Bristol-Myers Squibb to Present New Data Demonstrating Continued Research Expansion and Immuno-Oncology Advancements Across Multiple Blood Cancers at the 21st Congress of the European Hematology Association

PRINCETON, N.J.–(BUSINESS WIRE)–Bristol-Myers
Squibb Company (NYSE:BMY) announced today clinical data featuring
two of its Immuno-Oncology agents, Opdivo (nivolumab)and Empliciti
(elotuzumab), will be presented at the 21^st Congress of the
European Hematology Association (EHA) in Copenhagen, Denmark from June 9
– 12. Datawill be presentedfrom the Phase 2
CheckMate -205 trial evaluating Opdivo in patients with classical
Hodgkin lymphoma (cHL) who had relapsed or progressed after autologous
hematopoietic stem cell transplantation (auto-HSCT) and
post-transplantation brentuximab vedotin, as well as from the Phase 3
ELOQUENT-2 trial evaluating Empliciti in combination with
Revlimid (lenalidomide) and dexamethasonein patients with
multiple myeloma who had received one to three prior therapies. In
addition, subgroup analyses of long-term outcomes from the Phase 3
DASISION trial in newly diagnosed adults with chronic phase Philadelphia
chromosome-positive chronic myeloid leukemia (CML) with Sprycel
(dasatinib), the company’s first blood cancer agent, will be
presented.
“The research being presented at EHA demonstrates our commitment to
hematologic malignancies with high unmet need, including multiple
myeloma, classical Hodgkin lymphoma and chronic myeloid leukemia,” said
Jean Viallet, M.D., Global Clinical Research Lead, Oncology,
Bristol-Myers Squibb. “These data for Opdivo and Empliciti
provide additional understanding of how our therapies work and show the
potential for Immuno-Oncology treatment options in patients with
hematologic malignancies.”
Data to be presented during oral presentations include:

• CheckMate -205: Additional results from a Phase 2 study of Opdivo
  in patients with cHL following auto-HSCT and brentuximab vedotin
  (Abstract #S793) will be presented as an oral presentation during the
  “Relapsed Hodgkin Lymphoma & Primary Mediastinal Large B-Cell Lymphoma
  (PM-DLBCL)” session on Sunday, June 12, 8:00 – 8:15 a.m. CEST.
• SMM 011: First presentation of results from a study of Empliciti
  monotherapy in patients with high-risk smoldering multiple myeloma
  (Abstract #S815) will be presented as an oral presentation during the
  “Experimental Approaches for Plasma Disorders” session on Sunday, June
  12, 8:30 – 8:45 a.m. CEST.
• Preclinical I-O: Results from a study showing PD-1 blockade
  enhances the efficacy of elotuzumab in mouse models (Abstract #S450)
  will be presented as an oral presentation during the “New Biological
  Markers in MM” session on Saturday, June 11, 12:15 – 12:30 p.m. CEST.

The full set of data to be presented by Bristol-Myers Squibb includes:
Hodgkin Lymphoma

• Checkmate 205: a phase 2 study of nivolumab in patients with
  classical Hodgkin lymphoma following autologous stem cell
  transplantation and brentuximab vedotin
  Author: A. Engert
  Abstract
  #S793
  Oral Presentation, Relapsed Hodgkin Lymphoma & Primary
  Mediastinal Large B-Cell Lymphoma (PM-DLBCL) Session
  Sunday, June
  12, 8:00 – 8:15 a.m. CEST, Hall A2, The Bella Center

Multiple Myeloma

• Elotuzumab + lenalidomide/dexamethasone in patients with
  relapsed/refractory multiple myeloma: ELOQUENT-2 post-hoc analysis of
  PFS and tumor regrowth by time from diagnosis and prior lines of
  therapy
  Author: M. Dimopoulos
  Abstract #P280
  Poster
  Presentation, Innovative Therapies for MM 2
  Friday, June 10, 5:15
  – 6:45 p.m. CEST, Hall H, The Bella Center

