Bristol-Myers
Squibb Company (NYSE:BMY) today announced that the Committee for
Medicinal Products for Human Use (CHMP) of the European Medicines Agency
(EMA) has adopted a positive opinion recommending that Opdivo (nivolumab),
a PD-1 immune checkpoint inhibitor, be granted approval for use in both
first-line and previously treated patients with advanced (unresectable
or metastatic) melanoma. This is the first positive opinion given by the
CHMP for a PD-1 immune checkpoint inhibitor, and it will now be reviewed
by the European Commission, which has the authority to approve medicines
for the European Union (EU).
The EMA granted Bristol-Myers Squibb accelerated assessment of Opdivo
based on current regulations that fulfills its guidance about “medicinal
products of major interest from the point of view of public health and
in particular from the view point of therapeutic innovation.”
“We are pleased with today’s CHMP positive opinion, as it is a step
closer to us bringing this important medicine for those advanced
melanoma patients in Europe in need of new options,” said Michael
Giordano, senior vice president, Head of Development, Oncology. “Our
vision is to transform how we approach cancer – from clinical
practice to improved patient outcomes. We continue to expand the breadth
and depth of our immuno-oncology portfolio across the continuum of
melanoma and multiple other cancers, to provide more patients with the
potential opportunity for long-term survival.”
Positive Opinion based on CheckMate -066, -037
The CHMP positive opinion is based on data from two Phase III studies
(CheckMate -066 and -037), demonstrating the efficacy and safety of Opdivo
in advanced melanoma patients with important unmet needs. CheckMate
-066, a Phase III randomized double-blind study, comparing Opdivo
to the chemotherapy dacarbazine (DTIC) in patients with treatment-naïve
advanced melanoma, is the first Phase III trial of an investigational
PD-1 immune checkpoint inhibitor to demonstrate an overall survival
benefit in advanced melanoma, as well as a higher objective response
rate. A second study, CheckMate -037, is a Phase III randomized,
controlled open-label study of Opdivo versus investigator’s
choice chemotherapy in patients with advanced melanoma who were
previously treated with Yervoy (ipilimumab), which showed
improvement in objective response rates. These data are supported by a
Phase Ib study (Study -003) in relapsed advanced or metastatic melanoma,
which demonstrated the first characterization of Opdivo benefit/risk
in advanced melanoma. There was consistent Opdivo dosing of 3
mg/kg every two weeks across all three trials.
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
7,000 patients have been enrolled worldwide.
Opdivo became the first PD-1 immune checkpoint inhibitor to
receive regulatory approval anywhere in the world on July 4, 2014 when
Ono Pharmaceutical Co. announced that it received manufacturing and
marketing approval in Japan for the treatment of patients with
unresectable melanoma. In the U.S., the U.S. Food and Drug
Administration (FDA) granted its first approval for Opdivo for
the treatment of patients with unresectable or metastatic melanoma and
disease progression following Yervoy (ipilimumab) and, if BRAF V600
mutation positive, a BRAF inhibitor. On March 5, 2015, Opdivo
recently received its second FDA approval for the treatment of patients
with metastatic squamous non-small cell lung cancer (NSCLC) with
progression on or after platinum-based chemotherapy.
About Advanced Melanoma
Melanoma is a form of skin cancer characterized by the uncontrolled
growth of pigment-producing cells (melanocytes) located in the skin.
Metastatic melanoma is the deadliest form of the disease, and occurs
when cancer spreads beyond the surface of the skin to the other organs,
such as the lymph nodes, lungs, brain or other areas of the body. The
incidence of melanoma has been increasing for at least 30 years. In
2012, an estimated 232,130 melanoma cases were diagnosed globally.
Melanoma is mostly curable when treated in its early stages. However, in
its late stages, the average survival rate has historically been just
six months with a one-year mortality rate of 75%, making it one of the
most aggressive forms of cancer.
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 and
complementary 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,
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 Pharmaceutical
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.
IMPORTANT SAFETY INFORMATION
Immune-Mediated Pneumonitis
-
Severe pneumonitis or interstitial lung disease, including fatal
cases, occurred with OPDIVO treatment. Across the clinical trial
experience in 691 patients with solid tumors, fatal immune-mediated
pneumonitis occurred in 0.7% (5/691) of patients receiving OPDIVO; no
cases occurred in Trial 1 or Trial 3. In Trial 1, 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; one with Grade 3 and five with Grade 2. In
Trial 3, immune-mediated pneumonitis occurred in 6% (7/117) of
patients receiving OPDIVO, including, five Grade 3 and two Grade 2
cases. Monitor patients for signs and symptoms of pneumonitis.
