Nivolumab is the first PD-1 immune
checkpoint inhibitor to receive a positive opinion from the
CHMP in advanced non-small cell lung cancer
Opinion based on overall survival benefit
demonstrated in CheckMate -017
CHMP positive opinion marks the second for
nivolumab; positive opinion for advanced melanoma was received in
April 2015
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 nivolumab, a PD-1 immune checkpoint inhibitor, be
granted approval for the treatment of locally advanced or
metastatic squamous non-small cell lung cancer (NSCLC) after prior
chemotherapy in adults. The CHMP positive opinion will now be
reviewed by the European Commission, which has the authority to
approve medicines for the European Union (EU).
“We are moving at a ground-breaking pace to deliver on a mission
that looks to transform cancer treatment options for
patients,” said Michael Giordano, senior vice president, Head of
Development, Oncology. “Last month, we received a CHMP positive
opinion for nivolumab for the treatment of advanced
melanoma. Today’s announcement of a positive opinion for
nivolumab in NSCLC brings us closer to delivering on our promise of
changing the standard of care for lung cancer.”
Positive Opinion based on CheckMate
-017 and -063
The CHMP positive opinion is based on data from CheckMate -017
and CheckMate -063, two trials that demonstrated the efficacy and
safety of nivolumab in patients with advanced or metastatic
squamous NSCLC who had progressed following previous chemotherapy
treatment. CheckMate -017 was a Phase III, randomized, open-label
trial that included patients who had experienced disease
progression during or after one prior platinum doublet-based
chemotherapy regimen.
Results from a prespecified interim analysis of CheckMate -017,
demonstrated significantly superior overall survival (OS) with
nivolumab vs. docetaxel, with a 41% reduction in the risk of death
(hazard ratio: 0.59 [95% CI: 0.44, 0.79; p=0.00025]). This benefit
was observed regardless of PD-L1 expression status. The estimated
one-year survival rate was nearly doubled with nivolumab (42% [95%
CI: 34, 50]) compared to docetaxel (24% [95% CI: 17, 31]). The
median OS was 9.2 months in the nivolumab arm (95% CI: 7.3, 13.3)
and 6 months in the docetaxel arm (95% CI: 5.1, 7.3).
A second study, CheckMate -063, was a Phase II single-arm,
multinational, multicenter trial that included patients with
metastatic squamous NSCLC who had progressed after receiving a
platinum-based therapy and at least one additional systemic
treatment regimen (65% of patients had received ≥ 3 prior
therapies). In CheckMate -063, confirmed objective response rate,
the study’s primary endpoint, was 14.5% (17/117) (95% CI = 8.7,
22.2) with an estimated one-year survival rate of 40.8% (95% CI:
31.6, 49.7) and median overall survival of 8.2 months (95% CI: 6.1,
10.9).
In both CheckMate -017 and -063, there was consistent nivolumab
dosing of 3 mg/kg every two weeks. The safety profile of nivolumab
has been evaluated in thousands of patients enrolled in the broader
clinical program and treatment-related adverse events (AEs)
were generally managed using established safety algorithms. In
CheckMate -017, the safety profile of nivolumab was consistent with
prior studies and favorable versus docetaxel. Treatment-related
adverse events occurred less frequently with nivolumab than
docetaxel (grade 3–4, 6.9% vs. 55%, respectively).
About Nivolumab
Bristol-Myers Squibb has a broad, global development program to
study nivolumab in multiple tumor types consisting of more than 50
trials – as monotherapy or in combination with other therapies – in
which more than 8,000 patients have been enrolled worldwide.
Nivolumab 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 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.
In addition, nivolumab is being investigated in patients with
advanced non-squamous NSCLC. On April 17, 2015, an open-label,
randomized Phase III study (CheckMate -057) evaluating nivolumab
versus docetaxel in previously treated patients with advanced
non-squamous NSCLC was stopped early because an assessment
conducted by the independent Data Monitoring Committee (DMC)
concluded that the study met its endpoint, demonstrating superior
overall survival in patients receiving nivolumab compared to
docetaxel. The company plans to share these data with health
authorities.
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 and type of the
cancer when it is diagnosed. 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.
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.
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 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 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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version on businesswire.com: http://www.businesswire.com/news/home/20150522005319/en/
Bristol-Myers SquibbMedia:Carrie Fernandez,
215-859-2605carrie.fernandez@bms.comorInvestors:Ranya
Dajani, 609-252-5330ranya.dajani@bms.com
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