Opdivo is the first and only PD-1 inhibitor
approved to treat advanced renal cell carcinoma patients who have
received prior therapy
Opdivo is the first-ever agent to
demonstrate a significant improvement in overall survival, the
primary endpoint, in advanced renal cell carcinoma patients who
have received prior therapy vs. everolimus, based on Phase 3 study
CheckMate -025
With this approval, Opdivo is the
only PD-1 inhibitor approved in Europe to demonstrate overall
survival benefit versus standards of care in three distinct tumor
types
Bristol-Myers Squibb Company (NYSE:BMY) announced today that the
European Commission has approved Opdivo (nivolumab) monotherapy for
an additional indication in advanced renal cell carcinoma (RCC)
after prior therapy in adults. Opdivo is the first and only PD-1
immune checkpoint inhibitor approved in Europe to demonstrate an
overall survival (OS) benefit versus a standard of care in this
patient population. This approval allows for the expanded marketing
of Opdivo in previously treated advanced RCC in all 28 Member
States of the European Union.
Emmanuel Blin, senior vice president, Head of Commercialization,
Policy and Operations, Bristol-Myers Squibb, commented, “Today’s
approval is reflective of our commitment to bring Opdivo and the
potential for long-term survival to broad patient populations,
including previously treated advanced renal cell carcinoma. Opdivo
is the only PD-1 inhibitor approved in Europe to demonstrate a
significant survival advantage in this patient population. At
Bristol-Myers Squibb, we are driven to work with speed to deliver
new treatment options to help more patients, and in less than a
year, we have expanded the approval of Opdivo in Europe to include
three distinct types of advanced cancer.”
This approval is based on the results of the Phase 3 study
CheckMate -025, which were published in The New England Journal of
Medicine. In CheckMate -025, Opdivo was evaluated in patients with
advanced clear-cell RCC who received prior anti-angiogenic therapy
compared to everolimus. Patients treated with Opdivo achieved a
median OS of 25 months versus 19.6 months for everolimus (HR=0.73
[98.5% CI: 0.57-0.93; p=0.0018]), representing a greater than five
month improvement over a current standard of care. CheckMate -025
also evaluated patients’ quality of life (QoL) and found that
patients treated with Opdivo had improved survival and QoL compared
to everolimus throughout the duration of treatment.
Dr. Bernard Escudier, Chair of the Genitourinary Oncology
Committee, Institut Gustave Roussy in Villejuif, France, commented,
“For the first time, previously treated advanced renal cell
carcinoma patients in Europe will now have access to an
Immuno-Oncology agent that has demonstrated a significant overall
survival benefit along with a favorable safety profile compared to
everolimus. In addition to the clinical efficacy results, patients
treated with Opdivo experienced an improvement in their
health-related quality of life and had significantly lower symptom
burden throughout treatment compared to patients receiving
everolimus. Combined, these data support the use of Opdivo in
clinical practice and represent important progress toward
establishing a new standard of care in Europe.”
First PD-1 Inhibitor to Demonstrate
Significant Overall Survival Benefit In Previously Treated
Advanced RCC
CheckMate -025 is an open-label, randomized Phase 3 study, which
evaluated Opdivo versus everolimus in patients with advanced
clear-cell renal cell carcinoma (RCC) who have received prior
anti-angiogenic therapy, with overall survival (OS) as the primary
endpoint. Objective response rate (ORR) was evaluated as a
secondary endpoint. In the study, patients were randomized to
receive Opdivo (3 mg/kg administered intravenously every two weeks)
compared to everolimus (10 mg administered orally daily). The
prespecified interim analysis was conducted when 398 events were
observed (70% of the planned number of events for final
analysis).
Results from CheckMate -025 showed that patients treated with
Opdivo achieved a more than five month improvement in OS, with
median OS of 25 months for Opdivo and 19.6 months for everolimus
(HR=0.73 [98.5% CI: 0.57-0.93; p=0.0018]). An OS benefit was seen
regardless of PD-L1 expression. In addition to improving OS, Opdivo
demonstrated a superior ORR compared to everolimus (25.1% [95% CI:
21-29.6] vs. 5.4% [95% CI: 3.4-8.0]). Forty-nine (47.6%) Opdivo
responders had ongoing responses of up to 27.6 months.
In addition to the OS benefit observed with Opdivo, patients
treated with the drug also experienced an improvement over time in
disease related symptoms and non-disease specific quality of life
compared to patients receiving everolimus. Patients were assessed
using validated and reliable scales in the Functional Assessment of
Cancer Therapy-Kidney Symptom Index-Disease Related Symptoms
(FKSI-DRS) and the EuroQoL EQ-5D. Results showed that as early as
week 20, patients receiving Opdivo had a significant improvement in
disease related symptoms, while patients receiving everolimus
showed a significant deterioration by week 4.
