fbpx

China National Drug Administration Approves Countrys First Immuno-Oncology Agent, Opdivo (nivolumab injection), for Previously Treated Non-Small Cell Lung Cancer (NSCLC)

Bristol-Myers
Squibb Company (NYSE: BMY) announced today that the China National
Drug Administration (CNDA) has approved Opdivo (nivolumab
injection) for the treatment of locally advanced or metastatic non-small
cell lung cancer (NSCLC) after prior platinum-based chemotherapy in
adult patients without EGFR or ALK genomic tumor aberrations. This is
China’s first and only PD-1 inhibitor and is the only Immuno-Oncology
(I-O) agent to demonstrate a survival benefit compared with
chemotherapy, based on data from the pivotal Phase 3 CheckMate -078
trial, in which 90% of the patients enrolled were Chinese.

“Lung cancer is a major public health issue in China, representing the
highest incidence and mortality among all cancers in the country,” said
Professor Yi-Long Wu, a tenured director of Guangdong General Hospital
and the chair of the Chinese Thoracic Oncology Group. “With most lung
cancer patients already at an advanced stage when diagnosed, prolonging
survival is an important goal. The approval of Opdivo as the
first I-O agent in China is a significant therapeutic advance and is
great news for patients and clinicians alike, offering for the first
time an I-O treatment option that is proven to extend survival in
predominantly Chinese patients with previously treated NSCLC.”

The approval is based on results from the Phase 3 CheckMate -078 trial
of Opdivo versus chemotherapy among patients with previously
treated NSCLC, findings from which were presented at the American
Association for Cancer Research Annual Meeting in April 2018. In
November 2017, the trial was stopped early because the independent Data
Monitoring Committee concluded that Opdivo demonstrated superior
overall survival compared with chemotherapy. The application later
received priority review by the Center for Drug Evaluation in China.

Murdo
Gordon, executive vice president and chief commercial officer,
Bristol-Myers Squibb, commented, “With approvals in more than 60
countries, Opdivo is a global standard of care for previously
treated NSCLC, and we are proud to bring this foundational I-O treatment
option to patients and physicians in China. We look forward to
continuing to work together with the CNDA to usher in additional
healthcare innovations in China, with our shared commitment to moving
quickly to help patients.”

In CheckMate -078, Opdivo reduced the risk of death by 32% versus
chemotherapy, the primary endpoint (HR 0.68; 97.7% CI: 0.52 to 0.90;
p=0.0006), in patients with previously treated NSCLC. Both efficacy and
safety of Opdivo in this patient population were consistent with
the results of the landmark global CheckMate -017 and -057 studies. In
CheckMate -078, Grade 3-4 treatment-related adverse events (TRAEs)
occurred less frequently with Opdivo versus docetaxel (10% vs.
48%). Discontinuations due to Grade 3-4 TRAEs were also less frequent
with Opdivo (3%) than with docetaxel (5%).

“We are thrilled to be able to bring this proven treatment, Opdivo,
which has demonstrated superior overall survival versus chemotherapy in
previously treated NSCLC patients in China, and are committed to working
with stakeholders to ensure patients can quickly access Opdivo,”
said Fouad Namouni, M.D., head of development, Oncology, Bristol-Myers
Squibb. “With more than 7,500 cancer deaths per day estimated in China,
we will continue to work with urgency to integrate the unmet treatment
needs of Chinese patients in our ongoing I-O global development program,
with the goal of bringing them innovative therapies as quickly as
possible.”

About CheckMate -078

CheckMate -078 is a Phase 3, multinational, randomized study comparing Opdivo
with docetaxel in the treatment of patients with Stage IIIb/IV NSCLC
whose disease has progressed after platinum-based doublet chemotherapy.
The study was conducted primarily in China, with additional study sites
in Hong Kong, Russia and Singapore. The trial randomized 504 patients
(451 from China, 45 from Russia, 8 from Singapore) without EGFR
mutations and with both squamous and non-squamous NSCLC, across PD-L1
expression status of <1% and ?1%, to receive either Opdivo 3
mg/kg intravenously every two weeks (N=338) or docetaxel 75 mg/m2
intravenously every three weeks (N=166) until documented disease
progression or unacceptable toxicity.

The primary endpoint was overall survival (OS), including OS consistency
observed with the global CheckMate -017 and CheckMate -057 studies.
Secondary endpoints included objective response rate (ORR),
progression-free survival, time to treatment failure, efficacy across
subgroups, rates of treatment-related adverse events, and rate of
disease-related symptom deterioration, as measured by the Lung Cancer
Symptom Scale.

