First Immuno-Oncology agent approved in
Europe for lung cancer, and the first major treatment advance in
more than a decade
Approval based on Checkmate -017, which
showed nivolumab had a 41% reduction in the risk of death versus
docetaxel, and demonstrated nearly doubled overall survival at
one-year versus chemotherapy (42% vs. 24%); file also included data
from CheckMate -063
Safety profile of nivolumab is consistent
with previously-reported trials
Bristol-Myers Squibb Company (NYSE: BMY) today announced that
the European Commission has approved Nivolumab BMS for the
treatment of locally advanced or metastatic squamous (SQ) non-small
cell lung cancer (NSCLC) after prior chemotherapy. This approval
marks the first major treatment advance in SQ NSCLC in more than a
decade in the European Union (EU). Nivolumab is also the first and
only PD-1 immune checkpoint inhibitor to demonstrate overall
survival (OS) in previously-treated metastatic SQ NSCLC. This
approval allows for the marketing of nivolumab in all 28 Member
States of the EU.
“With the EU approval of nivolumab, patients in Europe have for
the first time in more than ten years access to an entirely new
treatment modality for advanced squamous non-small cell lung
cancer, which has the potential to replace the current standard of
care,” said Emmanuel Blin, senior vice president, Head of
Commercialization, Policy and Operations, Bristol-Myers Squibb.
“Bristol-Myers Squibb is passionate about changing survival
expectations and the way patients live with advanced cancers, and
is committed to continually deliver, with speed and urgency, new
approaches to pursue this goal.”
Approval is based on the results of CheckMate -017 and -063. In
the Phase III CheckMate -017 study, nivolumab demonstrated superior
clinical benefit across all endpoints versus docetaxel, the
standard of care, regardless of PD-L1 (programmed death ligand-1)
expression status, including a 41% reduction in the risk of death,
significantly superior OS rate of 42% versus 24% for docetaxel at
one-year and superior durable antitumor activity. In the Phase II
CheckMate -063 study, nivolumab showed an estimated 41% one-year
survival rate and a median OS of 8.2 months. The safety profile of
nivolumab is consistent with previously-reported trials, and in
Checkmate -017, is also favorable compared to docetaxel.
“Today’s approval of nivolumab for squamous non-small cell lung
cancer is truly a major advance for patients fighting this
devastating disease, and the providers that treat them,” said Rolf
Stahel, M.D., president of the European Society of Medical Oncology
and Professor at University Hospital Zurich. “Nivolumab has shown
statistically significant and clinically meaningful improvement in
efficacy versus standard of care in this patient population. This
approval reinforces the science behind Immuno-Oncology including
our understanding of the role of PD-L1 expression.”
In Europe, incidence and mortality rates for lung cancer are on
the rise, currently accounting for 20% of all cancer deaths. NSCLC
is one of the most common types of the disease and accounts for
approximately 85% of lung cancer cases. SQ NSCLC accounts for
approximately 25% to 30% of all lung cancers. For patients with
NSCLC, whose disease reoccurs or progresses despite chemotherapy,
the treatment options are limited and the prognosis is poor, with a
five-year survival rate of approximately 2%, globally.
About CheckMate -017,
-063
The European Commission’s approval is based on data from two
studies (Phase III CheckMate -017 and Phase II CheckMate -063).
Together, the trials investigated nivolumab at a dose of 3 mg/kg
every two weeks, which has been well-established across the Phase
III nivolumab clinical development program for various tumors.
CheckMate -017 is a landmark Phase III, open-label, randomized
clinical trial that evaluated nivolumab 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 SQ 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 progression-free
survival (PFS) and overall response rate (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 nivolumab (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 nivolumab and docetaxel,
respectively. Nivolumab also demonstrated consistent, statistically
significant and clinically meaningful improvements across secondary
endpoints, ORR and PFS, versus docetaxel in patients with
previously treated advanced SQ NSCLC. Survival benefit was observed
independent of PD-L1 expression across all pre-specified expression
levels (1%, 5% and 10%).
The safety profile of nivolumab in CheckMate -017 was consistent
with prior studies and favorable versus docetaxel.
Treatment-related adverse events (AEs) occurred less frequently
with nivolumab (any grade, 58%; grade 3-4, 6.9%; no grade 5 events)
than docetaxel (any grade, 86%; grade 3-5, 55%; grade 5, 2.3%),
including both hematology and non-hematology toxicities.
Treatment-related AEs led to discontinuation in 3.1% of patients in
the nivolumab arm compared to 10.1% for docetaxel. Pneumonitis
(1.5%) was the most common treatment-related AE leading to
discontinuation in the nivolumab arm and peripheral neuropathy
(3.1%) for the docetaxel arm.
Findings from CheckMate -017 were recently published in The
New England Journal of Medicine and presented during an oral
abstract session at the 2015 American Society of Clinical Oncology
Annual Meeting in May 2015.
CheckMate -063 is a Phase II, single-arm, open-label trial that
included patients with metastatic SQ NSCLC who had progressed
after two or more lines of therapy. In this trial, the confirmed
objective response rate by an independent radiology review
committee, the study’s primary endpoint, was 14.5% (95% CI: 8.47,
22.2) with an estimated one-year survival rate of 41% and median OS
of 8.21 months (95% CI: 6.05, 10.9). The safety profile of
nivolumab in CheckMate -063 was consistent with prior clinical
studies and managed using established treatment algorithms.
About Nivolumab
Bristol-Myers Squibb submitted two separate Marketing
Authorization Applications, one in advanced melanoma under the
tradename Opdivo and one for SQ NSCLC under the Nivolumab BMS
tradename in order to accelerate availability of nivolumab for
health care professionals in both indications. The goal is to have
these two marketing authorizations “reconciled” into a single
marketing authorization, under the Opdivo brand name toward the end
2015.
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.
Nivolumab is the first PD-1 immune checkpoint inhibitor to
receive regulatory approval 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. On December 22, 2014, the U.S. Food and Drug
Administration (FDA) granted its first approval for nivolumab 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 4,
2015, nivolumab 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. The European Commission announced approval of
nivolumab on June 19, 2015, for the treatment of advanced
(unresectable or metastatic) melanoma in adults, regardless of BRAF
status.
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.
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 percent of
cases. Survival rates vary depending on the stage, histology and
sub-type of lung cancer. The majority of NSCLC patients have
advanced stage disease at the time of diagnosis. Globally, the
five-year survival rate for Stage I NSCLC is between 47 and 50
percent; for Stage IV NSCLC, the five-year survival rate drops to
two percent.
Lung cancer has the highest economic burden of all cancers in
the European Union, costing an estimated €18.8 billion or 15
percent of overall cancer costs.
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 nivolumab will be 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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Bristol-Myers SquibbMedia:Carrie Fernandez,
215-859-2605carrie.fernandez@bms.comorInvestors:Ranya
Dajani, 609-252-5330ranya.dajani@bms.comorBill Szablewski,
609-252-5864william.szablewski@bms.com
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