This approval expands Opdivo’s
existing lung cancer indication in previously treated metastatic
squamous NSCLC to include the non-squamous patient population,
which together represents 85% of lung cancer cases
Opdivo is the only PD-1 inhibitor approved
for a broad range of patients with previously treated metastatic
NSCLC, regardless of PD-L1 expression
Opdivo represents the first and only
approved PD-1 inhibitor to demonstrate superior overall survival
compared to docetaxel, in previously treated metastatic
NSCLC
Bristol-Myers Squibb Company (NYSE:BMY) announced today that the
European Commission has approved Opdivo (nivolumab) monotherapy for
locally advanced or metastatic non-small cell lung cancer (NSCLC)
after prior chemotherapy in adults. Opdivo is the only approved
PD-1 inhibitor to demonstrate superior overall survival (OS) in two
separate Phase 3 trials in previously treated metastatic NSCLC; one
trial in squamous NSCLC (CheckMate -017) and the other in
non-squamous NSCLC (CheckMate -057), the basis of this approval.
Together, these trials confirm the benefit of Opdivo for patients
with previously treated metastatic NSCLC, regardless of PD-L1
expression. The approval allows for the expanded marketing of
Opdivo in previously treated metastatic NSCLC in all 28 Member
States of the European Union.
Emmanuel Blin, senior vice president, Head of Commercialization,
Policy and Operations, Bristol-Myers Squibb, commented, “At
Bristol-Myers Squibb, our goal is to help improve survival outcomes
for patients with hard-to-treat cancers, such as advanced non-small
cell lung cancer. Today’s approval is indicative of our commitment
to bringing our Immuno-Oncology science and the potential for
long-term survival to a broader range of lung cancer patients in
Europe. Opdivo is the only PD-1 inhibitor approved in Europe to
have demonstrated, in two separate Phase 3 trials, a significant
survival advantage in this patient population, offering a
much-needed new treatment option to patients fighting this
disease.”
The approval is based on the results of Phase 3 trial, CheckMate
-057, which were published in The New England Journal of Medicine.
In CheckMate -057, Opdivo was evaluated in patients with metastatic
non-squamous NSCLC compared to docetaxel, and included patients
regardless of PD-L1 expression. Opdivo demonstrated superior OS
compared to docetaxel, with a 27% reduction in the risk of death
(HR=0.73 [95% CI: 0.59-0.89; p=0.0015]) with a one-year survival
rate of 51% for Opdivo (95% CI: 44.6-56.1) versus 39% for docetaxel
(95% CI: 33.3-44.6). Biomarker testing for PD-L1 expression is not
required with Opdivo. The Summary of Product Characteristics (SmPC)
notes that physicians should consider the delayed onset of Opdivo
effect before initiating treatment in patients with poorer
prognostic features and/or aggressive disease. In non-squamous
NSCLC, a higher number of deaths within the first 3 months was
observed with Opdivo compared to docetaxel. Factors associated with
early deaths were poorer prognostic factors and/or more aggressive
disease combined with low or no tumor PD-L1 expression.
Luis Paz-Ares, M.D., Hospital Universitario Doce de Octubre,
Madrid, Spain, commented, “Today’s approval expands the
availability of Opdivo as a treatment option for a broader range of
lung cancer patients – previously treated metastatic squamous and
now non-squamous non-small cell lung cancer – which represents the
majority of diagnosed lung cancer cases. As the only approved PD-1
inhibitor proven to have demonstrated a survival benefit versus a
standard of care, regardless of PD-L1 expression, healthcare
providers can offer treatment with Opdivo to appropriate patients
who have received prior chemotherapy without the need to first
conduct biomarker testing to determine PD-L1 expression. This
approval is meaningful news for patients and their families who are
in need of new treatment options.”
Proven Superior Overall Survival Versus
Docetaxel in Previously Treated Metastatic NSCLC
CheckMate -057 is an open-label, randomized Phase 3 study, which
evaluated Opdivo versus docetaxel in patients with metastatic
non-squamous non-small cell lung cancer (NSCLC), with overall
survival (OS) as the primary endpoint. Objective response rate
(ORR) and progression-free survival (PFS) were evaluated as
secondary endpoints. This study included patients regardless of
PD-L1 expression level. In the study, patients were randomized to
receive Opdivo (3 mg/kg administered intravenously every two weeks)
versus docetaxel (75 mg/m2 administered intravenously every three
weeks). The prespecified interim analysis was conducted when 413
events were observed (93% of the planned number of events for final
analysis).
Opdivo demonstrated superior OS in previously treated metastatic
non-squamous NSCLC compared to docetaxel, with a 27% reduction in
the risk of death (HR=0.73 [95% CI: 0.59-0.89; p=0.0015]) with a
one-year survival rate of 51% for Opdivo (95% CI: 44.6-56.1)
compared to 39% for docetaxel (95% CI: 33.3-44.6). The median OS
was 12.2 months in patients receiving Opdivo (95% CI: 9.66-14.98)
and 9.4 months with docetaxel (95% CI: 8.0-10.68). The ORR in the
Opdivo arm was 19% (56/292; 4 complete responses, 52 partial
responses; 95% CI: 15-24) and 12% with docetaxel (36/290; 1
complete response, 35 partial responses; 95% CI: 9-17, p=0.0246).
For patients administered Opdivo, median duration of response was
17.2 months and 5.6 months for docetaxel. Median PFS was 2.3 months
for Opdivo versus 4.2 months for docetaxel (HR=0.92 [95% CI:
0.77-1.11, p=0.3932]).
