BMS compounds to be featured in more than 80 presentations spanning 20 types of cancer, with focus on research of precision therapies aimed at improving standards of care
First efficacy data for investigational anti-LAG-3 in combination with Opdivo in anti-PD-1/PD-L1 relapsed or refractory patients and for Opdivo in combination with epacadostat showcases next wave of cancer research approaches
Opdivo plus Yervoy data to be featured in 18 presentations across multiple tumor types, including advanced small cell lung cancer, melanoma and colorectal cancer
Bristol-Myers
Squibb Company (NYSE:BMY) today announced that more than 80
presentations, including 16 oral presentations and seven poster
discussions, highlighting data from Company-sponsored studies,
collaborations and investigator-sponsored research evaluating its
oncology compounds across 20 types of cancer, will be featured at the
American Society of Clinical Oncology (ASCO) Annual Meeting 2017 in
Chicago from June 2-6. Results to be presented represent the breadth of
the Company’s Oncology research portfolio, including monotherapy and
combination studies of Opdivo (nivolumab) and Yervoy
(ipilimumab), as well as studies of Empliciti (elotuzumab) and Sprycel
(dasatinib). The Company will also present updates from its robust
investigational pipeline, including proof-of-concept efficacy data for
its anti-lymphocyte activation gene-3 (LAG-3) monoclonal antibody in
combination with Opdivo and pharmacokinetic, pharmacodynamic and
safety data on its investigational glucocorticoid-induced tumor necrosis
factor receptor-related gene (GITR) agonist alone and for the first
time, in combination with Opdivo in advanced solid tumors.
Several presentations will report data from clinical collaborations
supportive of the Company’s efforts to advance understanding of the
potential role for Opdivo in combination with novel mechanisms of
action for several tumor types, including the first presentation of data
evaluating the safety and efficacy of Opdivo in combination with
epacadostat, Incyte’s selective IDO1 enzyme inhibitor. Presentations
featuring translational medicine research underscore Bristol-Myers
Squibb’s scientific leadership in driving understanding of how a
patient’s tumor biology can potentially guide treatment decisions.
Data from research on the Company’s medicines to be presented during the
meeting include:
Gastrointestinal Malignancies
-
Combination of nivolumab + ipilimumab in the treatment of patients
with deficient DNA mismatch repair/high microsatellite instability
metastatic colorectal cancer: CheckMate 142 study
Author:
Thierry Andre
Abstract #3531
Poster Session:
Gastrointestinal (Colorectal) Cancer
Saturday, June 3, 8:00–11:30
AM, Hall A
-
Concordance of DNA mismatch repair deficient/microsatellite
instability assessment by local and central testing in patients with
metastatic CRC receiving nivolumab in CheckMate 142
Author:
Scott Kopetz
Abstract #3548
Poster Session: Gastrointestinal
(Colorectal) Cancer
Saturday, June 3, 8:00–11:30 AM, Hall A
-
Nivolumab in sorafenib-naive and -experienced patients with
advanced hepatocellular carcinoma: The CheckMate 040 study
Author:
Todd S. Crocenzi
Abstract #4013
Poster Discussion Session:
Gastrointestinal (Noncolorectal) Cancer
Saturday, June 3,
8:00–11:30 AM, Hall A
Discussed at the Poster Discussion Session
on Saturday, June 3, 2017, 4:45–6:00 PM, Hall D2
-
CheckMate 577: A randomized, double-blind, phase 3 study of
adjuvant nivolumab or placebo in patients with resected esophageal or
gastroesophageal junction cancer
Author: Ronan Joseph Kelly
Abstract
#TPS4131
Poster Session: Gastrointestinal (Noncolorectal) Cancer
Saturday,
June 3, 8:00–11:30 AM, Hall A
-
CheckMate 649: A randomized, multicenter, open-label, phase 3 study
of nivolumab + ipilimumab or nivo + chemotherapy vs CTX alone in
patients with previously untreated advanced gastric or
gastroesophageal junction cancer
Author: Markus H. Moehler
Abstract
#TPS4132
Poster Session: Gastrointestinal (Noncolorectal) Cancer
Saturday,
June 3, 8:00–11:30 AM, Hall A
-
Nivolumab ± ipilimumab in patients with advanced/metastatic
chemotherapy-refractory gastric, esophageal or gastroesophageal
junction cancer: CheckMate 032 study
Author: Yelena Yuriy
Janjigian
Abstract #4014
Oral Abstract Session:
Gastrointestinal (Noncolorectal) Cancer
Sunday, June 4, 9:24–9:36
AM, Hall D2
Genitourinary Cancer
-
Health-related quality of life as a marker of treatment benefit
with nivolumab in platinum-refractory patients with metastatic or
unresectable urothelial carcinoma from CheckMate 275
Author:
Andrea Necchi
Abstract #4526
Poster Session: Genitourinary
(Nonprostate) Cancer
Sunday, June 4, 8:00–11:30 AM, Hall A