Minimum follow-up was 8.8 months. Median OS was 12.0 months in the Opdivo
arm and 9.6 months in the chemotherapy arm (HR 0.68; 95% CI: 0.52 to
0.90; p=0.0006). Improved OS with Opdivo versus docetaxel was
observed in patients with squamous (HR 0.61; 95% CI: 0.42 to 0.89) and
non-squamous (HR 0.76; 95% CI: 0.56 to 1.04) tumor histology, and across
all pre-defined subgroups based on tumor PD-L1 expression level. The
hazard ratios in patients with tumor PD-L1 expression ?1% and <1% were
0.62 (95% CI: 0.45 to 0.87) and 0.75 (95% CI: 0.52 to 1.09),
respectively. The ORR was 17% with Opdivo versus 4% with
docetaxel. Median duration of response was not reached in the Opdivo
arm versus 5.3 months in the docetaxel arm. Opdivo decreased risk
of disease progression by 23% versus docetaxel (HR 0.77; 95% CI: 0.62 to
0.95; p=0.0147).

About Lung Cancer

Lung cancer is the leading cause of cancer deaths globally, resulting in
nearly 1.7 million deaths each year, according to the World Health
Organization. Non-small cell lung cancer (NSCLC) is one of the most
common types of the disease and accounts for approximately 85% of
diagnoses. There are approximately 781,000 new cases of lung cancer
diagnosed in China each year, equaling approximately 15 new cases every
10 minutes. This number continues to rise, with more than 800,000 new
cases and 700,000 new deaths projected by 2020. Survival rates vary
depending on the stage and type of the cancer when diagnosed, with the
five-year survival rate lower than 5%. For patients with advanced
squamous cell lung cancer and non-squamous NSCLC without any known
driver genetic mutation, treatment measures are quite limited.
Therefore, long-term survival is the most urgent need of those patients.

Bristol-Myers Squibb & Immuno-Oncology:
Advancing Oncology Research

At Bristol-Myers Squibb, patients are at the center of everything we do.
Our vision for the future of cancer care is focused on researching and
developing transformational medicines, including Immuno-Oncology (I-O)
therapeutic approaches, for hard-to-treat cancers that could potentially
improve outcomes for these patients.

We are leading the integrated scientific understanding of both tumor
cell and immune system pathways, through our extensive portfolio of
investigational compounds and approved agents. Our differentiated
clinical development program is studying broad patient populations
across more than 50 types of cancers with 24 clinical-stage molecules
designed to target different immune system pathways. Our deep expertise
and innovative clinical trial designs position us to advance I-O/I-O,
I-O/chemotherapy, I-O/targeted therapies and I-O/radiation therapies
across multiple tumors and potentially deliver the next wave of
therapies with a sense of urgency. We also continue to pioneer research
that will help facilitate a deeper understanding of the role of immune
biomarkers and how a patient’s tumor biology can be used as a guide for
treatment decisions through their journey.

We understand making the promise of transformational medicines like I-O
therapies a reality for the many patients who may benefit from these
therapies requires not only innovation on our part but also close
collaboration with leading experts in the field. Our partnerships with
academia, government, advocacy and biotech companies support our
collective goal of providing new treatment options to advance the
standards of clinical practice.

About Opdivo

Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor
that is designed to uniquely harness the body’s own immune system to
help restore anti-tumor immune response. By harnessing the body’s own
immune system to fight cancer, Opdivo has become an important
treatment option across multiple cancers.

Opdivo’s leading global development program is based on
Bristol-Myers Squibb’s scientific expertise in the field of
Immuno-Oncology and includes a broad range of clinical trials across all
phases, including Phase 3, in a variety of tumor types. To date, the Opdivo
clinical development program has enrolled more than 25,000 patients. The Opdivo
trials have contributed to gaining a deeper understanding of the
potential role of biomarkers in patient care, particularly regarding how
patients may benefit from Opdivo across the continuum of PD-L1
expression.

In July 2014, Opdivo was the first PD-1 immune checkpoint
inhibitor to receive regulatory approval anywhere in the world. Opdivo
is currently approved in more than 60 countries, including the United
States, the European Union and Japan. In October 2015, the Company’s Opdivo
and Yervoy combination regimen was the first Immuno-Oncology
combination to receive regulatory approval for the treatment of
metastatic melanoma and is currently approved in more than 50 countries,
including the United States and the European Union.

