Long-term data from Opdivo plus Yervoy-based
combinations demonstrate durable survival in metastatic non-small
cell lung cancer (NSCLC) and metastatic melanoma, including results
from landmark five-year analysis of CheckMate -227 in NSCLC
First disclosure from PILOT study of
Breyanzi in second-line large B-cell lymphoma underscores important
role of cell therapy earlier in treatment paradigm
New data from pivotal MEDALIST and BELIEVE
studies of Reblozyl in myelodysplastic syndromes and beta
thalassemia highlight long-term anemia control in serious myeloid
diseases
Data from pivotal RELATIVITY -047 trial
studying Opdualag reinforce efficacy of LAG-3 mechanism in advanced
melanoma
Bristol Myers Squibb (NYSE: BMY) today announced the
presentation of scientific research across cancers and blood
disorders at the 2022 American Society of Clinical Oncology (ASCO)
Annual Meeting and the European Hematology Association (EHA)
Congress that underscores the company’s commitment to delivering
transformational therapies for patients. Data from more than 140
company-sponsored studies, investigator-sponsored studies and
collaborations evaluating compounds across 28 cancer types and
blood disorders will be featured at the two meetings.
“We have made significant progress for patients with cancer and
blood disorders by delivering clinically meaningful and
differentiated treatment choices across modalities such as CAR T,
immunotherapy and erythroid maturation,” said Samit Hirawat, M.D.,
executive vice president, chief medical officer, Global Drug
Development, Bristol Myers Squibb. “Driven by our deep
understanding of human biology and leading scientific research, the
results being presented at ASCO and EHA will provide greater
insight into the potential for improving long-term outcomes, and
rationale for moving innovative interventions into earlier lines of
treatment. Beyond our data, we are focused on improving care for
all patients through our Health Equity Commitments, aimed at
increasing diversity in clinical trials, addressing health
disparities, and investing in training for racially and ethnically
diverse clinical investigators.”
Key data being presented by Bristol Myers Squibb at ASCO and
EHA 2022 include:
Solid Tumor
- Landmark five-year analysis of CheckMate -227, the longest
reported follow-up of a Phase 3 immunotherapy combination study in
first-line metastatic non-small cell lung cancer (NSCLC),
demonstrate long-term, durable survival outcomes with Opdivo
(nivolumab) plus Yervoy (ipilimumab).
- Three-year follow-up data from CheckMate -9LA reinforce the
long-term, durable survival outcomes of Opdivo plus Yervoy with two
cycles of chemotherapy, in the first-line treatment of patients
with metastatic NSCLC, including those with PD-L1 expression
<1%.
- Analyses from the CheckMate -816 trial highlight the
association between pathological response and improved event-free
survival in patients with resectable NSCLC treated with Opdivo plus
chemotherapy in the neoadjuvant setting.
- Overall survival and overall response rate data from the
RELATIVITY-047 trial evaluating Opdualag (nivolumab and
relatlimab-rmbw), the combination of nivolumab, a PD-1 blocking
antibody, and relatlimab, a LAG-3 blocking antibody, demonstrate
the clinical benefit of the company’s third distinct checkpoint
inhibitor in patients with advanced melanoma. These data were first
disclosed at the March ASCO Plenary Series.
- With the longest reported follow-up of median overall survival
from a Phase 3 advanced melanoma trial, seven and a half-year
survival results will be presented on the combination of Opdivo
plus Yervoy from CheckMate -067 in patients with advanced
melanoma.
Cell Therapy
- First disclosure of data from the PILOT study of Breyanzi
(liso-cel), in patients with relapsed or refractory large B-cell
lymphoma after one line of therapy who were not intended for
transplant, show substantial durable responses. A patient-reported
outcomes analysis from PILOT also showed treatment with Breyanzi
improved health-related quality of life measures for patients.
- Correlative analysis of characteristics of patients treated
with Abecma (ide-cel) in the KarMMa and KarMMa-2 clinical trials,
with CAR T product quality attributes, informs further insights
into potentially optimizing patient selection for CAR T
manufacturing and improving clinical outcomes.
Hematology
- Long-term data from pivotal MEDALIST and BELIEVE studies
highlight continued benefit of Reblozyl (luspatercept-aamt) for
patients with lower-risk myelodysplastic syndromes and
transfusion-dependent beta thalassemia (ASCO/EHA).
- Long-term survival results from the pivotal Phase 3 QUAZAR®
AML-001 study, highlight the survival benefit of Onureg
(azacitidine tablets) following intensive chemotherapy (EHA).
Early Assets
- First dose expansion data for Eisai and Bristol Myers Squibb's
co-developed antibody-drug conjugate MORAb-202, demonstrate
anti-tumor activity in platinum-resistant ovarian cancer patients
at two dose levels as well as benefits of exploration of body
surface area dosing to optimize safety.
- Data from Phase 1 studies of CC-99282, a cereblon E3 ligase
modulator (CELMoD®) agent, and CC-95251, an anti-signal regulatory
protein-alpha (SIRPα) antibody combined with rituximab, show
promising activity in patients with relapsed or refractory
non-Hodgkin lymphoma (EHA).
- Health-related quality of life data from the Phase 1/2 MM-001
study of iberdomide plus dexamethasone, underscore the potential of
CELMoD® compounds in patients with relapsed or refractory multiple
myeloma (EHA).
Summary of Presentations
Select Bristol Myers Squibb studies at the 2022 ASCO Annual
Meeting include:
Abstract Title
Author
Presentation Type/#
Session Title
Session Date/ Time
Acute Myeloid Leukemia
Health-related quality of life (HRQoL)
with enasidenib versus conventional care regimens in older patients
with late-stage mutant-IDH2 relapsed or refractory acute myeloid
leukemia (R/R AML).
Courtney DiNardo
Poster
Abstract #7032
Hematologic Malignancies—Leukemia,
Myelodysplastic Syndromes, and Allotransplant
Saturday, June 4, 2022: 9:00 AM - 12:00 PM
EDT
Assessing eligibility for non-intensive
chemotherapy (IC) randomized clinical trials (RCT) in patients
(pts) with newly diagnosed (ND) AML from the Connect Myeloid
Disease Registry.
Harry Erba
Poster
Abstract #7029
Hematologic Malignancies—Leukemia,
Myelodysplastic Syndromes, and Allotransplant
Saturday, June 4, 2022: 9:00 AM - 12:00 PM
EDT
Overall survival by IDH2 mutant allele
(R140 or R172) in patients with late-stage mutant-IDH2 relapsed or
refractory acute myeloid leukemia treated with enasidenib or
conventional care regimens in the phase 3 IDHENTIFY trial.
Stephane De Botton
Oral
Abstract #7005
Hematologic Malignancies—Leukemia,
Myelodysplastic Syndromes, and Allotransplant
Tuesday, June 7, 2022: 10:45 AM - 1:45 PM
EDT
Gastrointestinal
Nivolumab (NIVO) plus chemotherapy (chemo)
or ipilimumab (IPI) versus chemo as first-line (1L) treatment for
advanced esophageal squamous cell carcinoma (ESCC): Expanded
efficacy and safety analyses from CheckMate 648.
Ian Chau
Poster
Abstract
#4035
Gastrointestinal Cancer—Gastroesophageal,
Pancreatic, and Hepatobiliary
Saturday, June 4, 2022: 9:00 AM - 12:00 PM
EDT
Nivolumab (NIVO) ± ipilimumab (IPI) in
patients (pts) with microsatellite instability-high/mismatch
repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC):
Five-year follow-up from CheckMate 142.
Michael Overman
Poster
Abstract
#3510
Gastrointestinal Cancer—Colorectal and
Anal
Saturday, June 4, 2022: 9:00 AM - 12:00 PM
EDT
Genitourinary
Association between depth of response
(DepOR) and clinical outcomes: Exploratory analysis in patients
with previously untreated advanced renal cell carcinoma (aRCC) in
CheckMate 9ER.
Cristina Suarez
Oral
Abstract
#4501
Genitourinary Cancer—Kidney and
Bladder
Friday, June 3, 2022: 3:45 PM - 6:45 PM
EDT
The relationship between health-related
quality of life (HRQoL) and clinical outcomes in patients with
advanced renal cell carcinoma (aRCC) in CheckMate (CM) 214.
David Cella
Oral
Abstract
#4502
Genitourinary Cancer—Kidney and
Bladder
Friday, June 3, 2022: 3:45 PM - 6:45 PM
EDT
Racial differences in treatment patterns
and outcomes of first-line (1L) therapies for advanced renal cell
carcinoma (aRCC) in the real-world (RW) setting.
Daniel Geynisman
Poster
Abstract
#4548
Genitourinary Cancer—Kidney and
Bladder
Saturday, June 4, 2022: 2:15 PM - 5:15 PM
EDT
Prognostic value of the lung immune
prognostic index in patients with untreated advanced renal cell
carcinoma (aRCC) receiving nivolumab plus ipilimumab (N+I) or
sunitinib (SUN) in the CheckMate 214 trial.
Lucia Carril-Ajuria
Poster
Abstract
#4538
Genitourinary Cancer—Kidney and
Bladder
Saturday, June 4, 2022: 2:15 PM - 5:15 PM
EDT
Results for patients with muscle-invasive
bladder cancer (MIBC) in the CheckMate 274 trial.
Alfred Witjes
Poster
Abstract
#4585
Genitourinary Cancer—Kidney and
Bladder
Saturday, June 4, 2022: 2:15 PM - 5:15 PM
EDT
Melanoma
Nivolumab (NIVO) + relatlimab (RELA)
versus NIVO in previously untreated metastatic or unresectable
melanoma: OS and ORR by key subgroups from RELATIVITY-047.
Hussein A. Tawbi
Oral
Abstract
#9505
Melanoma/Skin Cancers
Sunday, June 5, 2022: 10:45 AM - 1:45 PM
EDT
Relatlimab and nivolumab versus nivolumab
in previously untreated metastatic or unresectable melanoma:
Overall survival and response rates from RELATIVITY-047
(CA224-047).
Georgina V. Long
Oral
Abstract #360385
ASCO Plenary Series: Rapid Abstract
Updates
Sunday, June 5, 2022: 5:30 PM - 7:00 PM
EDT
Long-term survival in advanced melanoma
for patients treated with nivolumab plus ipilimumab in CheckMate
067.
F. Stephen Hodi
Poster
Abstract
#9522
Melanoma/Skin Cancers
Monday, June 6, 2022: 2:15 PM - 5:15 PM
EDT
Outcomes in patients with resected stage
IIIA melanoma treated with adjuvant nivolumab or monitored with
observation: A real-world study.
Anna C. Pavlick
Online only
Online only
Online only
Multiple Myeloma
Pomalidomide, bortezomib, and
dexamethasone in lenalidomide-pretreated multiple myeloma: A
subanalysis of OPTIMISMM by frailty.
Albert Oriol Rocafiguera
Poster
Abstract #8024
Hematologic Malignancies—Plasma Cell
Dyscrasia
Saturday, June 4, 2022: 9:00 AM - 12:00 PM
EDT
Characteristics of long-surviving patients
with multiple myeloma: Over 12 years of follow-up in the Connect MM
Registry.
Howard R. Terebelo
Poster
Abstract #8027
Hematologic Malignancies—Plasma Cell
Dyscrasia
Saturday, June 4, 2022: 9:00 AM - 12:00 PM
EDT
Correlative analysis to define patient
profiles associated with manufacturing and clinical endpoints in
relapsed/refractory multiple myeloma (RRMM) patients treated with
idecabtagene vicleucel (ide-cel; bb2121), an anti-BCMA CAR T cell
therapy.
Julie Rytlewski
Poster
Abstract
#8021
Hematologic Malignancies—Plasma Cell
Dyscrasia
Saturday, June 4, 2022: 5:30 PM - 7:00 PM
EDT
Myelodysplastic Syndromes
Long-term utilization and benefit of
luspatercept in patients (pts) with lower-risk myelodysplastic
syndromes (LR-MDS) from the MEDALIST trial.
Pierre Fenaux
Poster
Abstract #7056
Hematologic Malignancies—Leukemia,
Myelodysplastic Syndromes, and Allotransplant
Saturday, June 4, 2022: 9:00 AM - 12:00 PM
EDT
Real-world erythropoiesis-stimulating
agent (ESA) treatment patterns and outcomes among U.S. patients
with lower-risk myelodysplastic syndromes (LR-MDS).
Sudipto Mukherjee
Online only
N/A
Online only
Clinical outcomes and healthcare resource
utilization (HCRU) in patients (pts) with lower-risk
myelodysplastic syndromes (LR-MDS) reinitiating
erythropoiesis-stimulating agents (ESAs) following previous ESA
treatment.
Guillermo Garcia-Manero
Online only
N/A
Online only
Lymphoma
Lisocabtagene maraleucel (liso-cel) as
second-line (2L) therapy for R/R large B-cell lymphoma (LBCL) in
patients (pt) not intended for hematopoietic stem cell
transplantation (HSCT): Primary analysis from the phase 2 PILOT
study.
Alison Sehgal
Poster
Abstract
#7062
Hematologic Malignancies—Leukemia,
Myelodysplastic Syndromes, and Allotransplant
Saturday, June 4, 2022: 9:00 AM - 12:00 PM
EDT
Lisocabtagene maraleucel (liso-cel) as
second-line (2L) treatment (tx) for R/R large B-cell lymphoma
(LBCL) in patients (pt) not intended for hematopoietic stem cell
transplantation (HSCT): Patient-reported outcomes (PRO) from the
phase 2 PILOT study.