Glioblastoma
-
Histopathologic review of suspected disease progression in patients
with recurrent glioblastoma receiving nivolumab ± ipilimumab:
CheckMate 143
Author: Solmaz Sahebjam
Abstract #2001
Oral
Abstract Session: Central Nervous System Tumors
Sunday, June 4,
8:12–8:24 AM, S100a
-
Overall survival by line of therapy in Medicare-enrolled
glioblastoma multiforme patients
Author: Abdalla Aly
Abstract
#2039
Poster Session: Central Nervous System Tumors
Monday,
June 5, 1:15–4:45 PM, Hall A
Gynecologic Cancers
-
An open-label, multicohort, phase 1/2 study of nivolumab in
patients with virus-associated tumors (CheckMate 358): Efficacy and
safety in recurrent or metastatic cervical, vaginal and vulvar cancers
Author:
Antoine Hollebecque
Abstract #5504
Oral Abstract Session:
Gynecologic Cancer
Friday, June 2, 4:12–4:24 PM, S406
Head and Neck Cancer
-
Nivolumab vs investigator’s choice for platinum-refractory
recurrent or metastatic squamous cell carcinoma of the head and neck
(Checkmate 141): Outcomes in first-line R/M patients and updated
safety and efficacy
Author: Maura L. Gillison
Abstract
#6019
Poster Discussion Session: Head and Neck Cancer
Monday,
June 5, 1:15–4:45 PM, Hall A
Discussed at the Poster Discussion
Session on Monday, June 5, 2017, 4:45–6:00 PM, S406
-
Nivolumab vs investigator’s choice in patients with recurrent or
metastatic squamous cell carcinoma of the head and neck: Efficacy and
safety in CheckMate 141 by prior cetuximab use
Author: Robert
L. Ferris
Abstract #6020
Poster Discussion Session: Head and
Neck Cancer
Monday, June 5, 1:15–4:45 PM, Hall A
Discussed
at the Poster Discussion Session on Monday, June 5, 2017, 4:45–6:00
PM, S406
-
An open-label, multicohort, phase 1/2 study to evaluate nivolumab
in patients with virus-associated tumors (CheckMate 358): Efficacy and
safety in recurrent or metastatic nasopharyngeal carcinoma
Author:
Jean-Pierre Delord
Abstract #6025
Poster Session: Head and
Neck Cancer
Monday, June 5, 1:15–4:45 PM, Hall A
-
Characterization of potential predictive biomarkers of response to
nivolumab in CheckMate 141 in patients with squamous cell carcinoma of
the head and neck
Author: Fernando Concha-Benavente
Abstract
#6050
Poster Session: Head and Neck Cancer
Monday, June 5,
1:15–4:45 PM, Hall A
Hematologic Malignancies
-
Phase 2 trial of dasatinib in pediatric patients with chronic
myeloid leukemia in chronic phase
Author: Lia Gore
Abstract
#10511
Oral Abstract Session: Pediatric Oncology II
Monday,
June 5, 8:24–8:36 AM, S504
-
Impact of dose reductions on 5-year efficacy in newly diagnosed
patients with chronic myeloid leukemia in chronic phase from DASISION
Author:
Jorge E. Cortes
Abstract #7051
Poster Session: Hematologic
Malignancies—Leukemia, Myelodysplastic Syndromes, and Allotransplant
Monday,
June 5, 8:00–11:30 AM, Hall A
-
Phase 3 ELOQUENT-2 study: Extended four-year follow-up of
elotuzumab plus lenalidomide/dexamethasone vs Ld in
relapsed/refractory multiple myeloma
Author: Sagar Lonial
Abstract
#8028
Poster Session: Hematologic Malignancies—Plasma Cell
Dyscrasia
Monday, June 5, 8:00–11:30 AM, Hall A
-
Nivolumab in combination with daratumumab, with or without
pomalidomide and dexamethasone, for relapsed/refractory multiple
myeloma: 2 cohorts of the phase 1 CheckMate 039 safety study
Author:
Alexander M. Lesokhin
Abstract #TPS3102
Poster Session:
Developmental Therapeutics—Immunotherapy
Monday, June 5,
8:00–11:30 AM, Hall A
-
CheckMate 436: A phase 1/2 study to evaluate safety and efficacy of
nivolumab plus brentuximab vedotin in patients with CD30-expressing
relapsed/refractory non-Hodgkin lymphomas
Author: Paul M. Barr
Abstract
#TPS7577
Poster Session: Hematologic Malignancies—Lymphoma and
Chronic Lymphocytic Leukemia
Monday, June 5, 8:00–11:30 AM, Hall A
-
CheckMate 602: An open-label, randomized, phase 3 trial of
combinations of nivolumab, elotuzumab, pomalidomide and dexamethasone
in relapsed/refractory multiple myeloma
Author: Sagar Lonial
Abstract
#TPS8052
Poster Session: Hematologic Malignancies—Plasma Cell
Dyscrasia
Monday, June 5, 8:00–11:30 AM, Hall A
Melanoma
-
Overall survival analysis from an expanded access program of
nivolumab in combination with ipilimumab in patients with advanced
melanoma (CheckMate 218)
Author: David Hogg
Abstract
#9522
Poster Session: Melanoma/Skin Cancers
Saturday, June
3, 1:15–4:45 PM, Hall A
-
Association of distinct baseline tissue biomarkers with response to
nivolumab and ipilimumab in melanoma: CheckMate 064
Author:
Scott Rodig
Abstract #9515
Poster Discussion Session:
Melanoma/Skin Cancers
Saturday, June 3, 1:15–4:45 PM, Hall A
Discussed
at the Poster Discussion Session on Saturday, June 3, 2017, 4:45–6:00
PM, E354b
-