Administer corticosteroids for Grade 2 or greater pneumonitis.
Permanently discontinue OPDIVO for Grade 3 or 4 and withhold OPDIVO
until resolution for Grade 2.
Immune-Mediated Colitis
-
In Trial 1, 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; five with Grade 3 and one with Grade 2. In Trial 3, diarrhea
occurred in 21% (24/117) of patients receiving OPDIVO. Grade 3
immune-mediated colitis occurred in 0.9% (1/117) of patients. Monitor
patients for immune-mediated colitis. Administer corticosteroids for
Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold
OPDIVO for Grade 2 or 3. Permanently discontinue OPDIVO for Grade 4
colitis or recurrent colitis upon restarting OPDIVO.
Immune-Mediated Hepatitis
-
In Trial 1, 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; two with Grade 3 and one with
Grade 2. In Trial 3, the incidences of increased liver test values
were AST (16%), alkaline phosphatase (14%), ALT (12%), and total
bilirubin (2.7%). Monitor patients for abnormal liver tests prior to
and periodically during treatment. Administer corticosteroids for
Grade 2 or greater transaminase elevations. Withhold OPDIVO for Grade
2 and permanently discontinue OPDIVO for Grade 3 or 4 immune-mediated
hepatitis.
Immune-Mediated Nephritis and Renal Dysfunction
-
In Trial 1, 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 Trial 3, the
incidence of elevated creatinine was 22%. Immune-mediated renal
dysfunction (Grade 2) occurred in 0.9% (1/117) of patients. Monitor
patients for elevated serum creatinine prior to and periodically
during treatment. For Grade 2 or 3 serum creatinine elevation,
withhold OPDIVO and administer corticosteroids; if worsening or no
improvement occurs, permanently discontinue OPDIVO. Administer
corticosteroids for Grade 4 serum creatinine elevation and permanently
discontinue OPDIVO.
Immune-Mediated Hypothyroidism and Hyperthyroidism
-
In Trial 1, 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 Trial 3, hypothyroidism occurred in 4.3% (5/117) of
patients receiving OPDIVO. Hyperthyroidism occurred in 1.7% (2/117) of
patients, including one Grade 2 case. Monitor thyroid function prior
to and periodically during treatment. Administer hormone replacement
therapy for hypothyroidism. Initiate medical management for control of
hyperthyroidism.
Other Immune-Mediated Adverse Reactions
-
In Trial 1 and 3 (n=385), the following clinically significant
immune-mediated adverse reactions occurred in <2% of OPDIVO-treated
patients: adrenal insufficiency, uveitis, pancreatitis, facial and
abducens nerve paresis, demyeliniation, autoimmune neuropathy, motor
dysfunction, and vasculitis. Across clinical trials of OPDIVO
administered at doses 3 mg/kg and 10 mg/kg, additional clinically
significant, immune-mediated adverse reactions were identified:
hypophysitis, diabetic ketoacidosis, hypopituitarism, Guillain-Barré
syndrome, and myasthenic syndrome. Based on the severity of adverse
reaction, withhold OPDIVO, administer high-dose corticosteroids, and,
if appropriate, initiate hormone- replacement therapy.
Embryofetal 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 OPDIVO 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
OPDIVO, advise women to discontinue breastfeeding during treatment.
Serious Adverse Reactions
-
In Trial 1, 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 Trial 3, serious adverse reactions occurred in 59% of patients
receiving OPDIVO. The most frequent serious adverse drug reactions
reported in ≥2% of patients were dyspnea, pneumonia, chronic
obstructive pulmonary disease exacerbation, pneumonitis,
hypercalcemia, pleural effusion, hemoptysis, and pain.
Common Adverse Reactions
-
The most common adverse reactions (≥20%) reported with OPDIVO in Trial
1 were rash (21%) and in Trial 3 were fatigue (50%), dyspnea (38%),
musculoskeletal pain (36%), decreased appetite (35%), cough (32%),
nausea (29%), and constipation (24%).
Please see US
Full Prescribing Information for OPDIVO.
About Bristol-Myers Squibb
Bristol-Myers Squibb is a global pharmaceutical 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 in the European Union or, if approved, that it will
become a commercially successful product. 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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