Leo I. Gordon
Poster
Abstract #6567
Health Services Research and Quality
Improvement
Monday, June 6, 2022: 2:15 PM - 5:15 PM
EDT
Ovarian
Safety and efficacy of MORAb-202 in
patients (pts) with platinum-resistant ovarian cancer (PROC):
Results from the expansion part of a phase 1 trial.
Shin Nishio
Poster
Abstract
#5513
Gynecologic Cancer
Saturday, June 4, 2022: 5:30 PM - 7:00 PM
EDT
Dose optimization for MORAb-202, an
antibody-drug conjugate (ADC) highly selective for folate
receptor-alpha (FRα), using population pharmacokinetic (PPK) and
exposure-response (E-R) efficacy and safety analyses.
Seiichi Hayato
Poster
Abstract
#3090
Developmental Therapeutics-Molecularly
Targeted Agents and Tumor Biology
Sunday, June 5, 2022; 9:00 AM - 12:00 PM
EDT
Thoracic
Five-year survival outcomes with nivolumab
(NIVO) plus ipilimumab (IPI) versus chemotherapy (chemo) as
first-line (1L) treatment for metastatic non–small cell lung cancer
(NSCLC): Results from CheckMate 227.
Julie R. Brahmer
Poster
Abstract
#LBA9025
Lung Cancer—Non-Small Cell Metastatic
Monday, June 6, 2022: 9:00 AM - 12:00 PM
EDT
First-line (1L) nivolumab (NIVO) +
ipilimumab (IPI) + 2 cycles of chemotherapy (chemo) versus chemo
alone (4 cycles) in patients (pts) with metastatic non–small cell
lung cancer (NSCLC): 3-year update from CheckMate 9LA.
Luis G. Paz-Ares
Poster
Abstract
#LBA9026
Lung Cancer—Non-Small Cell Metastatic
Monday, June 6, 2022: 9:00 AM - 12:00 PM
EDT
Association of early tumor growth rate and
survival outcomes in first-line metastatic non–small cell lung
cancer (mNSCLC).
Antonio Tito Fojo
Poster
Abstract
#9063
Lung Cancer—Non-Small Cell Metastatic
Monday, June 6, 2022: 9:00 AM - 12:00 PM
EDT
Neoadjuvant nivolumab (NIVO) +
platinum-doublet chemotherapy (chemo) versus chemo for resectable
(IB–IIIA) non-small cell lung cancer (NSCLC): Association of
pathological regression with event-free survival (EFS) in CheckMate
816.
Mariano Provencio-Pulla
Poster
Abstract
#LBA8511
Lung Cancer—Non-Small Cell
Local-Regional/Small Cell/Other Thoracic Cancers
Monday, June 6, 2022: 12:30 PM - 2:00 PM
EDT
All abstracts except late-breaking abstracts will be available
on the ASCO website at 5:00 PM EDT on Thursday, May 26. All
late-breaking abstracts will be available on the ASCO website at
8:00 AM EDT on the day of the scientific session for the abstract
presentation.
Select Bristol Myers Squibb studies at the 2022 EHA Congress
include:
Abstract Title
Author
Presentation Type/#
Session Date/Time
Acute Myeloid Leukemia
Clinical and Biological Markers Associated
With Long-term Survival for Patients With Acute Myeloid Leukemia
(AML) in Remission After Chemotherapy in the QUAZAR AML-001 Trial
of Oral Azacitidine
Andrew Wei
Poster
Abstract #P498
Friday, June 10, 2022: 12:30 - 1:45 PM EDT
(6:30 - 7:45 PM CEST)
Real-World Efficacy Outcomes of Venetoclax
Plus Azacitidine vs. Intensive Chemotherapy for Induction Therapy
in Adult Patients with Acute Myeloid Leukemia
Amer Zeidan
Poster
Abstract #P570
Friday, June 10, 2022:
12:30 - 1:45 PM EDT (6:30 - 7:45 PM
CEST)
Oral Azacitidine vs. Midostaurin as
Maintenance Treatment for FLT3 Mutant Acute Myeloid Leukemia in
Complete Remission: An Indirect Treatment Comparison
Esther Natalie Olivia
Poster
Abstract #P571
Friday, June 10, 2022:
12:30 - 1:45 PM EDT (6:30 - 7:45 PM
CEST)
Beta thalassemia
Long-term Safety Results of the BELIEVE
Study of Luspatercept in Adults with Beta-thalassemia
Vip Viprakasit
Poster
Abstract #P1518
Friday, June 10, 2022:
12:30 - 1:45 PM EDT (6:30 - 7:45 PM
CEST)
Examining the Burden of Illness Associated
With Transfusion-Dependent Βeta-Thalassemia From the Patient's
Perspective
Russell L. Knoth
Poster
Abstract #P1741
Friday, June 10, 2022: 12:30 - 1:45 PM EDT
(6:30 - 7:45 PM CEST)
Systematic Literature Review of the Burden
of Illness and Outcome Analyses of Patients with Non-transfusion
Dependent Beta Thalassemia
Yesim Aydinok
Poster
Abstract #P1742
Friday, June 10, 2022:
12:30 - 1:45 PM EDT (6:30 - 7:45 PM
CEST)
Longer-term Analysis of Efficacy of
Luspatercept vs. Placebo in Patients with Transfusion-Dependent
Beta-thalassemia Enrolled in the BELIEVE Study
Maria Domenica Cappellini
Oral
Abstract #S270
Saturday, June 11, 2022: 12:30 - 1:45 PM
EDT (6:30 - 7:45 PM CEST)
Lymphoma
Accuracy of Predicting Long-Term Survival
of Chimeric Antigen Receptor (CAR) T Cell Therapies in Large B-Cell
Lymphoma (LBCL)
Elisabeth J.M Verburg-Baltussen
Poster
Abstract #P1744
Friday, June 10, 2022:
12:30 - 1:45 PM EDT (6:30 - 7:45 PM
CEST)
Treatment Patterns and Real-World Outcomes
in Patients (PT) with Large B-Cell Lymphoma (LBCL) who received
Second-Line (2L) Therapy
Matthew A. Lunning
Poster
Abstract #P1204
Friday, June 10, 2022:
12:30 - 1:45 PM EDT (6:30 - 7:45 PM
CEST)
Lisocabtagene Maraleucel (liso-cel) as
Second-Line Therapy for R/R Large B-Cell Lymphoma (LBCL) in
Patients not Intended for HSCT: Primary Analysis from the Phase 2
PILOT Study
Alison Sehgal
Oral
Abstract #S258
Saturday, June 11, 2022: 12:30 - 1:45 PM
EDT (6:30 - 7:45 PM CEST)
Clinical Activity of CC-99282, a Cereblon
E3 Ligase Modulator (CELMoD) Agent, in Patients (PTS) With
Relapsed/Refractory Non-Hodgkin Lymphoma (R/R NHL) – Results From a
Phase 1, Open-Label Study
Jean-Marie Michot
Oral
Abstract #S216
Sunday, June 12, 2022:
12:30 PM - 1:45 PM
EDT (6:30 - 7:45 PM CEST)
First Clinical Study of the Anti-Signal
Regulatory Protein-alpha (SIRPα) Antibody CC-95251 Combined With
Rituximab in Patients With Relapsed/Refractory (R/R) Non-Hodgkin
Lymphoma (NHL)
Paolo Strati
Oral
Abstract #S219
Sunday, June 12, 2022:
12:30 - 1:45 PM EDT (6:30 - 7:45 PM
CEST)
Multiple Myeloma
Tumor Profiling of Idecabtagene Vicleucel
(Ide-cel; bb2121) Patients in KarMMa Showed Comparable Responses in
Existing Molecular High-risk Subsets and Preliminary Gene Signature
of Durable Response
Nathan Martin
Poster
Abstract #P867
Friday, June 10,2022:
12:30 - 1:45 PM EDT (6:30 - 7:45 PM
CEST)
Health-Related Quality of Life in Patients
with Relapsed/Refractory Multiple Myeloma (RRMM) Treated with
Idecabtagene Vicleucel vs. Belantamab Mafodotin: a
Matching-Adjusted Indirect Comparison Study
Nina Shah
Poster
Abstract #P1740
Friday, June 10, 2022:
12:30 - 1:45 PM EDT (6:30 - 7:45 PM
CEST)
Biomarker Analysis to Support Dose
Optimization of Iberdomide as Monotherapy and in Combination with
Standard of Care Treatments for Multiple Myeloma From a Phase 1/2
Trial
Michael Amatangelo
Poster
Abstract #P865
Friday, June 10, 2022:
12:30 - 1:45 PM EDT (6:30 - 7:45 PM
CEST)
The EHA presentations will be available on
demand on Monday, June 20.
Bristol Myers Squibb: Creating a Better
Future for People with Cancer
Bristol Myers Squibb is inspired by a single vision —
transforming patients’ lives through science. The goal of the
company’s cancer research is to deliver medicines that offer each
patient a better, healthier life and to make cure a possibility.
Building on a legacy across a broad range of cancers that have
changed survival expectations for many, Bristol Myers Squibb
researchers are exploring new frontiers in personalized medicine,
and through innovative digital platforms, are turning data into
insights that sharpen their focus. Deep scientific expertise,
cutting-edge capabilities and discovery platforms enable the
company to look at cancer from every angle. Cancer can have a
relentless grasp on many parts of a patient’s life, and Bristol
Myers Squibb is committed to taking actions to address all aspects
of care, from diagnosis to survivorship. Because as a leader in
cancer care, Bristol Myers Squibb is working to empower all people
with cancer to have a better future.
OPDIVO Indications
OPDIVO® (nivolumab), as a single agent, is indicated for the
treatment of adult patients with unresectable or metastatic
melanoma.
OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab),
is indicated for the treatment of adult patients with unresectable
or metastatic melanoma.
OPDIVO® (nivolumab) is indicated for the adjuvant treatment of
adult patients with melanoma with involvement of lymph nodes or
metastatic disease who have undergone complete resection.
OPDIVO® (nivolumab), in combination with platinum-doublet
chemotherapy, is indicated as neoadjuvant treatment of adult
patients with resectable (tumors ≥4 cm or node positive) non-small
cell lung cancer (NSCLC).
OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab),
is indicated for the first-line treatment of adult patients with
metastatic non-small cell lung cancer (NSCLC) whose tumors express
PD-L1 (≥1%) as determined by an FDA-approved test, with no EGFR or
ALK genomic tumor aberrations.
OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab)
and 2 cycles of platinum-doublet chemotherapy, is indicated for the
first-line treatment of adult patients with metastatic or recurrent
non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic
tumor aberrations.
OPDIVO® (nivolumab) is indicated for the treatment of adult
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), in combination with YERVOY® (ipilimumab),
is indicated for the first-line treatment of adult patients with
unresectable malignant pleural mesothelioma (MPM).
OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab),
is indicated for the first-line treatment of adult patients with
intermediate or poor risk advanced renal cell carcinoma (RCC).
OPDIVO® (nivolumab), in combination with cabozantinib, is
indicated for the first-line treatment of adult patients with
advanced renal cell carcinoma (RCC).
OPDIVO® (nivolumab) is indicated for the treatment of adult
patients with advanced renal cell carcinoma (RCC) who have received
prior anti-angiogenic therapy.
OPDIVO® (nivolumab) is indicated for the treatment of adult
patients with classical Hodgkin lymphoma (cHL) that has relapsed or
progressed after autologous hematopoietic stem cell transplantation
(HSCT) and brentuximab vedotin or after 3 or more lines of systemic
therapy that includes autologous HSCT. This indication is approved
under accelerated approval based on overall response rate.
Continued approval for this indication may be contingent upon
verification and description of clinical benefit in confirmatory
trials.
OPDIVO® (nivolumab) is indicated for the treatment of adult
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 adult
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.
OPDIVO® (nivolumab), as a single agent, is indicated for the
adjuvant treatment of adult patients with urothelial carcinoma (UC)
who are at high risk of recurrence after undergoing radical
resection of UC.
OPDIVO® (nivolumab), as a single agent, is indicated for the
treatment of adult and pediatric (12 years and older) patients with
microsatellite instability-high (MSI-H) or mismatch repair
deficient (dMMR) metastatic colorectal cancer (CRC) that has
progressed following treatment with a fluoropyrimidine,
oxaliplatin, and irinotecan. This indication is approved under
accelerated approval based on overall response rate and duration of
response. Continued approval for this indication may be contingent
upon verification and description of clinical benefit in
confirmatory trials.
OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab),
is indicated for the treatment of adults and pediatric patients 12
years and older with microsatellite instability-high (MSI-H) or
mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC)
that has progressed following treatment with a fluoropyrimidine,
oxaliplatin, and irinotecan. This indication is approved under
accelerated approval based on overall response rate and duration of
response. Continued approval for this indication may be contingent
upon verification and description of clinical benefit in
confirmatory trials.
OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab),
is indicated for the treatment of adult patients with
hepatocellular carcinoma (HCC) who have been previously treated
with sorafenib. This indication is approved under accelerated
approval based on overall response rate and duration of response.
Continued approval for this indication may be contingent upon
verification and description of clinical benefit in the
confirmatory trials.
OPDIVO® (nivolumab) is indicated for the treatment of adult
patients with unresectable advanced, recurrent or metastatic
esophageal squamous cell carcinoma (ESCC) after prior
fluoropyrimidine- and platinum-based chemotherapy.
OPDIVO® (nivolumab) is indicated for the adjuvant treatment of
completely resected esophageal or gastroesophageal junction cancer
with residual pathologic disease in adult patients who have
received neoadjuvant chemoradiotherapy (CRT).
