Submission based on overall survival data
from CheckMate -025, a Phase 3 study comparing Opdivo versus
everolimus in this patient population
Agency previously granted Opdivo
Breakthrough Therapy Designation for this indication
Bristol-Myers Squibb Company (NYSE: BMY) today announced that
the U.S. Food and Drug Administration (FDA) has accepted for filing
and priority review a supplemental Biologics License Application
(sBLA) for Opdivo for the treatment of patients with advanced renal
cell carcinoma (RCC) who have received prior anti-angiogenic
therapy. The FDA previously granted Opdivo Breakthrough Therapy
Designation for this indication, underscoring the critical need for
new treatment options for patients with advanced RCC who have
received prior therapy. The projected FDA action date is March 16,
2016.
Michael Giordano, M.D., senior vice president, head of Oncology
Development, Bristol-Myers Squibb, commented, “There remains a
significant unmet medical need for advanced renal cell carcinoma
patients who have received prior therapy and are often repeatedly
treated with agents that are similar in mechanism. We are pleased
the FDA has accepted our sBLA for Opdivo in RCC, and we will
continue to work with urgency to bring Opdivo to patients with this
cancer.”
This sBLA submission is based on CheckMate -025, a Phase 3 study
that evaluated the overall survival of Opdivo in patients with
previously treated advanced RCC versus everolimus, a current
standard of care in this patient population. The trial was stopped
early in July 2015 because an assessment conducted by the
independent Data Monitoring Committee (DMC) concluded that the
study met its primary endpoint of overall survival. Data from
CheckMate -025 were recently presented at the 2015 European Cancer
Congress and simultaneously published in The New England Journal of
Medicine.
About Renal Cell
Carcinoma
Renal cell carcinoma (RCC) is the most common type of kidney
cancer in adults, accounting for more than 100,000 deaths worldwide
each year. Clear-cell RCC is the most prevalent type of RCC and
constitutes 80% to 90% of all cases. RCC is approximately twice as
common in men as in women, with the highest rates of the disease
found in North America and Europe. Globally, the five-year survival
rate for those diagnosed with metastatic, or advanced, kidney
cancer is 12.1%.
About Opdivo
Bristol-Myers Squibb has a broad, global development program to
study Opdivo in multiple tumor types consisting of more than 50
trials – as monotherapy or in combination with other therapies – in
which more than 8,000 patients have been enrolled worldwide. Opdivo
is the first PD-1 immune checkpoint inhibitor to receive regulatory
approval anywhere in the world in July 2014, and currently has
regulatory approval in more than 37 countries including the United
States, Japan, and in the European Union.
Indications and Important Safety Information for
OPDIVO® (nivolumab)
INDICATIONS
OPDIVO® (nivolumab) is indicated for the treatment of
unresectable or metastatic melanoma as a single agent in patients
with disease progression following ipilimumab and, if BRAF V600
mutation positive, a BRAF inhibitor and in combination with
ipilimumab in patients with BRAF V600 wild-type melanoma.
These indications are approved under accelerated approval based
on tumor response rate and durability of response. Continued
approval for these indications 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.
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
Immune-mediated pneumonitis or interstitial lung disease,
including fatal cases, occurred with OPDIVO treatment. Across the
clinical trial experience with solid tumors, fatal immune-mediated
pneumonitis occurred in 0.5% (5/978) of patients receiving OPDIVO
as a single agent. Monitor patients for signs with radiographic
imaging and symptoms of pneumonitis. Administer corticosteroids for
Grade 2 or greater pneumonitis. Permanently discontinue for Grade 3
or 4 and withhold until resolution for Grade 2. In Checkmate 037,
pneumonitis, including interstitial lung disease, occurred in 3.4%
(9/268) of patients receiving OPDIVO and none of the 102 patients
receiving chemotherapy. Immune-mediated pneumonitis occurred in
2.2% (6/268) of patients receiving OPDIVO; Grade 3 (n=1) and Grade
2 (n=5).