Results of a post-hoc, exploratory multivariate analysis
conducted in support of the SmPC development, indicated that
Opdivo-treated patients with poorer prognostic features and/or
aggressive disease when combined with low or no tumor PD-L1
expression may be at higher risk of death within the first 3 months
(Opdivo arm [59/292, 20.2%] as compared to the docetaxel arm
[44/290, 15.2%]). There were no early deaths due to study drug
toxicity in either arm.
The safety profile of Opdivo in CheckMate -057 was consistent
with prior studies. Serious adverse reactions occurred in 47% of
patients receiving Opdivo. In the overall patient population, the
most frequent serious adverse reactions in at least 2% of patients
receiving Opdivo were pneumonia, pulmonary embolism, dyspnea,
pleural effusions and respiratory failure. Opdivo was discontinued
in 13% of patients and was delayed in 29% of patients for an
adverse reaction. The most common adverse reactions in patients
treated with Opdivo (reported in >20% of patients) were fatigue
(49%), musculoskeletal pain (36%), cough (30%), decreased appetite
(29%) and constipation (23%).
The PD-L1 IHC 28-8 PharmDx, a test which was used to assess
PD-L1 expression in the CheckMate -057 trial, is now Conformité
Européene (CE) marked in Europe, and can be used to provide
additional information for physicians. PD-L1 testing is not
required to initiate Opdivo treatment for locally advanced or
metastatic NSCLC patients.
CheckMate -017 is a landmark, Phase 3, open-label, randomized
clinical trial that evaluated Opdivo 3mg/kg intravenously over 60
minutes every two weeks versus standard of care, docetaxel 75 mg/m2
intravenously administered every three weeks in patients with
advanced squamous NSCLC who had progressed during or after one
prior platinum doublet-based chemotherapy regimen. The study’s
primary endpoint was OS and secondary endpoints included PFS and
ORR. The trial included patients regardless of their PD-L1
expression status.
Results from CheckMate -017 showed a 41% reduction in the risk
of death with a one-year survival rate of 42% for Opdivo (42.1%
[95% CI: 33.7, 50.3]) versus 24% (23.7% [95% CI: 16.9, 31.1]) for
docetaxel (HR=0.59 [96.8% CI: 0.43, 0.81; p=0.0002]). Median OS was
9.2 months versus 6 months for Opdivo and docetaxel, respectively.
Opdivo also demonstrated consistent, statistically significant and
clinically meaningful improvements across secondary endpoints, ORR
and PFS, versus docetaxel in patients with previously treated
advanced squamous NSCLC. Survival benefit was observed regardless
of PD-L1 expression across all pre-specified expression levels (1%,
5% and 10%). The safety profile of Opdivo in CheckMate -017 was
consistent with prior studies. Findings from CheckMate -017 were
published in The New England Journal of Medicine and presented at
the 2015 American Society of Clinical Oncology Annual Meeting.
About Lung Cancer
Lung cancer is the leading cause of cancer deaths globally,
resulting in more than 1.5 million deaths each year, according to
the World Health Organization. NSCLC is one of the most common
types of the disease and accounts for approximately 85% of cases.
About 25% to 30% of all lung cancers are squamous cell carcinomas,
and non-squamous NSCLC accounts for approximately 50% to 65% of all
lung cancer cases. Survival rates vary depending on the stage and
type of the cancer when it is diagnosed. Globally, the five-year
survival rate for Stage I NSCLC is between 47% and 50%; for Stage
IV NSCLC, the five-year survival rate drops to 2%.
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 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
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 057,
immune-mediated pneumonitis, including interstitial lung disease,
occurred in 3.4% (10/287) of patients: Grade 3 (n=5), Grade 2
(n=2), and Grade 1 (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 Checkmate 057, diarrhea or colitis occurred
in 17% (50/287) of patients receiving OPDIVO. Immune-mediated
colitis occurred in 2.4% (7/287) of patients: Grade 3 (n=3), Grade
2 (n=2), and Grade 1 (n=2).
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 057, one patient (0.3%) developed immune-mediated
hepatitis.
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 057, 0.3% (1/287) of OPDIVO-treated patients
developed adrenal insufficiency. Grade 1 or 2 hypothyroidism,
including thyroiditis, occurred in 7% (20/287) and elevated thyroid
stimulating hormone occurred in 17% of patients receiving OPDIVO.
Grade 1 or 2 hyperthyroidism occurred in 1.4% (4/287) of
patients.
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 057, Grade 2 immune-mediated
renal dysfunction occurred in 0.3% (1/287) of patients receiving
OPDIVO.
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
057, immune-mediated rash occurred in 6% (17/287) of patients
receiving OPDIVO including four Grade 3 cases.
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. In
Checkmate 057, fatal limbic encephalitis occurred in one patient
(0.3%) receiving OPDIVO.
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
057, Grade 2 infusion reactions requiring corticosteroids occurred
in 1.0% (3/287) of patients receiving OPDIVO.
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 057, serious adverse reactions occurred in 47% of
patients receiving OPDIVO. The most frequent serious adverse
reactions reported in ≥2% of patients were pneumonia, pulmonary
embolism, dyspnea, pleural effusion, and respiratory failure.
Common Adverse Reactions
In Checkmate 057, the most common adverse reactions (≥20%)
reported with OPDIVO were fatigue (49%), musculoskeletal pain
(36%), cough (30%), decreased appetite (29%), and constipation
(23%).
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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