Variations include Opdivo in
previously treated non-squamous, non-small cell lung cancer (NSCLC)
and Opdivo in combination with Yervoy (ipilimumab) in advanced
melanoma
Bristol-Myers Squibb Company (NYSE:BMY) today announced that the
European Medicines Agency (EMA) has validated two of the company’s
type II variation applications, which seek to extend the current
indication for its Immuno-Oncology agent, Opdivo. Validation of the
applications confirms that the submissions are complete and starts
the EMA's centralized review process.
In lung cancer, the proposed new indication addresses the
non-squamous NSCLC population -- Opdivo as monotherapy for the
treatment of locally advanced or metastatic non-squamous NSCLC
after prior chemotherapy in adults. In melanoma, the proposed new
indication aims to extend the use of Opdivo monotherapy to its use
in combination -- Opdivo in combination with Yervoy for the
treatment of advanced (unresectable or metastatic) melanoma in
adults.
“The starting of the EMA’s centralized review process marks a
significant milestone in our commitment to make Opdivo available
for a broader range of appropriate patients with advanced melanoma
and lung cancer in Europe,” said Michael Giordano, M.D., senior
vice president, head of Oncology Development, Bristol-Myers Squibb.
“Today’s announcement also is a step forward in realizing our
vision to change survival expectations, transform the standard of
cancer care, and the way patients live with cancer across multiple
tumor types. We look forward to working with the EMA during its
review process.”
The type II variation submitted to the EMA in non-squamous NSCLC
is supported by data from the landmark, global Phase 3 study,
CheckMate -057, which evaluated the survival of patients with
advanced non-squamous NSCLC who had progressed during or after one
prior platinum doublet-based chemotherapy regimen. The type II
variation application in advanced melanoma is based on data from
two studies: CheckMate -067, a pivotal Phase 3 study that evaluated
the Opdivo+Yervoy regimen or Opdivo monotherapy vs. Yervoy
monotherapy in adults with previously-untreated advanced melanoma,
and the Phase 2 CheckMate -069, the first randomized trial
evaluating the Opdivo+Yervoy regimen in patients with
previously-untreated advanced melanoma, as well as supportive data
from the Phase 1b CA209004 study in advanced melanoma.
About the Marketing Authorization
Applications
Bristol-Myers Squibb submitted two separate Marketing
Authorization Applications (MAA), one in advanced melanoma under
the tradename Opdivo and one for squamous NSCLC under the tradename
Nivolumab BMS in order to accelerate availability of nivolumab for
health care professionals in both indications. The EMA has accepted
Bristol-Myers Squibb’s application to “reconcile” the MAAs into a
single marketing authorization under the tradename Opdivo. The goal
is to have the MAAs reconciled toward the end 2015.
About Opdivo and Yervoy
Cancer cells may exploit “regulatory” pathways, such as
checkpoint pathways, to hide from the immune system and shield the
tumor from immune attack. Opdivo and Yervoy are both monoclonal
antibodies and immune checkpoint inhibitors that target separate,
distinct checkpoint pathways. Inhibition of these immune checkpoint
pathways results in enhanced T-cell function greater than the
effects of either antibody alone.
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 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 and, if BRAF V600 mutation
positive, a BRAF inhibitor. On March 4, 2015, Opdivo received its
second FDA approval for the treatment of patients with advanced
squamous non-small cell lung cancer (NSCLC) with progression on or
after platinum-based chemotherapy. The European Commission (EC)
announced approval of Opdivo on June 19, 2015, for the treatment of
advanced (unresectable or metastatic) melanoma in adults,
regardless of BRAF status, and on June 20, 2015, the EC announced
it approved Nivolumab BMS for the treatment of locally advanced or
metastatic squamous NSCLC after prior chemotherapy.
On March 25, 2011, the FDA approved Yervoy 3 mg/kg monotherapy
for patients with unresectable or metastatic melanoma. In July
2011, approval of Yervoy was granted in Europe by the European
Commission for the treatment of advanced melanoma patients after
prior treatment; the Marketing Authorization was extended in May
2013 to the untreated advanced melanoma population. Yervoy is now
approved in more than 40 countries.
Bristol-Myers Squibb has a broad, global development program
with over 8,000 patients enrolled in more than 50 trials evaluating
nivolumab across multiple tumor types – as monotherapy or in
combination with other therapies.
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 U.S. Full Prescribing Information for OPDIVO
here.
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, Bristol-Myers Squibb expanded its territorial
rights to develop and commercialize nivolumab 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.
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 be approved for an additional indication in lung
cancer in Europe, that the combination treatment of Opdivo and
Yervoy will receive regulatory approval, 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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version on businesswire.com: http://www.businesswire.com/news/home/20150723005361/en/
Bristol-Myers Squibb CompanyMedia:Carrie Fernandez,
215-859-2605, carrie.fernandez@bms.comorInvestors:Ranya
Dajani, 609-252-5330, ranya.dajani@bms.comBill Szablewski,
609-252-5864, william.szablewski@bms.com
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