AbbVie and Bristol-Myers Squibb Announce Oncology Clinical Collaboration to Evaluate the Combination of Rova-T plus Opdivo and Opdivo + Yervoy Regimen

NORTH CHICAGO, Ill. & NEW YORK–(BUSINESS WIRE)– AbbVie
(NYSE:ABBV) and Bristol-Myers
Squibb Company (NYSE:BMY) today announced a clinical trial
collaboration to evaluate the safety, tolerability and efficacy of
AbbVie’s investigational biomarker-specific antibody drug conjugate
Rova-T (rovalpituuzumab tesirine) in combination with Bristol-Myers
Squibb’s Opdivo (nivolumab) and Opdivo + Yervoy (ipilimumab)
regimen as a treatment for relapsed extensive-stage small cell lung
cancer (SCLC).

The Phase 1/2 clinical program will explore the potential of combining
Bristol-Myers Squibb’s immuno-oncology agents, which are designed to
alleviate immune suppression, in conjunction with AbbVie’s
investigational antibody drug conjugate, Rova-T, to drive improved and
sustained efficacy and tolerability above the current standard of care.
Rova-T is a novel antibody drug conjugate that targets and eliminates
tumor initiating cells and other bulk tumor cells. This collaboration
will determine if the targeted cell killing and antigen release caused
by Rova-T may further enhance the effect of immunotherapy.

“We are excited to explore the potential benefits of combining
Bristol-Myers Squibb’s immunotherapies with a targeted approach like
Rova-T in small cell lung cancer where the need for new therapies is
particularly acute for this aggressive form of lung cancer,” said Jean
Viallet, M.D., Global Clinical Research Lead, Oncology, Bristol-Myers
Squibb. “As the science around cancer research continues to rapidly
evolve, we are building on our leadership in Immuno-Oncology with
numerous collaborations that may help advance new therapies for cancers
in need of better options.”

“We believe the combination of these cancer-fighting agents may offer
patients a new treatment option in a disease with limited therapies,”
said Scott J. Dylla, Ph.D., vice president, research and development,
AbbVie. “By combining immune-checkpoint inhibitors that prime the body’s
immune system to fight cancer cells with Rova-T’s approach to target
cancer stem cells, we hope to build on our goal to develop
differentiated treatments with therapeutic benefit that elevate the
standard of care for small cell lung cancer patients.”

Small cell lung cancer is a difficult-to-treat form of cancer that
accounts for approximately 15 percent of all lung cancers. The five-year
survival rate for extensive-stage SCLC is less than 5 percent and
treatment options are limited for the more than 234,000 people diagnosed
annually.

Rova-T is a novel biomarker-specific therapy that targets cancer stem
cells and combines a targeted antibody that delivers a cytotoxic agent
directly to cancer cells expressing a delta-like protein 3 (DLL3). DLL3
is expressed in more than 80 percent of SCLC patient tumors and is not
present in healthy tissue. Rova-T is currently in investigational
studies as a third-line treatment for SCLC. AbbVie will initiate a
first-line clinical study for Rova-T in SCLC and several other types of
tumors in the near term.

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 54 countries including the United
States, Japan, and in the European Union. Yervoy is a CTLA-4
immune checkpoint inhibitor approved in 50 countries globally for
patients with unresectable or metastatic melanoma.

About AbbVie in Oncology

AbbVie is striving to outsmart cancer by working with scientists,
physicians, industry peers, patient advocacy groups and most
importantly, patients, to discover, develop and provide new therapies
that will have a remarkable impact on the lives of people around the
world affected by cancer. Our goal is to provide medicines that make a
transformational improvement in cancer treatment and outcomes for cancer
patients. By exploring and investing in new pathways, technologies and
approaches, AbbVie is breaking ground in some of the most widespread and
difficult-to-treat cancers. We are also exploring solutions to help
patients obtain access to our cancer medicines. With the acquisition of
Pharmacyclics in 2015 and Stemcentrx in 2016, and through several
collaborations, AbbVie’s oncology portfolio consists of marketed
medicines and a pipeline containing multiple new molecules being
evaluated worldwide in nearly two hundred clinical trials in 20
different tumor types. For more information about AbbVie Oncology,
please visit https://abbvieoncology.com.

