdominal
pain (21% vs 23%). The most common immune-mediated adverse
reactions were rash (16%), diarrhea/colitis (6%), and hepatitis
(3%).
In a separate Phase 3 study of YERVOY 3 mg/kg, the most common
adverse reactions (≥5%) in patients who received YERVOY at 3 mg/kg
were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and
colitis (8%).
Recommended Dose Modifications
Interrupt or slow the rate of infusion in patients with mild or
moderate infusion reactions. Discontinue in patients with severe or
life-threatening infusion reactions.
Endocrine: Withhold YERVOY for symptomatic endocrinopathy.
Resume YERVOY in patients with complete or partial resolution of
adverse reactions (Grade 0-1) and who are receiving <7.5 mg
prednisone or equivalent per day. Permanently discontinue YERVOY
for symptomatic reactions lasting 6 weeks or longer or an inability
to reduce corticosteroid dose to 7.5 mg prednisone or equivalent
per day.
Ophthalmologic: Permanently discontinue YERVOY for Grade 2-4
reactions not improving to Grade 1 within 2 weeks while receiving
topical therapy or requiring systemic treatment.
All Other Organ Systems: Withhold YERVOY for Grade 2 adverse
reactions. Resume YERVOY in patients with complete or partial
resolution of adverse reactions (Grade 0-1) and who are receiving
<7.5 mg prednisone or equivalent per day. Permanently
discontinue YERVOY for Grade 2 reactions lasting 6 weeks or longer,
an inability to reduce corticosteroid dose to 7.5 mg prednisone or
equivalent per day, and Grade 3 or 4 adverse reactions.
Immune-Mediated Enterocolitis
Immune-mediated enterocolitis, including fatal cases, can occur
with YERVOY. Monitor patients for signs and symptoms of
enterocolitis (such as diarrhea, abdominal pain, mucus or blood in
stool, with or without fever) and of bowel perforation (such as
peritoneal signs and ileus). In symptomatic patients, rule out
infectious etiologies and consider endoscopic evaluation for
persistent or severe symptoms. Withhold YERVOY for moderate
enterocolitis; administer anti-diarrheal treatment and, if
persistent for >1 week, initiate systemic corticosteroids (0.5
mg/kg/day prednisone or equivalent). Permanently discontinue YERVOY
in patients with severe enterocolitis and initiate systemic
corticosteroids (1-2 mg/kg/day of prednisone or equivalent). Upon
improvement to ≤Grade 1, initiate corticosteroid taper and continue
over at least 1 month. In clinical trials, rapid corticosteroid
tapering resulted in recurrence or worsening symptoms of
enterocolitis in some patients. Consider adding anti-TNF or other
immunosuppressant agents for management of immune-mediated
enterocolitis unresponsive to systemic corticosteroids within 3-5
days or recurring after symptom improvement, if other causes are
excluded. In patients receiving YERVOY 3 mg/kg in MDX010-20,
severe, life-threatening, or fatal (diarrhea of ≥7 stools above
baseline, fever, ileus, peritoneal signs; Grade 3-5)
immune-mediated enterocolitis occurred in 34 YERVOY-treated
patients (7%) and moderate (diarrhea with up to 6 stools above
baseline, abdominal pain, mucus or blood in stool; Grade 2)
enterocolitis occurred in 28 YERVOY-treated patients (5%). Across
all YERVOY-treated patients (n=511), 5 (1%) developed intestinal
perforation, 4 (0.8%) died as a result of complications, and 26
(5%) were hospitalized for severe enterocolitis. Infliximab was
administered to 5 (8%) of the 62 patients with moderate, severe, or
life-threatening immune-mediated enterocolitis following inadequate
response to corticosteroids. In patients receiving YERVOY 10 mg/kg
in CA184-029, Grade 3-5 immune-mediated enterocolitis occurred in
76 patients (16%) and Grade 2 enterocolitis occurred in 68 patients
(14%). Seven (1.5%) developed intestinal perforation and 3 patients
(0.6%) died as a result of complications.