Management of gastrointestinal toxicity associated with nivolumab
plus ipilimumab (IPI) or IPI alone in phase 2 and 3 trials in advanced
melanoma
Author: Jeffrey S. Weber
Abstract #9523
Poster
Session: Melanoma/Skin Cancers
Saturday, June 3, 1:15–4:45 PM,
Hall A
-
Efficacy and safety of nivolumab in patients with advanced melanoma
and poor prognostic factors who progressed on or after ipilimumab:
Results from a phase 2 study (CheckMate 172)
Author: Dirk
Schadendorf
Abstract #9524
Poster Session: Melanoma/Skin
Cancers
Saturday, June 3, 1:15–4:45 PM, Hall A
-
Efficacy and safety of nivolumab plus ipilimumab in patients with
melanoma metastatic to the brain: Results of the phase 2 study
CheckMate 204
Author: Hussein Abdul-Hassan Tawbi
Abstract
#9507
Oral Abstract Session: Melanoma/Skin Cancers
Sunday,
June 4, 10:12–10:24 AM, Arie Crown Theater
Thoracic Malignancies
-
Nivolumab plus ipilimumab as first-line treatment for advanced
NSCLC: 2-year OS and long-term outcomes from CheckMate 012
Author:
Jonathan Wade Goldman
Abstract #9093
Poster Session: Lung
Cancer—Non-Small Cell Metastatic
Saturday, June 3, 8:00–11:30 AM,
Hall A
-
Checkmate 816: A phase 3, randomized, open-label trial of nivolumab
plus ipilimumab vs platinum-doublet chemotherapy as neoadjuvant
treatment for early-stage NSCLC
Author: Patrick M. Forde
Abstract
#TPS8577
Poster Session: Lung Cancer—Non-Small Cell
Local-Regional/Small Cell/Other Thoracic Cancers
Saturday, June
3, 8:00–11:30 AM, Hall A
-
Checkmate 743: A phase 3, randomized, open-label trial of nivolumab
plus ipilimumab vs pemetrexed plus cisplatin or carboplatin as
first-line therapy in unresectable pleural mesothelioma
Author:
Gerard Zalcman
Abstract #TPS8581
Poster Session: Lung
Cancer—Non-Small Cell Local-Regional/Small Cell/Other Thoracic Cancers
Saturday,
June 3, 8:00–11:30 AM, Hall A
-
Nivolumab ± ipilimumab in advanced small cell lung cancer: first
report of a randomized expansion cohort from CheckMate 032
Author:
Matthew David Hellmann
Abstract #8503
Oral Abstract Session:
Lung Cancer—Non-Small Cell Local-Regional/Small Cell/Other Thoracic
Cancers
Monday, June 5, 9:00–9:12 AM, Hall B1
Pipeline
-
FRACTION (Fast Real-time Assessment of Combination Therapies in
Immuno-ONcology)-gastric cancer (GC): A randomized, open-label,
adaptive phase 2 study of nivolumab in combination with other
immuno-oncology agents in patients with advanced GC
Author:
Praveen Aanur
Abstract #TPS4137
Poster Session:
Gastrointestinal (Noncolorectal) Cancer
Saturday, June 3,
8:00–11:30 AM, Hall A
-
Initial efficacy of anti-lymphocyte activation gene-3 (anti–LAG-3;
BMS-986016) in combination with nivolumab in patients with melanoma
previously treated with anti–PD-1/PD-L1 therapy
Author: Paolo
Antonio Ascierto
Abstract #9520
Poster Discussion Session:
Melanoma/Skin Cancers
Saturday, June 3, 1:15–4:45 PM, Hall A
Discussed
at the Poster Discussion Session on Saturday, June 3, 2017, 4:45–6:00
PM, E354b
-
Preliminary results of a phase 1/2a study of BMS-986156
(glucocorticoid-induced tumor necrosis factor receptor–related gene
[GITR] agonist), alone and in combination with nivolumab in patients
with advanced solid tumors
Author: Lillian L. Siu
Abstract
#104
Clinical Science Symposium: "Check" This Out: The Step
Beyond PD-1 Blockade
Sunday, June 4, 10:12–10:24 AM, Hall D1
Clinical Collaborations
-
Nivolumab + nab-paclitaxel + carboplatin in patients with non-small
cell lung cancer: Interim results from a multicenter phase 1 study
Author:
David Michael Waterhouse
Abstract #9095
Poster Session: Lung
Cancer—Non-Small Cell Metastatic
Saturday, June 3, 8:00–11:30 AM,
Hall A
-
Ceritinib plus nivolumab in patients with anaplastic lymphoma
kinase positive (ALK+) advanced non-small cell lung cancer
Author:
Enriqueta Felip
Abstract #2502
Oral Abstract Session:
Developmental Therapeutics—Clinical Pharmacology and Experimental
Therapeutics
Saturday, June 3, 1:39–1:51 PM, E450ab
-
Effect of a novel IL-2 cytokine immune agonist (NKTR-214) on
proliferating CD8+T cells and PD-1 expression on immune cells in the
tumor microenvironment in patients with prior checkpoint therapy
Author:
Chantale Bernatchez
Abstract #2545
Poster Session:
Developmental Therapeutics—Clinical Pharmacology and Experimental
Therapeutics
Monday, June 5, 8:00–11:30 AM, Hall A
-
A phase I study of enadenotucirev (EnAd), an oncolytic Ad11/Ad3
chimeric group B adenovirus, in combination with nivolumab in tumors
of epithelial origin
Author: Wael A. Harb
Abstract
#TPS3115
Poster Session: Developmental Therapeutics—Immunotherapy
Monday,
June 5, 8:00–11:30 AM, Hall A
-
Epacadostat plus nivolumab in patients with advanced solid tumors:
Preliminary phase 1/2 results of ECHO-204
Author: Raymond P.