OPDIVO® (nivolumab), in combination with fluoropyrimidine- and
platinum- containing chemotherapy, is indicated for the treatment
of adult patients with advanced or metastatic gastric cancer,
gastroesophageal junction cancer, and esophageal
adenocarcinoma.
Important Safety
Information
Severe and Fatal Immune-Mediated Adverse Reactions
Immune-mediated adverse reactions listed herein may not include
all possible severe and fatal immune-mediated adverse
reactions.
Immune-mediated adverse reactions, which may be severe or fatal,
can occur in any organ system or tissue. While immune-mediated
adverse reactions usually manifest during treatment, they can also
occur after discontinuation of OPDIVO or YERVOY. Early
identification and management are essential to ensure safe use of
OPDIVO and YERVOY. Monitor for signs and symptoms that may be
clinical manifestations of underlying immune-mediated adverse
reactions. Evaluate clinical chemistries including liver enzymes,
creatinine, adrenocorticotropic hormone (ACTH) level, and thyroid
function at baseline and periodically during treatment with OPDIVO
and before each dose of YERVOY. In cases of suspected
immune-mediated adverse reactions, initiate appropriate workup to
exclude alternative etiologies, including infection. Institute
medical management promptly, including specialty consultation as
appropriate.
Withhold or permanently discontinue OPDIVO and YERVOY depending
on severity (please see section 2 Dosage and Administration in the
accompanying Full Prescribing Information). In general, if OPDIVO
or YERVOY interruption or discontinuation is required, administer
systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or
equivalent) until improvement to Grade 1 or less. Upon improvement
to Grade 1 or less, initiate corticosteroid taper and continue to
taper over at least 1 month. Consider administration of other
systemic immunosuppressants in patients whose immune-mediated
adverse reactions are not controlled with corticosteroid therapy.
Toxicity management guidelines for adverse reactions that do not
necessarily require systemic steroids (e.g., endocrinopathies and
dermatologic reactions) are discussed below.
Immune-Mediated Pneumonitis
OPDIVO and YERVOY can cause immune-mediated pneumonitis. The
incidence of pneumonitis is higher in patients who have received
prior thoracic radiation. In patients receiving OPDIVO monotherapy,
immune- mediated pneumonitis occurred in 3.1% (61/1994) of
patients, including Grade 4 (<0.1%), Grade 3 (0.9%), and Grade 2
(2.1%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg
every 3 weeks, immune-mediated pneumonitis occurred in 7% (31/456)
of patients, including Grade 4 (0.2%), Grade 3 (2.0%), and Grade 2
(4.4%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg
every 3 weeks, immune-mediated pneumonitis occurred in 3.9%
(26/666) of patients, including Grade 3 (1.4%) and Grade 2 (2.6%).
In NSCLC patients receiving OPDIVO 3 mg/kg every 2 weeks with
YERVOY 1 mg/kg every 6 weeks, immune-mediated pneumonitis occurred
in 9% (50/576) of patients, including Grade 4 (0.5%), Grade 3
(3.5%), and Grade 2 (4.0%). Four patients (0.7%) died due to
pneumonitis.
In Checkmate 205 and 039, pneumonitis, including interstitial
lung disease, occurred in 6.0% (16/266) of patients receiving
OPDIVO. Immune-mediated pneumonitis occurred in 4.9% (13/266) of
patients receiving OPDIVO, including Grade 3 (n=1) and Grade 2
(n=12).
Immune-Mediated Colitis
OPDIVO and YERVOY can cause immune-mediated colitis, which may
be fatal. A common symptom included in the definition of colitis
was diarrhea. Cytomegalovirus (CMV) infection/reactivation has been
reported in patients with corticosteroid-refractory immune-mediated
colitis. In cases of corticosteroid-refractory colitis, consider
repeating infectious workup to exclude alternative etiologies. In
patients receiving OPDIVO monotherapy, immune-mediated colitis
occurred in 2.9% (58/1994) of patients, including Grade 3 (1.7%)
and Grade 2 (1%). In patients receiving OPDIVO 1 mg/kg with YERVOY
3 mg/kg every 3 weeks, immune-mediated colitis occurred in 25%
(115/456) of patients, including Grade 4 (0.4%), Grade 3 (14%) and
Grade 2 (8%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1
mg/kg every 3 weeks, immune-mediated colitis occurred in 9%
(60/666) of patients, including Grade 3 (4.4%) and Grade 2
(3.7%).
Immune-Mediated Hepatitis and
Hepatotoxicity
OPDIVO and YERVOY can cause immune-mediated hepatitis. In
patients receiving OPDIVO monotherapy, immune-mediated hepatitis
occurred in 1.8% (35/1994) of patients, including Grade 4 (0.2%),
Grade 3 (1.3%), and Grade 2 (0.4%). In patients receiving OPDIVO 1
mg/kg with YERVOY 3 mg/kg every 3 weeks, immune- mediated hepatitis
occurred in 15% (70/456) of patients, including Grade 4 (2.4%),
Grade 3 (11%), and Grade 2 (1.8%). In patients receiving OPDIVO 3
mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated hepatitis
occurred in 7% (48/666) of patients, including Grade 4 (1.2%),
Grade 3 (4.9%), and Grade 2 (0.4%).
OPDIVO in combination with cabozantinib can cause hepatic
toxicity with higher frequencies of Grade 3 and 4 ALT and AST
elevations compared to OPDIVO alone. Consider more frequent
monitoring of liver enzymes as compared to when the drugs are
administered as single agents. In patients receiving OPDIVO and
cabozantinib, Grades 3 and 4 increased ALT or AST were seen in 11%
of patients.
Immune-Mediated
Endocrinopathies
OPDIVO and YERVOY can cause primary or secondary adrenal
insufficiency, immune-mediated hypophysitis, immune-mediated
thyroid disorders, and Type 1 diabetes mellitus, which can present
with diabetic ketoacidosis. Withhold OPDIVO and YERVOY depending on
severity (please see section 2 Dosage and Administration in the
accompanying Full Prescribing Information). For Grade 2 or higher
adrenal insufficiency, initiate symptomatic treatment, including
hormone replacement as clinically indicated. Hypophysitis can
present with acute symptoms associated with mass effect such as
headache, photophobia, or visual field defects. Hypophysitis can
cause hypopituitarism; initiate hormone replacement as clinically
indicated. Thyroiditis can present with or without endocrinopathy.
Hypothyroidism can follow hyperthyroidism; initiate hormone
replacement or medical management as clinically indicated. Monitor
patients for hyperglycemia or other signs and symptoms of diabetes;
initiate treatment with insulin as clinically indicated.
In patients receiving OPDIVO monotherapy, adrenal insufficiency
occurred in 1% (20/1994), including Grade 3 (0.4%) and Grade 2
(0.6%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg
every 3 weeks, adrenal insufficiency occurred in 8% (35/456),
including Grade 4 (0.2%), Grade 3 (2.4%), and Grade 2 (4.2%). In
patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3
weeks, adrenal insufficiency occurred in 7% (48/666) of patients,
including Grade 4 (0.3%), Grade 3 (2.5%), and Grade 2 (4.1%). In
patients receiving OPDIVO and cabozantinib, adrenal insufficiency
occurred in 4.7% (15/320) of patients, including Grade 3 (2.2%) and
Grade 2 (1.9%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3
mg/kg every 3 weeks, adrenal insufficiency occurred in 8% (35/456),
including Grade 4 (0.2%), Grade 3 (2.4%), and Grade 2 (4.2%). In
patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3
weeks, adrenal insufficiency occurred in 7% (48/666) of patients,
including Grade 4 (0.3%), Grade 3 (2.5%), and Grade 2 (4.1%). In
patients receiving OPDIVO and cabozantinib, adrenal insufficiency
occurred in 4.7% (15/320) of patients, including Grade 3 (2.2%) and
Grade 2 (1.9%).
In patients receiving OPDIVO monotherapy, hypophysitis occurred
in 0.6% (12/1994) of patients, including Grade 3 (0.2%) and Grade 2
(0.3%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg
every 3 weeks, hypophysitis occurred in 9% (42/456), including
Grade 3 (2.4%) and Grade 2 (6%). In patients receiving OPDIVO 3
mg/kg with YERVOY 1 mg/kg every 3 weeks, hypophysitis occurred in
4.4% (29/666) of patients, including Grade 4 (0.3%), Grade 3
(2.4%), and Grade 2 (0.9%).
In patients receiving OPDIVO monotherapy, thyroiditis occurred
in 0.6% (12/1994) of patients, including Grade 2 (0.2%). In
patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3
weeks, thyroiditis occurred in 2.7% (22/666) of patients, including
Grade 3 (4.5%) and Grade 2 (2.2%).
In patients receiving OPDIVO monotherapy, hyperthyroidism
occurred in 2.7% (54/1994) of patients, including Grade 3
(<0.1%) and Grade 2 (1.2%). In patients receiving OPDIVO 1 mg/kg
with YERVOY 3 mg/kg every 3 weeks, hyperthyroidism occurred in 9%
(42/456) of patients, including Grade 3 (0.9%) and Grade 2 (4.2%).
In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3
weeks, hyperthyroidism occurred in 12% (80/666) of patients,
including Grade 3 (0.6%) and Grade 2 (4.5%).
In patients receiving OPDIVO monotherapy, hypothyroidism
occurred in 8% (163/1994) of patients, including Grade 3 (0.2%) and
Grade 2 (4.8%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3
mg/kg every 3 weeks, hypothyroidism occurred in 20% (91/456) of
patients, including Grade 3 (0.4%) and Grade 2 (11%). In patients
receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks,
hypothyroidism occurred in 18% (122/666) of patients, including
Grade 3 (0.6%) and Grade 2 (11%).
In patients receiving OPDIVO monotherapy, diabetes occurred in
0.9% (17/1994) of patients, including Grade 3 (0.4%) and Grade 2
(0.3%), and 2 cases of diabetic ketoacidosis. In patients receiving
OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, diabetes occurred
in 2.7% (15/666) of patients, including Grade 4 (0.6%), Grade 3
(0.3%), and Grade 2 (0.9%).
Immune-Mediated Nephritis with Renal
Dysfunction
OPDIVO and YERVOY can cause immune-mediated nephritis. In
patients receiving OPDIVO monotherapy, immune-mediated nephritis
and renal dysfunction occurred in 1.2% (23/1994) of patients,
including Grade 4 (<0.1%), Grade 3 (0.5%), and Grade 2 (0.6%).
In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3
weeks, immune-mediated nephritis with renal dysfunction occurred in
4.1% (27/666) of patients, including Grade 4 (0.6%), Grade 3
(1.1%), and Grade 2 (2.2%).
Immune-Mediated Dermatologic Adverse
Reactions
OPDIVO can cause immune-mediated rash or dermatitis. Exfoliative
dermatitis, including Stevens-Johnson syndrome (SJS), toxic
epidermal necrolysis (TEN), and drug rash with eosinophilia and
systemic symptoms (DRESS) has occurred with PD-1/PD-L1 blocking
antibodies. Topical emollients and/or topical corticosteroids may
be adequate to treat mild to moderate nonexfoliative rashes.
YERVOY can cause immune-mediated rash or dermatitis, including
bullous and exfoliative dermatitis, SJS, TEN, and DRESS. Topical
emollients and/or topical corticosteroids may be adequate to treat
mild to moderate non- bullous/exfoliative rashes.
Withhold or permanently discontinue OPDIVO and YERVOY depending
on severity (please see section 2 Dosage and Administration in the
accompanying Full Prescribing Information).
In patients receiving OPDIVO monotherapy, immune-mediated rash
occurred in 9% (171/1994) of patients, including Grade 3 (1.1%) and
Grade 2 (2.2%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3
mg/kg every 3 weeks, immune-mediated rash occurred in 28% (127/456)
of patients, including Grade 3 (4.8%) and Grade 2 (10%). In
patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3
weeks, immune-mediated rash occurred in 16% (108/666) of patients,
including Grade 3 (3.5%) and Grade 2 (4.2%).
Other Immune-Mediated Adverse
Reactions
The following clinically significant immune-mediated adverse
reactions occurred at an incidence of <1% (unless otherwise
noted) in patients who received OPDIVO monotherapy or OPDIVO in
combination with YERVOY or were reported with the use of other
PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been
reported for some of these adverse reactions: cardiac/vascular:
myocarditis, pericarditis, vasculitis; nervous system: meningitis,
encephalitis, myelitis and demyelination, myasthenic
syndrome/myasthenia gravis (including exacerbation), Guillain-Barré
syndrome, nerve paresis, autoimmune neuropathy; ocular: uveitis,
iritis, and other ocular inflammatory toxicities can occur;
gastrointestinal: pancreatitis to include increases in serum
amylase and lipase levels, gastritis, duodenitis; musculoskeletal
and connective tissue: myositis/polymyositis, rhabdomyolysis, and
associated sequelae including renal failure, arthritis, polymyalgia
rheumatica; endocrine: hypoparathyroidism; other
(hematologic/immune): hemolytic anemia, aplastic anemia,
hemophagocytic lymphohistiocytosis (HLH), systemic inflammatory
response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi
lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid
organ transplant rejection.
In addition to the immune-mediated adverse reactions listed
above, across clinical trials of YERVOY monotherapy or in
combination with OPDIVO, the following clinically significant
immune-mediated adverse reactions, some with fatal outcome,
occurred in <1% of patients unless otherwise specified: nervous
system: autoimmune neuropathy (2%), myasthenic syndrome/myasthenia
gravis, motor dysfunction; cardiovascular: angiopathy, temporal
arteritis; ocular: blepharitis, episcleritis, orbital myositis,
scleritis; gastrointestinal: pancreatitis (1.3%); other
(hematologic/immune): conjunctivitis, cytopenias (2.5%),
eosinophilia (2.1%), erythema multiforme, hypersensitivity
vasculitis, neurosensory hypoacusis, psoriasis.
