Opdivo also previously received FDA
Breakthrough Therapy Designation, the seventh time Opdivo has
received the designation
Application based on results from Phase 3
CheckMate -238 study
Bristol-Myers Squibb Company (NYSE: BMY) announced today that
the U.S. Food and Drug Administration (FDA) has accepted for
priority review its supplemental Biologics License Application
(sBLA) for Opdivo (nivolumab) to treat patients with melanoma who
are at high risk of disease recurrence following complete surgical
resection. The FDA also previously granted Breakthrough Therapy
Designation for this application, which is the seventh indication
for which Opdivo has received this designation.
“Priority review of our sBLA and the granting of breakthrough
designation are positive steps forward in our goal to address the
high unmet need that exists among patients with resected advanced
melanoma, many of whom experience disease recurrence,” said Murdo
Gordon, executive vice president and chief commercial officer,
Bristol-Myers Squibb.
The application is based on data from the ongoing Phase 3
CheckMate -238 study, which evaluated Opdivo in patients who have
undergone complete resection of stage IIIb/c or stage IV melanoma.
In the study, Opdivo 3 mg/kg met the primary endpoint by
significantly decreasing the risk of disease recurrence compared to
Yervoy (ipilimumab) 10 mg/kg, an FDA-approved treatment for stage
III adjuvant melanoma. The results of the study were recently
presented at the European Society for Medical Oncology (ESMO) 2017
Congress and published simultaneously in the New England Journal of
Medicine.
The Breakthrough Therapy Designation is an FDA program intended
to expedite the development and review of medicines with early
signals of potential clinical benefit in serious diseases to help
ensure patients have access to new therapies as soon as
possible.
About CheckMate -238
CheckMate -238 is an ongoing phase 3, randomized double-blind
study of Opdivo versus Yervoy in patients who have undergone
complete resection of stage IIIb/c or stage IV melanoma. The trial
randomized 906 patients 1:1 to receive either Opdivo 3 mg/kg
intravenously (IV) every two weeks or Yervoy 10 mg/kg IV every
three weeks for four doses and then every 12 weeks starting at week
24. Patients were treated until disease recurrence, unacceptable
toxicity or consent withdrawal for up to one year. The primary
endpoint is RFS defined as the time between randomization and the
date of first recurrence or death. Secondary endpoints include
overall survival, recurrence free survival by PD-L1 tumor
expression, quality of life and safety.
Adjuvant Therapy in
Melanoma
Melanoma is separated into five staging categories (stages 0 to
4) based on the in-situ feature, thickness and ulceration of the
tumor, whether the cancer has spread to the lymph nodes, and how
far the cancer has spread beyond lymph nodes.
Stage III melanoma has reached the regional lymph nodes but has
not yet spread to distant lymph nodes or to other parts of the body
(metastasized), and requires surgical resection of the primary
tumor as well as the involved lymph nodes. Some patients may also
be treated with adjuvant therapy. Despite surgical intervention and
possible adjuvant treatment, most patients experience disease
recurrence and progress to metastatic disease. By five years, the
majority of stage IIIb and IIIc patients (68% and 89%,
respectively) experience disease recurrence.
Bristol-Myers Squibb &
Immuno-Oncology: Advancing Oncology Research
At Bristol-Myers Squibb, patients are at the center of
everything we do. Our vision for the future of cancer care is
focused on researching and developing transformational
Immuno-Oncology (I-O) medicines for hard-to-treat cancers that
could potentially improve outcomes for these patients.
We are leading the scientific understanding of I-O through our
extensive portfolio of investigational compounds and approved
agents. Our differentiated clinical development program is studying
broad patient populations across more than 50 types of cancers with
14 clinical-stage molecules designed to target different immune
system pathways. Our deep expertise and innovative clinical trial
designs position us to advance the I-O/I-O, I-O/chemotherapy,
I-O/targeted therapies and I-O radiation therapies across multiple
tumors and potentially deliver the next wave of therapies with a
sense of urgency. We also continue to pioneer research that will
help facilitate a deeper understanding of the role of immune
biomarkers and how a patient’s tumor biology can be used as a guide
for treatment decisions throughout their journey.