Perez
Abstract #3003
Oral Abstract Session: Developmental
Therapeutics—Immunotherapy
Monday, June 5, 2:15–2:27 PM, Hall D1
-
Clinical results with combination of anti-CD27 agonist
antibody, varlilumab, with anti-PD1 antibody nivolumab in advanced
cancer patients
Author: Rachel E. Sanborn
Abstract #3007
Oral
Abstract Session: Developmental Therapeutics—Immunotherapy
Monday,
June 5, 3:27–3:39 PM, Hall D1
International Immuno-Oncology Network (II-ON)
-
Function and expression of checkpoint inhibitors and immune
agonists on immune cells in monoclonal gammopathy of undetermined
significance, smoldering multiple myeloma and MM and tumor-specific T
lymphocytes
Author: Jooeun Bae
Abstract #11577
Poster
Session: Tumor Biology
Saturday, June 3, 1:15–4:45 PM, Hall A
-
Loss-of-function of PBRM1 to predict response to anti-PD-1/PD-L1
therapy in metastatic renal cell carcinoma
Author: Diana Miao
Abstract
#3016
Poster Session: Developmental Therapeutics—Immunotherapy
Monday,
June 5, 8:00–11:30 AM, Hall A
Discussed at the Poster Discussion
Session on Monday, June 5, 2017, 4:45–6:00 PM, Hall D1
-
Metabolomic correlates of response in nivolumab-treated renal cell
carcinoma and melanoma patients
Author: Marios Giannakis
Abstract
#3036
Poster Session: Developmental Therapeutics—Immunotherapy
Monday,
June 5, 8:00–11:30 AM, Hall A
Bristol-Myers Squibb & Immuno-Oncology:
Advancing Oncology Research
At Bristol-Myers Squibb, patients are at the center of everything we do.
Our vision for the future of cancer care is focused on researching and
developing transformational Immuno-Oncology (I-O) medicines for
hard-to-treat cancers that could potentially improve outcomes for these
patients.
We are leading the scientific understanding of I-O through our extensive
portfolio of investigational compounds and approved agents. Our
differentiated clinical development program is studying broad patient
populations across more than 35 types of cancers with 14 clinical-stage
molecules designed to target different immune system pathways. Our deep
expertise and innovative clinical trial designs position us to advance
I-O/I-O, I-O/chemotherapy, I-O/targeted therapies and I-O/radiation
therapies across multiple tumors and potentially deliver the next wave
of therapies with a sense of urgency. We also continue to pioneer
research that will help facilitate a deeper understanding of the role of
immune biomarkers and how patients’ individual tumor biology can be used
as a guide for treatment decisions throughout their journey.
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 the International Immuno-Oncology Network
(II-ON)
The II-ON, formed in 2012, is a global peer-to-peer collaboration
between Bristol-Myers Squibb and academia advancing the science of
Immuno-Oncology (I-O) through a series of preclinical, translational and
biology-focused research objectives. The research in the collaboration
is focused on three fundamental scientific pillars: understanding the
mechanisms of resistance to immunotherapy; identifying patient
populations likely to benefit from immunotherapy; and exploring novel
combination therapies that may enhance anti-tumor response through
complementary mechanisms of action. The II-ON facilitates the
translation of scientific research findings into drug discovery and
development, with the goal of introducing new treatment options into
clinical practice.
In addition to Bristol-Myers Squibb, the II-ON currently comprises 15
leading cancer research institutions, including: Clinica Universidad
Navarra, Columbia University Medical Center, Dana-Farber Cancer
Institute, The Earle A. Chiles Research Institute (Providence Health &
Services), Institut Gustave Roussy, Istituto Nazionale per lo Studio e
la Cura dei Tumori “Fondazione G. Pascale”, Bloomberg-Kimmel Institute
for Cancer Immunotherapy at the Johns Hopkins Kimmel Cancer Center,
Memorial Sloan Kettering Cancer Center, National Cancer Center Japan,
The Netherlands Cancer Institute, Peter MacCallum Cancer Centre, The
Royal Marsden NHS Foundation Trust and The Institute of Cancer Research,
University College London, The University of Chicago and West German
Cancer Center/University Hospital Essen.
About Opdivo
Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor
that is designed to uniquely harness the body’s own immune system to
help restore anti-tumor immune response. By harnessing the body’s own
immune system to fight cancer, Opdivo has become an important
treatment option across multiple cancers.