Some ocular IMAR cases can be associated with retinal
detachment. Various grades of visual impairment, including
blindness, can occur. If uveitis occurs in combination with other
immune-mediated adverse reactions, consider a
Vogt-Koyanagi-Harada–like syndrome, which has been observed in
patients receiving OPDIVO and YERVOY, as this may require treatment
with systemic corticosteroids to reduce the risk of permanent
vision loss.
Infusion-Related Reactions
OPDIVO and YERVOY can cause severe infusion-related reactions.
Discontinue OPDIVO and YERVOY in patients with severe (Grade 3) or
life-threatening (Grade 4) infusion-related reactions. Interrupt or
slow the rate of infusion in patients with mild (Grade 1) or
moderate (Grade 2) infusion-related reactions. In patients
receiving OPDIVO monotherapy as a 60-minute infusion,
infusion-related reactions occurred in 6.4% (127/1994) of patients.
In a separate trial in which patients received OPDIVO monotherapy
as a 60-minute infusion or a 30- minute infusion, infusion-related
reactions occurred in 2.2% (8/368) and 2.7% (10/369) of patients,
respectively. Additionally, 0.5% (2/368) and 1.4% (5/369) of
patients, respectively, experienced adverse reactions within 48
hours of infusion that led to dose delay, permanent discontinuation
or withholding of OPDIVO. In melanoma patients receiving OPDIVO 1
mg/kg with YERVOY 3 mg/kg every 3 weeks, infusion-related reactions
occurred in 2.5% (10/407) of patients. In HCC patients receiving
OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, infusion-related
reactions occurred in 8% (4/49) of patients. In RCC patients
receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks,
infusion-related reactions occurred in 5.1% (28/547) of patients.
In MSI- H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1
mg/kg every 3 weeks, infusion-related reactions occurred in 4.2%
(5/119) of patients. In MPM patients receiving OPDIVO 3 mg/kg every
2 weeks with YERVOY 1 mg/kg every 6 weeks, infusion-related
reactions occurred in 12% (37/300) of patients.
Complications of Allogeneic Hematopoietic Stem Cell
Transplantation
Fatal and other serious complications can occur in patients who
receive allogeneic hematopoietic stem cell transplantation (HSCT)
before or after being treated with OPDIVO or YERVOY.
Transplant-related complications include hyperacute
graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic
veno-occlusive disease (VOD) after reduced intensity conditioning,
and steroid-requiring febrile syndrome (without an identified
infectious cause). These complications may occur despite
intervening therapy between OPDIVO or YERVOY and allogeneic
HSCT.
Follow patients closely for evidence of transplant-related
complications and intervene promptly. Consider the benefit versus
risks of treatment with OPDIVO and YERVOY prior to or after an
allogeneic HSCT.
Embryo-Fetal Toxicity
Based on its mechanism of action and findings from animal
studies, OPDIVO and YERVOY can cause fetal harm when administered
to a pregnant woman. The effects of YERVOY are likely to be greater
during the second and third trimesters of pregnancy. Advise
pregnant women of the potential risk to a fetus. Advise females of
reproductive potential to use effective contraception during
treatment with OPDIVO and YERVOY and for at least 5 months after
the last dose.
Increased Mortality in Patients with Multiple Myeloma when
OPDIVO is Added to a Thalidomide Analogue and Dexamethasone
In randomized clinical trials in patients with multiple myeloma,
the addition of OPDIVO to a thalidomide analogue plus dexamethasone
resulted in increased mortality. Treatment of patients with
multiple myeloma with a PD-1 or PD-L1 blocking antibody in
combination with a thalidomide analogue plus dexamethasone is not
recommended outside of controlled clinical trials.
Lactation
There are no data on the presence of OPDIVO or YERVOY in human
milk, the effects on the breastfed child, or the effects on milk
production. Because of the potential for serious adverse reactions
in breastfed children, advise women not to breastfeed during
treatment and for 5 months after the last 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 (74%
and 44%), adverse reactions leading to permanent discontinuation
(47% and 18%) or to dosing delays (58% and 36%), and Grade 3 or 4
adverse reactions (72% and 51%) 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 2.2%), colitis (10% and 1.9%), and pyrexia (10% and 1.0%).
In Checkmate 238, serious adverse reactions occurred in 18% of
patients receiving OPDIVO (n=452). Grade 3 or 4 adverse reactions
occurred in 25% of OPDIVO-treated patients (n=452). The most
frequent Grade 3 and 4 adverse reactions reported in ≥2% of
OPDIVO-treated patients were diarrhea and increased lipase and
amylase. In Checkmate 816, serious adverse reactions occurred in
30% of patients (n=176) who were treated with OPDIVO in combination
with platinum-doublet chemotherapy. Serious adverse reactions in
>2% included pneumonia and vomiting. No fatal adverse reactions
occurred in patients who received OPDIVO in combination with
platinum-doublet chemotherapy. In Checkmate 227, serious adverse
reactions occurred in 58% of patients (n=576). The most frequent
(≥2%) serious adverse reactions were pneumonia, diarrhea/colitis,
pneumonitis, hepatitis, pulmonary embolism, adrenal insufficiency,
and hypophysitis. Fatal adverse reactions occurred in 1.7% of
patients; these included events of pneumonitis (4 patients),
myocarditis, acute kidney injury, shock, hyperglycemia,
multi-system organ failure, and renal failure. In Checkmate 9LA,
serious adverse reactions occurred in 57% of patients (n=358). The
most frequent (>2%) serious adverse reactions were pneumonia,
diarrhea, febrile neutropenia, anemia, acute kidney injury,
musculoskeletal pain, dyspnea, pneumonitis, and respiratory
failure. Fatal adverse reactions occurred in 7 (2%) patients, and
included hepatic toxicity, acute renal failure, sepsis,
pneumonitis, diarrhea with hypokalemia, and massive hemoptysis in
the setting of thrombocytopenia. 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
≥2% of patients receiving OPDIVO were pneumonia, pulmonary
embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and
respiratory failure. In Checkmate 057, fatal adverse reactions
occurred; these included events of infection (7 patients, including
one case of Pneumocystis jirovecii pneumonia), pulmonary embolism
(4 patients), and limbic encephalitis (1 patient). In Checkmate
743, serious adverse reactions occurred in 54% of patients
receiving OPDIVO plus YERVOY. The most frequent serious adverse
reactions reported in ≥2% of patients were pneumonia, pyrexia,
diarrhea, pneumonitis, pleural effusion, dyspnea, acute kidney
injury, infusion-related reaction, musculoskeletal pain, and
pulmonary embolism. Fatal adverse reactions occurred in 4 (1.3%)
patients and included pneumonitis, acute heart failure, sepsis, and
encephalitis. In Checkmate 214, serious adverse reactions occurred
in 59% of patients receiving OPDIVO plus YERVOY (n=547). The most
frequent serious adverse reactions reported in ≥2% of patients were
diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute
kidney injury, dyspnea, adrenal insufficiency, and colitis. In
Checkmate 9ER, serious adverse reactions occurred in 48% of
patients receiving OPDIVO and cabozantinib (n=320). The most
frequent serious adverse reactions reported in ≥2% of patients were
diarrhea, pneumonia, pneumonitis, pulmonary embolism, urinary tract
infection, and hyponatremia. Fatal intestinal perforations occurred
in 3 (0.9%) patients. 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, adverse reactions leading
to discontinuation occurred in 7% and dose delays due to adverse
reactions occurred in 34% of patients (n=266). Serious adverse
reactions occurred in 26% of patients. The most frequent serious
adverse reactions reported in ≥1% of patients were pneumonia,
infusion-related reaction, pyrexia, colitis or diarrhea, pleural
effusion, pneumonitis, and rash. Eleven patients died from causes
other than disease progression: 3 from adverse reactions within 30
days of the last OPDIVO dose, 2 from infection 8 to 9 months after
completing OPDIVO, and 6 from complications of allogeneic HSCT. In
Checkmate 141, serious adverse reactions occurred in 49% of
patients receiving OPDIVO (n=236). The most frequent serious
adverse reactions reported in ≥2% of patients receiving OPDIVO were
pneumonia, dyspnea, respiratory failure, respiratory tract
infection, and sepsis. In Checkmate 275, serious adverse reactions
occurred in 54% of patients receiving OPDIVO (n=270). The most
frequent serious adverse reactions reported in ≥2% of patients
receiving OPDIVO were urinary tract infection, sepsis, diarrhea,
small intestine obstruction, and general physical health
deterioration. In Checkmate 274, serious adverse reactions occurred
in 30% of patients receiving OPDIVO (n=351). The most frequent
serious adverse reaction reported in ≥2% of patients receiving
OPDIVO was urinary tract infection. Fatal adverse reactions
occurred in 1% of patients; these included events of pneumonitis
(0.6%). In Checkmate 142 in MSI-H/dMMR mCRC patients receiving
OPDIVO with YERVOY (n=119), serious adverse reactions occurred in
47% of patients. The most frequent serious adverse reactions
reported in ≥2% of patients were colitis/diarrhea, hepatic events,
abdominal pain, acute kidney injury, pyrexia, and dehydration. In
Checkmate 040, serious adverse reactions occurred in 59% of
patients receiving OPDIVO with YERVOY (n=49). Serious adverse
reactions reported in ≥4% of patients were pyrexia, diarrhea,
anemia, increased AST, adrenal insufficiency, ascites, esophageal
varices hemorrhage, hyponatremia, increased blood bilirubin, and
pneumonitis. In Attraction-3, serious adverse reactions occurred in
38% of patients receiving OPDIVO (n=209). Serious adverse reactions
reported in ≥2% of patients who received OPDIVO were pneumonia,
esophageal fistula, interstitial lung disease, and pyrexia. The
following fatal adverse reactions occurred in patients who received
OPDIVO: interstitial lung disease or pneumonitis (1.4%), pneumonia
(1.0%), septic shock (0.5%), esophageal fistula (0.5%),
gastrointestinal hemorrhage (0.5%), pulmonary embolism (0.5%), and
sudden death (0.5%). In Checkmate 577, serious adverse reactions
occurred in 33% of patients receiving OPDIVO (n=532). A serious
adverse reaction reported in ≥2% of patients who received OPDIVO
was pneumonitis. A fatal reaction of myocardial infarction occurred
in one patient who received OPDIVO. In Checkmate 649, serious
adverse reactions occurred in 52% of patients treated with OPDIVO
in combination with chemotherapy (n=782). The most frequent serious
adverse reactions reported in ≥2% of patients treated with OPDIVO
in combination with chemotherapy were vomiting (3.7%), pneumonia
(3.6%), anemia (3.6%), pyrexia (2.8%), diarrhea (2.7%), febrile
neutropenia (2.6%), and pneumonitis (2.4%). Fatal adverse reactions
occurred in 16 (2.0%) patients who were treated with OPDIVO in
combination with chemotherapy; these included pneumonitis (4
patients), febrile neutropenia (2 patients), stroke (2 patients),
gastrointestinal toxicity, intestinal mucositis, septic shock,
pneumonia, infection, gastrointestinal bleeding, mesenteric vessel
thrombosis, and disseminated intravascular coagulation.
