European Medicines Agency Validates Bristol-Myers Squibb’s Type II Variation Application for Opdivo (nivolumab) in Previously Treated Advanced Renal Cell Carcinoma

Overall survival results from CheckMate -025, a landmark Phase 3
study comparing
Opdivo versus everolimus in this patient
population, serves as basis for application

PRINCETON, N.J.–(BUSINESS WIRE)–Bristol-Myers
Squibb Company
(NYSE:BMY) today announced that the
European Medicines Agency (EMA) validated a type II variation
application, which seeks to extend the current indication for Opdivo to
include the treatment of adult patients with advanced renal cell
carcinoma (RCC) after prior therapy. Validation of the application
confirms the submission is complete and begins the EMA’s centralized
review process.

Michael Giordano, M.D., senior vice president, head of Development,
Oncology, Bristol-Myers Squibb, commented, “Europe has one of the
highest incidence rates of renal cell carcinoma, and a significant
percentage of these patients are diagnosed at an advanced stage of the
disease. The validation of our application by the EMA is an important
step in the regulatory review process in the European Union, and we will
continue to work with the utmost speed to bring Opdivo to
patients with this cancer.”

The type II variation submitted is based on data from CheckMate -025, a
Phase 3 study that evaluated, as the primary endpoint, the overall
survival of Opdivo versus everolimus, a current standard of care,
in advanced or metastatic clear-cell RCC after prior anti-angiogenic
treatment. Results from CheckMate -025 were recently presented at the
2015 European Cancer Congress, and published in The New England
Journal of Medicine
.

About Renal Cell Carcinoma

Renal cell carcinoma (RCC) is the most common type of kidney cancer in
adults, accounting for more than 100,000 deaths worldwide each year.
Clear-cell RCC is the most prevalent type of RCC and constitutes 80% to
90% of all cases. RCC is approximately twice as common in men as it is
in women, with the highest rates of the disease found in North America
and Europe. Globally, the five-year survival rate for those diagnosed
with advanced kidney cancer is 12.1%.

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
8,000 patients have been enrolled worldwide. Opdivo is the first
PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere
in the world in July 2014, and currently has regulatory approval in more
than 37 countries including the United States, Japan, and in the
European Union.

IMPORTANT SAFETY INFORMATION

Immune-Mediated Pneumonitis

Immune-mediated pneumonitis or interstitial lung disease, including
fatal cases, occurred with OPDIVO treatment. Across the clinical trial
experience with solid tumors, fatal immune-mediated pneumonitis occurred
in 0.5% (5/978) of patients receiving OPDIVO as a single agent. In
Checkmate 037, 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 Checkmate 057, immune-mediated pneumonitis,
including interstitial lung disease, occurred in 3.4% (10/287) of
patients receiving OPDIVO including five Grade 3, two Grade 2, and three
Grade 1 cases. Monitor patients for signs with radiographic imaging and
symptoms of pneumonitis. Administer corticosteroids for Grade 2 or
greater pneumonitis. Permanently discontinue OPDIVO for Grade 3 or 4 and
withhold until resolution for Grade 2.

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. Withhold
OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4 or
recurrent colitis upon restarting OPDIVO.
In Checkmate 037,
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 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
including three Grade 3, two Grade 2, and two Grade 1 cases.

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 OPDIVO for Grade 2 and permanently
discontinue for Grade 3 or 4 immune-mediated hepatitis.
In
Checkmate 037, 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 Checkmate
057, one patient (0.3%) developed immune-mediated hepatitis.

Immune-Mediated Endocrinopathies

Hypophysitis, adrenal insufficiency, and thyroid disorders can occur
with OPDIVO treatment. Monitor patients for signs and symptoms of
hypophysitis, signs and symptoms of adrenal insufficiency during and
after treatment, and thyroid function prior to and periodically during
treatment. Administer corticosteroids for Grade 2 or greater
hypophysitis. Withhold OPDIVO for Grade 2 or 3 and permanently
discontinue for Grade 4 hypophysitis. Administer corticosteroids for
Grade 3 or 4 adrenal insufficiency. Withhold OPDIVO 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. Adrenal insufficiency
occurred in 1% (n=555) of patients receiving OPDIVO as a single agent.
In Checkmate 037, 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 Checkmate 057, Grade 1 or 2 hypothyroidism, including
thyroiditis, occurred in 7% (20/287) and elevated TSH 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 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. In
Checkmate 037, 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 Checkmate 057,
Grade 2 immune-mediated renal dysfunction occurred in 0.3% (1/287) of
patients.

Immune-Mediated Rash

Immune-mediated rash can occur with OPDIVO treatment. Monitor patients
for rash. Administer corticosteroids for Grade 3 or 4 rash. Withhold
OPDIVO for Grade 3 and permanently discontinue for Grade 4 rash. . In
Checkmate 057, immune-mediated rash occurred in 6% (17/287) of patients
receiving OPDIVO including 4 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. Across clinical trials of 8490
patients receiving OPDIVO as a single agent or in combination with
ipilimumab, <1% of patients were identified as having 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. The following
clinically significant immune-mediated adverse reactions occurred in <2%
(n=555) of single-agent OPDIVO-treated patients: uveitis, pancreatitis,
abducens nerve paresis, demyelination, polymyalgia rheumatica, and
autoimmune neuropathy,. Across clinical trials of OPDIVO as a single
agent administered at doses 3 mg/kg and 10 mg/kg, additional clinically
significant, immune-mediated adverse reactions were identified: facial
nerve paralysis, motor dysfunction, vasculitis, diabetic ketoacidosis,
and myasthenic syndrome.

Infusion Reactions

Severe infusion reactions have been reported in <1% of patients in
clinical trials of OPDIVO. In Checkmate 057, Grade 2 infusion reactions
occurred in 1% (3/287) of patients receiving OPDIVO. Discontinue OPDIVO
in patients with severe or life-threatening infusion reactions.
Interrupt or slow the rate of infusion in patients with mild or moderate
infusion reactions.

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-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
OPDIVO-containing regimen, advise women to discontinue breastfeeding
during treatment.

Serious Adverse Reactions

In Checkmate 037, 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 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 037, the most common adverse reaction (≥20%) reported with
OPDIVO was rash (21%).

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%).

Please see U.S. 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 the Bristol-Myers Squibb and Ono
Pharmaceutical Collaboration

In 2011, through a collaboration with Ono Pharmaceutical Co.,
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.

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 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 for the additional indication described in this
release. 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.

Contacts

Bristol-Myers Squibb
Media:
Carrie Fernandez,
215-859-2605
carrie.fernandez@bms.com
or
Investors:
Ranya
Dajani, 609-252-5330
ranya.dajani@bms.com
or
Bill
Szablewski, 609-252-5864
william.szablewski@bms.com