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
Immune-mediated hepatitis, including fatal cases, can occur with
YERVOY. Monitor LFTs (hepatic transaminase and bilirubin levels)
and assess patients for signs and symptoms of hepatotoxicity before
each dose of YERVOY. In patients with hepatotoxicity, rule out
infectious or malignant causes and increase frequency of LFT
monitoring until resolution. Withhold YERVOY in patients with Grade
2 hepatotoxicity. Permanently discontinue YERVOY in patients with
Grade 3-4 hepatotoxicity and administer systemic corticosteroids
(1-2 mg/kg/day of prednisone or equivalent). When LFTs show
sustained improvement or return to baseline, initiate
corticosteroid tapering and continue over 1 month. Across the
clinical development program for YERVOY, mycophenolate treatment
has been administered in patients with persistent severe hepatitis
despite high-dose corticosteroids. In patients receiving YERVOY 3
mg/kg in MDX010-20, severe, life-threatening, or fatal
hepatotoxicity (AST or ALT elevations >5× the ULN or total
bilirubin elevations >3× the ULN; Grade 3-5) occurred in 8
YERVOY-treated patients (2%), with fatal hepatic failure in 0.2%
and hospitalization in 0.4%. An additional 13 patients (2.5%)
experienced moderate hepatotoxicity manifested by LFT abnormalities
(AST or ALT elevations >2.5× but ≤5× the ULN or total bilirubin
elevation >1.5× but ≤3× the ULN; Grade 2). In a dose-finding
trial, Grade 3 increases in transaminases with or without
concomitant increases in total bilirubin occurred in 6 of 10
patients who received concurrent YERVOY (3 mg/kg) and vemurafenib
(960 mg BID or 720 mg BID). In patients receiving YERVOY 10 mg/kg
in CA184-029, Grade 3-4 immune-mediated hepatitis occurred in 51
patients (11%) and moderate Grade 2 immune-mediated hepatitis
occurred in 22 patients (5%). Liver biopsy performed in 6 patients
with Grade 3-4 hepatitis showed evidence of toxic or autoimmune
hepatitis.
Immune-Mediated Dermatitis
Immune-mediated dermatitis, including fatal cases, can occur
with YERVOY. Monitor patients for signs and symptoms of dermatitis
such as rash and pruritus. Unless an alternate etiology has been
identified, signs or symptoms of dermatitis should be considered
immune-mediated. Treat mild to moderate dermatitis (e.g., localized
rash and pruritus) symptomatically; administer topical or systemic
corticosteroids if there is no improvement within 1 week. Withhold
YERVOY in patients with moderate to severe signs and symptoms.
Permanently discontinue YERVOY in patients with severe,
life-threatening, or fatal immune-mediated dermatitis (Grade 3-5).
Administer systemic corticosteroids (1-2 mg/kg/day of prednisone or
equivalent). When dermatitis is controlled, corticosteroid tapering
should occur over a period of at least 1 month. In patients
receiving YERVOY 3 mg/kg in MDX010-20, severe, life-threatening, or
fatal immune-mediated dermatitis (e.g., Stevens-Johnson syndrome,
toxic epidermal necrolysis, or rash complicated by full thickness
dermal ulceration, or necrotic, bullous, or hemorrhagic
manifestations; Grade 3-5) occurred in 13 YERVOY-treated patients
(2.5%); 1 patient (0.2%) died as a result of toxic epidermal
necrolysis and 1 additional patient required hospitalization for
severe dermatitis. There were 63 patients (12%) with moderate
(Grade 2) dermatitis. In patients receiving YERVOY 10 mg/kg in
CA184-029, Grade 3-4 immune-mediated dermatitis occurred in 19
patients (4%). There were 99 patients (21%) with moderate Grade 2
dermatitis.
Immune-Mediated Neuropathies
Immune-mediated neuropathies, including fatal cases, can occur
with YERVOY. Monitor for symptoms of motor or sensory neuropathy
such as unilateral or bilateral weakness, sensory alterations, or
paresthesia. Withhold YERVOY in patients with moderate neuropathy
(not interfering with daily activities). Permanently discontinue
YERVOY in patients with severe neuropathy (interfering with daily
activities), such as Guillain-Barré-like syndromes. Institute
medical intervention as appropriate for management for severe
neuropathy. Consider initiation of systemic corticosteroids (1-2
mg/kg/day of prednisone or equivalent) for severe neuropathies. In
patients receiving YERVOY 3 mg/kg in MDX010-20, 1 case of fatal
Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral
motor neuropathy were reported. Across the clinical development
program of YERVOY, myasthenia gravis and additional cases of
Guillain-Barré syndrome have been reported. In patients receiving
YERVOY 10 mg/kg in CA184-029, Grade 3-5 immune-mediated neuropathy
occurred in 8 patients (2%); the sole fatality was due to
complications of Guillain-Barré syndrome. Moderate Grade 2
immune-mediated neuropathy occurred in 1 patient (0.2%).