We understand making the promise of I-O a reality for the many
patients who may benefit from these therapies requires not only
innovation on our part but also close collaboration with leading
experts in the field. Our partnerships with academia, government,
advocacy and biotech companies support our collective goal of
providing new treatment options to advance the standards of
clinical practice.
About Opdivo
Opdivo is a programmed death-1 (PD-1) immune checkpoint
inhibitor that is designed to uniquely harness the body’s own
immune system to help restore anti-tumor immune response. By
harnessing the body’s own immune system to fight cancer, Opdivo has
become an important treatment option across multiple cancers.
Opdivo’s leading global development program is based on
Bristol-Myers Squibb’s scientific expertise in the field of
Immuno-Oncology and includes a broad range of clinical trials
across all phases, including Phase 3, in a variety of tumor types.
To date, the Opdivo clinical development program has enrolled more
than 25,000 patients. The Opdivo trials have contributed to gaining
a deeper understanding of the potential role of biomarkers in
patient care, particularly regarding how patients may benefit from
Opdivo across the continuum of PD-L1 expression.
In July 2014, Opdivo was the first PD-1 immune checkpoint
inhibitor to receive regulatory approval anywhere in the world.
Opdivo is currently approved in more than 60 countries, including
the United States, the European Union and Japan. 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 BRAF V600 mutation-positive unresectable
or metastatic melanoma. This indication is approved under
accelerated approval based on progression-free survival. Continued
approval for this indication may be contingent upon verification
and description of clinical benefit in the confirmatory trials.
OPDIVO® (nivolumab) as a single agent is indicated for the
treatment of patients with BRAF V600 wild-type unresectable or
metastatic melanoma.
OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab),
is indicated for the treatment of patients with unresectable or
metastatic melanoma. This indication is approved under accelerated
approval based on progression-free survival. Continued approval for
this indication may be contingent upon verification and description
of clinical benefit in the confirmatory trials.
OPDIVO® (nivolumab) is indicated for the treatment of patients
with metastatic non-small cell lung cancer (NSCLC) with progression
on or after platinum-based chemotherapy. Patients with EGFR or ALK
genomic tumor aberrations should have disease progression on
FDA-approved therapy for these aberrations prior to receiving
OPDIVO.
OPDIVO® (nivolumab) is indicated for the treatment of patients
with advanced renal cell carcinoma (RCC) who have received prior
anti-angiogenic therapy.
OPDIVO® (nivolumab) is indicated for the treatment of 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) is indicated for the treatment of adults 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) 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.
IMPORTANT SAFETY
INFORMATION
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 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. In patients
receiving OPDIVO monotherapy, immune-mediated colitis occurred in
2.9% (58/1994) of patients.
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 Checkmate 040, immune-mediated hepatitis requiring systemic
corticosteroids occurred in 5% (8/154) of patients receiving
OPDIVO.
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
monotherapy, adrenal insufficiency occurred in 1% (20/1994) 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 monotherapy, diabetes occurred in 0.9% (17/1994) of
patients.
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.
Immune-Mediated Skin Adverse Reactions
OPDIVO can cause immune-mediated rash, including Stevens-Johnson
syndrome (SJS) and toxic epidermal necrolysis (TEN), some cases
with fatal outcome. Administer corticosteroids for Grade 3 or 4
rash. Withhold for Grade 3 and permanently discontinue for Grade 4
rash. For symptoms or signs of SJS or TEN, withhold OPDIVO and
refer the patient for specialized care for assessment and
treatment; if confirmed, permanently discontinue. In patients
receiving OPDIVO monotherapy, immune-mediated rash occurred in 9%
(171/1994) of patients.
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.
Other Immune-Mediated Adverse Reactions
Based on the severity of adverse reaction, permanently
discontinue or withhold treatment, administer high-dose
corticosteroids, and, if appropriate, initiate hormone-replacement
therapy. Across clinical trials of OPDIVO the following clinically
significant immune-mediated adverse reactions occurred in <1.0%
of patients receiving OPDIVO: 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), myositis, myocarditis, rhabdomyolysis, motor
dysfunction, vasculitis, and myasthenic syndrome.
