Bristol-Myers Squibb Enters into New Collaboration with Johns Hopkins Focused on Immuno-Oncology
Research
Bristol-Myers Squibb Company (NYSE:BMY) announced today that the company has entered into a five-year research
collaboration with the Johns Hopkins University. The collaboration is designed to identify mechanisms of response and resistance in
patients whose cancer is being treated with checkpoint inhibitor-based immunotherapies, including Opdivo (nivolumab) monotherapy, or Opdivo in combination with Yervoy (ipilimumab) or other investigational immunotherapies.
Under the collaboration, Bristol-Myers Squibb and Johns Hopkins’ scientists will launch an interdisciplinary research program
that will study patient tumor samples in four primary research areas: characterization of tumor antigens and tumor antigen-specific
T-cells, multifaceted profiling of the tumor microenvironment, assessment of microbiome components that modulate systemic
anti-tumor immunity, and elucidation of novel tumor and immuno-metabolism factors that modify responsiveness to immunotherapy.
“This important collaboration with Johns Hopkins University, a leader in the field of translational Immuno-Oncology
research, builds upon our strong working relationship and will enhance our scientific understanding of the role of various
immunotherapies both alone and in combination, and at different points in the treatment continuum,” said Francis Cuss, MB, BChir, FRCP, chief scientific officer, Bristol-Myers Squibb. “We believe that findings
from this research may help to inform the future of immunotherapy drug development as it relates to patient selection, clinical
trial design and the identification of new biomarkers.”
“We’re at an inflection point of understanding the root causes of response and resistance to immunotherapy, and this
collaboration will help propel the research needed to identify ways to expand immunotherapy effectiveness to more patients,” says
Drew Pardoll, M.D., Ph.D., Director of the Bloomberg~Kimmel Institute for Cancer Immunotherapy.
Bristol-Myers Squibb and Johns Hopkins will also explore several early-stage clinical trials primarily focused on, but not
limited to, the study of neoadjuvant immunotherapeutic interventions.
This agreement builds on the productive track record of collaboration between Bristol-Myers Squibb and the Johns Hopkins Kimmel
Cancer Center- both leaders in the transformative field of Immuno-Oncology. Johns Hopkins is a founding member of the International
Immuno-Oncology Network (II-ON), a global collaboration between Bristol-Myers Squibb and 13 academia centers that aims to further
the scientific understanding of immuno-oncology. The two organizations also entered into an agreement in November 2015 as part of
Bristol-Myers Squibb’s Immuno-Oncology Rare Population Malignancy (I-O RPM) program in the U.S.
Bristol-Myers Squibb: At the Forefront of Immuno-Oncology Science & Innovation
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 Immuno-Oncology (I-O) medicines that will raise survival expectations in hard-to-treat
cancers and will change the way patients live with cancer.
We are leading the scientific understanding of I-O through our extensive portfolio of investigational and approved agents,
including the first combination of two I-O agents in metastatic melanoma, and our differentiated clinical development program,
which is studying broad patient populations across more than 20 types of cancers with 11 clinical-stage molecules designed to
target different immune system pathways. Our deep expertise and innovative clinical trial designs uniquely position us to advance
the science of combinations across multiple tumors and potentially deliver the next wave of I-O combination regimens 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 inform which patients will benefit most from I-O therapies.
We understand making the promise of I-O 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 57 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 47 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 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
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 Squib 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 or Yervoy will receive regulatory approval
for an additional indication. 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.
Bristol-Myers Squibb
Media:
Ken Dominski, 609-252-5251
ken.dominski@bms.com
or
Investors
Tim Power, 609-252-7509
timothy.power@bms.com
Bill Szablewski, 609-252-5894
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