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 (62%), diarrhea (54%),
rash (53%), nausea (44%), pyrexia (40%), pruritus (39%),
musculoskeletal pain (32%), vomiting (31%), decreased appetite
(29%), cough (27%), headache (26%), dyspnea (24%), upper
respiratory tract infection (23%), arthralgia (21%), and increased
transaminases (25%). In Checkmate 067, the most common (≥20%)
adverse reactions in the OPDIVO arm (n=313) were fatigue (59%),
rash (40%), musculoskeletal pain (42%), diarrhea (36%), nausea
(30%), cough (28%), pruritus (27%), upper respiratory tract
infection (22%), decreased appetite (22%), headache (22%),
constipation (21%), arthralgia (21%), and vomiting (20%). In
Checkmate 238, the most common adverse reactions (≥20%) reported in
OPDIVO- treated patients (n=452) vs ipilimumab-treated patients
(n=453) were fatigue (57% vs 55%), diarrhea (37% vs 55%), rash (35%
vs 47%), musculoskeletal pain (32% vs 27%), pruritus (28% vs 37%),
headache (23% vs 31%), nausea (23% vs 28%), upper respiratory
infection (22% vs 15%), and abdominal pain (21% vs 23%). The most
common immune-mediated adverse reactions were rash (16%),
diarrhea/colitis (6%), and hepatitis (3%). In Checkmate 816, the
most common (>20%) adverse reactions in the OPDIVO plus
chemotherapy arm (n=176) were nausea (38%), constipation (34%),
fatigue (26%), decreased appetite (20%), and rash (20%). In
Checkmate 227, the most common (≥20%) adverse reactions were
fatigue (44%), rash (34%), decreased appetite (31%),
musculoskeletal pain (27%), diarrhea/colitis (26%), dyspnea (26%),
cough (23%), hepatitis (21%), nausea (21%), and pruritus (21%). In
Checkmate 9LA, the most common (>20%) adverse reactions were
fatigue (49%), musculoskeletal pain (39%), nausea (32%), diarrhea
(31%), rash (30%), decreased appetite (28%), constipation (21%),
and pruritus (21%). 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 743, the most common adverse reactions
(≥20%) in patients receiving OPDIVO plus YERVOY were fatigue (43%),
musculoskeletal pain (38%), rash (34%), diarrhea (32%), dyspnea
(27%), nausea (24%), decreased appetite (24%), cough (23%), and
pruritus (21%). In Checkmate 214, the most common adverse reactions
(≥20%) reported in patients treated with OPDIVO plus YERVOY (n=547)
were fatigue (58%), rash (39%), diarrhea (38%), musculoskeletal
pain (37%), pruritus (33%), nausea (30%), cough (28%), pyrexia
(25%), arthralgia (23%), decreased appetite (21%), dyspnea (20%),
and vomiting (20%). In Checkmate 9ER, the most common adverse
reactions (≥20%) in patients receiving OPDIVO and cabozantinib
(n=320) were diarrhea (64%), fatigue (51%), hepatotoxicity (44%),
palmar-plantar erythrodysaesthesia syndrome (40%), stomatitis
(37%), rash (36%), hypertension (36%), hypothyroidism (34%),
musculoskeletal pain (33%), decreased appetite (28%), nausea (27%),
dysgeusia (24%), abdominal pain (22%), cough (20%) and upper
respiratory tract infection (20%). In Checkmate 025, the most
common adverse reactions (≥20%) reported in patients receiving
OPDIVO (n=406) vs everolimus (n=397) were fatigue (56% vs 57%),
cough (34% vs 38%), nausea (28% vs 29%), rash (28% vs 36%), dyspnea
(27% vs 31%), diarrhea (25% vs 32%), constipation (23% vs 18%),
decreased appetite (23% vs 30%), back pain (21% vs 16%), and
arthralgia (20% vs 14%). In Checkmate 205 and 039, the most common
adverse reactions (≥20%) reported in patients receiving OPDIVO
(n=266) were upper respiratory tract infection (44%), fatigue
(39%), cough (36%), diarrhea (33%), pyrexia (29%), musculoskeletal
pain (26%), rash (24%), nausea (20%) and pruritus (20%). In
Checkmate 141, the most common adverse reactions (≥10%) in patients
receiving OPDIVO (n=236) were cough (14%) and dyspnea (14%) at a
higher incidence than investigator’s choice. In Checkmate 275, the
most common adverse reactions (≥20%) reported in patients receiving
OPDIVO (n=270) were fatigue (46%), musculoskeletal pain (30%),
nausea (22%), and decreased appetite (22%). In Checkmate 274, the
most common adverse reactions (≥20%) reported in patients receiving
OPDIVO (n=351) were rash (36%), fatigue (36%), diarrhea (30%),
pruritus (30%), musculoskeletal pain (28%), and urinary tract
infection (22%). In Checkmate 142 in MSI-H/dMMR mCRC patients
receiving OPDIVO as a single agent (n=74), the most common adverse
reactions (≥20%) were fatigue (54%), diarrhea (43%), abdominal pain
(34%), nausea (34%), vomiting (28%), musculoskeletal pain (28%),
cough (26%), pyrexia (24%), rash (23%), constipation (20%), and
upper respiratory tract infection (20%). In Checkmate 142 in
MSI-H/dMMR mCRC patients receiving OPDIVO with YERVOY (n=119), the
most common adverse reactions (≥20%) were fatigue (49%), diarrhea
(45%), pyrexia (36%), musculoskeletal pain (36%), abdominal pain
(30%), pruritus (28%), nausea (26%), rash (25%), decreased appetite
(20%), and vomiting (20%). In Checkmate 040, the most common
adverse reactions (≥20%) in patients receiving OPDIVO with YERVOY
(n=49), were rash (53%), pruritus (53%), musculoskeletal pain
(41%), diarrhea (39%), cough (37%), decreased appetite (35%),
fatigue (27%), pyrexia (27%), abdominal pain (22%), headache (22%),
nausea (20%), dizziness (20%), hypothyroidism (20%), and weight
decreased (20%). In Attraction-3, the most common adverse reactions
(≥20%) in OPDIVO-treated patients (n=209) were rash (22%) and
decreased appetite (21%). In Checkmate 577, the most common adverse
reactions (≥20%) in patients receiving OPDIVO (n=532) were fatigue
(34%), diarrhea (29%), nausea (23%), rash (21%), musculoskeletal
pain (21%), and cough (20%). In Checkmate 649, the most common
adverse reactions (≥20%) in patients treated with OPDIVO in
combination with chemotherapy (n=782) were peripheral neuropathy
(53%), nausea (48%), fatigue (44%), diarrhea (39%), vomiting (31%),
decreased appetite (29%), abdominal pain (27%), constipation (25%),
and musculoskeletal pain (20%).
Please see US Full Prescribing Information for OPDIVO and
YERVOY.
Clinical Trials and Patient Populations
Checkmate 037–previously treated metastatic melanoma; Checkmate
066-previously untreated metastatic melanoma; Checkmate
067–previously untreated metastatic melanoma, as a single agent or
in combination with YERVOY; Checkmate 238–adjuvant treatment of
melanoma; Checkmate 816–neoadjuvant non-small cell lung cancer, in
combination with platinum-doublet chemotherapy; Checkmate
227-previously untreated metastatic non-small cell lung cancer, in
combination with YERVOY; Checkmate 9LA–previously untreated
recurrent or metastatic non-small cell lung cancer in combination
with YERVOY and 2 cycles of platinum-doublet chemotherapy by
histology; Checkmate 017–second-line treatment of metastatic
squamous non-small cell lung cancer; Checkmate 057–second-line
treatment of metastatic non-squamous non-small cell lung cancer;
Checkmate 743–previously untreated unresectable malignant pleural
mesothelioma, in combination with YERVOY; Checkmate 214–previously
untreated renal cell carcinoma, in combination with YERVOY;
Checkmate 9ER–previously untreated renal cell carcinoma, in
combination with cabozantinib; Checkmate 025–previously treated
renal cell carcinoma; Checkmate 205/039–classical Hodgkin lymphoma;
Checkmate 141–recurrent or metastatic squamous cell carcinoma of
the head and neck; Checkmate 275–previously treated advanced or
metastatic urothelial carcinoma; Checkmate 274–adjuvant treatment
of urothelial carcinoma; Checkmate 142– MSI-H or dMMR metastatic
colorectal cancer, as a single agent or in combination with YERVOY;
Checkmate 142–MSI-H or dMMR metastatic colorectal cancer, as a
single agent or in combination with YERVOY; Checkmate
040–hepatocellular carcinoma, in combination with YERVOY;
Attraction-3–esophageal squamous cell carcinoma; Checkmate
577–adjuvant treatment of esophageal or gastroesophageal junction
cancer; Checkmate 649– previously untreated advanced or metastatic
gastric or gastroesophageal junction or esophageal
adenocarcinoma
OPDUALAG Indication
OpdualagTM (nivolumab and relatlimab-rmbw) is indicated for the
treatment of adult and pediatric patients 12 years of age or older
with unresectable or metastatic melanoma.
OPDUALAG Important Safety
Information
Severe and Fatal Immune-Mediated Adverse Reactions
Immune-mediated adverse reactions (IMARs) listed herein may not
include all possible severe and fatal immune-mediated adverse
reactions.
IMARs which may be severe or fatal, can occur in any organ
system or tissue. IMARs can occur at any time after starting
treatment with a LAG-3 and PD-1/PD-L1 blocking antibodies. While
IMARs usually manifest during treatment, they can also occur after
discontinuation of Opdualag. Early identification and management of
IMARs are essential to ensure safe use. Monitor patients closely
for symptoms and signs that may be clinical manifestations of
underlying IMARs. Evaluate clinical chemistries including liver
enzymes, creatinine, and thyroid function at baseline and
periodically during treatment. In cases of suspected IMARs,
initiate appropriate workup to exclude alternative etiologies,
including infection. Institute medical management promptly,
including specialty consultation as appropriate.
Withhold or permanently discontinue Opdualag depending on
severity (please see section 2 Dosage and Administration in the
accompanying Full Prescribing Information). In general, if Opdualag
requires interruption or discontinuation, administer systemic
corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent)
until improvement to Grade 1 or less. Upon improvement to Grade 1
or less, initiate corticosteroid taper and continue to taper over
at least 1 month. Consider administration of other systemic
immunosuppressants in patients whose IMARs are not controlled with
corticosteroid therapy. Toxicity management guidelines for adverse
reactions that do not necessarily require systemic steroids (e.g.,
endocrinopathies and dermatologic reactions) are discussed
below.
Immune-Mediated Pneumonitis
Opdualag can cause immune-mediated pneumonitis, which may be
fatal. In patients treated with other PD-1/PD-L1 blocking
antibodies, the incidence of pneumonitis is higher in patients who
have received prior thoracic radiation. Immune-mediated pneumonitis
occurred in 3.7% (13/355) of patients receiving Opdualag, including
Grade 3 (0.6%), and Grade 2 (2.3%) adverse reactions. Pneumonitis
led to permanent discontinuation of Opdualag in 0.8% and
withholding of Opdualag in 1.4% of patients.
Immune-Mediated Colitis
Opdualag can cause immune-mediated colitis, defined as requiring
use of corticosteroids and no clear alternate etiology. A common
symptom included in the definition of colitis was diarrhea.
Cytomegalovirus infection/reactivation has been reported in
patients with corticosteroid-refractory immune-mediated colitis. In
cases of corticosteroid-refractory colitis, consider repeating
infectious workup to exclude alternative etiologies.
Immune-mediated diarrhea or colitis occurred in 7% (24/355) of
patients receiving Opdualag, including Grade 3 (1.1%) and Grade 2
(4.5%) adverse reactions. Colitis led to permanent discontinuation
of Opdualag in 2% and withholding of Opdualag in 2.8% of
patients.
Immune-Mediated Hepatitis
Opdualag can cause immune-mediated hepatitis, defined as
requiring the use of corticosteroids and no clear alternate
etiology.
Immune-mediated hepatitis occurred in 6% (20/355) of patients
receiving Opdualag, including Grade 4 (0.6%), Grade 3 (3.4%), and
Grade 2 (1.4%) adverse reactions. Hepatitis led to permanent
discontinuation of Opdualag in 1.7% and withholding of Opdualag in
2.3% of patients.
Immune-Mediated
Endocrinopathies
Opdualag can cause primary or secondary adrenal insufficiency,
hypophysitis, thyroid disorders, and Type 1 diabetes mellitus,
which can be present with diabetic ketoacidosis. Withhold or
permanently discontinue Opdualag depending on severity (please see
section 2 Dosage and Administration in the accompanying Full
Prescribing Information).
For Grade 2 or higher adrenal insufficiency, initiate
symptomatic treatment, including hormone replacement as clinically
indicated. In patients receiving Opdualag, adrenal insufficiency
occurred in 4.2% (15/355) of patients receiving Opdualag, including
Grade 3 (1.4%) and Grade 2 (2.5%) adverse reactions. Adrenal
insufficiency led to permanent discontinuation of Opdualag in 1.1%
and withholding of Opdualag in 0.8% of patients.
Hypophysitis can present with acute symptoms associated with
mass effect such as headache, photophobia, or visual field defects.
Hypophysitis can cause hypopituitarism; initiate hormone
replacement as clinically indicated. Hypophysitis occurred in 2.5%
(9/355) of patients receiving Opdualag, including Grade 3 (0.3%)
and Grade 2 (1.4%) adverse reactions. Hypophysitis led to permanent
discontinuation of Opdualag in 0.3% and withholding of Opdualag in
0.6% of patients.
Thyroiditis can present with or without endocrinopathy.
Hypothyroidism can follow hyperthyroidism; initiate hormone
replacement or medical management as clinically indicated.
Thyroiditis occurred in 2.8% (10/355) of patients receiving
Opdualag, including Grade 2 (1.1%) adverse reactions. Thyroiditis
did not lead to permanent discontinuation of Opdualag. Thyroiditis
led to withholding of Opdualag in 0.3% of patients. Hyperthyroidism
occurred in 6% (22/355) of patients receiving Opdualag, including
Grade 2 (1.4%) adverse reactions. Hyperthyroidism did not lead to
permanent discontinuation of Opdualag. Hyperthyroidism led to
withholding of Opdualag in 0.3% of patients. Hypothyroidism
occurred in 17% (59/355) of patients receiving Opdualag, including
Grade 2 (11%) adverse reactions. Hypothyroidism led to the
permanent discontinuation of Opdualag in 0.3% and withholding of
Opdualag in 2.5% of patients.
Monitor patients for hyperglycemia or other signs and symptoms
of diabetes; initiate treatment with insulin as clinically
indicated. Diabetes occurred in 0.3% (1/355) of patients receiving
Opdualag, a Grade 3 (0.3%) adverse reaction, and no cases of
diabetic ketoacidosis. Diabetes did not lead to the permanent
discontinuation or withholding of Opdualag in any patient.
Immune-Mediated Nephritis with Renal
Dysfunction
Opdualag can cause immune-mediated nephritis, which is defined
as requiring use of steroids and no clear etiology. In patients
receiving Opdualag, immune-mediated nephritis and renal dysfunction
occurred in 2% (7/355) of patients, including Grade 3 (1.1%) and
Grade 2 (0.8%) adverse reactions. Immune-mediated nephritis and
renal dysfunction led to permanent discontinuation of Opdualag in
0.8% and withholding of Opdualag in 0.6% of patients.
Withhold or permanently discontinue Opdualag depending on
severity (please see section 2 Dosage and Administration in the
accompanying Full Prescribing Information).
Immune-Mediated Dermatologic Adverse
Reactions
Opdualag can cause immune-mediated rash or dermatitis, defined
as requiring use of steroids and no clear alternate etiology.