U.S. FDA-APPROVED INDICATIONS FOR OPDIVO®

OPDIVO® (nivolumab) as a single agent is indicated for the treatment of
patients with BRAF V600 mutation-positive unresectable or metastatic
melanoma. This indication is approved under accelerated approval based
on progression-free survival. Continued approval for this indication may
be contingent upon verification and description of clinical benefit in
the confirmatory trials.

OPDIVO® (nivolumab) as a single agent is indicated for the treatment of
patients with BRAF V600 wild-type unresectable or metastatic melanoma.

OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab), is
indicated for the treatment of patients with unresectable or metastatic
melanoma. This indication is approved under accelerated approval based
on progression-free survival. Continued approval for this indication may
be contingent upon verification and description of clinical benefit in
the confirmatory trials.

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.

OPDIVO® (nivolumab) is indicated for the treatment of patients with
advanced renal cell carcinoma (RCC) who have received prior
anti-angiogenic therapy.

OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab), is
indicated for the treatment of patients with intermediate or poor-risk,
previously untreated advanced renal cell carcinoma (RCC).

OPDIVO® (nivolumab) is indicated for the treatment of adult patients
with classical Hodgkin lymphoma (cHL) that has relapsed or progressed
after autologous hematopoietic stem cell transplantation (HSCT) and
brentuximab vedotin or after 3 or more lines of systemic therapy that
includes autologous HSCT. This indication is approved under accelerated
approval based on overall response rate. Continued approval for this
indication may be contingent upon verification and description of
clinical benefit in confirmatory trials.

OPDIVO® (nivolumab) is indicated for the treatment of patients with
recurrent or metastatic squamous cell carcinoma of the head and neck
(SCCHN) with disease progression on or after platinum-based therapy.

OPDIVO® (nivolumab) is indicated for the treatment of patients with
locally advanced or metastatic urothelial carcinoma who have disease
progression during or following platinum-containing chemotherapy or have
disease progression within 12 months of neoadjuvant or adjuvant
treatment with platinum-containing chemotherapy. This indication is
approved under accelerated approval based on tumor response rate and
duration of response. Continued approval for this indication may be
contingent upon verification and description of clinical benefit in
confirmatory trials.

OPDIVO® (nivolumab) is indicated for the treatment of adult and
pediatric (12 years and older) patients with microsatellite instability
high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal
cancer (CRC) that has progressed following treatment with a
fluoropyrimidine, oxaliplatin, and irinotecan. This indication is
approved under accelerated approval based on overall response rate and
duration of response. Continued approval for this indication may be
contingent upon verification and description of clinical benefit in
confirmatory trials.

OPDIVO® (nivolumab) is indicated for the treatment of patients with
hepatocellular carcinoma (HCC) who have been previously treated with
sorafenib. This indication is approved under accelerated approval based
on tumor response rate and durability of response. Continued approval
for this indication may be contingent upon verification and description
of clinical benefit in the confirmatory trials.

OPDIVO® (nivolumab) is indicated for the adjuvant treatment of patients
with melanoma with involvement of lymph nodes or metastatic disease who
have undergone complete resection.

OPDIVO® (10 mg/mL) is an injection for intravenous (IV) use.

IMPORTANT SAFETY INFORMATION

WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS

YERVOY can result in severe and fatal immune-mediated adverse
reactions. These immune-mediated reactions may involve any organ system;
however, the most common severe immune-mediated adverse reactions are
enterocolitis, hepatitis, dermatitis (including toxic epidermal
necrolysis), neuropathy, and endocrinopathy. The majority of these
immune-mediated reactions initially manifested during treatment;
however, a minority occurred weeks to months after discontinuation of
YERVOY.

Assess patients for signs and symptoms of enterocolitis, dermatitis,
neuropathy, and endocrinopathy and evaluate clinical chemistries
including liver function tests (LFTs), adrenocorticotropic hormone
(ACTH) level, and thyroid function tests at baseline and before each
dose.

Permanently discontinue YERVOY and initiate systemic high-dose
corticosteroid therapy for severe immune-mediated reactions.