About Rovalpituzumab Tesirine (Rova-T)

Rova-T is an investigational antibody drug conjugate targeting the
cancer-stem cell-associated target delta-like protein 3 (DLL3), which is
expressed in more than 80 percent of small cell lung cancer (SCLC)
patient tumors, where it is prevalent on tumor cells, including cancer
stem cells, but not present in healthy tissue. Rova-T combines a
targeted antibody that delivers a cytotoxic agent directly to the
DLL3-expressing cancer cells while minimizing toxicity to healthy cells.
Rova-T is under investigation as a third-line treatment in SCLC. Studies
evaluating Rova-T as a first-line SCLC regimen will be starting in the
near term. The expression of DLL3 suggests Rova-T may be useful across
multiple tumor types, including metastatic melanoma, glioblastoma
multiforme and some prostate, pancreatic and colorectal cancers.

Rova-T is an investigational compound and its efficacy and safety have
not been established by the FDA or any other health authority.

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 overall survival
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 and
pharmaceutical 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 overall survival 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.

INDICATIONS & IMPORTANT SAFETY INFORMATION

INDICATIONS

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

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
confirmatory trials.

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) is indicated for the treatment of patients with
classical Hodgkin lymphoma (cHL) that has relapsed or progressed after
autologous hematopoietic stem cell transplantation (HSCT) and
post-transplantation brentuximab vedotin. 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.

Please refer to the end of the Important Safety Information for a
brief description of the patient populations studied in the CheckMate
trials.

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

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. In addition, in
Checkmate 069, there were six patients who died without resolution of
abnormal respiratory findings. 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 069 and 067, immune-mediated pneumonitis occurred in 6%
(25/407) of patients receiving OPDIVO with YERVOY: Fatal (n=1), Grade 3
(n=6), Grade 2 (n=17), and Grade 1 (n=1). In Checkmate 037, 066, and
067, immune-mediated pneumonitis occurred in 1.8% (14/787) of patients
receiving OPDIVO: Grade 3 (n=2) and Grade 2 (n=12). 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). In Checkmate 025, pneumonitis, including interstitial
lung disease, occurred in 5% (21/406) of patients receiving OPDIVO and
18% (73/397) of patients receiving everolimus. Immune-mediated
pneumonitis occurred in 4.4% (18/406) of patients receiving OPDIVO:
Grade 4 (n=1), Grade 3 (n=4), Grade 2 (n=12), and Grade 1 (n=1). In
Checkmate 205 and 039, pneumonitis, including interstitial lung disease,
occurred in 4.9% (13/263) of patients receiving OPDIVO. Immune-mediated
pneumonitis occurred in 3.4% (9/263) of patients receiving OPDIVO: Grade
3 (n=1) and Grade 2 (n=8).

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. When administered
with YERVOY, withhold OPDIVO for Grade 2 and permanently discontinue for
Grade 3 or 4 or recurrent colitis upon restarting OPDIVO. In Checkmate
069 and 067, diarrhea or colitis occurred in 56% (228/407) of patients
receiving OPDIVO with YERVOY. Immune-mediated colitis occurred in 26%
(107/407) of patients: Grade 4 (n=2), Grade 3 (n=60), Grade 2 (n=32),
and Grade 1 (n=13). In Checkmate 037, 066, and 067, diarrhea or colitis
occurred in 31% (242/787) of patients receiving OPDIVO. Immune-mediated
colitis occurred in 4.1% (32/787) of patients: Grade 3 (n=20), Grade 2
(n=10), and Grade 1 (n=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: Grade 3 (n=3), Grade 2
(n=2), and Grade 1 (n=2). In Checkmate 025, diarrhea or colitis occurred
in 25% (100/406) of patients receiving OPDIVO and 32% (126/397) of
patients receiving everolimus. Immune-mediated diarrhea or colitis
occurred in 3.2% (13/406) of patients receiving OPDIVO: Grade 3 (n=5),
Grade 2 (n=7), and Grade 1 (n=1). In Checkmate 205 and 039, diarrhea or
colitis occurred in 30% (80/263) of patients receiving OPDIVO.
Immune-mediated diarrhea (Grade 3) occurred in 1.1% (3/263) 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