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, infusion-related reactions
occurred in 6.4% (127/1994) of patients.
Complications of Allogeneic HSCT after OPDIVO
Complications, including fatal events, occurred in patients who
received allogeneic HSCT after OPDIVO. Outcomes were evaluated in
17 patients from Checkmate 205 and 039, who underwent allogeneic
HSCT after discontinuing OPDIVO (15 with reduced-intensity
conditioning, 2 with myeloablative conditioning). Thirty-five
percent (6/17) of patients died from complications of allogeneic
HSCT after OPDIVO. Five deaths occurred in the setting of severe or
refractory GVHD. Grade 3 or higher acute GVHD was reported in 29%
(5/17) of patients. Hyperacute GVHD was reported in 20% (n=2) of
patients. A steroid-requiring febrile syndrome, without an
identified infectious cause, was reported in 35% (n=6) of patients.
Two cases of encephalitis were reported: Grade 3 (n=1) lymphocytic
encephalitis without an identified infectious cause, and Grade 3
(n=1) suspected viral encephalitis. Hepatic veno-occlusive disease
(VOD) occurred in one patient, who received reduced-intensity
conditioned allogeneic HSCT and died of GVHD and multi-organ
failure. Other cases of hepatic VOD after reduced-intensity
conditioned allogeneic HSCT have also been reported in patients
with lymphoma who received a PD-1 receptor blocking antibody before
transplantation. Cases of fatal hyperacute GVHD have also been
reported. These complications may occur despite intervening therapy
between PD-1 blockade and allogeneic HSCT.
Follow patients closely for early evidence of transplant-related
complications such as hyperacute GVHD, severe (Grade 3 to 4) acute
GVHD, steroid-requiring febrile syndrome, hepatic VOD, and other
immune-mediated adverse reactions, and intervene promptly.
Embryo-Fetal Toxicity
Based on its mechanism of action, OPDIVO 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-
containing regimen and for at least 5 months after the last dose of
OPDIVO.
Lactation
It is not known whether OPDIVO 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.
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 017 and 057, serious adverse
reactions occurred in 46% of patients receiving OPDIVO (n=418). The
most frequent serious adverse reactions reported in at least 2% of
patients receiving OPDIVO were pneumonia, pulmonary embolism,
dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory
failure. 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. The most frequent serious adverse
reactions reported in at least 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 at least 2% of
patients receiving OPDIVO were urinary tract infection, sepsis,
diarrhea, small intestine obstruction, and general physical health
deterioration. In Checkmate 040, serious adverse reactions occurred
in 49% of patients (n=154). The most frequent serious adverse
reactions reported in at least 2% of patients were pyrexia,
ascites, back pain, general physical health deterioration,
abdominal pain, and pneumonia.
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 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 025, the
most common adverse reactions (≥20%) reported in patients receiving
OPDIVO (n=406) vs everolimus (n=397) were asthenic conditions (56%
vs 57%), cough (34% vs 38%), nausea (28% vs 29%), rash (28% vs
36%), dyspnea (27% vs 31%), diarrhea (25% vs 32%), constipation
(23% vs 18%), decreased appetite (23% vs 30%), back pain (21% vs
16%), and arthralgia (20% vs 14%). In Checkmate 205 and 039, 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 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 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%). The most common adverse
reactions (≥20%) in patients who received OPDIVO as a single agent
were fatigue, rash, musculoskeletal pain, pruritus, diarrhea,
nausea, asthenia, cough, dyspnea, constipation, decreased appetite,
back pain, arthralgia, upper respiratory tract infection, and
pyrexia.
Indications and Important Safety Information for YERVOY®
(ipilimumab)
Indications
YERVOY® (ipilimumab) is indicated for the adjuvant treatment of
patients with cutaneous melanoma with pathologic involvement of
regional lymph nodes of more than 1 mm who have undergone complete
resection, including total lymphadenectomy.
Important Safety Information
WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS
YERVOY (ipilimumab) 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.
