Breyanzi demonstrated a 73%
overall response rate and 54% complete response (CR) rate in the
largest pivotal trial in 3L+ LBCL, TRANSCEND NHL 001 trial
Breyanzi demonstrated sustained responses in
patients who achieved a CR with median duration of response not
reached
Grade ≥3 cytokine release syndrome
and Grade ≥3 neurologic toxicities following Breyanzi treatment
occurred in 4% and 12% of patients, respectively
Bristol Myers Squibb (NYSE: BMY) today announced that the U.S.
Food and Drug Administration (FDA) has approved Breyanzi
(lisocabtagene maraleucel; liso-cel), a CD19-directed chimeric
antigen receptor (CAR) T cell therapy for the treatment of adult
patients with relapsed or refractory (R/R) large B-cell lymphoma
(LBCL) 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 not indicated for the treatment of
patients with primary central nervous system lymphoma.1 Breyanzi is
a CD19-directed 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 enhances the expansion and persistence of
Breyanzi. Breyanzi offers a potentially definitive treatment. A
single dose of Breyanzi contains 50 to 110 x 106 CAR-positive
viable T cells (consisting of 1:1 CAR-positive viable T cells of
the CD8 and CD4 components). Please see the Important Safety
Information section below, including Boxed WARNINGS for
Breyanzi regarding Cytokine Release Syndrome (CRS) and Neurologic
Toxicities (NT).
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“Breyanzi, a CAR T cell therapy, will have an important role in
clinical practice, offering people living with relapsed or
refractory large B-cell lymphoma the chance for sustained response
with an individualized treatment experience,” said Samit Hirawat,
M.D., chief medical officer, Bristol Myers Squibb. “Today’s FDA
approval reflects our deep commitment to advancing cell therapy
research, developing innovative treatments and supporting patients
at every step of their treatment journey.”
Bristol Myers Squibb plans to manufacture Breyanzi for each
individual patient at its state-of-the-art cellular immunotherapy
manufacturing facility in Bothell, Washington. Breyanzi offers a
24-day target turnaround time, and inpatient or outpatient
administration options. To help support broad patient access,
Bristol Myers Squibb plans to launch Breyanzi across an expansive
network of treatment centers. Treatment centers will be Risk
Evaluation and Mitigation Strategy (REMS) certified to support the
appropriate use of Breyanzi, which is available only through the
Breyanzi REMS program. Healthcare facilities, including hospitals
and associated outpatient clinics, must enroll and comply with REMS
requirements and be trained on the management of CRS and NT.
Bristol Myers Squibb is also supporting the patient and physician
treatment experience by providing Cell Therapy 360, a digital
service platform, which optimizes access to relevant information,
manufacturing updates, patient and caregiver support, and
outpatient management resources to support patients. BMS will offer
patients disposable wearable technology during the initial
post-infusion monitoring period, which will help them track their
temperature in real time through a smartphone when away from the
treatment center.
“In TRANSCEND NHL 001, Breyanzi produced sustained responses in
a significant proportion of patients with relapsed or refractory
large B-cell lymphoma. TRANSCEND also demonstrated feasibility of
outpatient administration, which is meaningful for patients,
physicians and the healthcare system,” said Jeremy Abramson, M.D.,
M.M.Sc., director of the lymphoma program at Massachusetts General
Hospital and principal investigator for TRANSCEND NHL 001. “With
this approval, we now have an important new treatment option for
patients with relapsed or refractory large B-cell lymphoma who have
undergone at least two prior lines of systemic therapy.”
Diffuse large B-cell lymphoma (DLBCL) is a rapidly growing,
aggressive disease and the most common form of non-Hodgkin lymphoma
(NHL), accounting for one out of every three cases diagnosed.2
Seventy-three percent of patients will not respond to or will
relapse following second-line treatment or later.3 For patients who
relapse or do not respond to initial therapies, conventional
treatment options that provide sustained responses are limited and
median life expectancy is about six months.3 The goal of treatment
in DLBCL is curative intent with definitive therapy.3 Additional
options are needed in R/R DLBCL to deliver sustained responses to
these patients.
“People battling relapsed or refractory large B-cell lymphoma
continue to face a challenging treatment journey, both physically
and emotionally,” said Meghan Gutierrez, chief executive officer,
Lymphoma Research Foundation. “Breyanzi is an innovative treatment
that offers a new option for patients, and another reason for this
community to maintain hope for the future.”