Immune-Mediated Pneumonitis

OPDIVO can cause immune-mediated pneumonitis. Fatal cases have been
reported. Monitor patients for signs with radiographic imaging and for
symptoms of pneumonitis. Administer corticosteroids for Grade 2 or more
severe pneumonitis. Permanently discontinue for Grade 3 or 4 and
withhold until resolution for Grade 2. In patients receiving OPDIVO
monotherapy, fatal cases of immune-mediated pneumonitis have occurred.
Immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients. In
patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated
pneumonitis occurred in 6% (25/407) of patients. In patients receiving
OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated pneumonitis occurred
in 4.4% (24/547) of patients.

In Checkmate 205 and 039, pneumonitis, including interstitial lung
disease, occurred in 6.0% (16/266) of patients receiving OPDIVO.
Immune-mediated pneumonitis occurred in 4.9% (13/266) of patients
receiving OPDIVO: Grade 3 (n=1) and Grade 2 (n=12).

Immune-Mediated Colitis

OPDIVO can cause immune-mediated colitis. 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 monotherapy for
Grade 2 or 3 and permanently discontinue for Grade 4 or recurrent
colitis upon re-initiation of OPDIVO. When administered with YERVOY,
withhold OPDIVO and YERVOY for Grade 2 and permanently discontinue for
Grade 3 or 4 or recurrent colitis. In patients receiving OPDIVO
monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of
patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg,
immune-mediated colitis occurred in 26% (107/407) of patients including
three fatal cases. In patients receiving OPDIVO 3 mg/kg with YERVOY 1
mg/kg, immune-mediated colitis occurred in 10% (52/547) of patients.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening,
or fatal (diarrhea of ?7 stools above baseline, fever, ileus, peritoneal
signs; Grade 3-5) immune-mediated enterocolitis occurred in 34 (7%)
patients. Across all YERVOY-treated patients in that study (n=511), 5
(1%) developed intestinal perforation, 4 (0.8%) died as a result of
complications, and 26 (5%) were hospitalized for severe enterocolitis.

Immune-Mediated Hepatitis

OPDIVO can cause immune-mediated hepatitis. Monitor patients for
abnormal liver tests prior to and periodically during treatment.
Administer corticosteroids for Grade 2 or greater transaminase
elevations. For patients without HCC, withhold OPDIVO for Grade 2 and
permanently discontinue OPDIVO for Grade 3 or 4. For patients with HCC,
withhold OPDIVO and administer corticosteroids if AST/ALT is within
normal limits at baseline and increases to >3 and up to 5 times the
upper limit of normal (ULN), if AST/ALT is >1 and up to 3 times ULN at
baseline and increases to >5 and up to 10 times the ULN, and if AST/ALT
is >3 and up to 5 times ULN at baseline and increases to >8 and up to 10
times the ULN. Permanently discontinue OPDIVO and administer
corticosteroids if AST or ALT increases to >10 times the ULN or total
bilirubin increases >3 times the ULN. In patients receiving OPDIVO
monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of
patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg,
immune-mediated hepatitis occurred in 13% (51/407) of patients. In
patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated
hepatitis occurred in 7% (38/547) of patients.

In Checkmate 040, immune-mediated hepatitis requiring systemic
corticosteroids occurred in 5% (8/154) of patients receiving OPDIVO.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening,
or fatal hepatotoxicity (AST or ALT elevations >5x the ULN or total
bilirubin elevations >3x the ULN; Grade 3-5) occurred in 8 (2%) patients,
with fatal hepatic failure in 0.2% and hospitalization in 0.4%.

Immune-Mediated Neuropathies

In a separate Phase 3 study of YERVOY 3 mg/kg, 1 case of fatal
Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor
neuropathy were reported.

Immune-Mediated Endocrinopathies

OPDIVO can cause immune-mediated hypophysitis, immune-mediated adrenal
insufficiency, autoimmune thyroid disorders, and Type 1 diabetes
mellitus. Monitor patients for signs and symptoms of hypophysitis, signs
and symptoms of adrenal insufficiency, thyroid function prior to and
periodically during treatment, and hyperglycemia. Administer hormone
replacement as clinically indicated and 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. Withhold OPDIVO for Grade 3
and permanently discontinue for Grade 4 hyperglycemia.