• PD-1 blockade enhances the efficacy of elotuzumab in mouse tumor
  models
  Author: N. Bezman
  Abstract #S450
  Oral
  Presentation, New Biological Markers in MM
  Saturday, June 11,
  12:15 – 12:30 p.m. CEST, Auditorium 2, The Bella Center

• A phase 2, open-label, multicenter study of elotuzumab monotherapy
  in patients with high-risk smoldering multiple myeloma
  Author:
  P. Richardson
  Abstract #S815
  Oral Presentation, Experimental
  Approaches for Plasma Disorders Session
  Sunday, June 12, 8:30 –
  8:45 a.m. CEST, Hall C14, The Bella Center

• Differential effects of elotuzumab (anti-SLAMF7) and anti-CD38
  monoclonal antibodies in preclinical models
  Author: N. Bezman
  Abstract
  #P646
  Poster Presentation, Novel Targets for MM
  Saturday,
  June 11, 5:30 – 7:00 p.m. CEST, Hall H, The Bella Center

• An ongoing multinational observational study in multiple myeloma
  (PREAMBLE): preliminary report on progression-free survival
  Author:
  D. Kuter
  Abstract #E1261
  E-Poster, Myeloma and Other
  Monoclonal Gammopathies – Clinical
  Friday, June 10, 9:30 a.m.
  CEST – Saturday, June 11, 7:00 p.m. CEST

• Fc-gamma receptor polymorphisms and progression-free survival:
  analysis of three clinical trials of elotuzumab in multiple myeloma
  Author:
  V. Poulart
  Abstract #E1281
  E-Poster, Myeloma and Other
  Monoclonal Gammopathies – Clinical
  Friday, June 10, 9:30 a.m.
  CEST – Saturday, June 11, 7:00 p.m. CEST

• Clinical characteristics, treatment patterns and healthcare
  resource utilization among Italian patients with relapsed refractory
  multiple myeloma: results from a prospective observational study
  Author:
  A. Palumbo
  Abstract #E1438
  E-Poster, Quality of Life,
  Palliative Care, Ethics and Health Economics
  Friday, June 10,
  9:30 a.m. CEST – Saturday, June 11, 7:00 p.m. CEST

• Real-world characteristics, treatment pathways and healthcare
  resource use in patients treated for relapsed refractory multiple
  myeloma in Spain: preliminary results from the PREMIERE study
  Author:
  J. Martinez-Lopez
  Abstract #PB2097
  Publication Only, Quality
  of Life, Palliative Care, Ethics and Health Economics

Chronic Myeloid Leukemia

• The impact of early molecular response on long‐term outcomes in
  patients with chronic myeloid leukemia in chronic phase (CML‐CP)
  treated with dasatinib or imatinib from the DASISION trial
  Author:
  F. Stegelmann
  Abstract #P617
  Poster Presentation, Chronic
  Myeloid Leukemia – Clinical 2
  Saturday, June 11, 5:30 – 7:00 p.m.
  CEST, Hall H, The Bella Center

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
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.
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 51 countries including the United States, Japan
and in the European Union.
OPDIVO U.S. 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 carcinoma (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 Empliciti
Empliciti is an immunostimulatory antibody that specifically
targets Signaling Lymphocyte Activation Molecule Family member 7
(SLAMF7), a cell-surface glycoprotein. SLAMF7 is expressed on myeloma
cells independent of cytogenetic abnormalities. SLAMF7 also is expressed
on Natural Killer cells, plasma cells and at lower levels on specific
immune cell subsets of differentiated cells within the hematopoietic
lineage.
Empliciti has a dual mechanism-of-action. It directly activates
the immune system through Natural Killer cells via the SLAMF7 pathway. Empliciti
also targets SLAMF7 on myeloma cells, tagging these malignant cells for
Natural Killer cell-mediated destruction via antibody-dependent cellular
toxicity.
On November 30, 2015, the U.S. Food and Drug Administration (FDA)
approved Empliciti in combination with lenalidomide and
dexamethasone in patients with multiple myeloma who have received one to
three prior therapies. On May 11, 2016, the European Commission approved Empliciti
in combination with lenalidomide and dexamethasone in patients with
multiple myeloma who have received at least one prior therapy. The
safety and efficacy of Empliciti is being evaluated by other
health authorities.
Bristol-Myers Squibb and AbbVie are co-developing Empliciti, with
Bristol-Myers Squibb solely responsible for commercial activities.
EMPLICITI U.S. INDICATION & IMPORTANT SAFETY INFORMATION
INDICATION
EMPLICITI™ (elotuzumab) is indicated in combination with lenalidomide
and dexamethasone for the treatment of patients with multiple myeloma
who have received one to three prior therapies.
IMPORTANT SAFETY INFORMATION
Infusion Reactions