Recommended Dose Modifications
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. In patients receiving YERVOY 10 mg/kg in Trial 2,
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.
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 10
mg/kg in Trial 2, 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 10 mg/kg in Trial 2, 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-Barre-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 10 mg/kg in Trial 2, 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 10 mg/kg in Trial
2, 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, Including Ocular
Manifestations
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. Administer corticosteroid
eye drops for uveitis, iritis, or episcleritis. Permanently
discontinue YERVOY for immune-mediated ocular disease unresponsive
to local immunosuppressive therapy. In Trial 2, the following
clinically significant immune-mediated adverse reactions were seen
in <1% of YERVOY-treated patients unless specified: 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:
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, hemolytic anemia, 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 a YERVOY-containing regimen and
for 3 months after the last dose of YERVOY.
Lactation
It is not known whether YERVOY is secreted in human milk. Advise
women to discontinue nursing during treatment with YERVOY and for 3
months following the final dose.
Common Adverse Reactions
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 067 – advanced melanoma alone or in combination
with YERVOY; Checkmate 037 and 066 – advanced melanoma;
Checkmate 017 – squamous non-small cell lung cancer (NSCLC);
Checkmate 057 – non-squamous NSCLC; Checkmate 025 –
renal cell carcinoma; Checkmate 205/039 – classical Hodgkin
lymphoma; Checkmate 141 – squamous cell carcinoma of the
head and neck; Checkmate 275 – urothelial carcinoma;
Checkmate 040 – hepatocellular carcinoma.
About the Bristol-Myers Squibb and Ono
Pharmaceutical Co., Ltd. Collaboration
In 2011, through a collaboration agreement with Ono
Pharmaceutical Co., Ltd (Ono), Bristol-Myers Squibb expanded its
territorial rights to develop and commercialize Opdivo globally
except in Japan, South Korea and Taiwan, where Ono had retained all
rights to the compound at the time. On July 23, 2014, Bristol-Myers
Squibb and Ono further expanded the companies’ strategic
collaboration agreement to jointly develop and commercialize
multiple immunotherapies – as single agents and combination
regimens – for patients with cancer in Japan, South Korea and
Taiwan.
About Bristol-Myers Squibb
Bristol-Myers Squibb is a global biopharmaceutical company whose
mission is to discover, develop and deliver innovative medicines
that help patients prevail over serious diseases. For more
information about Bristol-Myers Squibb, visit us at BMS.com or
follow us on LinkedIn, Twitter, YouTube and Facebook.
Bristol-Myers Squibb Forward-Looking
Statement
This press release contains "forward-looking statements" as that
term is defined in the Private Securities Litigation Reform Act of
1995 regarding the research, development and commercialization of
pharmaceutical products. Such forward-looking statements are based
on current expectations and involve inherent risks and
uncertainties, including factors that could delay, divert or change
any of them, and could cause actual outcomes and results to differ
materially from current expectations. No forward-looking statement
can be guaranteed. Among other risks, there can be no guarantee
that Opdivo will receive regulatory approval for an additional
indication. Forward-looking statements in this press release should
be evaluated together with the many uncertainties that affect
Bristol-Myers Squibb's business, particularly those identified in
the cautionary factors discussion in Bristol-Myers Squibb's Annual
Report on Form 10-K for the year ended December 31, 2016 in our
Quarterly Reports on Form 10-Q and our Current Reports on Form 8-K.
Bristol-Myers Squibb undertakes no obligation to publicly update
any forward-looking statement, whether as a result of new
information, future events or otherwise.
# # #
View source
version on businesswire.com: http://www.businesswire.com/news/home/20171016006134/en/
Bristol-Myers SquibbMedia:Audrey Abernathy, cell:
919-605-4521audrey.abernathy@bms.comorInvestor:Tim Power,
609-252-7509timothy.power@bms.comorBill Szablewski,
609-252-5894william.szablewski@bms.com
Bristol Myers Squibb (NYSE:BMY)
Historical Stock Chart
From Mar 2024 to Apr 2024
Bristol Myers Squibb (NYSE:BMY)
Historical Stock Chart
From Apr 2023 to Apr 2024