Immune-Mediated Endocrinopathies
Immune-mediated endocrinopathies, including life-threatening
cases, can occur with YERVOY. Monitor patients for clinical signs
and symptoms of hypophysitis, adrenal insufficiency (including
adrenal crisis), and hyper- or hypothyroidism. Patients may present
with fatigue, headache, mental status changes, abdominal pain,
unusual bowel habits, and hypotension, or nonspecific symptoms
which may resemble other causes such as brain metastasis or
underlying disease. Unless an alternate etiology has been
identified, signs or symptoms should be considered immune-mediated.
Monitor clinical chemistries, adrenocorticotropic hormone (ACTH)
level, and thyroid function tests at the start of treatment, before
each dose, and as clinically indicated based on symptoms. In a
limited number of patients, hypophysitis was diagnosed by imaging
studies through enlargement of the pituitary gland. Withhold YERVOY
in symptomatic patients and consider referral to an
endocrinologist. Initiate systemic corticosteroids (1-2 mg/kg/day
of prednisone or equivalent) and initiate appropriate hormone
replacement therapy. In patients receiving YERVOY 3 mg/kg in
MDX010-20, severe to life-threatening immune-mediated
endocrinopathies (requiring hospitalization, urgent medical
intervention, or interfering with activities of daily living; Grade
3-4) occurred in 9 YERVOY-treated patients (1.8%). 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. Moderate endocrinopathy (requiring hormone
replacement or medical intervention; Grade 2) occurred in 12
patients (2.3%) and consisted of hypothyroidism, adrenal
insufficiency, hypopituitarism, and 1 case each of hyperthyroidism
and Cushing's syndrome. The median time to onset of moderate to
severe immune-mediated endocrinopathy was 2.5 months and ranged up
to 4.4 months after the initiation of YERVOY. In patients receiving
YERVOY 10 mg/kg in CA184-029, Grade 3-4 immune-mediated
endocrinopathies occurred in 39 patients (8%) and Grade 2
immune-mediated endocrinopathies occurred in 93 patients (20%). Of
the 39 patients with Grade 3-4 immune-mediated endocrinopathies, 35
patients had hypopituitarism (associated with 1 or more secondary
endocrinopathies, e.g., adrenal insufficiency, hypogonadism, and
hypothyroidism), 3 patients had hyperthyroidism, and 1 had primary
hypothyroidism. The median time to onset of Grade 3-4
immune-mediated endocrinopathy was 2.2 months (range: 2 days-8
months). Twenty-seven (69.2%) of the 39 patients were hospitalized
for immune-mediated endocrinopathies. Of the 93 patients with Grade
2 immune-mediated endocrinopathy, 74 had primary hypopituitarism
(associated with 1 or more secondary endocrinopathy, e.g., adrenal
insufficiency, hypogonadism, and hypothyroidism), 9 had primary
hypothyroidism, 3 had hyperthyroidism, 3 had thyroiditis with hypo-
or hyperthyroidism, 2 had hypogonadism, 1 had both hyperthyroidism
and hypopituitarism, and 1 subject developed Graves’
ophthalmopathy. The median time to onset of Grade 2 immune-mediated
endocrinopathy was 2.1 months (range: 9 days-19.3 months).
Other Immune-Mediated Adverse Reactions
Permanently discontinue YERVOY for clinically significant or
severe immune-mediated adverse reactions. Initiate systemic
corticosteroids (1-2 mg/kg/day of prednisone or equivalent) for
severe immune-mediated adverse reactions. Monitor patients for
signs or symptoms of ocular toxicity, which may include blurred
vision and reduced visual acuity. Immune-mediated ocular toxicity
may be associated with retinal detachment or permanent vision loss.