In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6%
(12/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY
3 mg/kg, hypophysitis occurred in 9% (36/407) of patients. In patients
receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, hypophysitis occurred in
4.6% (25/547) of patients In patients receiving OPDIVO monotherapy,
adrenal insufficiency occurred in 1% (20/1994) of patients. In patients
receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, adrenal insufficiency
occurred in 5% (21/407) of patients. In patients receiving OPDIVO 3
mg/kg with YERVOY 1 mg/kg, adrenal insufficiency occurred in 7% (41/547)
of patients. In patients receiving OPDIVO monotherapy, hypothyroidism or
thyroiditis resulting in hypothyroidism occurred in 9% (171/1994) of
patients. Hyperthyroidism occurred in 2.7% (54/1994) of patients
receiving OPDIVO monotherapy. In patients receiving OPDIVO 1 mg/kg with
YERVOY 3 mg/kg, hypothyroidism or thyroiditis resulting in
hypothyroidism occurred in 22% (89/407) of patients. Hyperthyroidism
occurred in 8% (34/407) of patients receiving this dose of OPDIVO with
YERVOY. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg,
hypothyroidism or thyroiditis resulting in hypothyroidism occurred in
22% (119/547) of patients. Hyperthyroidism occurred in 12% (66/547) of
patients receiving this dose of OPDIVO with YERVOY. In patients
receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of
patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg,
diabetes occurred in 1.5% (6/407) of patients. In patients receiving
OPDIVO 3 mg/kg with YERVOY 1 mg/kg, diabetes occurred in 2.7% (15/547)
of patients.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe to
life-threatening immune-mediated endocrinopathies (requiring
hospitalization, urgent medical intervention, or interfering with
activities of daily living; Grade 3-4) occurred in 9 (1.8%) patients.
All 9 patients had hypopituitarism, and some had additional concomitant
endocrinopathies such as adrenal insufficiency, hypogonadism, and
hypothyroidism. 6 of the 9 patients were hospitalized for severe
endocrinopathies.

Immune-Mediated Nephritis and Renal Dysfunction

OPDIVO can cause immune-mediated nephritis. Monitor patients for
elevated serum creatinine prior to and periodically during treatment.
Administer corticosteroids for Grades 2-4 increased serum creatinine.
Withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4
increased serum creatinine. In patients receiving OPDIVO monotherapy,
immune-mediated nephritis and renal dysfunction occurred in 1.2%
(23/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY
3 mg/kg, immune-mediated nephritis and renal dysfunction occurred in
2.2% (9/407) of patients. In patients receiving OPDIVO 3 mg/kg with
YERVOY 1 mg/kg, immune-mediated nephritis and renal dysfunction occurred
in 4.6% (25/547) of patients.

Immune-Mediated Skin Adverse Reactions and Dermatitis

OPDIVO can cause immune-mediated rash, including Stevens-Johnson
syndrome (SJS) and toxic epidermal necrolysis (TEN), some cases with
fatal outcome. Administer corticosteroids for Grade 3 or 4 rash.
Withhold for Grade 3 and permanently discontinue for Grade 4 rash. For
symptoms or signs of SJS or TEN, withhold OPDIVO and refer the patient
for specialized care for assessment and treatment; if confirmed,
permanently discontinue. In patients receiving OPDIVO monotherapy,
immune-mediated rash occurred in 9% (171/1994) of patients. In patients
receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated rash
occurred in 22.6% (92/407) of patients. In patients receiving OPDIVO 3
mg/kg with YERVOY 1 mg/kg, immune-mediated rash occurred in 16.6%
(91/547) of patients.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening,
or fatal immune-mediated dermatitis (eg, Stevens-Johnson syndrome, toxic
epidermal necrolysis, or rash complicated by full thickness dermal
ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade
3-5) occurred in 13 (2.5%) patients. 1 (0.2%) patient died as a result
of toxic epidermal necrolysis. 1 additional patient required
hospitalization for severe dermatitis.

Immune-Mediated Encephalitis

OPDIVO can cause immune-mediated encephalitis. Evaluation of patients
with neurologic symptoms may include, but not be limited to,
consultation with a neurologist, brain MRI, and lumbar puncture.
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 patients
receiving OPDIVO monotherapy, encephalitis occurred in 0.2% (3/1994) of
patients. Fatal limbic encephalitis occurred in one patient after 7.2
months of exposure despite discontinuation of OPDIVO and administration
of corticosteroids. Encephalitis occurred in one patient receiving
OPDIVO 1 mg/kg with YERVOY 3 mg/kg (0.2%) after 1.7 months of exposure.
Encephalitis occurred in one patient receiving OPDIVO 3 mg/kg with
YERVOY 1 mg/kg (0.2%) after approximately 4 months of exposure.