Opdivo’s leading global development program is based on
Bristol-Myers Squibb’s scientific expertise in the field of
Immuno-Oncology and includes a broad range of clinical trials across all
phases, including Phase 3, in a variety of tumor types. To date, the Opdivo
clinical development program has enrolled more than 25,000 patients. The Opdivo
trials have contributed to gaining a deeper understanding of the
potential role of biomarkers in patient care, particularly regarding how
patients may benefit from Opdivo across the continuum of PD-L1
expression.
In July 2014, Opdivo was the first PD-1 immune checkpoint
inhibitor to receive regulatory approval anywhere in the world. Opdivo
is currently approved in more than 60 countries, including the United
States, the European Union and Japan. In October 2015, the company’s Opdivo
and Yervoy combination regimen was the first Immuno-Oncology
combination to receive regulatory approval for the treatment of
metastatic melanoma and is currently approved in more than 50 countries,
including the United States and the European Union.
U.S. FDA-APPROVED INDICATIONS FOR OPDIVO
®
OPDIVO® (nivolumab) as a single agent is indicated for the
treatment of patients with BRAF V600 mutation-positive unresectable or
metastatic melanoma. This indication is approved under accelerated
approval based on progression-free survival. Continued approval for this
indication may be contingent upon verification and description of
clinical benefit in the confirmatory trials.
OPDIVO® (nivolumab) as a single agent is indicated for the
treatment of patients with BRAF V600 wild-type unresectable or
metastatic melanoma.
OPDIVO® (nivolumab), in combination with YERVOY®
(ipilimumab), is indicated for the treatment of patients with
unresectable or metastatic melanoma. This indication is approved under
accelerated approval based on progression-free survival. Continued
approval for this indication may be contingent upon verification and
description of clinical benefit in the confirmatory trials.
OPDIVO® (nivolumab) is indicated for the treatment of
patients with metastatic non-small cell lung cancer (NSCLC) with
progression on or after platinum-based chemotherapy. Patients with EGFR
or ALK genomic tumor aberrations should have disease progression on
FDA-approved therapy for these aberrations prior to receiving OPDIVO.
OPDIVO® (nivolumab) is indicated for the treatment of
patients with advanced renal cell carcinoma (RCC) who have received
prior anti-angiogenic therapy.
OPDIVO® (nivolumab) 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.
OPDIVO® (nivolumab) is indicated for the treatment of
patients with recurrent or metastatic squamous cell carcinoma of the
head and neck (SCCHN) with disease progression on or after
platinum-based therapy.
OPDIVO® (nivolumab) is indicated for the treatment of
patients with locally advanced or metastatic urothelial carcinoma who
have disease progression during or following platinum-containing
chemotherapy or have disease progression within 12 months of neoadjuvant
or adjuvant treatment with platinum-containing chemotherapy. This
indication is approved under accelerated approval based on tumor
response rate and duration of response. Continued approval for this
indication may be contingent upon verification and description of
clinical benefit in confirmatory trials.
IMPORTANT SAFETY INFORMATION
WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS
YERVOY can result in severe and fatal immune-mediated adverse
reactions. These immune-mediated reactions may involve any organ system;
however, the most common severe immune-mediated adverse reactions are
enterocolitis, hepatitis, dermatitis (including toxic epidermal
necrolysis), neuropathy, and endocrinopathy. The majority of these
immune-mediated reactions initially manifested during treatment;
however, a minority occurred weeks to months after discontinuation of
YERVOY.
Assess patients for signs and symptoms of enterocolitis, dermatitis,
neuropathy, and endocrinopathy and evaluate clinical chemistries
including liver function tests (LFTs), adrenocorticotropic hormone
(ACTH) level, and thyroid function tests at baseline and before each
dose.
Permanently discontinue YERVOY and initiate systemic high-dose
corticosteroid therapy for severe immune-mediated reactions.
Immune-Mediated Pneumonitis
OPDIVO can cause immune-mediated pneumonitis. Fatal cases have been
reported. Monitor patients for signs with radiographic imaging and for
symptoms of pneumonitis. Administer corticosteroids for Grade 2 or more
severe pneumonitis. Permanently discontinue for Grade 3 or 4 and
withhold until resolution for Grade 2. In patients receiving OPDIVO
monotherapy, fatal cases of immune-mediated pneumonitis have occurred.
Immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients. In
patients receiving OPDIVO with YERVOY, immune-mediated pneumonitis
occurred in 6% (25/407) of patients.
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
OPDIVO can cause immune-mediated colitis. Monitor patients for signs and
symptoms of colitis. Administer corticosteroids for Grade 2 (of more
than 5 days duration), 3, or 4 colitis. Withhold OPDIVO monotherapy for
Grade 2 or 3 and permanently discontinue for Grade 4 or recurrent
colitis upon re-initiation of OPDIVO. When administered with YERVOY,
withhold OPDIVO and YERVOY for Grade 2 and permanently discontinue for
Grade 3 or 4 or recurrent colitis. In patients receiving OPDIVO
monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of
patients. In patients receiving OPDIVO with YERVOY, immune-mediated
colitis occurred in 26% (107/407) of patients including three fatal
cases.