• EMPLICITI can cause infusion reactions. Common symptoms include fever,
  chills, and hypertension. Bradycardia and hypotension also developed
  during infusions. In the trial, 5% of patients required interruption
  of the administration of EMPLICITI for a median of 25 minutes due to
  infusion reactions, and 1% of patients discontinued due to infusion
  reactions. Of the patients who experienced an infusion reaction, 70%
  (23/33) had them during the first dose. If a Grade 2 or higher
  infusion reaction occurs, interrupt the EMPLICITI infusion and
  institute appropriate medical and supportive measures. If the infusion
  reaction recurs, stop the EMPLICITI infusion and do not restart it on
  that day. Severe infusion reactions may require permanent
  discontinuation of EMPLICITI therapy and emergency treatment.
• Premedicate with dexamethasone, H1 Blocker, H2 Blocker, and
  acetaminophen prior to infusing with EMPLICITI.

Infections

• In a clinical trial of patients with multiple myeloma (N=635),
  infections were reported in 81.4% of patients in the EMPLICITI with
  lenalidomide/dexamethasone arm (ERd) and 74.4% in the
  lenalidomide/dexamethasone arm (Rd). Grade 3-4 infections were 28%
  (ERd) and 24.3% (Rd). Opportunistic infections were reported in 22%
  (ERd) and 12.9% (Rd). Fungal infections were 9.7% (ERd) and 5.4% (Rd).
  Herpes zoster was 13.5% (ERd) and 6.9% (Rd). Discontinuations due to
  infections were 3.5% (ERd) and 4.1% (Rd). Fatal infections were 2.5%
  (ERd) and 2.2% (Rd). Monitor patients for development of infections
  and treat promptly.

Second Primary Malignancies

• In a clinical trial of patients with multiple myeloma (N=635),
  invasive second primary malignancies (SPM) were 9.1% (ERd) and 5.7%
  (Rd). The rate of hematologic malignancies were the same between ERd
  and Rd treatment arms (1.6%). Solid tumors were reported in 3.5% (ERd)
  and 2.2% (Rd). Skin cancer was reported in 4.4% (ERd) and 2.8% (Rd).
  Monitor patients for the development of SPMs.

Hepatotoxicity

• Elevations in liver enzymes (AST/ALT greater than 3 times the upper
  limit, total bilirubin greater than 2 times the upper limit, and
  alkaline phosphatase less than 2 times the upper limit) consistent
  with hepatotoxicity were 2.5% (ERd) and 0.6% (Rd). Two patients
  experiencing hepatotoxicity discontinued treatment; however, 6 out of
  8 patients had resolution and continued treatment. Monitor liver
  enzymes periodically. Stop EMPLICITI upon Grade 3 or higher elevation
  of liver enzymes. After return to baseline values, continuation of
  treatment may be considered.

Interference with Determination of Complete Response

• EMPLICITI is a humanized IgG kappa monoclonal antibody that can be
  detected on both the serum protein electrophoresis and immunofixation
  assays used for the clinical monitoring of endogenous M-protein. This
  interference can impact the determination of complete response and
  possibly relapse from complete response in patients with IgG kappa
  myeloma protein.

Pregnancy/Females and Males of Reproductive Potential

• There are no studies with EMPLICITI with pregnant women to inform any
  drug associated risks.
• There is a risk of fetal harm, including severe life-threatening human
  birth defects associated with lenalidomide and it is contraindicated
  for use in pregnancy. Refer to the lenalidomide full prescribing
  information for requirements regarding contraception and the
  prohibitions against blood and/or sperm donation due to presence and
  transmission in blood and/or semen and for additional information.