The safety profile of Opdivo in CheckMate -025 was consistent
with prior studies. Serious adverse events occurred in 47% of
patients receiving Opdivo. The most frequent serious adverse
reactions reported in at least 2% of patients receiving Opdivo were
acute kidney injury, pleural effusion, pneumonia, diarrhea, and
hypercalcemia. In the study, the most common adverse reactions
(≥20%) reported in patients receiving Opdivo versus everolimus 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%).
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
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 &
Immuno-Oncology: Advancing Oncology Research
At Bristol-Myers Squibb, we have a vision for the future of
cancer care that is focused on Immuno-Oncology, now considered a
major treatment choice alongside surgery, radiation, chemotherapy
and targeted therapies for certain types of cancer.
We have a comprehensive clinical portfolio of investigational
and approved Immuno-Oncology agents, many of which were discovered
and developed by our scientists. Our ongoing Immuno-Oncology
clinical program is looking at broad patient populations, across
multiple solid tumors and hematologic malignancies, and lines of
therapy and histologies, with the intent of powering our trials for
OS and other important measures like durability of response. We
pioneered the research leading to the first regulatory approval for
the combination of two Immuno-Oncology agents, and continue to
study the role of combinations in cancer.
We are also investigating other immune system pathways in the
treatment of cancer including CTLA-4, CD-137, KIR, SLAMF7, PD-1,
GITR, CSF1R, IDO, and LAG-3. These pathways may lead to potential
new treatment options – in combination or monotherapy – to help
patients fight different types of cancers.
Our collaboration with academia, as well as small and large
biotech companies, to research the potential of Immuno-Oncology and
non-Immuno-Oncology combinations, helps achieve our goal of
providing new treatment options in clinical practice. At
Bristol-Myers Squibb, we are committed to changing survival
expectations in hard-to-treat cancers and the way patients live
with cancer.
About Opdivo
Cancer cells may exploit “regulatory” pathways, such as
checkpoint pathways, to hide from the immune system and shield the
tumor from immune attack. Opdivo is a PD-1 immune checkpoint
inhibitor that binds to the checkpoint receptor PD-1 expressed on
activated T-cells, and blocks the binding of PD-L1 and PD-L2,
preventing the PD-1 pathway’s suppressive signaling on the immune
system, including the interference with an anti-tumor immune
response.
Opdivo’s broad global development program is based on
Bristol-Myers Squibb’s understanding of the biology behind
Immuno-Oncology. Our company is at the forefront of researching the
potential of Immuno-Oncology to extend survival in hard to treat
cancers. This scientific expertise serves as the basis for the
Opdivo development program, which includes a broad range of Phase 3
clinical trials evaluating OS as the primary endpoint across a
variety of tumor types. The Opdivo trials have also contributed
toward the clinical and scientific understanding of the role of
biomarkers and how patients may benefit from Opdivo across the
continuum of PD-L1 expression. To date, the Opdivo clinical
development program has enrolled more than 18,000 patients.
Opdivo was the first PD-1 immune checkpoint inhibitor to receive
regulatory approval anywhere in the world in July 2014, and
currently has regulatory approval in 48 countries including the
United States, Japan, and in the European Union.
U.S. FDA APPROVED
INDICATIONS
OPDIVO® (nivolumab) is indicated for the treatment of
patients with advanced renal cell carcinoma (RCC) who have received
prior anti-angiogenic therapy.
IMPORTANT SAFETY
INFORMATION
Immune-Mediated Pneumonitis
Immune-mediated pneumonitis, including fatal cases, occurred
with OPDIVO treatment. Across the clinical trial experience with
solid tumors, fatal immune-mediated pneumonitis occurred with
OPDIVO. 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 025,
pneumonitis, including interstitial lung disease, occurred in 5%
(21/406) of patients receiving OPDIVO and 18% (73/397) of patients
receiving everolimus. Immune-mediated pneumonitis occurred in 4.4%
(18/406) of patients receiving OPDIVO: Grade 4 (n=1), Grade 3
(n=4), Grade 2 (n=12), and Grade 1 (n=1).
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 Checkmate 025, diarrhea or colitis occurred
in 25% (100/406) of patients receiving OPDIVO and 32% (126/397) of
patients receiving everolimus. Immune-mediated diarrhea or colitis
occurred in 3.2% (13/406) of patients receiving OPDIVO: Grade 3
(n=5), Grade 2 (n=7), and Grade 1 (n=1).