Exfoliative dermatitis, including Stevens-Johnson syndrome, toxic
epidermal necrolysis, and Drug Rash with eosinophilia and systemic
symptoms has occurred with PD-1/L-1 blocking antibodies. Topical
emollients and/or topical corticosteroids may be adequate to treat
mild to moderate non-exfoliative rashes.
Withhold or permanently discontinue Opdualag depending on
severity (please see section 2 Dosage and Administration in the
accompanying Full Prescribing Information).
Immune-mediated rash occurred in 9% (33/355) of patients,
including Grade 3 (0.6%) and Grade 2 (3.4%) adverse reactions.
Immune-mediated rash did not lead to permanent discontinuation of
Opdualag. Immune-mediated rash led to withholding of Opdualag in
1.4% of patients.
Immune-Mediated Myocarditis
Opdualag can cause immune-mediated myocarditis, which is defined
as requiring use of steroids and no clear alternate etiology. The
diagnosis of immune-mediated myocarditis requires a high index of
suspicion. Patients with cardiac or cardio-pulmonary symptoms
should be assessed for potential myocarditis. If myocarditis is
suspected, withhold dose, promptly initiate high dose steroids
(prednisone or methylprednisolone 1 to 2 mg/kg/day) and promptly
arrange cardiology consultation with diagnostic workup. If
clinically confirmed, permanently discontinue Opdualag for Grade
2-4 myocarditis.
Myocarditis occurred in 1.7% (6/355) of patients receiving
Opdualag, including Grade 3 (0.6%), and Grade 2 (1.1%) adverse
reactions. Myocarditis led to permanent discontinuation of Opdualag
in 1.7% of patients.
Other Immune-Mediated Adverse
Reactions
The following clinically significant IMARs occurred at an
incidence of <1% (unless otherwise noted) in patients who
received Opdualag or were reported with the use of other PD-1/PD-L1
blocking antibodies. Severe or fatal cases have been reported for
some of these adverse reactions: Cardiac/Vascular: pericarditis,
vasculitis; Nervous System: meningitis, encephalitis, myelitis and
demyelination, myasthenic syndrome/myasthenia gravis (including
exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune
neuropathy; Ocular: uveitis, iritis, and other ocular inflammatory
toxicities can occur. Some cases can be associated with retinal
detachment. Various grades of visual impairment, including
blindness, can occur. If uveitis occurs in combination with other
IMARs, consider a Vogt-Koyanagi-Harada–like syndrome, as this may
require treatment with systemic steroids to reduce the risk of
permanent vision loss; Gastrointestinal: pancreatitis including
increases in serum amylase and lipase levels, gastritis,
duodenitis; Musculoskeletal and Connective Tissue:
myositis/polymyositis, rhabdomyolysis (and associated sequelae
including renal failure), arthritis, polymyalgia rheumatica;
Endocrine: hypoparathyroidism; Other (Hematologic/Immune):
hemolytic anemia, aplastic anemia, hemophagocytic
lymphohistiocytosis, systemic inflammatory response syndrome,
histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis),
sarcoidosis, immune thrombocytopenic purpura, solid organ
transplant rejection.
Infusion-Related Reactions
Opdualag can cause severe infusion-related reactions.
Discontinue Opdualag in patients with severe or life-threatening
infusion-related reactions. Interrupt or slow the rate of infusion
in patients with mild to moderate infusion-related reactions. In
patients who received Opdualag as a 60-minute intravenous infusion,
infusion-related reactions occurred in 7% (23/355) of patients.
Complications of Allogeneic Hematopoietic Stem Cell
Transplantation (HSCT)
Fatal and other serious complications can occur in patients who
receive allogeneic hematopoietic stem cell transplantation (HSCT)
before or after being treated with a PD-1/PD-L1 receptor blocking
antibody. Transplant-related complications include hyperacute
graft-versus-host disease (GVHD), acute GVHD, chronic GVHD, hepatic
veno-occlusive disease after reduced intensity conditioning, and
steroid-requiring febrile syndrome (without an identified
infectious cause). These complications may occur despite
intervening therapy between PD-1/PD-L1 blockade and allogeneic
HSCT. Follow patients closely for evidence of transplant-related
complications and intervene promptly. Consider the benefit versus
risks of treatment with a PD-1/PD-L1 receptor blocking antibody
prior to or after an allogeneic HSCT.
Embryo-Fetal Toxicity
Based on its mechanism of action and data from animal studies,
Opdualag 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 Opdualag for at least 5 months
after the last dose of Opdualag.
Lactation
There are no data on the presence of Opdualag in human milk, the
effects on the breastfed child, or the effect on milk production.
Because nivolumab and relatlimab may be excreted in human milk and
because of the potential for serious adverse reactions in a
breastfed child, advise patients not to breastfeed during treatment
with Opdualag and for at least 5 months after the last dose.
Serious Adverse Reactions
In Relativity-047, fatal adverse reaction occurred in 3 (0.8%)
patients who were treated with Opdualag; these included
hemophagocytic lymphohistiocytosis, acute edema of the lung, and
pneumonitis. Serious adverse reactions occurred in 36% of patients
treated with Opdualag. The most frequent serious adverse reactions
reported in ≥1% of patients treated with Opdualag were adrenal
insufficiency (1.4%), anemia (1.4%), colitis (1.4%), pneumonia
(1.4%), acute myocardial infarction (1.1%), back pain (1.1%),
diarrhea (1.1%), myocarditis (1.1%), and pneumonitis (1.1%).
Common Adverse Reactions and Laboratory Abnormalities
The most common adverse reactions reported in ≥20% of the
patients treated with Opdualag were musculoskeletal pain (45%),
fatigue (39%), rash (28%), pruritus (25%), and diarrhea (24%).
The most common laboratory abnormalities that occurred in ≥20%
of patients treated with Opdualag were decreased hemoglobin (37%),
decreased lymphocytes (32%), increased AST (30%), increased ALT
(26%), and decreased sodium (24%).
Please see U.S. Full Prescribing Information for Opdualag.
BREYANZI Indication
Breyanzi is a CD19-directed chimeric antigen receptor (CAR) T
cell therapy with a defined composition and 4-1BB costimulatory
domain. Breyanzi is administered as a defined composition to reduce
variability of the CD8 and CD4 component dose. The 4-1BB signaling
domain enhances the expansion and persistence of the CAR T cells.
In the EU, Breyanzi is administered via a single infusion
containing 100 × 106 CAR+ viable T cells (consisting of a target
1:1 ratio of CD8+ and CD4+ cell components) within a range of 44 to
120 × 106 CAR+ viable T cells.
Breyanzi is approved by the U.S. Food and Drug Administration
for the treatment of adult patients with relapsed or refractory
(R/R) large B-cell lymphoma after two or more lines of systemic
therapy, including diffuse large B cell lymphoma (DLBCL) not
otherwise specified (including DLBCL arising from indolent
lymphoma), high-grade B-cell lymphoma, primary mediastinal large
B-cell lymphoma, and follicular lymphoma grade 3B. Breyanzi is also
approved in Japan for the treatment of patients with third-line
plus R/R LBCL and follicular lymphoma.
Important Safety
Information
BOXED WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGIC
TOXICITIES
- Cytokine Release Syndrome (CRS), including fatal or
life-threatening reactions, occurred in patients receiving
BREYANZI. Do not administer BREYANZI to patients with active
infection or inflammatory disorders. Treat severe or
life-threatening CRS with tocilizumab with or without
corticosteroids.
- Neurologic toxicities, including fatal or life-threatening
reactions, occurred in patients receiving BREYANZI, including
concurrently with CRS, after CRS resolution or in the absence of
CRS. Monitor for neurologic events after treatment with BREYANZI.
Provide supportive care and/or corticosteroids as needed.
- BREYANZI is available only through a restricted program under a
Risk Evaluation and Mitigation Strategy (REMS) called the BREYANZI
REMS.
Cytokine Release Syndrome (CRS)
CRS, including fatal or life-threatening reactions, occurred
following treatment with BREYANZI. CRS occurred in 46% (122/268) of
patients receiving BREYANZI, including ≥ Grade 3 (Lee grading
system) CRS in 4% (11/268) of patients. One patient had fatal CRS
and 2 had ongoing CRS at time of death. The median time to onset
was 5 days (range: 1 to 15 days). CRS resolved in 119 of 122
patients (98%) with a median duration of 5 days (range: 1 to 17
days). Median duration of CRS was 5 days (range 1 to 30 days) in
all patients, including those who died or had CRS ongoing at time
of death.
Among patients with CRS, the most common manifestations of CRS
include fever (93%), hypotension (49%), tachycardia (39%), chills
(28%), and hypoxia (21%). Serious events that may be associated
with CRS include cardiac arrhythmias (including atrial fibrillation
and ventricular tachycardia), cardiac arrest, cardiac failure,
diffuse alveolar damage, renal insufficiency, capillary leak
syndrome, hypotension, hypoxia, and hemophagocytic
lymphohistiocytosis/macrophage activation syndrome (HLH/MAS).
Ensure that 2 doses of tocilizumab are available prior to
infusion of BREYANZI.
Sixty-one of 268 (23%) patients received tocilizumab and/or a
corticosteroid for CRS after infusion of BREYANZI. Twenty-seven
(10%) patients received tocilizumab only, 25 (9%) received
tocilizumab and a corticosteroid, and 9 (3%) received
corticosteroids only.
Neurologic Toxicities
Neurologic toxicities that were fatal or life-threatening,
occurred following treatment with BREYANZI. CAR T cell-associated
neurologic toxicities occurred in 35% (95/268) of patients
receiving BREYANZI, including ≥ Grade 3 in 12% (31/268) of
patients. Three patients had fatal neurologic toxicity and 7 had
ongoing neurologic toxicity at time of death. The median time to
onset of the first event was 8 days (range: 1 to 46 days). The
onset of all neurologic events occurred within the first 8 weeks
following BREYANZI infusion. Neurologic toxicities resolved in 81
of 95 patients (85%) with a median duration of 12 days (range: 1 to
87 days). Three of four patients with ongoing neurologic toxicity
at data cutoff had tremor and one subject had encephalopathy.
Median duration of neurologic toxicity was 15 days (range: 1 to 785
days) in all patients, including those with ongoing neurologic
events at the time of death or at data cutoff.
Seventy-eight (78) of 95 (82%) patients with neurologic toxicity
experienced CRS. Neurologic toxicity overlapped with CRS in 57
patients. The onset of neurologic toxicity was after onset of CRS
in 30 patients, before CRS onset in 13 patients, same day as CRS
onset in 7 patients, and same day as CRS resolution in 7
patients.
Neurologic toxicity resolved in three patients before the onset
of CRS. Eighteen patients experienced neurologic toxicity after
resolution of CRS.
The most common neurologic toxicities included encephalopathy
(24%), tremor (14%), aphasia (9%), delirium (7%), headache (7%),
dizziness (6%), and ataxia (6%). Serious events including cerebral
edema and seizures occurred with BREYANZI. Fatal and serious cases
of leukoencephalopathy, some attributable to fludarabine, have
occurred in patients treated with BREYANZI.
CRS and Neurologic Toxicities Monitoring
Monitor patients daily at a certified healthcare facility during
the first week following infusion, for signs and symptoms of CRS
and neurologic toxicities. Monitor patients for signs and symptoms
of CRS and neurologic toxicities for at least 4 weeks after
infusion; evaluate and treat promptly. Counsel patients to seek
immediate medical attention should signs or symptoms of CRS or
neurologic toxicity occur at any time. At the first sign of CRS,
institute treatment with supportive care, tocilizumab or
tocilizumab and corticosteroids as indicated.
BREYANZI REMS
Because of the risk of CRS and neurologic toxicities, BREYANZI
is available only through a restricted program under a Risk
Evaluation and Mitigation Strategy (REMS) called the BREYANZI REMS.
The required components of the BREYANZI REMS are:
- Healthcare facilities that dispense and administer BREYANZI
must be enrolled and comply with the REMS requirements.
- Certified healthcare facilities must have on-site, immediate
access to tocilizumab.
- Ensure that a minimum of 2 doses of tocilizumab are available
for each patient for infusion within 2 hours after BREYANZI
infusion, if needed for treatment of CRS.
- Certified healthcare facilities must ensure that healthcare
providers who prescribe, dispense, or administer BREYANZI are
trained on the management of CRS and neurologic toxicities.
Further information is available at www.BreyanziREMS.com, or
contact Bristol-Myers Squibb at 1-888-423-5436.
Hypersensitivity Reactions
Allergic reactions may occur with the infusion of BREYANZI.
Serious hypersensitivity reactions, including anaphylaxis, may be
due to dimethyl sulfoxide (DMSO).
Serious Infections
Severe infections, including life-threatening or fatal
infections, have occurred in patients after BREYANZI infusion.
Infections (all grades) occurred in 45% (121/268) of patients.
Grade 3 or higher infections occurred in 19% of patients. Grade 3
or higher infections with an unspecified pathogen occurred in 16%
of patients, bacterial infections occurred in 5%, and viral and
fungal infections occurred in 1.5% and 0.4% of patients,
respectively. Monitor patients for signs and symptoms of infection
before and after BREYANZI administration and treat appropriately.
Administer prophylactic antimicrobials according to standard
institutional guidelines.
Febrile neutropenia has been observed in 9% (24/268) of patients
after BREYANZI infusion and may be concurrent with CRS. In the
event of febrile neutropenia, evaluate for infection and manage
with broad spectrum antibiotics, fluids, and other supportive care
as medically indicated.
Avoid administration of BREYANZI in patients with clinically
significant active systemic infections.