Adverse Reactions

• Infusion reactions were reported in approximately 10% of patients
  treated with EMPLICITI with lenalidomide and dexamethasone. All
  reports of infusion reaction were Grade 3 or lower. Grade 3 infusion
  reactions occurred in 1% of patients.
• Serious adverse reactions were 65.4% (ERd) and 56.5% (Rd). The most
  frequent serious adverse reactions in the ERd arm compared to the Rd
  arm were: pneumonia (15.4%, 11%), pyrexia (6.9%, 4.7%), respiratory
  tract infection (3.1%, 1.3%), anemia (2.8%, 1.9%), pulmonary embolism
  (3.1%, 2.5%), and acute renal failure (2.5%, 1.9%).
• The most common adverse reactions in ERd and Rd, respectively (>20%)
  were fatigue (61.6%, 51.7%), diarrhea (46.9%, 36.0%), pyrexia (37.4%,
  24.6%), constipation (35.5%, 27.1%), cough (34.3%, 18.9%), peripheral
  neuropathy (26.7%, 20.8%), nasopharyngitis (24.5%, 19.2%), upper
  respiratory tract infection (22.6%, 17.4%), decreased appetite (20.8%,
  12.6%), and pneumonia (20.1%, 14.2%).

Please see the full Prescribing Information for Empliciti.
About Sprycel
Sprycel was first approved by the FDA in 2006 for the treatment
of adults with Philadelphia chromosome-positive (Ph+) chronic myeloid
leukemia (CML) in chronic phase (CP) who are resistant or intolerant to
prior therapy including imatinib. At that time, Sprycel was also
approved for adults with Ph+ acute lymphoblastic leukemia (ALL) who are
resistant or intolerant to prior therapy. It is the first and only
BCR-ABL kinase inhibitor with survival data in its label for CP Ph+ CML
patients who are resistant or intolerant to Gleevec (imatinib mesylate). Sprycel
is approved and marketed worldwide for these indications in more than 60
countries.
Sprycel is also an FDA-approved treatment for adults with newly
diagnosed CP Ph+ CML (since October 2010). Sprycel received
accelerated FDA approval for this indication. Additional country
approvals for this indication total more than 50.
SPRYCEL U.S. INDICATIONS & IMPORTANT SAFETY INFORMATION
INDICATIONS
SPRYCEL^® (dasatinib) is indicated for the treatment of adults
with:

• Newly diagnosed adults with Philadelphia chromosome-positive (Ph+)
  chronic myeloid leukemia (CML) in chronic phase.
• Chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with
  resistance or intolerance to prior therapy including imatinib.
• Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+
  ALL) with resistance or intolerance to prior therapy.

IMPORTANT SAFETY INFORMATION
Myelosuppression:
Treatment with SPRYCEL is associated with severe (NCI CTC Grade 3/4)
thrombocytopenia, neutropenia, and anemia, which occur earlier and more
frequently in patients with advanced phase CML or Ph+ ALL than in
patients with chronic phase CML. Myelosuppression was reported in
patients with normal baseline laboratory values as well as in patients
with pre-existing laboratory abnormalities.

• In patients with chronic phase CML, perform complete blood counts
  (CBCs) every 2 weeks for 12 weeks, then every 3 months thereafter, or
  as clinically indicated
• In patients with advanced phase CML or Ph+ ALL, perform CBCs weekly
  for the first 2 months and then monthly thereafter, or as clinically
  indicated
• Myelosuppression is generally reversible and usually managed by
  withholding SPRYCEL temporarily and/or dose reduction

• In clinical studies, myelosuppression may have also been managed by
  discontinuation of study therapy
• Hematopoietic growth factor has been used in patients with resistant
  myelosuppression

Bleeding-Related Events:
SPRYCEL caused thrombocytopenia in human subjects. In addition,
dasatinib caused platelet dysfunction in vitro. In all CML or Ph+
ALL clinical studies, ≥grade 3 central nervous system (CNS) hemorrhages,
including fatalities, occurred in <1% of patients receiving SPRYCEL.
Grade 3 or greater gastrointestinal hemorrhage, including fatalities,
occurred in 4% of patients and generally required treatment
interruptions and transfusions. Other cases of ≥grade 3 hemorrhage
occurred in 2% of patients.