In Checkmate 057, immune-mediated pneumonitis, including
interstitial lung disease, occurred in 3.4% (10/287) of patients
receiving OPDIVO as a single agent: Grade 3 (n=5), Grade 2 (n=2),
and Grade 1 (n=3). Across the clinical trial experience in 188
patients with melanoma who received OPDIVO in combination with
YERVOY, in Checkmate 069 (n=94) and an additional dose-finding
study (n=94), fatal immune-mediated pneumonitis occurred in 0.5%
(1/188) of patients. In Checkmate 069, there were six additional
patients who died without resolution of abnormal respiratory
findings. In Checkmate 069, pneumonitis, including interstitial
lung disease, occurred in 10% (9/94) of patients receiving OPDIVO
in combination with YERVOY and 2.2% (1/46) of patients receiving
YERVOY. Immune-mediated pneumonitis occurred in 6% (6/94) of
patients receiving OPDIVO in combination with YERVOY: Grade 5
(n=1), Grade 3 (n=2) and Grade 2 (n=3).
Immune-Mediated Colitis
Immune-mediated colitis can occur with OPDIVO treatment. Monitor
patients for signs and symptoms of colitis. Administer
corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4
colitis. As a single agent, withhold OPDIVO for Grade 2 or 3 and
permanently discontinue for Grade 4 or recurrent colitis upon
restarting OPDIVO. In combination with YERVOY, withhold OPDIVO for
Grade 2 and permanently discontinue for Grade 3 or 4 or recurrent
colitis upon restarting OPDIVO. In Checkmate 037, diarrhea or
colitis occurred in 21% (57/268) of patients receiving OPDIVO and
18% (18/102) of patients receiving chemotherapy. Immune-mediated
colitis occurred in 2.2% (6/268) of patients receiving OPDIVO;
Grade 3 (n=5) and Grade 2 (n=1). In Checkmate 057, diarrhea or
colitis occurred in 17% (50/287) of patients receiving OPDIVO as a
single agent. Immune-mediated colitis occurred in 2.4% (7/287) of
patients: Grade 3 (n=3), Grade 2 (n=2), and Grade 1 (n=2). In
Checkmate 069, diarrhea or colitis occurred in 57% (54/94) of
patients receiving OPDIVO in combination with YERVOY and 46%
(21/46) of patients receiving YERVOY. Immune-mediated colitis
occurred in 33% (31/94) of patients receiving OPDIVO in combination
with YERVOY: Grade 4 (n=1), Grade 3 (n=16), Grade 2 (n=9), and
Grade 1 (n=5).
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
Immune-mediated hepatitis can occur with OPDIVO treatment.
Monitor patients for abnormal liver tests prior to and periodically
during treatment. Administer corticosteroids for Grade 2 or greater
transaminase elevations. Withhold for Grade 2 and permanently
discontinue for Grade 3 or 4 immune-mediated hepatitis. In
Checkmate 037, there was an increased incidence of liver test
abnormalities in the OPDIVO-treated group as compared to the
chemotherapy-treated group, with increases in AST (28% vs 12%),
alkaline phosphatase (22% vs 13%), ALT (16% vs 5%), and total
bilirubin (9% vs 0). Immune-mediated hepatitis occurred in 1.1%
(3/268) of patients receiving OPDIVO; Grade 3 (n=2) and Grade 2
(n=1). In Checkmate 057, one patient (0.3%) developed
immune-mediated hepatitis. In Checkmate 069, immune-mediated
hepatitis occurred in 15% (14/94) of patients receiving OPDIVO in
combination with YERVOY: Grade 4 (n=3), Grade 3 (n=9), and Grade 2
(n=2).
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 Dermatitis
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 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
Hypophysitis, adrenal insufficiency, and thyroid disorders can
occur with OPDIVO treatment. Monitor patients for signs and
symptoms of hypophysitis, signs and symptoms of adrenal
insufficiency during and after treatment, and thyroid function
prior to and periodically during treatment. Administer
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.
In Checkmate 069, hypophysitis occurred in 13% (12/94) of
patients receiving OPDIVO in combination with YERVOY: Grade 3 (n=2)
and Grade 2 (n=10). Adrenal insufficiency occurred in 1% (n=555) of
patients receiving OPDIVO as a single agent. In Checkmate 069,
adrenal insufficiency occurred in 9% (8/94) of patients receiving
OPDIVO in combination with YERVOY: Grade 3 (n=3), Grade 2 (n=4),
and Grade 1 (n=1). In Checkmate 069, hypothyroidism occurred in 19%
(18/94) of patients receiving OPDIVO in combination with YERVOY.