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 069
and 067, immune-mediated hepatitis occurred in 13% (51/407) of patients
receiving OPDIVO with YERVOY: Grade 4 (n=8), Grade 3 (n=37), Grade 2
(n=5), and Grade 1 (n=1). In Checkmate 037, 066, and 067,
immune-mediated hepatitis occurred in 2.3% (18/787) of patients
receiving OPDIVO: Grade 4 (n=3), Grade 3 (n=11), and Grade 2 (n=4). In
Checkmate 057, one patient (0.3%) developed immune-mediated hepatitis.
In Checkmate 025, there was an increased incidence of liver test
abnormalities compared to baseline in AST (33% vs 39%), alkaline
phosphatase (32% vs 32%), ALT (22% vs 31%), and total bilirubin (9% vs
3.5%) in the OPDIVO and everolimus arms, respectively. Immune-mediated
hepatitis requiring systemic immunosuppression occurred in 1.5% (6/406)
of patients receiving OPDIVO: Grade 3 (n=5) and Grade 2 (n=1). In
Checkmate 205 and 039, hepatitis occurred in 11% (30/263) of patients
receiving OPDIVO. Immune-mediated hepatitis occurred in 3.4% (9/263):
Grade 3 (n=7) and Grade 2 (n=2).

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 Dermatitis

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 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

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 069 and 067, hypophysitis occurred in 9% (36/407) of
patients receiving OPDIVO with YERVOY: Grade 3 (n=8), Grade 2 (n=25),
and Grade 1 (n=3). In Checkmate 037, 066, and 067, hypophysitis occurred
in 0.9% (7/787) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2
(n=3), and Grade 1 (n=2). In Checkmate 025, hypophysitis occurred in
0.5% (2/406) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 1
(n=1). In Checkmate 069 and 067, adrenal insufficiency occurred in 5%
(21/407) of patients receiving OPDIVO with YERVOY: Grade 4 (n=1), Grade
3 (n=7), Grade 2 (n=11), and Grade 1 (n=2). In Checkmate 037, 066, and
067, adrenal insufficiency occurred in 1% (8/787) of patients receiving
OPDIVO: Grade 3 (n=2), Grade 2 (n=5), and Grade 1 (n=1). In Checkmate
057, 0.3% (1/287) of OPDIVO-treated patients developed adrenal
insufficiency. In Checkmate 025, adrenal insufficiency occurred in 2.0%
(8/406) of patients receiving OPDIVO: Grade 3 (n=3), Grade 2 (n=4), and
Grade 1 (n=1). In Checkmate 205 and 039, adrenal insufficiency (Grade 2)
occurred in 0.4% (1/263) of patients receiving OPDIVO. In Checkmate 069
and 067, hypothyroidism or thyroiditis occurred in 22% (89/407) of
patients receiving OPDIVO with YERVOY: Grade 3 (n=6), Grade 2 (n=47),
and Grade 1 (n=36). Hyperthyroidism occurred in 8% (34/407) of patients:
Grade 3 (n=4), Grade 2 (n=17), and Grade 1 (n=13). In Checkmate 037,
066, and 067, hypothyroidism or thyroiditis occurred in 9% (73/787) of
patients receiving OPDIVO: Grade 3 (n=1), Grade 2 (n=37), Grade 1
(n=35). Hyperthyroidism occurred in 4.4% (35/787) of patients receiving
OPDIVO: Grade 3 (n=1), Grade 2 (n=12), and Grade 1 (n=22). In Checkmate
057, 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. In Checkmate 025, thyroid disease occurred in 11%
(43/406) of patients receiving OPDIVO, including one Grade 3 event, and
in 3.0% (12/397) of patients receiving everolimus.
Hypothyroidism/thyroiditis occurred in 8% (33/406) of patients receiving
OPDIVO: Grade 3 (n=2), Grade 2 (n=17), and Grade 1 (n=14).
Hyperthyroidism occurred in 2.5% (10/406) of patients receiving OPDIVO:
Grade 2 (n=5) and Grade 1 (n=5). In Checkmate 205 and 039,
hypothyroidism/thyroiditis occurred in 12% (32/263) of patients
receiving OPDIVO: Grade 2 (n=18) and Grade 1: (n=14). Hyperthyroidism
occurred in 1.5% (4/263) of patients receiving OPDIVO: Grade 2: (n=3)
and Grade 1 (n=1). In Checkmate 069 and 067, diabetes mellitus or
diabetic ketoacidosis occurred in 1.5% (6/407) of patients: Grade 4
(n=3), Grade 3 (n=1), Grade 2 (n=1), and Grade 1 (n=1). In Checkmate
037, 066, and 067, diabetes mellitus or diabetic ketoacidosis occurred
in 0.8% (6/787) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2
(n=3), and Grade 1 (n=1). In Checkmate 025, hyperglycemic adverse events
occurred in 9% (37/406) patients. Diabetes mellitus or diabetic
ketoacidosis occurred in 1.5% (6/406) of patients receiving OPDIVO:
Grade 3 (n=3), Grade 2 (n=2), and Grade 1 (n=1). In Checkmate 205 and
039, diabetes mellitus occurred in 0.8% (2/263) of patients receiving
OPDIVO: Grade 3 (n=1) and Grade 1 (n=1).