• Most bleeding events in clinical studies were associated with severe
  thrombocytopenia
• Concomitant medications that inhibit platelet function or
  anticoagulants may increase the risk of hemorrhage

Fluid Retention:
SPRYCEL may cause fluid retention. After 5 years of follow-up in the
randomized newly diagnosed chronic phase CML study (n=258), grade 3/4
fluid retention was reported in 5% of patients, including 3% of patients
with grade 3/4 pleural effusion. In patients with newly diagnosed or
imatinib resistant or intolerant chronic phase CML, grade 3/4 fluid
retention occurred in 6% of patients treated with SPRYCEL at the
recommended dose (n=548). In patients with advanced phase CML or Ph+ ALL
treated with SPRYCEL at the recommended dose (n=304), grade 3/4 fluid
retention was reported in 8% of patients, including grade 3/4 pleural
effusion reported in 7% of patients.

• Patients who develop symptoms of pleural effusion or other fluid
  retention, such as new or worsened dyspnea on exertion or at rest,
  pleuritic chest pain, or dry cough should be evaluated promptly with a
  chest x-ray or additional diagnostic imaging as appropriate
• Fluid retention events were typically managed by supportive care
  measures that may include diuretics or short courses of steroids
• Severe pleural effusion may require thoracentesis and oxygen therapy
• Consider dose reduction or treatment interruption

Cardiovascular Events:
After 5 years of follow-up in the randomized newly diagnosed chronic
phase CML trial (n=258), the following cardiac adverse events occurred:

• Cardiac ischemic events (3.9% dasatinib vs 1.6% imatinib), cardiac
  related fluid retention (8.5% dasatinib vs 3.9% imatinib), and
  conduction system abnormalities, most commonly arrhythmia and
  palpitations (7.0% dasatinib vs 5.0% imatinib). Two cases (0.8%) of
  peripheral arterial occlusive disease occurred with imatinib and 2
  (0.8%) transient ischemic attacks occurred with dasatinib

Monitor patients for signs or symptoms consistent with cardiac
dysfunction and treat appropriately.
Pulmonary Arterial Hypertension (PAH):
SPRYCEL may increase the risk of developing PAH, which may occur any
time after initiation, including after more than 1 year of treatment.
Manifestations include dyspnea, fatigue, hypoxia, and fluid retention.
PAH may be reversible on discontinuation of SPRYCEL.

• Evaluate patients for signs and symptoms of underlying cardiopulmonary
  disease prior to initiating SPRYCEL and during treatment. If PAH is
  confirmed, SPRYCEL should be permanently discontinued

QT Prolongation:
In vitro data suggest that dasatinib has the potential to prolong
cardiac ventricular repolarization (QT interval).

• In clinical trials of patients treated with SPRYCEL at all doses
  (n=2440), 16 patients (<1%) had QTc prolongation reported as an
  adverse reaction. Twenty-two patients (1%) experienced a QTcF >500 ms
• In 865 patients with leukemia treated with SPRYCEL in five Phase 2
  single-arm studies, the maximum mean changes in QTcF (90% upper bound
  CI) from baseline ranged from 7.0 to 13.4 ms
• SPRYCEL may increase the risk of prolongation of QTc in patients
  including those with hypokalemia or hypomagnesemia, patients with
  congenital long QT syndrome, patients taking antiarrhythmic medicines
  or other medicinal products that lead to QT prolongation, and
  cumulative high-dose anthracycline therapy

• Correct hypokalemia or hypomagnesemia prior to and during SPRYCEL
  administration

Severe Dermatologic Reactions:
Cases of severe mucocutaneous dermatologic reactions, including
Stevens-Johnson syndrome and erythema multiforme, have been reported in
patients treated with SPRYCEL.