All were Grade 1 or 2 in severity except for one patient who
experienced Grade 3 autoimmune thyroiditis. Grade 1 hyperthyroidism
occurred in 2.1% (2/94) of patients receiving OPDIVO in combination
with YERVOY. In Checkmate 037, Grade 1 or 2 hypothyroidism occurred
in 8% (21/268) of patients receiving OPDIVO and none of the 102
patients receiving chemotherapy. Grade 1 or 2 hyperthyroidism
occurred in 3% (8/268) of patients receiving OPDIVO and 1% (1/102)
of patients receiving chemotherapy. In Checkmate 057, Grade 1 or 2
hypothyroidism, including thyroiditis, occurred in 7% (20/287) and
elevated TSH occurred in 17% of patients receiving OPDIVO as a
single agent. Grade 1 or 2 hyperthyroidism occurred in 1.4% (4/287)
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. 6 of the 9
patients were hospitalized for severe endocrinopathies.
Immune-Mediated Nephritis and Renal Dysfunction
Immune-mediated nephritis can occur with OPDIVO treatment.
Monitor patients for elevated serum creatinine prior to and
periodically during treatment. For Grade 2 or 3 increased serum
creatinine, withhold and administer corticosteroids; if worsening
or no improvement occurs, permanently discontinue. Administer
corticosteroids for Grade 4 serum creatinine elevation and
permanently discontinue. In Checkmate 037, there was an increased
incidence of elevated creatinine in the OPDIVO-treated group as
compared to the chemotherapy-treated group (13% vs 9%). Grade 2 or
3 immune-mediated nephritis or renal dysfunction occurred in 0.7%
(2/268) of patients. In Checkmate 057, Grade 2 immune-mediated
renal dysfunction occurred in 0.3% (1/287) of patients receiving
OPDIVO as a single agent. In Checkmate 069, Grade 2 or higher
immune-mediated nephritis or renal dysfunction occurred in 2.1%
(2/94) of patients. One patient died without resolution of renal
dysfunction.
Immune-Mediated Rash
Immune-mediated rash can occur with OPDIVO treatment. Monitor
patients for rash. Administer corticosteroids for Grade 3 or 4
rash. Withhold for Grade 3 and permanently discontinue for Grade 4.
In Checkmate 037 (n=268), the incidence of rash was 21%; the
incidence of Grade 3 or 4 rash was 0.4%. In Checkmate 057,
immune-mediated rash occurred in 6% (17/287) of patients receiving
OPDIVO as a single agent including four Grade 3 cases. In Checkmate
069, immune-mediated rash occurred in 37% (35/94) of patients
receiving OPDIVO in combination with YERVOY: Grade 3 (n=6), Grade 2
(n=10), and Grade 1 (n=19).
Immune-Mediated Encephalitis
Immune-mediated encephalitis can occur with OPDIVO treatment.
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.
Across clinical trials of 8490 patients receiving OPDIVO as a
single agent or in combination with YERVOY, <1% of patients were
identified as having encephalitis. In Checkmate 057, fatal limbic
encephalitis occurred in one patient (0.3%) receiving OPDIVO as a
single agent.
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. The following clinically significant immune-mediated
adverse reactions occurred in <2% (n=555) of single-agent
OPDIVO-treated patients: uveitis, pancreatitis, abducens nerve
paresis, demyelination, polymyalgia rheumatica, and autoimmune
neuropathy. Across clinical trials of OPDIVO administered as a
single agent at doses 3 mg/kg and 10 mg/kg, additional clinically
significant, immune-mediated adverse reactions were identified:
facial nerve paralysis, motor dysfunction, vasculitis, diabetic
ketoacidosis, and myasthenic syndrome. In Checkmate 069, the
following additional immune-mediated adverse reactions occurred in
1% of patients treated with OPDIVO in combination with YERVOY:
Guillain-Barré syndrome and hypopituitarism. Across clinical trials
of OPDIVO in combination with YERVOY, the following additional
clinically significant, immune-mediated adverse reactions were
identified: uveitis, sarcoidosis, duodenitis, pancreatitis, and
gastritis.