Other Immune-Mediated Adverse Reactions

Based on the severity of the adverse reaction, permanently discontinue
or withhold OPDIVO, administer high-dose corticosteroids, and, if
appropriate, initiate hormone-replacement therapy. Across clinical
trials of OPDIVO monotherapy or in combination with YERVOY, the
following clinically significant immune-mediated adverse reactions, some
with fatal outcome, occurred in <1.0% of patients receiving OPDIVO:
myocarditis, rhabdomyolysis, myositis, uveitis, iritis, pancreatitis,
facial and abducens nerve paresis, demyelination, polymyalgia
rheumatica, autoimmune neuropathy, Guillain-Barré syndrome,
hypopituitarism, systemic inflammatory response syndrome, gastritis,
duodenitis, sarcoidosis, histiocytic necrotizing lymphadenitis (Kikuchi
lymphadenitis), motor dysfunction, vasculitis, aplastic anemia,
pericarditis, and myasthenic syndrome.

If uveitis occurs in combination with other immune-mediated adverse
reactions, consider a Vogt-Koyanagi-Harada-like syndrome, which has been
observed in patients receiving OPDIVO and may require treatment with
systemic steroids to reduce the risk of permanent vision loss.

Infusion Reactions

OPDIVO can cause severe infusion reactions, which have been reported in
<1.0% of patients in clinical trials. 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 patients receiving OPDIVO
monotherapy as a 60-minute infusion, infusion-related reactions occurred
in 6.4% (127/1994) of patients. In a separate study in which patients
received OPDIVO monotherapy as a 60-minute infusion or a 30-minute
infusion, infusion-related reactions occurred in 2.2% (8/368) and 2.7%
(10/369) of patients, respectively. Additionally, 0.5% (2/368) and 1.4%
(5/369) of patients, respectively, experienced adverse reactions within
48 hours of infusion that led to dose delay, permanent discontinuation
or withholding of OPDIVO. In patients receiving OPDIVO 1 mg/kg with
ipilimumab 3 mg/kg every 3 weeks, infusion-related reactions occurred in
2.5% (10/407) of patients. In patients receiving OPDIVO 3 mg/kg with
YERVOY 1 mg/kg, infusion-related reactions occurred in 5.1% (28/547) of
patients.

Complications of Allogeneic HSCT after OPDIVO

Complications, including fatal events, occurred in patients who received
allogeneic HSCT after OPDIVO. Outcomes were evaluated in 17 patients
from Checkmate 205 and 039, who underwent allogeneic HSCT after
discontinuing OPDIVO (15 with reduced-intensity conditioning, 2 with
myeloablative conditioning). Thirty-five percent (6/17) of patients died
from complications of allogeneic HSCT after OPDIVO. Five deaths occurred
in the setting of severe or refractory GVHD. Grade 3 or higher acute
GVHD was reported in 29% (5/17) of patients. Hyperacute GVHD was
reported in 20% (n=2) of patients. A steroid-requiring febrile syndrome,
without an identified infectious cause, was reported in 35% (n=6) of
patients. Two cases of encephalitis were reported: Grade 3 (n=1)
lymphocytic encephalitis without an identified infectious cause, and
Grade 3 (n=1) suspected viral encephalitis. Hepatic veno-occlusive
disease (VOD) occurred in one patient, who received reduced-intensity
conditioned allogeneic HSCT and died of GVHD and multi-organ failure.
Other cases of hepatic VOD after reduced-intensity conditioned
allogeneic HSCT have also been reported in patients with lymphoma who
received a PD-1 receptor blocking antibody before transplantation. Cases
of fatal hyperacute GVHD have also been reported. These complications
may occur despite intervening therapy between PD-1 blockade and
allogeneic HSCT.

Follow patients closely for early evidence of transplant-related
complications such as hyperacute GVHD, severe (Grade 3 to 4) acute GVHD,
steroid-requiring febrile syndrome, hepatic VOD, and other
immune-mediated adverse reactions, and intervene promptly.

Embryo-Fetal Toxicity

Based on their mechanisms of action, OPDIVO and YERVOY 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- or YERVOY-
containing regimen and for at least 5 months after the last dose of
OPDIVO.

Lactation

It is not known whether OPDIVO or YERVOY 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. Advise women to discontinue
breastfeeding during treatment with YERVOY and for 3 months following
the final dose.