In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening,
or fatal (diarrhea of ≥7 stools above baseline, fever, ileus, peritoneal
signs; Grade 3-5) immune-mediated enterocolitis occurred in 34 (7%)
patients. Across all YERVOY-treated patients in that study (n=511), 5
(1%) developed intestinal perforation, 4 (0.8%) died as a result of
complications, and 26 (5%) were hospitalized for severe enterocolitis.
Immune-Mediated Hepatitis
OPDIVO can cause immune-mediated hepatitis. Monitor patients for
abnormal liver tests prior to and periodically during treatment.
Administer corticosteroids for Grade 2 or greater transaminase
elevations. Withhold for Grade 2 and permanently discontinue for Grade 3
or 4 immune-mediated hepatitis. In patients receiving OPDIVO
monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of
patients. In patients receiving OPDIVO with YERVOY, immune-mediated
hepatitis occurred in 13% (51/407) of patients.
In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening,
or fatal hepatotoxicity (AST or ALT elevations >5x the ULN or total
bilirubin elevations >3x the ULN; Grade 3-5) occurred in 8 (2%)
patients, with fatal hepatic failure in 0.2% and hospitalization in 0.4%.
Immune-Mediated Neuropathies
In a separate Phase 3 study of YERVOY 3 mg/kg, 1 case of fatal
Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor
neuropathy were reported.
Immune-Mediated Endocrinopathies
OPDIVO can cause immune-mediated hypophysitis, immune-mediated adrenal
insufficiency, autoimmune thyroid disorders, and Type 1 diabetes
mellitus. Monitor patients for signs and symptoms of hypophysitis, signs
and symptoms of adrenal insufficiency, thyroid function prior to and
periodically during treatment, and hyperglycemia. Administer hormone
replacement as clinically indicated and corticosteroids for Grade 2 or
greater hypophysitis. Withhold for Grade 2 or 3 and permanently
discontinue for Grade 4 hypophysitis. Administer corticosteroids for
Grade 3 or 4 adrenal insufficiency. Withhold for Grade 2 and permanently
discontinue for Grade 3 or 4 adrenal insufficiency. Administer
hormone-replacement therapy for hypothyroidism. Initiate medical
management for control of hyperthyroidism. Withhold OPDIVO for Grade 3
and permanently discontinue for Grade 4 hyperglycemia.
In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6%
(12/1994) of patients. In patients receiving OPDIVO with YERVOY,
hypophysitis occurred in 9% (36/407) of patients. In patients receiving
OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994) of
patients. In patients receiving OPDIVO with YERVOY, adrenal
insufficiency occurred in 5% (21/407) of patients. In patients receiving
OPDIVO monotherapy, hypothyroidism or thyroiditis resulting in
hypothyroidism occurred in 9% (171/1994) of patients. Hyperthyroidism
occurred in 2.7% (54/1994) of patients receiving OPDIVO monotherapy. In
patients receiving OPDIVO with YERVOY, hypothyroidism or thyroiditis
resulting in hypothyroidism occurred in 22% (89/407) of patients.
Hyperthyroidism occurred in 8% (34/407) of patients receiving OPDIVO
with YERVOY. In patients receiving OPDIVO monotherapy, diabetes occurred
in 0.9% (17/1994) of patients. In patients receiving OPDIVO with YERVOY,
diabetes occurred in 1.5% (6/407) of patients.
In a separate Phase 3 study of YERVOY 3 mg/kg, severe to
life-threatening immune-mediated endocrinopathies (requiring
hospitalization, urgent medical intervention, or interfering with
activities of daily living; Grade 3-4) occurred in 9 (1.8%) patients.
All 9 patients had hypopituitarism, and some had additional concomitant
endocrinopathies such as adrenal insufficiency, hypogonadism, and
hypothyroidism. 6 of the 9 patients were hospitalized for severe
endocrinopathies.
Immune-Mediated Nephritis and Renal Dysfunction
OPDIVO can cause immune-mediated nephritis. Monitor patients for
elevated serum creatinine prior to and periodically during treatment.
Administer corticosteroids for Grades 2-4 increased serum creatinine.
Withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4
increased serum creatinine. In patients receiving OPDIVO monotherapy,
immune-mediated nephritis and renal dysfunction occurred in 1.2%
(23/1994) of patients. In patients receiving OPDIVO with YERVOY,
immune-mediated nephritis and renal dysfunction occurred in 2.2% (9/407)
of patients.
Immune-Mediated Skin Adverse Reactions and Dermatitis
OPDIVO can cause immune-mediated rash, including Stevens-Johnson
syndrome (SJS) and toxic epidermal necrolysis (TEN), some cases with
fatal outcome. Administer corticosteroids for Grade 3 or 4 rash.
Withhold for Grade 3 and permanently discontinue for Grade 4 rash. For
symptoms or signs of SJS or TEN, withhold OPDIVO and refer the patient
for specialized care for assessment and treatment; if confirmed,
permanently discontinue. In patients receiving OPDIVO monotherapy,
immune-mediated rash occurred in 9% (171/1994) of patients. In patients
receiving OPDIVO with YERVOY, immune-mediated rash occurred in 22.6%
(92/407) of patients.
In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening,
or fatal immune-mediated dermatitis (eg, Stevens-Johnson syndrome, toxic
epidermal necrolysis, or rash complicated by full thickness dermal
ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade
3-5) occurred in 13 (2.5%) patients. 1 (0.2%) patient died as a result
of toxic epidermal necrolysis. 1 additional patient required
hospitalization for severe dermatitis.