Infusion Reactions
Severe infusion reactions have been reported in <1% of
patients in clinical trials of OPDIVO as a single agent. In
Checkmate 057, Grade 2 infusion reactions occurred in 1% (3/287) of
patients receiving OPDIVO as a single agent. In Checkmate 069,
Grade 2 infusion reactions occurred in 3% (3/94) of patients
receiving OPDIVO in combination with YERVOY. Discontinue OPDIVO in
patients with severe or life-threatening infusion reactions.
Interrupt or slow the rate of infusion in patients with mild or
moderate infusion reactions.
Embryofetal 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.
Lactation
It is not known whether OPDIVO or YERVOY is present in human
milk. Because many drugs, including antibodies, are excreted in
human milk and because of the potential for serious adverse
reactions in nursing infants from OPDIVO-containing regimen, advise
women to discontinue breastfeeding during treatment. Advise women
to discontinue nursing 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. 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 057,
serious adverse reactions occurred in 47% of patients receiving
OPDIVO as a single agent. The most frequent serious adverse
reactions reported in ≥2% of patients were pneumonia, pulmonary
embolism, dyspnea, pleural effusion, and respiratory failure. In
Checkmate 069, serious adverse reactions occurred in 62% of
patients receiving OPDIVO; the most frequent serious adverse events
with OPDIVO in combination with YERVOY, as compared to YERVOY
alone, were colitis (17% vs 9%), diarrhea (9% vs 7%), pyrexia (6%
vs 7%), and pneumonitis (5% vs 0).
Common Adverse Reactions
In Checkmate 037, the most common adverse reaction (≥20%)
reported with OPDIVO was rash (21%). In Checkmate 057, the most
common adverse reactions (≥20%) reported with OPDIVO as a single
agent were fatigue (49%), musculoskeletal pain (36%), cough (30%),
decreased appetite (29%), and constipation (23%). In Checkmate 069,
the most common adverse reactions (≥20%) reported in patients
receiving OPDIVO in combination with YERVOY vs YERVOY alone were
rash (67% vs 57%), pruritus (37% vs 26%), headache (24% vs 20%),
vomiting (23% vs 15%), and colitis (22% vs 11%).
In a separate Phase 3 study of YERVOY 3 mg/kg, the most common
adverse reactions (≥5%) in patients who received YERVOY at 3 mg/kg
were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and
colitis (8%).
Please see U.S. Full Prescribing Information, including Boxed
WARNING regarding immune-mediated adverse reactions, for
YERVOY.
Please see U.S. Full Prescribing Information for OPDIVO.
Immuno-Oncology at Bristol-Myers
Squibb
Surgery, radiation, cytotoxic or targeted therapies have
represented the mainstay of cancer treatment over the last several
decades, but long-term survival and a positive quality of life have
remained elusive for many patients with advanced disease.
To address this unmet medical need, Bristol-Myers Squibb is
leading research in an innovative field of cancer research and
treatment known as Immuno-Oncology, which involves agents whose
primary mechanism is to work directly with the body’s immune system
to fight cancer. The company is exploring a variety of compounds
and immunotherapeutic approaches for patients with different types
of cancer, including researching the potential of combining
Immuno-Oncology agents that target different pathways in the
treatment of cancer.
Bristol-Myers Squibb is committed to advancing the science of
Immuno-Oncology, with the goal of changing survival expectations
and the way patients live with cancer.
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, 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 www.bms.com, or
follow us on Twitter at http://twitter.com/bmsnews.
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 the additional
indication described in this release. 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, 2014 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.
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Bristol-Myers SquibbMedia:Carrie Fernandez,
609-419-5448, cell:
215-859-2605carrie.fernandez@bms.comorInvestors:Ranya
Dajani, 609-252-5330, cell: 215-666-1515ranya.dajani@bms.comorBill
Szablewski, 609-252-5894, cell:
215-801-0906william.szablewski@bms.com
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