Administer corticosteroid eye drops for uveitis, iritis, or
episcleritis. Permanently discontinue YERVOY for immune-mediated
ocular disease unresponsive to local immunosuppressive therapy. 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 YERVOY and may require
treatment with systemic steroids to reduce the risk of permanent
vision loss. Fatal or serious graft-versus-host disease (GVHD) can
occur in patients who receive a CTLA-4 receptor blocking antibody
either before or after allogeneic hematopoietic stem cell
transplantation (HSCT). Follow patients closely for evidence of
GVHD and intervene promptly. Consider the benefit versus risks of
treatment with a CTLA-4 receptor blocking antibody after allogeneic
HSCT. In MDX010-20, the following clinically significant
immune-mediated adverse reactions were seen in <1% of
YERVOY-treated patients: cytopenias, nephritis, pneumonitis,
meningitis, pericarditis, uveitis, and iritis. In CA184-029, the
following clinically significant immune-mediated adverse reactions
were seen in <1% of YERVOY-treated patients unless specified:
cytopenias, eosinophilia (2.1%), pancreatitis (1.3%), meningitis,
pneumonitis, sarcoidosis, pericarditis, uveitis, and fatal
myocarditis. Across 21 dose-ranging trials administering YERVOY at
doses of 0.1 to 20 mg/kg (n=2478), the following likely
immune-mediated adverse reactions were also reported with <1%
incidence unless specified: angiopathy, temporal arteritis,
vasculitis, polymyalgia rheumatica, conjunctivitis, blepharitis,
episcleritis, scleritis, iritis, leukocytoclastic vasculitis,
erythema multiforme, psoriasis, arthritis, autoimmune thyroiditis,
neurosensory hypoacusis, autoimmune central neuropathy
(encephalitis), myositis, polymyositis, ocular myositis, cytopenias
(2.5%), and nephritis.
Embryo-Fetal Toxicity
Based on its mechanism of action, 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 YERVOY and for 3 months after
the last dose.
Lactation
It is not known whether YERVOY is secreted in human milk. Advise
women not to breastfeed during treatment with YERVOY and for 3
months after the last dose.
Common Adverse Reactions
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%). The most common adverse
reactions (≥5%) in patients who received YERVOY at 10 mg/kg were
rash (50%), diarrhea (49%), fatigue (46%), pruritus (45%), headache
(33%), weight loss (32%), nausea (25%), pyrexia (18%), colitis
(16%), decreased appetite (14%), vomiting (13%), and insomnia
(10%).
Please see U.S. Full Prescribing Information for OPDIVO and
YERVOY, including Boxed WARNING regarding immune-mediated
adverse reactions for YERVOY.
Checkmate Trials and Patient Populations
Checkmate 037–previously treated metastatic melanoma;
Checkmate 066–previously untreated metastatic melanoma;
Checkmate 067–previously untreated metastatic melanoma, as a
single agent or in combination with YERVOY; Checkmate
017–second-line treatment of metastatic squamous non-small cell
lung cancer; Checkmate 057–second-line treatment of
metastatic non-squamous non-small cell lung cancer; Checkmate
032–small cell lung cancer; Checkmate 025–previously
treated renal cell carcinoma; Checkmate 214–previously
untreated renal cell carcinoma, in combination with YERVOY;
Checkmate 205/039–classical Hodgkin lymphoma; Checkmate
141–recurrent or metastatic squamous cell carcinoma of the head
and neck; Checkmate 275–urothelial carcinoma; Checkmate
142–MSI-H or dMMR metastatic colorectal cancer, as a single
agent or in combination with YERVOY; Checkmate
040–hepatocellular carcinoma; Checkmate 238–adjuvant
treatment of melanoma.
About the Bristol-Myers Squibb and Ono
Pharmaceutical Collaboration
In 2011, through a collaboration agreement with Ono
Pharmaceutical Co., Bristol-Myers Squibb expanded its territorial
rights to develop and commercialize Opdivo globally, except in
Japan, South Korea and Taiwan, where Ono had retained all rights to
the compound at the time. On July 23, 2014, Ono and Bristol-Myers
Squibb further expanded the companies’ strategic collaboration
agreement to jointly develop and commercialize multiple
immunotherapies – as single agents and combination regimens – for
patients with cancer in Japan, South Korea and Taiwan.
About Bristol-Myers
Squibb
Bristol-Myers Squibb is a global biopharmaceutical company whose
mission is to discover, develop and deliver innovative medicines
that help patients prevail over serious diseases. For more
information about Bristol-Myers Squibb, visit us at BMS.com or
follow us on LinkedIn, Twitter, YouTube, 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, whether Opdivo for the 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,
2018, as updated by our subsequent Quarterly Reports on Form 10-Q,
Current Reports on Form 8-K and other filings with the Securities
and Exchange Commission. The forward-looking statements included in
this document are made only as of the date of this document and
except as otherwise required by 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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