Immune-Mediated Encephalitis
OPDIVO can cause immune-mediated encephalitis. Evaluation of patients
with neurologic symptoms may include, but not be limited to,
consultation with a neurologist, brain MRI, and lumbar puncture.
Withhold OPDIVO in patients with new-onset moderate to severe neurologic
signs or symptoms and evaluate to rule out other causes. If other
etiologies are ruled out, administer corticosteroids and permanently
discontinue OPDIVO for immune-mediated encephalitis. In patients
receiving OPDIVO monotherapy, encephalitis occurred in 0.2% (3/1994) of
patients. Fatal limbic encephalitis occurred in one patient after 7.2
months of exposure despite discontinuation of OPDIVO and administration
of corticosteroids. Encephalitis occurred in one patient receiving
OPDIVO with YERVOY (0.2%) after 1.7 months of exposure.
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. Across clinical
trials of OPDIVO the following clinically significant immune-mediated
adverse reactions occurred in <1.0% of patients receiving OPDIVO:
uveitis, iritis, pancreatitis, facial and abducens nerve paresis,
demyelination, polymyalgia rheumatica, autoimmune neuropathy,
Guillain-Barré syndrome, hypopituitarism, systemic inflammatory response
syndrome, gastritis, duodenitis, sarcoidosis, histiocytic necrotizing
lymphadenitis (Kikuchi lymphadenitis), myositis, myocarditis,
rhabdomyolysis, motor dysfunction, vasculitis, and myasthenic syndrome.
Infusion Reactions
OPDIVO can cause severe infusion reactions, which have been reported in
<1.0% of patients in clinical trials. Discontinue OPDIVO in patients
with Grade 3 or 4 infusion reactions. Interrupt or slow the rate of
infusion in patients with Grade 1 or 2. In patients receiving OPDIVO
monotherapy, infusion-related reactions occurred in 6.4% (127/1994) of
patients. In patients receiving OPDIVO with YERVOY, infusion-related
reactions occurred in 2.5% (10/407) of patients.
Complications of Allogeneic HSCT after OPDIVO
Complications, including fatal events, occurred in patients who received
allogeneic HSCT after OPDIVO. Outcomes were evaluated in 17 patients
from Checkmate 205 and 039, who underwent allogeneic HSCT after
discontinuing OPDIVO (15 with reduced-intensity conditioning, 2 with
myeloablative conditioning). Thirty-five percent (6/17) of patients died
from complications of allogeneic HSCT after OPDIVO. Five deaths occurred
in the setting of severe or refractory GVHD. Grade 3 or higher acute
GVHD was reported in 29% (5/17) of patients. Hyperacute GVHD was
reported in 20% (n=2) of patients. A steroid-requiring febrile syndrome,
without an identified infectious cause, was reported in 35% (n=6) of
patients. Two cases of encephalitis were reported: Grade 3 (n=1)
lymphocytic encephalitis without an identified infectious cause, and
Grade 3 (n=1) suspected viral encephalitis. Hepatic veno-occlusive
disease (VOD) occurred in one patient, who received reduced-intensity
conditioned allogeneic HSCT and died of GVHD and multi-organ failure.
Other cases of hepatic VOD after reduced-intensity conditioned
allogeneic HSCT have also been reported in patients with lymphoma who
received a PD-1 receptor blocking antibody before transplantation. Cases
of fatal hyperacute GVHD have also been reported. These complications
may occur despite intervening therapy between PD-1 blockade and
allogeneic HSCT.
Follow patients closely for early evidence of transplant-related
complications such as hyperacute GVHD, severe (Grade 3 to 4) acute GVHD,
steroid-requiring febrile syndrome, hepatic VOD, and other
immune-mediated adverse reactions, and intervene promptly.
Embryo-Fetal Toxicity
Based on their mechanisms of action, OPDIVO and YERVOY can cause fetal
harm when administered to a pregnant woman. Advise pregnant women of the
potential risk to a fetus. Advise females of reproductive potential to
use effective contraception during treatment with an OPDIVO- or YERVOY-
containing regimen and for at least 5 months after the last dose of
OPDIVO.
Lactation
It is not known whether OPDIVO or YERVOY is present in human milk.
Because many drugs, including antibodies, are excreted in human milk and
because of the potential for serious adverse reactions in nursing
infants from an OPDIVO-containing regimen, advise women to discontinue
breastfeeding during treatment. Advise women to discontinue nursing
during treatment with YERVOY and for 3 months following the final dose.
Serious Adverse Reactions
In Checkmate 037, serious adverse reactions occurred in 41% of patients
receiving OPDIVO (n=268). Grade 3 and 4 adverse reactions occurred in
42% of patients receiving OPDIVO. The most frequent Grade 3 and 4
adverse drug reactions reported in 2% to <5% of patients receiving
OPDIVO were abdominal pain, hyponatremia, increased aspartate
aminotransferase, and increased lipase. In Checkmate 066, serious
adverse reactions occurred in 36% of patients receiving OPDIVO (n=206).