Viral reactivation: Hepatitis B virus (HBV) reactivation, in
some cases resulting in fulminant hepatitis, hepatic failure, and
death, can occur in patients treated with drugs directed against B
cells. Ten of the 11 patients in the TRANSCEND study with a prior
history of HBV were treated with concurrent antiviral suppressive
therapy to prevent HBV reactivation during and after treatment with
BREYANZI. Perform screening for HBV, HCV, and HIV in accordance
with clinical guidelines before collection of cells for
manufacturing.
Prolonged Cytopenias
Patients may exhibit cytopenias not resolved for several weeks
following lymphodepleting chemotherapy and BREYANZI infusion. Grade
3 or higher cytopenias persisted at Day 29 following BREYANZI
infusion in 31% (84/268) of patients, and included thrombocytopenia
(26%), neutropenia (14%), and anemia (3%). Monitor complete blood
counts prior to and after BREYANZI administration.
Hypogammaglobulinemia
B-cell aplasia and hypogammaglobulinemia can occur in patients
receiving treatment with BREYANZI. The adverse event of
hypogammaglobulinemia was reported as an adverse reaction in 14%
(37/268) of patients; laboratory IgG levels fell below 500 mg/dL
after infusion in 21% (56/268) of patients. Hypogammaglobulinemia,
either as an adverse reaction or laboratory IgG level below 500
mg/dL after infusion, was reported in 32% (85/268) of patients.
Monitor immunoglobulin levels after treatment with BREYANZI and
manage using infection precautions, antibiotic prophylaxis, and
immunoglobulin replacement as clinically indicated.
Live vaccines: The safety of immunization with live viral
vaccines during or following BREYANZI treatment has not been
studied. Vaccination with live virus vaccines is not recommended
for at least 6 weeks prior to the start of lymphodepleting
chemotherapy, during BREYANZI treatment, and until immune recovery
following treatment with BREYANZI.
Secondary Malignancies
Patients treated with BREYANZI may develop secondary
malignancies. Monitor lifelong for secondary malignancies. In the
event that a secondary malignancy occurs, contact Bristol-Myers
Squibb at 1-888-805-4555 for reporting and to obtain instructions
on collection of patient samples for testing.
Effects on Ability to Drive and Use Machines
Due to the potential for neurologic events, including altered
mental status or seizures, patients receiving BREYANZI are at risk
for altered or decreased consciousness or impaired coordination in
the 8 weeks following BREYANZI administration. Advise patients to
refrain from driving and engaging in hazardous occupations or
activities, such as operating heavy or potentially dangerous
machinery, during this initial period.
Adverse Reactions
Serious adverse reactions occurred in 46% of patients. The most
common nonlaboratory, serious adverse reactions (> 2%) were CRS,
encephalopathy, sepsis, febrile neutropenia, aphasia, pneumonia,
fever, hypotension, dizziness, and delirium. Fatal adverse
reactions occurred in 4% of patients.
The most common nonlaboratory adverse reactions of any grade (≥
20%) were fatigue, CRS, musculoskeletal pain, nausea, headache,
encephalopathy, infections (pathogen unspecified), decreased
appetite, diarrhea, hypotension, tachycardia, dizziness, cough,
constipation, abdominal pain, vomiting, and edema.
Please see full Prescribing Information, including Boxed
WARNINGS and Medication Guide.
ABECMA Indication
ABECMA (idecabtagene vicleucel) is a B-cell maturation antigen
(BCMA)-directed genetically modified autologous T cell
immunotherapy indicated for the treatment of adult patients with
relapsed or refractory multiple myeloma after four or more prior
lines of therapy, including an immunomodulatory agent, a proteasome
inhibitor, and an anti-CD38 monoclonal antibody.
Important Safety
Information
BOXED WARNING: CYTOKINE RELEASE SYNDROME, NEUROLOGIC
TOXICITIES, HLH/MAS, AND PROLONGED CYTOPENIA
- Cytokine Release Syndrome (CRS), including fatal or
life-threatening reactions, occurred in patients following
treatment with ABECMA. Do not administer ABECMA to patients with
active infection or inflammatory disorders. Treat severe or
life-threatening CRS with tocilizumab or tocilizumab and
corticosteroids.
- Neurologic Toxicities, which may be severe or life-threatening,
occurred following treatment with ABECMA, including concurrently
with CRS, after CRS resolution, or in the absence of CRS. Monitor
for neurologic events after treatment with ABECMA. Provide
supportive care and/or corticosteroids as needed.
- Hemophagocytic Lymphohistiocytosis/Macrophage Activation
Syndrome (HLH/MAS) including fatal and life-threatening reactions,
occurred in patients following treatment with ABECMA. HLH/MAS can
occur with CRS or neurologic toxicities.
- Prolonged Cytopenia with bleeding and infection, including
fatal outcomes following stem cell transplantation for
hematopoietic recovery, occurred following treatment with
ABECMA.
- ABECMA is available only through a restricted program under a
Risk Evaluation and Mitigation Strategy (REMS) called the ABECMA
REMS.
Cytokine Release Syndrome (CRS): CRS, including fatal or
life-threatening reactions, occurred following treatment with
ABECMA. CRS occurred in 85% (108/127) of patients receiving ABECMA.
Grade 3 or higher CRS (Lee grading system) occurred in 9% (12/127)
of patients, with Grade 5 CRS reported in one (0.8%) patient. The
median time to onset of CRS, any grade, was 1 day (range: 1 - 23
days) and the median duration of CRS was 7 days (range: 1 - 63
days) in all patients including the patient who died. The most
common manifestations of CRS included pyrexia (98%), hypotension
(41%), tachycardia (35%), chills (31%), hypoxia (20%), fatigue
(12%), and headache (10%). Grade 3 or higher events that may be
associated with CRS include hypotension, hypoxia,
hyperbilirubinemia, hypofibrinogenemia, acute respiratory distress
syndrome (ARDS), atrial fibrillation, hepatocellular injury,
metabolic acidosis, pulmonary edema, multiple organ dysfunction
syndrome and HLH/MAS.
Identify CRS based on clinical presentation. Evaluate for and
treat other causes of fever, hypoxia, and hypotension. CRS has been
reported to be associated with findings of HLH/MAS, and the
physiology of the syndromes may overlap. HLH/MAS is a potentially
life-threatening condition. In patients with progressive symptoms
of CRS or refractory CRS despite treatment, evaluate for evidence
of HLH/MAS.
Fifty four percent (68/127) of patients received tocilizumab;
35% (45/127) received a single dose while 18% (23/127) received
more than 1 dose of tocilizumab. Overall, across the dose levels,
15% (19/127) of patients received at least 1 dose of
corticosteroids for treatment of CRS. All patients that received
corticosteroids for CRS received tocilizumab.
Overall rate of CRS was 79% and rate of Grade 2 CRS was 23% in
patients treated in the 300 x 106 CAR+ T cell dose cohort. For
patients treated in the 450 x 106 CAR+ T cell dose cohort, the
overall rate of CRS was 96% and rate of Grade 2 CRS was 40%. Rate
of Grade 3 or higher CRS was similar across the dose range. The
median duration of CRS for the 450 x 106 CAR+ T cell dose cohort
was 7 days (range: 1-63 days) and for the 300 x 106 CAR+ T cell
dose cohort was 6 days (range: 2-28 days). In the 450 x 106 CAR+ T
cell dose cohort, 68% (36/53) of patients received tocilizumab and
23% (12/53) received at least 1 dose of corticosteroids for
treatment of CRS. In the 300 x 106 CAR+ T cell dose cohort, 44%
(31/70) of patients received tocilizumab and 10% (7/70) received
corticosteroids. All patients that received corticosteroids for CRS
also received tocilizumab. Ensure that a minimum of 2 doses of
tocilizumab are available prior to infusion of ABECMA.
Monitor patients at least daily for 7 days following ABECMA
infusion at the REMS-certified healthcare facility for signs and
symptoms of CRS. Monitor patients for signs or symptoms of CRS for
at least 4 weeks after infusion. At the first sign of CRS,
institute treatment with supportive care, tocilizumab and/or
corticosteroids as indicated.
Counsel patients to seek immediate medical attention should
signs or symptoms of CRS occur at any time.
Neurologic Toxicities: Neurologic toxicities, which may
be severe or life-threatening, occurred following treatment with
ABECMA, including concurrently with CRS, after CRS resolution, or
in the absence of CRS. CAR T cell-associated neurotoxicity occurred
in 28% (36/127) of patients receiving ABECMA, including Grade 3 in
4% (5/127) of patients. One patient had ongoing Grade 2
neurotoxicity at the time of death. Two patients had ongoing Grade
1 tremor at the time of data cutoff. The median time to onset of
neurotoxicity was 2 days (range: 1 - 42 days). CAR T
cell-associated neurotoxicity resolved in 92% (33/36) of patients
with a median duration of neurotoxicity was 5 days (range: 1 - 61
days). The median duration of neurotoxicity was 6 days (range: 1 -
578) in all patients including those with ongoing neurotoxicity at
the time of death or data cut off. Thirty-four patients with
neurotoxicity had CRS. Neurotoxicity had onset in 3 patients
before, 29 patients during, and 2 patients after CRS. The rate of
Grade 3 neurotoxicity was 8% in the 450 x 106 CAR+ T cell dose
cohort and 1.4% in the 300 x 106 CAR+ T cell dose cohort. The most
frequently reported (greater than or equal to 5%) manifestations of
CAR T cell-associated neurotoxicity include encephalopathy (20%),
tremor (9%), aphasia (7%), and delirium (6%). Grade 4 neurotoxicity
and cerebral edema in 1 patient has been reported with ABECMA in
another study in multiple myeloma. Grade 3 myelitis and Grade 3
parkinsonism have been reported after treatment with ABECMA in
another study in multiple myeloma.
Monitor patients at least daily for 7 days following ABECMA
infusion at the REMS-certified healthcare facility for signs and
symptoms of neurologic toxicities. Rule out other causes of
neurologic symptoms. Monitor patients for signs or symptoms of
neurologic toxicities for at least 4 weeks after infusion and treat
promptly. Neurologic toxicity should be managed with supportive
care and/or corticosteroids as needed.
Counsel patients to seek immediate medical attention should
signs or symptoms of neurologic toxicity occur at any time.
Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage
Activation Syndrome (MAS): HLH/MAS occurred in 4% (5/127) of
patients receiving ABECMA. One patient treated in the 300 x 106
CAR+ T cell dose cohort developed fatal multi-organ HLH/MAS with
CRS. In another patient with fatal bronchopulmonary aspergillosis,
HLH/MAS was contributory to the fatal outcome. Three cases of Grade
2 HLH/MAS resolved. The rate of HLH/MAS was 8% in the 450 x 106
CAR+ T cell dose cohort and 1% in the 300 x 106 CAR+ T cell dose
cohort. All events of HLH/MAS had onset within 10 days of receiving
ABECMA with a median onset of 7 days (range: 4-9 days) and occurred
in the setting of ongoing or worsening CRS. Two patients with
HLH/MAS had overlapping neurotoxicity. The manifestations of
HLH/MAS include hypotension, hypoxia, multiple organ dysfunction,
renal dysfunction, and cytopenia. HLH/MAS is a potentially
life-threatening condition with a high mortality rate if not
recognized early and treated. Treatment of HLH/MAS should be
administered per institutional standards.
ABECMA REMS: Due to the risk of CRS and neurologic
toxicities, ABECMA is available only through a restricted program
under a Risk Evaluation and Mitigation Strategy (REMS) called the
ABECMA REMS. Further information is available at www.AbecmaREMS.com or 18884235436.
Hypersensitivity Reactions: Allergic reactions may occur
with the infusion of ABECMA. Serious hypersensitivity reactions,
including anaphylaxis, may be due to dimethyl sulfoxide (DMSO) in
ABECMA.
Infections: ABECMA should not be administered to patients
with active infections or inflammatory disorders. Severe,
life-threatening, or fatal infections occurred in patients after
ABECMA infusion. Infections (all grades) occurred in 70% of
patients. Grade 3 or 4 infections occurred in 23% of patients.
Overall, 4 patients had Grade 5 infections (3%); 2 patients (1.6%)
had Grade 5 events of pneumonia, 1 patient (0.8%) had Grade 5
bronchopulmonary aspergillosis, and 1 patient (0.8%) had
cytomegalovirus (CMV) pneumonia associated with Pneumocystis
jirovecii. Monitor patients for signs and symptoms of infection
before and after ABECMA infusion and treat appropriately.
Administer prophylactic, preemptive, and/or therapeutic
antimicrobials according to standard institutional guidelines.
Febrile neutropenia was observed in 16% (20/127) of patients
after ABECMA infusion and may be concurrent with CRS. In the event
of febrile neutropenia, evaluate for infection and manage with
broad spectrum antibiotics, fluids, and other supportive care as
medically indicated.
Viral Reactivation: Cytomegalovirus (CMV) infection resulting in
pneumonia and death has occurred following ABECMA administration.
Monitor and treat for CMV reactivation in accordance with clinical
guidelines. Hepatitis B virus (HBV) reactivation, in some cases
resulting in fulminant hepatitis, hepatic failure, and death, can
occur in patients treated with drugs directed against plasma cells.
Perform screening for CMV, HBV, hepatitis C virus (HCV), and human
immunodeficiency virus (HIV) in accordance with clinical guidelines
before collection of cells for manufacturing.