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

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 069 and
067, immune-mediated nephritis and renal dysfunction occurred in 2.2%
(9/407) of patients: Grade 4 (n=4), Grade 3 (n=3), and Grade 2 (n=2). In
Checkmate 037, 066, and 067, nephritis and renal dysfunction of any
grade occurred in 5% (40/787) of patients receiving OPDIVO.
Immune-mediated nephritis and renal dysfunction occurred in 0.8% (6/787)
of patients: Grade 3 (n=4) and Grade 2 (n=2). In Checkmate 057, Grade 2
immune-mediated renal dysfunction occurred in 0.3% (1/287) of patients
receiving OPDIVO. In Checkmate 025, renal injury occurred in 7% (27/406)
of patients receiving OPDIVO and 3.0% (12/397) of patients receiving
everolimus. Immune-mediated nephritis and renal dysfunction occurred in
3.2% (13/406) of patients receiving OPDIVO: Grade 5 (n=1), Grade 4
(n=1), Grade 3 (n=5), and Grade 2 (n=6). In Checkmate 205 and 039,
nephritis and renal dysfunction occurred in 4.9% (13/263) of patients
treated with OPDIVO. This included one reported case (0.3%) of Grade 3
autoimmune nephritis.

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 069 and 067,
immune-mediated rash occurred in 22.6% (92/407) of patients receiving
OPDIVO with YERVOY: Grade 3 (n=15), Grade 2 (n=31), and Grade 1 (n=46).
In Checkmate 037, 066, and 067, immune-mediated rash occurred in 9%
(72/787) of patients receiving OPDIVO: Grade 3 (n=7), Grade 2 (n=15),
and Grade 1 (n=50). In Checkmate 057, immune-mediated rash occurred in
6% (17/287) of patients receiving OPDIVO including four Grade 3 cases.
In Checkmate 025, rash occurred in 28% (112/406) of patients receiving
OPDIVO and 36% (143/397) of patients receiving everolimus.
Immune-mediated rash, defined as a rash treated with systemic or topical
corticosteroids, occurred in 7% (30/406) of patients receiving OPDIVO:
Grade 3 (n=4), Grade 2 (n=7), and Grade 1 (n=19). In Checkmate 205 and
039, rash occurred in 22% (58/263) of patients receiving OPDIVO.
Immune-mediated rash occurred in 7% (18/263) of patients on OPDIVO:
Grade 3 (n=4), Grade 2 (n=3), and Grade 1 (n=11).

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 067, encephalitis was
identified in one patient (0.2%) receiving OPDIVO with YERVOY. In
Checkmate 057, fatal limbic encephalitis occurred in one patient (0.3%)
receiving OPDIVO. In Checkmate 205 and 039, encephalitis occurred in
0.8% (2/263) of patients after allogeneic HSCT after 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, iritis, 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 069 and 067, infusion- related
reactions occurred in 2.5% (10/407) of patients receiving OPDIVO with
YERVOY: Grade 2 (n=6) and Grade 1 (n=4). In Checkmate 037, 066, and 067,
Grade 2 infusion related reactions occurred in 2.7% (21/787) of patients
receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=8), and Grade 1 (n=11). In
Checkmate 057, Grade 2 infusion reactions requiring corticosteroids
occurred in 1.0% (3/287) of patients receiving OPDIVO. In Checkmate 025,
hypersensitivity/infusion-related reactions occurred in 6% (25/406) of
patients receiving OPDIVO and 1.0% (4/397) of patients receiving
everolimus. In Checkmate 205 and 039, hypersensitivity/infusion-related
reactions occurred in 16% (42/263) of patients receiving OPDIVO: Grade 3
(n=2), Grade 2 (n=24), and Grade 1 (n=16).

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 SCT 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 nursing
during treatment with YERVOY and for 3 months following the final dose.