Bristol Myers Squibb offers various programs and resources to
address the needs of patients and caregivers, and provide support
that allows for access to therapies, including Breyanzi.
Breyanzi has been granted Priority Medicines (PRIME) designation
for R/R DLBCL in the European Union and a Marketing Authorization
Application (MAA) is currently under review by the European
Medicines Agency.
TRANSCEND NHL 001 Pivotal Trial
Results
The FDA approval of Breyanzi is based on data from the TRANSCEND
NHL 001 (017001) trial in which 268 patients with R/R LBCL received
Breyanzi, the largest pivotal trial in third-line plus R/R LBCL
that included patients with a broad range of histologies and
high-risk disease. In the trial, Breyanzi was administered in the
inpatient and outpatient settings.1
In the study, 192 patients were treated with Breyanzi at the
dose of 50 to 110 x 106 CAR-positive viable T cells and evaluated
for efficacy. Of these patients, 73% achieved a response (95% CI:
67%-80%), including 54% who had minimal or no detectable lymphoma
remaining following treatment (CR; 95% CI: 47%-61%) and 19% who
achieved a partial response (PR; 95% CI: 14%-26%). Median duration
of response was 16.7 months in all responders (95% CI: 5.3 – NR),
and for patients who achieved a CR, median duration of response was
not reached (95% CI: 16.7 – NR); for patients with a best response
of PR, median duration of response was 1.4 months (95% CI: 1.1 –
2.2). Of 104 patients treated with Breyanzi who achieved a best
overall response of CR, 65% had remission lasting at least six
months and 62% had remission lasting at least nine months.
In the study, 268 patients treated with Breyanzi were evaluated
for safety. Any grade CRS occurred in 46% (122/268) of patients
using the Lee grading system.4 Grade ≥3 CRS occurred in 4% (11/268)
of patients. One patient had fatal CRS and two had ongoing CRS at
the time of death. The most common manifestations of CRS included
fever (93%), hypotension (49%), tachycardia (39%), chills (28%) and
hypoxia (21%). The median duration of CRS was five days (range:
1-30 days) and median time to onset was five days (range: 1-15
days). Any grade neurologic toxicities (NT) occurred in 35%
(95/268) of patients receiving Breyanzi. Grade ≥3 NT occurred in
12% (31/268) of patients. Three patients had fatal neurologic
toxicity and seven had ongoing neurologic toxicity at time of
death. The most common NT included encephalopathy (24%), tremor
(14%), aphasia (9%), delirium (7%), headache (7%), ataxia (6%), and
dizziness (6%). Neurologic toxicities resolved in 81 of 95 patients
(85%), with a median duration of 12 days (range: 1-87 days). The
median time to onset of the first event was eight days (range: 1-46
days).1 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.
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.
Indication
BREYANZI is a CD19-directed genetically modified autologous T
cell immunotherapy indicated 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.
Limitations of Use: BREYANZI is not indicated for the treatment
of patients with primary central nervous system 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.
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.
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.
Juno Therapeutics, Inc. is a wholly owned subsidiary of
Bristol-Myers Squibb Company. The approval of Breyanzi is based on
a Biologics License Application that was submitted by Juno
Therapeutics. 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.
Bristol Myers Squibb 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, whether Breyanzi for the indication described in this
release will be commercially successful and that continued approval
of such product candidate for such indication described in this
release may be contingent upon verification and description of
clinical benefit in confirmatory trials. 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, 2019, 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.
corporatefinancial-news
References
- Breyanzi Prescribing Information. Bristol Myers Squibb;
February 2021.
- American Cancer Society. Types of B cell Lymphoma. Available
at:
https://www.cancer.org/cancer/non-hodgkin-lymphoma/about/b-cell-lymphoma.html.
Accessed February 2021.
- Crump M., et al. Outcomes in refractory diffuse large B-cell
lymphoma: results from the international SCHOLAR-1 study. Blood.
2017; 130(16): 1800-1808.
- Lee DW, et al. Current concepts in the diagnosis and management
of cytokine release syndrome. Blood. 2014;124:188-195.
View source
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Bristol-Myers Squibb Company Media Inquiries:
media@bms.com Kimberly Whitefield Kimberly.whitefield@bms.com
Investors: Tim Power 609-252-7509 timothy.power@bms.com
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