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 025, there was an increased incidence of liver test
abnormalities compared to baseline in AST (33% vs 39%), alkaline
phosphatase (32% vs 32%), ALT (22% vs 31%), and total bilirubin (9%
vs 3.5%) in the OPDIVO and everolimus arms, respectively.
Immune-mediated hepatitis requiring systemic immunosuppression
occurred in 1.5% (6/406) of patients receiving OPDIVO: Grade 3
(n=5) and Grade 2 (n=1).
Immune-Mediated Endocrinopathies
Hypophysitis, adrenal insufficiency, thyroid disorders, and type
1 diabetes mellitus can occur with OPDIVO treatment. Monitor
patients for signs and symptoms of hypophysitis, signs and symptoms
of adrenal insufficiency during and after treatment, thyroid
function prior to and periodically during treatment, and
hyperglycemia. 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. Administer insulin for
type 1 diabetes. Withhold OPDIVO for Grade 3 and permanently
discontinue for Grade 4 hyperglycemia.
In Checkmate 025, hypophysitis occurred in 0.5% (2/406) of
patients receiving OPDIVO: Grade 3 (n=1) and Grade 1 (n=1). Adrenal
insufficiency occurred in 2.0% (8/406) of patients receiving
OPDIVO: Grade 3 (n=3), Grade 2 (n=4), and Grade 1 (n=1). Thyroid
disease occurred in 11% (43/406) of patients receiving OPDIVO,
including one Grade 3 event, and in 3.0% (12/397) of patients
receiving everolimus. Hypothyroidism/thyroiditis occurred in 8%
(33/406) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2
(n=17), and Grade 1 (n=14). Hyperthyroidism occurred in 2.5%
(10/406) of patients receiving OPDIVO: Grade 2 (n=5) and Grade 1
(n=5). Hyperglycemic adverse events occurred in 9% (37/406)
patients. Diabetes mellitus or diabetic ketoacidosis occurred in
1.5% (6/406) of patients receiving OPDIVO: Grade 3 (n=3), Grade 2
(n=2), and Grade 1 (n=1).
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 025, renal injury occurred in
7% (27/406) of patients receiving OPDIVO and 3.0% (12/397) of
patients receiving everolimus. Immune-mediated nephritis and renal
dysfunction occurred in 3.2% (13/406) of patients receiving OPDIVO:
Grade 5 (n=1), Grade 4 (n=1), Grade 3 (n=5), and Grade 2 (n=6).
Immune-Mediated Rash
Immune-mediated rash can occur with OPDIVO treatment. Severe
rash (including rare cases of fatal toxic epidermal necrolysis)
occurred in the clinical program of OPDIVO. Monitor patients for
rash. Administer corticosteroids for Grade 3 or 4 rash. Withhold
for Grade 3 and permanently discontinue for Grade 4. In Checkmate
025, rash occurred in 28% (112/406) of patients receiving OPDIVO
and 36% (143/397) of patients receiving everolimus. Immune-mediated
rash, defined as a rash treated with systemic or topical
corticosteroids, occurred in 7% (30/406) of patients receiving
OPDIVO: Grade 3 (n=4), Grade 2 (n=7), 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.
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. In < 1.0% of patients receiving OPDIVO, the following
clinically significant, immune-mediated adverse reactions occurred:
uveitis, pancreatitis, facial and abducens nerve paresis,
demyelination, polymyalgia rheumatica, autoimmune neuropathy,
Guillain-Barré syndrome, hypopituitarism, systemic inflammatory
response syndrome, gastritis, duodenitis, and sarcoidosis. Across
clinical trials of OPDIVO as a single agent administered at doses
of 3 mg/kg and 10 mg/kg, additional clinically significant,
immune-mediated adverse reactions were identified: motor
dysfunction, vasculitis, and myasthenic syndrome.
Infusion Reactions
Severe infusion reactions have been reported in <1.0% of
patients in clinical trials of OPDIVO. 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 Checkmate
025, hypersensitivity/infusion-related reactions occurred in 6%
(25/406) of patients receiving OPDIVO and 1.0% (4/397) of patients
receiving everolimus.
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 025, serious adverse reactions occurred in 47% of
patients receiving OPDIVO. The most frequent serious adverse
reactions reported in ≥2% of patients were acute kidney injury,
pleural effusion, pneumonia, diarrhea, and hypercalcemia.
Common Adverse Reactions
In Checkmate 025, the most common adverse reactions (≥20%)
reported in patients receiving OPDIVO vs everolimus 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%).
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 www.bms.com or
follow us on LinkedIn, Twitter, and YouTube.
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. 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,
2015 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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