Serious Adverse Reactions

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 relative
to the OPDIVO arm. 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 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 066, serious
adverse reactions occurred in 36% of patients receiving OPDIVO. 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 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. In
Checkmate 025, serious adverse reactions occurred in 47% of patients
receiving OPDIVO. The most frequent serious adverse reactions reported
in ≥2% of patients were acute kidney injury, pleural effusion,
pneumonia, diarrhea, and hypercalcemia. In Checkmate 205 and 039, among
all patients (safety population [n=263]), adverse reactions leading to
discontinuation (4.2%) or to dosing delays (23%) occurred. The most
frequent serious adverse reactions reported in ≥1% of patients were
infusion-related reaction, pneumonia, pleural effusion, pyrexia, rash
and pneumonitis. Ten patients died from causes other than disease
progression, including 6 who died from complications of allogeneic HSCT.
Serious adverse reactions occurred in 21% of patients in the safety
population (n=263) and 27% of patients in the subset of patients
evaluated for efficacy (efficacy population [n=95]).

Common Adverse Reactions

In Checkmate 067, the most common (≥20%) adverse reactions in the OPDIVO
plus YERVOY arm 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 arm were fatigue (53%), rash
(40%), diarrhea (31%), and nausea (28%). In Checkmate 037, the most
common adverse reaction (≥20%) reported with OPDIVO was rash (21%). In
Checkmate 066, the most common adverse reactions (≥20%) reported with
OPDIVO vs dacarbazine were fatigue (49% vs 39%), musculoskeletal pain
(32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%). 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%). In Checkmate 025, the most
common adverse reactions (≥20%) reported in patients receiving OPDIVO vs
everolimus were asthenic conditions (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
205 and 039, among all patients (safety population [n=263]) and the
subset of patients in the efficacy population (n=95), respectively, the
most common adverse reactions (reported in at least 20%) were fatigue
(32% and 43%), upper respiratory tract infection (28% and 48%), pyrexia
(24% and 35%), diarrhea (23% and 30%), and cough (22% and 35%). In the
subset of patients in the efficacy population (n=95), the most common
adverse reactions also included rash (31%), musculoskeletal pain (27%),
pruritus (25%), nausea (23%), arthralgia (21%), and peripheral
neuropathy (21%).

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 069 and 067 – advanced melanoma alone or in combination
with YERVOY; Checkmate 037 and 066 – advanced melanoma; Checkmate
057 – non-squamous non-small cell lung cancer (NSCLC); Checkmate
025 – renal cell carcinoma; Checkmate 205/039 – classical
Hodgkin lymphoma

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

Please
see U.S. Full Prescribing Information for OPDIVO.

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.

About AbbVie

AbbVie is a global, research-based biopharmaceutical company formed in
2013 following separation from Abbott Laboratories. The company’s
mission is to use its expertise, dedicated people and unique approach to
innovation to develop and market advanced therapies that address some of
the world’s most complex and serious diseases. Together with its
wholly-owned subsidiary, Pharmacyclics, AbbVie employs more than 28,000
people worldwide and markets medicines in more than 170 countries. For
further information on the company and its people, portfolio and
commitments, please visit www.abbvie.com. Follow
@abbvie
on Twitter or view careers on our Facebook or
LinkedIn
page.

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 in combination
with a Live Attenuated Double–Deleted (LADD) Listerial monocytogenes
cancer vaccine, expressing mesothelin and EGFRvIII (ADU-214), will
receive regulatory approval for the treatment of cancer. 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.

AbbVie Forward-Looking Statement

Some statements in this news release may be forward-looking
statements for purposes of the Private Securities Litigation Reform Act
of 1995. The words « believe, » « expect, » « anticipate, » « project » and
similar expressions, among others, generally identify forward-looking
statements. AbbVie cautions that these forward-looking statements are
subject to risks and uncertainties that may cause actual results to
differ materially from those indicated in the forward-looking
statements. Such risks and uncertainties include, but are not limited
to, challenges to intellectual property, competition from other
products, difficulties inherent in the research and development process,
adverse litigation or government action, and changes to laws and
regulations applicable to our industry. Additional information about the
economic, competitive, governmental, technological and other factors
that may affect AbbVie’s operations is set forth in Item 1A, « Risk
Factors, » in AbbVie’s 2015 Annual Report on Form 10-K, which has been
filed with the Securities and Exchange Commission. AbbVie undertakes no
obligation to release publicly any revisions to forward-looking
statements as a result of subsequent events or developments, except as
required by law.

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