Serious Adverse Reactions

In Checkmate 037, serious adverse reactions occurred in 41% of patients
receiving OPDIVO (n=268). 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 066, serious
adverse reactions occurred in 36% of patients receiving OPDIVO (n=206).
Grade 3 and 4 adverse reactions occurred in 41% of patients receiving
OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported in
?2% of patients receiving OPDIVO were gamma-glutamyltransferase increase
(3.9%) and diarrhea (3.4%). In Checkmate 067, serious adverse reactions
(73% and 37%), adverse reactions leading to permanent discontinuation
(43% and 14%) or to dosing delays (55% and 28%), and Grade 3 or 4
adverse reactions (72% and 44%) all occurred more frequently in the
OPDIVO plus YERVOY arm (n=313) relative to the OPDIVO arm (n=313). The
most frequent (?10%) serious adverse reactions in the OPDIVO plus YERVOY
arm and the OPDIVO arm, respectively, were diarrhea (13% and 2.6%),
colitis (10% and 1.6%), and pyrexia (10% and 0.6%). In Checkmate 017 and
057, serious adverse reactions occurred in 46% of patients receiving
OPDIVO (n=418). The most frequent serious adverse reactions reported in
at least 2% of patients receiving OPDIVO were pneumonia, pulmonary
embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and
respiratory failure. In Checkmate 025, serious adverse reactions
occurred in 47% of patients receiving OPDIVO (n=406). The most frequent
serious adverse reactions reported in ?2% of patients were acute kidney
injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. In
Checkmate 214, serious adverse reactions occurred in 59% of patients
receiving OPDIVO plus YERVOY and in 43% of patients receiving sunitinib.
The most frequent serious adverse reactions reported in at least 2% of
patients were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis,
acute kidney injury, dyspnea, adrenal insufficiency, and colitis; in
patients treated with sunitinib, they were pneumonia, pleural effusion,
and dyspnea. In Checkmate 205 and 039, adverse reactions leading to
discontinuation occurred in 7% and dose delays due to adverse reactions
occurred in 34% of patients (n=266). Serious adverse reactions occurred
in 26% of patients. The most frequent serious adverse reactions reported
in ?1% of patients were pneumonia, infusion-related reaction, pyrexia,
colitis or diarrhea, pleural effusion, pneumonitis, and rash. Eleven
patients died from causes other than disease progression: 3 from adverse
reactions within 30 days of the last OPDIVO dose, 2 from infection 8 to
9 months after completing OPDIVO, and 6 from complications of allogeneic
HSCT. In Checkmate 141, serious adverse reactions occurred in 49% of
patients receiving OPDIVO (n=236). The most frequent serious adverse
reactions reported in at least 2% of patients receiving OPDIVO were
pneumonia, dyspnea, respiratory failure, respiratory tract infection,
and sepsis. In Checkmate 275, serious adverse reactions occurred in 54%
of patients receiving OPDIVO (n=270). The most frequent serious adverse
reactions reported in at least 2% of patients receiving OPDIVO were
urinary tract infection, sepsis, diarrhea, small intestine obstruction,
and general physical health deterioration. In Checkmate 040, serious
adverse reactions occurred in 49% of patients (n=154). The most frequent
serious adverse reactions reported in at least 2% of patients were
pyrexia, ascites, back pain, general physical health deterioration,
abdominal pain, and pneumonia. In Checkmate 238, Grade 3 or 4 adverse
reactions occurred in 25% of OPDIVO-treated patients (n=452). The most
frequent Grade 3 and 4 adverse reactions reported in at least 2% of
OPDIVO-treated patients were diarrhea and increased lipase and amylase.
Serious adverse reactions occurred in 18% of OPDIVO-treated patients.