• Discontinue permanently in patients who experience a severe
  mucocutaneous reaction during treatment if no other etiology can be
  identified

Tumor Lysis Syndrome (TLS):
TLS has been reported in patients with resistance to prior imatinib
therapy, primarily in advanced phase disease.

• Due to potential for TLS, maintain adequate hydration, correct uric
  acid levels prior to initiating therapy with SPRYCEL, and monitor
  electrolyte levels
• Patients with advanced stage disease and/or high tumor burden may be
  at increased risk and should be monitored more frequently

Embryo-Fetal Toxicity:
Based on limited human data, SPRYCEL can cause fetal harm when
administered to a pregnant woman. Hydrops fetalis, fetal leukopenia and
fetal thrombocytopenia have been reported with maternal exposure to
SPRYCEL. Transplacental transfer of dasatinib has been measured in fetal
plasma and amniotic fluid at concentrations comparable to those in
maternal plasma.

• Advise females of reproductive potential to avoid pregnancy, which may
  include the use of effective contraception, during treatment with
  SPRYCEL and for 30 days after the final dose

Lactation:
No data are available regarding the presence of dasatinib in human milk,
the effects of the drug on the breastfed infant or the effects of the
drug on milk production. However, dasatinib is present in the milk of
lactating rats.

• Because of the potential for serious adverse reactions in nursing
  infants from SPRYCEL, breastfeeding is not recommended during
  treatment with SPRYCEL and for 2 weeks after the final dose

Drug Interactions:
SPRYCEL is a CYP3A4 substrate and a weak time-dependent inhibitor of
CYP3A4.

• Drugs that may increase SPRYCEL plasma concentrations are:

• CYP3A4 inhibitors: Concomitant use of SPRYCEL and drugs that
  inhibit CYP3A4 should be avoided. If administration of a potent CYP3A4
  inhibitor cannot be avoided, close monitoring for toxicity and a
  SPRYCEL dose reduction should be considered
• Strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole,
  clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir,
  ritonavir, saquinavir, telithromycin, voriconazole). If SPRYCEL must
  be administered with a strong CYP3A4 inhibitor, a dose decrease or
  temporary discontinuation should be considered

• Grapefruit juice may also increase plasma concentrations of
  SPRYCEL and should be avoided

• Drugs that may decrease SPRYCEL plasma concentrations are:

• CYP3A4 inducers: If SPRYCEL must be administered with a CYP3A4
  inducer, a dose increase in SPRYCEL should be considered
• Strong CYP3A4 inducers (eg, dexamethasone, phenytoin,
  carbamazepine, rifampin, rifabutin, phenobarbital) should be avoided.
  Alternative agents with less enzyme induction potential should be
  considered. If the dose of SPRYCEL is increased, the patient should be
  monitored carefully for toxicity

• St John’s Wort may decrease SPRYCEL plasma concentrations
  unpredictably and should be avoided

• Antacids may decrease SPRYCEL drug levels. Simultaneous
  administration of SPRYCEL and antacids should be avoided. If antacid
  therapy is needed, the antacid dose should be administered at least 2
  hours prior to or 2 hours after the dose of SPRYCEL
• H₂ antagonists/proton pump inhibitors (eg,
  famotidine and omeprazole): Long-term suppression of gastric acid
  secretion by use of H₂ antagonists or proton pump
  inhibitors is likely to reduce SPRYCEL exposure. Therefore,
  concomitant use of H₂ antagonists or proton pump inhibitors
  with SPRYCEL is not recommended

• Drugs that may have their plasma concentration altered by SPRYCEL are:

• CYP3A4 substrates (eg, simvastatin) with a narrow therapeutic
  index should be administered with caution in patients receiving SPRYCEL

Adverse Reactions:
The safety data reflects exposure to SPRYCEL at all doses tested in
clinical studies including 324 patients with newly diagnosed chronic
phase CML and 2388 patients with imatinib resistant or intolerant
chronic or advanced phase CML or Ph+ ALL.
The median duration of therapy in all 2712 SPRYCEL-treated patients was
19.2 months (range 0–93.2 months). Median duration of therapy in:

• 1618 patients with chronic phase CML was 29 months (range 0–92.9
  months)

• Median duration for 324 patients in the newly diagnosed chronic phase
  CML trial was approximately 60 months

• 1094 patients with advanced phase CML or Ph+ ALL was 6.2 months (range
  0–93.2 months)

In the newly diagnosed chronic phase CML trial, after a minimum of 60
months of follow-up, the cumulative discontinuation rate for 258
patients was 39%.
In the overall population of 2712 SPRYCEL-treated patients, 88% of
patients experienced adverse reactions at some time and 19% experienced
adverse reactions leading to treatment discontinuation.
Among the 1618 SPRYCEL-treated patients with chronic phase CML,
drug-related adverse events leading to discontinuation were reported in
329 (20.3%) patients.

• In the newly diagnosed chronic phase CML trial, drug was discontinued
  for adverse reactions in 16% of SPRYCEL-treated patients with a
  minimum of 60 months of follow-up

Among the 1094 SPRYCEL-treated patients with advanced phase CML or Ph+
ALL, drug-related adverse events leading to discontinuation were
reported in 191 (17.5%) patients.
Patients ≥65 years are more likely to experience the commonly reported
adverse reactions of fatigue, pleural effusion, diarrhea, dyspnea,
cough, lower gastrointestinal hemorrhage, and appetite disturbance, and
more likely to experience the less frequently reported adverse reactions
of abdominal distention, dizziness, pericardial effusion, congestive
heart failure, hypertension, pulmonary edema and weight decrease, and
should be monitored closely.

• In newly diagnosed chronic phase CML patients:

• Drug-related serious adverse events (SAEs) were reported for 16.7% of
  SPRYCEL-treated patients. Serious adverse reactions reported in ≥5% of
  patients included pleural effusion (5%)
• The most common adverse reactions (≥15%) included myelosuppression,
  fluid retention, and diarrhea
• Grade 3/4 laboratory abnormalities included neutropenia (29%),
  thrombocytopenia (22%), anemia (13%), hypophosphatemia (7%),
  hypocalcemia (4%), elevated bilirubin (1%), and elevated creatinine
  (1%)

• In patients resistant or intolerant to prior imatinib therapy:

• Drug-related SAEs were reported for 26.1% of SPRYCEL-treated patients
  treated at the recommended dose of 100 mg once daily in the randomized
  dose-optimization trial of patients with chronic phase CML resistant
  or intolerant to prior imatinib therapy. Serious adverse reactions
  reported in ≥5% of patients included pleural effusion (10%)
• The most common adverse reactions (≥15%) included myelosuppression,
  fluid retention events, diarrhea, headache, fatigue, dyspnea, skin
  rash, nausea, hemorrhage and musculoskeletal pain
• Grade 3/4 hematologic laboratory abnormalities in chronic phase CML
  patients resistant or intolerant to prior imatinib therapy who
  received SPRYCEL 100 mg once daily with a minimum follow up of 60
  months included neutropenia (36%), thrombocytopenia (24%), and anemia
  (13%). Other grade 3/4 laboratory abnormalities included:
  hypophosphatemia (10%), and hypokalemia (2%)
• Among chronic phase CML patients with resistance or intolerance to
  prior imatinib therapy, cumulative grade 3/4 cytopenias were similar
  at 2 and 5 years including: neutropenia (36% vs 36%), thrombocytopenia
  (23% vs 24%), and anemia (13% vs 13%)

• Grade 3/4 elevations of transaminases or bilirubin and Grade 3/4
  hypocalcemia, hypokalemia, and hypophosphatemia were reported in
  patients with all phases of CML

• Elevations in transaminases or bilirubin were usually managed with
  dose reduction or interruption
• Patients developing Grade 3/4 hypocalcemia during the course of
  SPRYCEL therapy often had recovery with oral calcium supplementation

Please see the full Prescribing Information here.
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
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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, 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.