Grade 3 and 4 adverse reactions occurred in 41% of patients receiving
OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported in
≥2% of patients receiving OPDIVO were gamma-glutamyltransferase increase
(3.9%) and diarrhea (3.4%). In Checkmate 067, serious adverse reactions
(73% and 37%), adverse reactions leading to permanent discontinuation
(43% and 14%) or to dosing delays (55% and 28%), and Grade 3 or 4
adverse reactions (72% and 44%) all occurred more frequently in the
OPDIVO plus YERVOY arm (n=313) relative to the OPDIVO arm (n=313). The
most frequent (≥10%) serious adverse reactions in the OPDIVO plus YERVOY
arm and the OPDIVO arm, respectively, were diarrhea (13% and 2.6%),
colitis (10% and 1.6%), and pyrexia (10% and 0.6%). In Checkmate 017 and
057, serious adverse reactions occurred in 46% of patients receiving
OPDIVO (n=418). The most frequent serious adverse reactions reported in
at least 2% of patients receiving OPDIVO were pneumonia, pulmonary
embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and
respiratory failure. In Checkmate 025, serious adverse reactions
occurred in 47% of patients receiving OPDIVO (n=406). The most frequent
serious adverse reactions reported in ≥2% of patients were acute kidney
injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. In
Checkmate 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]).
In Checkmate 141, serious adverse reactions occurred in 49% of patients
receiving OPDIVO. The most frequent serious adverse reactions reported
in at least 2% of patients receiving OPDIVO were pneumonia, dyspnea,
respiratory failure, respiratory tract infections, and sepsis. In
Checkmate 275, serious adverse reactions occurred in 54% of patients
receiving OPDIVO (n=270). The most frequent serious adverse reactions
reported in at least 2% of patients receiving OPDIVO were urinary tract
infection, sepsis, diarrhea, small intestine obstruction, and general
physical health deterioration.
Common Adverse Reactions
In Checkmate 037, the most common adverse reaction (≥20%) reported with
OPDIVO (n=268) was rash (21%). In Checkmate 066, the most common adverse
reactions (≥20%) reported with OPDIVO (n=206) vs dacarbazine (n=205)
were fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash (28%
vs 12%), and pruritus (23% vs 12%). In Checkmate 067, the most common
(≥20%) adverse reactions in the OPDIVO plus YERVOY arm (n=313) were
fatigue (59%), rash (53%), diarrhea (52%), nausea (40%), pyrexia (37%),
vomiting (28%), and dyspnea (20%). The most common (≥20%) adverse
reactions in the OPDIVO (n=313) arm were fatigue (53%), rash (40%),
diarrhea (31%), and nausea (28%). In Checkmate 017 and 057, the most
common adverse reactions (≥20%) in patients receiving OPDIVO (n=418)
were fatigue, musculoskeletal pain, cough, dyspnea, and decreased
appetite. In Checkmate 025, the most common adverse reactions (≥20%)
reported in patients receiving OPDIVO (n=406) vs everolimus (n=397) were
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 (≥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 Checkmate 141, the most common adverse reactions (≥10%) in patients
receiving OPDIVO were cough and dyspnea at a higher incidence than
investigator’s choice. In Checkmate 275, the most common adverse
reactions (≥ 20%) reported in patients receiving OPDIVO (n=270) were
fatigue (46%), musculoskeletal pain (30%), nausea (22%), and decreased
appetite (22%).
In a separate Phase 3 study of YERVOY 3 mg/kg, the most common adverse
reactions (≥5%) in patients who received YERVOY at 3 mg/kg were fatigue
(41%), diarrhea (32%), pruritus (31%), rash (29%), and colitis (8%).
Checkmate Trials and Patient Populations
Checkmate 067 - advanced melanoma alone or in combination with
YERVOY; Checkmate 037 and 066 - advanced melanoma; Checkmate
017 - squamous non-small cell lung cancer (NSCLC); Checkmate 057
- non-squamous NSCLC; Checkmate 025 - renal cell carcinoma; Checkmate
205/039 - classical Hodgkin lymphoma; Checkmate 141 -
squamous cell carcinoma of the head and neck; Checkmate 275 -
urothelial carcinoma.
Please see U.S. Full Prescribing Information for OPDIVO
and YERVOY,
including Boxed WARNING regarding immune-mediated adverse reactions
for YERVOY.
About the Bristol-Myers Squibb and Ono
Pharmaceutical Co., Ltd. Collaboration
In 2011, through a collaboration agreement with Ono Pharmaceutical Co.,
Ltd (Ono), Bristol-Myers Squibb expanded its territorial rights to
develop and commercialize Opdivo globally except in Japan, South
Korea and Taiwan, where Ono had retained all rights to the compound at
the time. On July 23, 2014, Bristol-Myers Squibb and Ono further
expanded the companies’ strategic collaboration agreement to jointly
develop and commercialize multiple immunotherapies – as single agents
and combination regimens – for patients with cancer in Japan, South
Korea and Taiwan.
About 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.
U.S. FDA-APPROVED INDICATION FOR EMPLICITI
™
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. 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.
U.S. FDA-APPROVED INDICATIONS FOR SPRYCEL
®
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
-
H
2
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 for SPRYCEL.
About Bristol-Myers Squibb
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the cautionary factors discussion in Bristol-Myers Squibb's Annual
Report on Form 10-K for the year ended December 31, 2016, in our
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