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
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is defined in the Private Securities Litigation Reform Act of 1995
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including factors that could delay, divert or change any of them, and
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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.
Bristol-Myers Squibb CompanyMedia:Audrey Abernathy, 609-419-5375Cell: 919-605-4521audrey.abernathy@bms.comorInvestors:Ranya Dajani, 609-252-5330Cell: 215-666-1515ranya.dajani@bms.comorBill Szablewski, 609-252-5894Cell: 215-801-0906william.szablewski@bms.com