Common Adverse Reactions

In Checkmate 037, the most common adverse reaction (?20%) reported with
OPDIVO (n=268) was rash (21%). In Checkmate 066, the most common adverse
reactions (?20%) reported with OPDIVO (n=206) vs dacarbazine (n=205)
were fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash (28%
vs 12%), and pruritus (23% vs 12%). In Checkmate 067, the most common
(?20%) adverse reactions in the OPDIVO plus YERVOY arm (n=313) were
fatigue (59%), rash (53%), diarrhea (52%), nausea (40%), pyrexia (37%),
vomiting (28%), and dyspnea (20%). The most common (?20%) adverse
reactions in the OPDIVO (n=313) arm were fatigue (53%), rash (40%),
diarrhea (31%), and nausea (28%). In Checkmate 017 and 057, the most
common adverse reactions (?20%) in patients receiving OPDIVO (n=418)
were fatigue, musculoskeletal pain, cough, dyspnea, and decreased
appetite. In Checkmate 025, the most common adverse reactions (?20%)
reported in patients receiving OPDIVO (n=406) vs everolimus (n=397) were
fatigue (56% vs 57%), cough (34% vs 38%), nausea (28% vs 29%), rash (28%
vs 36%), dyspnea (27% vs 31%), diarrhea (25% vs 32%), constipation (23%
vs 18%), decreased appetite (23% vs 30%), back pain (21% vs 16%), and
arthralgia (20% vs 14%). In Checkmate 214, the most common adverse
reactions (?20%) reported in patients treated with OPDIVO plus YERVOY
(n=547) vs sunitinib (n=535) were fatigue (58% vs 69%), rash (39% vs
25%), diarrhea (38% vs 58%), musculoskeletal pain (37% vs 40%), pruritus
(33% vs 11%), nausea (30% vs 43%), cough (28% vs 25%), pyrexia (25% vs
17%), arthralgia (23% vs 16%), and decreased appetite (21% vs 29%). In
Checkmate 205 and 039, the most common adverse reactions (?20%) reported
in patients receiving OPDIVO (n=266) were upper respiratory tract
infection (44%), fatigue (39%), cough (36%), diarrhea (33%), pyrexia
(29%), musculoskeletal pain (26%), rash (24%), nausea (20%) and pruritus
(20%). In Checkmate 141, the most common adverse reactions (?10%) in
patients receiving OPDIVO (n=236) were cough and dyspnea at a higher
incidence than investigator’s choice. In Checkmate 275, the most common
adverse reactions (? 20%) reported in patients receiving OPDIVO (n=270)
were fatigue (46%), musculoskeletal pain (30%), nausea (22%), and
decreased appetite (22%). In Checkmate 040, the most common adverse
reactions (?20%) in patients receiving OPDIVO (n=154) were fatigue
(38%), musculoskeletal pain (36%), abdominal pain (34%), pruritus (27%),
diarrhea (27%), rash (26%), cough (23%), and decreased appetite (22%).
In Checkmate 238, the most common adverse reactions (?20%) reported in
OPDIVO-treated patients (n=452) vs ipilimumab-treated patients (n=453)
were fatigue (57% vs 55%), diarrhea (37% vs 55%), rash (35% vs 47%),
musculoskeletal pain (32% vs 27%), pruritus (28% vs 37%), headache (23%
vs 31%), nausea (23% vs 28%), upper respiratory infection (22% vs 15%),
and abdominal pain (21% vs 23%). The most common immune-mediated adverse
reactions were rash (16%), diarrhea/colitis (6%), and hepatitis (3%).
The most common adverse reactions (?20%) in patients who received OPDIVO
as a single agent were fatigue, rash, musculoskeletal pain, pruritus,
diarrhea, nausea, asthenia, cough, dyspnea, constipation, decreased
appetite, back pain, arthralgia, upper respiratory tract infection,
pyrexia, headache, and abdominal pain.

In a separate Phase 3 study of YERVOY 3 mg/kg, the most common adverse
reactions (?5%) in patients who received YERVOY at 3 mg/kg were fatigue
(41%), diarrhea (32%), pruritus (31%), rash (29%), and colitis (8%).

Checkmate Trials and Patient Populations

Checkmate 067–advanced melanoma alone or in combination with
YERVOY® (ipilimumab); Checkmate 037 and 066–advanced
melanoma; Checkmate 017–squamous non-small cell lung cancer
(NSCLC); Checkmate 057–non-squamous NSCLC; Checkmate 025–renal
cell carcinoma; Checkmate 205/039–classical Hodgkin lymphoma; Checkmate
141–squamous cell carcinoma of the head and neck; Checkmate 275–urothelial
carcinoma; Checkmate 040–hepatocellular carcinoma, Checkmate
238–adjuvant treatment of melanoma.

Please see U.S. Full Prescribing Information for OPDIVO
and YERVOY,
including Boxed WARNING regarding immune-mediated adverse reactions
for YERVOY.

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 BMS.com
or follow us on LinkedIn,
Twitter,
YouTube
and Facebook.

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, 2017 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.

View source version on businesswire.com: https://www.businesswire.com/news/home/20180615005364/en/