Prolonged Cytopenias: Patients may exhibit prolonged
cytopenias following lymphodepleting chemotherapy and ABECMA
infusion. In the KarMMa study, 41% of patients (52/127) experienced
prolonged Grade 3 or 4 neutropenia and 49% (62/127) experienced
prolonged Grade 3 or 4 thrombocytopenia that had not resolved by
Month 1 following ABECMA infusion. Rate of prolonged neutropenia
was 49% in the 450 x 106 CAR+ T cell dose cohort and 34% in the 300
x 106 CAR+ T cell dose cohort. In 83% (43/52) of patients who
recovered from Grade 3 or 4 neutropenia after Month 1, the median
time to recovery from ABECMA infusion was 1.9 months. In 65%
(40/62) of patients who recovered from Grade 3 or 4
thrombocytopenia, the median time to recovery was 2.1 months.
Median time to cytopenia recovery was similar across the 300 and
450 x 106 dose cohort.
Three patients underwent stem cell therapy for hematopoietic
reconstitution due to prolonged cytopenia. Two of the three
patients died from complications of prolonged cytopenia. Monitor
blood counts prior to and after ABECMA infusion. Manage cytopenia
with myeloid growth factor and blood product transfusion support
according to institutional guidelines.
Hypogammaglobulinemia: Plasma cell aplasia and
hypogammaglobulinemia can occur in patients receiving treatment
with ABECMA. Hypogammaglobulinemia was reported as an adverse event
in 21% (27/127) of patients; laboratory IgG levels fell below 500
mg/dl after infusion in 25% (32/127) of patients treated with
ABECMA.
Monitor immunoglobulin levels after treatment with ABECMA and
administer IVIG for IgG <400 mg/dl. Manage per local
institutional guidelines, including infection precautions and
antibiotic or antiviral prophylaxis.
The safety of immunization with live viral vaccines during or
following ABECMA treatment has not been studied. Vaccination with
live virus vaccines is not recommended for at least 6 weeks prior
to the start of lymphodepleting chemotherapy, during ABECMA
treatment, and until immune recovery following treatment with
ABECMA.
Secondary Malignancies: Patients treated with ABECMA may
develop secondary malignancies. Monitor life-long for secondary
malignancies. If a secondary malignancy occurs, contact Bristol
Myers Squibb at 1-888-805-4555 to obtain instructions on patient
samples to collect for testing of secondary malignancy of T cell
origin.
Effects on Ability to Drive and Operate Machinery: Due to
the potential for neurologic events, including altered mental
status or seizures, patients receiving ABECMA are at risk for
altered or decreased consciousness or coordination in the 8 weeks
following ABECMA infusion. Advise patients to refrain from driving
and engaging in hazardous occupations or activities, such as
operating heavy or potentially dangerous machinery, during this
initial period.
Adverse Reactions: The most common nonlaboratory adverse
reactions (incidence greater than or equal to 20%) include CRS,
infections – pathogen unspecified, fatigue, musculoskeletal pain,
hypogammaglobulinemia, diarrhea, upper respiratory tract infection,
nausea, viral infections, encephalopathy, edema, pyrexia, cough,
headache, and decreased appetite.
Please see full Prescribing Information, including Boxed
WARNINGS and Medication Guide.
REBLOZYL Indication
REBLOZYL is indicated for the treatment of anemia in adult
patients with beta thalassemia who require regular red blood cell
(RBC) transfusions
REBLOZYL is indicated for the treatment of anemia failing an
erythropoiesis stimulating agent and requiring 2 or more red blood
cell units over 8 weeks in adult patients with very low- to
intermediate-risk myelodysplastic syndromes with ring sideroblasts
(MDS-RS) or with myelodysplastic/ myeloproliferative neoplasm with
ring sideroblasts and thrombocytosis (MDS/MPN-RS-T)
REBLOZYL is not indicated for use as a substitute for RBC
transfusions in patients who require immediate correction of
anemia
Important Safety
Information
WARNINGS AND PRECAUTIONS
Thrombosis/Thromboembolism
In adult patients with beta thalassemia, thromboembolic events
(TEE) were reported in 8/223 (3.6%) REBLOZYL-treated patients. TEEs
included deep vein thrombosis, pulmonary embolus, portal vein
thrombosis, and ischemic stroke. Patients with known risk factors
for thromboembolism (splenectomy or concomitant use of hormone
replacement therapy) may be at further increased risk of
thromboembolic conditions. Consider thromboprophylaxis in patients
at increased risk of TEE. Monitor patients for signs and symptoms
of thromboembolic events and institute treatment promptly.
Hypertension
Hypertension was reported in 10.7% (61/571) of REBLOZYL-treated
patients. Across clinical studies, the incidence of Grade 3 to 4
hypertension ranged from 1.8% to 8.6%. In patients with beta
thalassemia with normal baseline blood pressure, 13 (6.2%) patients
developed systolic blood pressure (SBP) ≥130 mm Hg and 33 (16.6%)
patients developed diastolic blood pressure (DBP) ≥80 mm Hg. In
adult patients with MDS with normal baseline blood pressure, 26
(29.9%) patients developed SBP ≥130 mm Hg and 23 (16.4%) patients
developed DBP ≥80 mm Hg. Monitor blood pressure prior to each
administration. Manage new or exacerbations of preexisting
hypertension using anti-hypertensive agents.
Embryo-Fetal Toxicity
REBLOZYL may cause fetal harm when administered to a pregnant
woman. REBLOZYL caused increased post-implantation loss, decreased
litter size, and an increased incidence of skeletal variations in
pregnant rat and rabbit studies. Advise pregnant women of the
potential risk to a fetus. Advise females of reproductive potential
to use effective contraception during treatment and for at least 3
months after the final dose.
ADVERSE REACTIONS
Beta-Thalassemia
- Serious adverse reactions occurred in 3.6% of patients on
REBLOZYL. Serious adverse reactions occurring in 1% of patients
included cerebrovascular accident and deep vein thrombosis. A fatal
adverse reaction occurred in 1 patient treated with REBLOZYL who
died due to an unconfirmed case of acute myeloid leukemia
(AML)
- Most common adverse reactions (at least 10% for REBLOZYL and 1%
more than placebo) were headache (26% vs 24%), bone pain (20% vs
8%), arthralgia (19% vs 12%), fatigue (14% vs 13%), cough (14% vs
11%), abdominal pain (14% vs 12%), diarrhea (12% vs 10%) and
dizziness (11% vs 5%)
Myelodysplastic
Syndromes
- Grade >3 (≥2%) adverse
reactions included fatigue, hypertension, syncope and
musculoskeletal pain. A fatal adverse reaction occurred in 5 (2.1%)
patients
- The most common (≥10%) adverse reactions included fatigue,
musculoskeletal pain, dizziness, diarrhea, nausea, hypersensitivity
reactions, hypertension, headache, upper respiratory tract
infection, bronchitis, and urinary tract infection
LACTATION
It is not known whether REBLOZYL is excreted into human milk or
absorbed systemically after ingestion by a nursing infant. REBLOZYL
was detected in milk of lactating rats. When a drug is present in
animal milk, it is likely that the drug will be present in human
milk. Because many drugs are excreted in human milk, and because of
the unknown effects of REBLOZYL in infants, a decision should be
made whether to discontinue nursing or to discontinue treatment.
Because of the potential for serious adverse reactions in the
breastfed child, breastfeeding is not recommended during treatment
and for 3 months after the last dose.
Please see full Prescribing Information for REBLOZYL.
ONUREG U.S. Indication
ONUREG® (azacitidine tablets) is approved in the U.S. for
continued treatment of adult patients with acute myeloid leukemia
who achieved first complete remission (CR) or complete remission
with incomplete blood count recovery (CRi) following intensive
induction chemotherapy and are not able to complete intensive
curative therapy.
U.S. IMPORTANT SAFETY
INFORMATION
CONTRAINDICATIONS
- ONUREG is contraindicated in patients with known severe
hypersensitivity to azacitidine or its components.
WARNINGS AND PRECAUTIONS
- Risks of Substitution with Other
Azacitidine Products: Due to substantial differences in
the pharmacokinetic parameters, the recommended dose and schedule
for ONUREG are different from those for the intravenous or
subcutaneous azacitidine products. Treatment of patients using
intravenous or subcutaneous azacitidine at the recommended dosage
of ONUREG may result in a fatal adverse reaction. Treatment with
ONUREG at the doses recommended for intravenous or subcutaneous
azacitidine may not be effective. Do not substitute ONUREG for
intravenous or subcutaneous azacitidine.
- Myelosuppression: New or
worsening Grade 3 or 4 neutropenia and thrombocytopenia occurred in
49% and 22% of patients who received ONUREG. Febrile neutropenia
occurred in 12%. A dose reduction was required for 7% and 2% of
patients due to neutropenia and thrombocytopenia. Less than 1% of
patients discontinued ONUREG due to either neutropenia or
thrombocytopenia. Monitor complete blood counts and modify the
dosage as recommended. Provide standard supportive care, including
hematopoietic growth factors, if myelosuppression occurs.
- Increased Early Mortality in Patients
with Myelodysplastic Syndromes (MDS): In AZA-MDS-003,
216 patients with red blood cell transfusion-dependent anemia and
thrombocytopenia due to MDS were randomized to ONUREG or placebo.
107 received a median of 5 cycles of ONUREG 300 mg daily for 21
days of a 28-day cycle. Enrollment was discontinued early due to a
higher incidence of early fatal and/or serious adverse reactions in
the ONUREG arm compared with placebo. The most frequent fatal
adverse reaction was sepsis. Safety and effectiveness of ONUREG for
MDS have not been established. Treatment of MDS with ONUREG is not
recommended outside of controlled trials.
- Embryo-Fetal Toxicity:
ONUREG can cause fetal harm when administered to a pregnant woman.
Azacitidine caused fetal death and anomalies in pregnant rats via a
single intraperitoneal dose less than the recommended human daily
dose of oral azacitidine on a mg/m2 basis. Advise pregnant women of
the potential risk to a fetus. Advise females of reproductive
potential to use effective contraception during treatment with
ONUREG and for at least 6 months after the last dose. Advise males
with female partners of reproductive potential to use effective
contraception during treatment with ONUREG and for at least 3
months after the last dose.
ADVERSE REACTIONS
- Serious adverse reactions occurred in 15% of patients who
received ONUREG. Serious adverse reactions in ≥2% included
pneumonia (8%) and febrile neutropenia (7%). One fatal adverse
reaction (sepsis) occurred in a patient who received ONUREG.
- Most common (≥10%) adverse reactions with ONUREG vs placebo
were nausea (65%, 24%), vomiting (60%, 10%), diarrhea (50%, 21%),
fatigue/asthenia (44%, 25%), constipation (39%, 24%), pneumonia
(27%, 17%), abdominal pain (22%, 13%), arthralgia (14%, 10%),
decreased appetite (13%, 6%), febrile neutropenia (12%, 8%),
dizziness (11%, 9%), pain in extremity (11%, 5%).
LACTATION
- There are no data regarding the presence of azacitidine in
human milk or the effects on the breastfed child or milk
production. Because of the potential for serious adverse reactions
in the breastfed child, advise women not to breastfeed during
treatment with ONUREG and for 1 week after the last dose
Please see full Prescribing Information for ONUREG.
About the Bristol Myers Squibb and Ono
Pharmaceutical Collaboration
In 2011, through a collaboration agreement with Ono
Pharmaceutical Co., 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, Ono and Bristol Myers
Squibb further expanded the companies’ strategic collaboration
agreement to jointly develop and commercialize multiple
immunotherapies – as single agents and combination regimens – for
patients with cancer in Japan, South Korea and Taiwan.
About Bristol Myers
Squibb
Bristol Myers Squibb is a global biopharmaceutical company whose
mission is to discover, develop and deliver innovative medicines
that help patients prevail over serious diseases. For more
information about Bristol Myers Squibb, visit us at BMS.com or
follow us on LinkedIn, Twitter, YouTube, Facebook and
Instagram.
Celgene and Juno Therapeutics are wholly owned subsidiaries of
Bristol-Myers Squibb Company. In certain countries outside the
U.S., due to local laws, Celgene and Juno Therapeutics are referred
to as, Celgene, a Bristol Myers Squibb company and Juno
Therapeutics, a Bristol Myers Squibb company.
Cautionary Statement Regarding
Forward-Looking Statements
This press release contains “forward-looking statements” within
the meaning of the Private Securities Litigation Reform Act of 1995
regarding, among other things, the research, development and
commercialization of pharmaceutical products. All statements that
are not statements of historical facts are, or may be deemed to be,
forward-looking statements. Such forward-looking statements are
based on historical performance and current expectations and
projections about our future financial results, goals, plans and
objectives and involve inherent risks, assumptions and
uncertainties, including internal or external factors that could
delay, divert or change any of them in the next several years, that
are difficult to predict, may be beyond our control and could cause
our future financial results, goals, plans and objectives to differ
materially from those expressed in, or implied by, the statements.
These risks, assumptions, uncertainties and other factors include,
among others, that future study results will be consistent with the
results to date, that the treatments and combination treatments may
not receive regulatory approval for the indications described in
this release in the currently anticipated timeline or at all and,
if approved, whether such treatments or combination treatments for
such indications described in this release will be commercially
successful. No forward-looking statement can be guaranteed.
Forward-looking statements in this press release should be
evaluated together with the many risks and uncertainties that
affect Bristol Myers Squibb’s business and market, particularly
those identified in the cautionary statement and risk factors
discussion in Bristol Myers Squibb’s Annual Report on Form 10-K for
the year ended December 31, 2021, as updated by our subsequent
Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and
other filings with the Securities and Exchange Commission. The
forward-looking statements included in this document are made only
as of the date of this document and except as otherwise required by
applicable law, Bristol Myers Squibb undertakes no obligation to
publicly update or revise any forward-looking statement, whether as
a result of new information, future events, changed circumstances
or otherwise.
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