Application based on the TRANSCEND FL trial
in which Breyanzi showed deep and durable responses and a
consistent and well-established safety profile
Breyanzi also received approval in Japan for
the treatment of relapsed or refractory follicular lymphoma (FL)
after one prior line of systemic therapy in patients with high-risk
FL and after two or more lines of systemic therapy, making it the
first and only CAR T treatment approved for this high-risk
population with unmet need
Bristol Myers Squibb (NYSE: BMY) today announced that the
European Medicines Agency (EMA) has validated its Type II variation
application to expand the indication for Breyanzi® (lisocabtagene
maraleucel; liso-cel), a CD19-directed chimeric antigen receptor
(CAR) T cell therapy, to include the treatment of adult patients
with relapsed or refractory follicular lymphoma (FL) who have
received two or more prior lines of systemic therapy. Validation of
the application confirms the submission is complete and allows the
scientific review to begin under the EMA’s centralized review
procedure.
“Follicular lymphoma impacts a significant number of people, and
those with relapsed or refractory disease tend to experience
shorter responses with each new line of therapy,” said Anne Kerber,
senior vice president, head of Late Clinical Development,
Hematology, Oncology and Cell Therapy (HOCT), Bristol Myers Squibb.
“Breyanzi represents a differentiated CAR T cell therapy, and we
look forward to working with the European Medicines Agency to bring
this important treatment option to patients with relapsed or
refractory follicular lymphoma with the goal of improving outcomes
and providing lasting remission.”
The application is supported by data from the Phase 2 TRANSCEND
FL study, the largest clinical trial to date to evaluate a CAR T
cell therapy in patients with relapsed or refractory indolent
non-Hodgkin lymphoma (NHL), including FL. The study enrolled adults
with relapsed or refractory FL treated with Breyanzi in the
high-risk second-line and third-line plus setting. In the study,
Breyanzi demonstrated a high overall response rate, the study’s
primary endpoint, with responses being deep and durable. The safety
of Breyanzi in FL is consistent with the well-established and
manageable safety profile of Breyanzi observed across clinical
trials.
Follicular lymphoma is the second most common form of NHL,
accounting for 20 to 30 percent of all NHL cases. FL has
historically been considered an incurable disease with patients
frequently relapsing following front-line therapy and prognosis
worsening after each subsequent relapse. Despite advances in
treatment, there remains an unmet need for additional options that
offer treatment-free intervals with durable, complete
responses.
Breyanzi is currently approved in the European Union for the
treatment of adult patients with relapsed or refractory diffuse
large B-cell lymphoma (DLBCL), high grade B-cell lymphoma (HGBCL),
primary mediastinal large B-cell lymphoma (PMBCL) and FL grade 3B
(FL3B), who relapsed within 12 months from completion of, or are
refractory to, first-line chemoimmunotherapy, and for the treatment
of adult patients with relapsed or refractory DLBCL, PMBCL, and
FL3B after two or more lines of systemic therapy.
A supplemental New Drug Application for Breyanzi for the
treatment of relapsed or refractory follicular lymphoma after one
prior line of systemic therapy in patients with high-risk FL and
after two or more lines of systemic therapy has also been approved
by Japan’s Ministry of Health, Labour and Welfare based on results
of the TRANSCEND FL study, making it the first CAR T approved in
the second-line setting anywhere and the third approval for
Breyanzi in Japan.
About TRANSCEND FL
TRANSCEND FL (NCT04245839) is an open-label, global,
multicenter, Phase 2, single-arm study to determine the efficacy
and safety of Breyanzi in adult patients with relapsed or
refractory indolent B-cell non-Hodgkin lymphoma, including
follicular lymphoma. The primary outcome measure is overall
response rate, including best overall response of complete response
or partial response as determined by an Independent Review
Committee. Secondary outcome measures include complete response
rate, duration of response, progression-free survival, and
safety.
About Breyanzi
Breyanzi is a CD19-directed CAR T cell therapy with a 4-1BB
costimulatory domain, which enhances the expansion and persistence
of the CAR T cells. Breyanzi is made from a patient’s own T cells,
which are collected and genetically reengineered to become CAR T
cells that are then delivered via infusion as a one-time
treatment.
Breyanzi is approved in the U.S. for the treatment of relapsed
or refractory large B-cell lymphoma (LBCL) after at least one prior
line of therapy, has received accelerated approval for the
treatment of relapsed or refractory chronic lymphocytic leukemia or
small lymphocytic lymphoma after at least two prior lines of
therapy and relapsed or refractory follicular lymphoma in the
third-line plus setting, and is approved for the treatment of
relapsed or refractory mantle cell lymphoma (MCL) in the third-line
plus setting. Breyanzi is also approved in Japan, the European
Union (EU), and Switzerland for the second-line treatment of
relapsed or refractory LBCL; in Japan, the EU, Switzerland, the UK
and Canada for relapsed and refractory LBCL after two or more lines
of systemic therapy; and in Japan for the treatment of relapsed or
refractory patients with high-risk follicular lymphoma after one
prior line of systemic therapy and in patients after two or more
lines of systemic therapy.
Bristol Myers Squibb’s clinical development program for Breyanzi
includes clinical studies in other types of lymphoma. For more
information, visit clinicaltrials.gov.
Full European Summary of Product Characteristics for Breyanzi is
available from the EMA website at www.ema.europa.eu.
U.S. FDA-Approved Indications
BREYANZI is a CD19-directed genetically modified autologous T
cell immunotherapy indicated for the treatment of:
- adult patients with large B-cell lymphoma (LBCL), 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, who have:
- refractory disease to first-line chemoimmunotherapy or relapse
within 12 months of first-line chemoimmunotherapy; or
- refractory disease to first-line chemoimmunotherapy or relapse
after first-line chemoimmunotherapy and are not eligible for
hematopoietic stem cell transplantation (HSCT) due to comorbidities
or age; or
- relapsed or refractory disease after two or more lines of
systemic therapy.
Limitations of Use: BREYANZI is not
indicated for the treatment of patients with primary central
nervous system lymphoma.
- adult patients with relapsed or refractory chronic lymphocytic
leukemia (CLL) or small lymphocytic lymphoma (SLL) who have
received at least 2 prior lines of therapy, including a Bruton
tyrosine kinase (BTK) inhibitor and a B-cell lymphoma 2 (BCL-2)
inhibitor. This indication is approved under accelerated approval
based on response rate and duration of response. Continued approval
for this indication may be contingent upon verification and
description of clinical benefit in confirmatory trial(s).
- adult patients with relapsed or refractory follicular lymphoma
(FL) who have received 2 or more prior lines of systemic therapy.
This indication is approved under accelerated approval based on
response rate and duration of response. Continued approval for this
indication may be contingent upon verification and description of
clinical benefit in confirmatory trial(s).
- adult patients with relapsed or refractory mantle cell lymphoma
(MCL) who have received at least 2 prior lines of systemic therapy,
including a Bruton tyrosine kinase (BTK) inhibitor.
U.S. Important Safety
Information
WARNING: CYTOKINE RELEASE SYNDROME, NEUROLOGIC TOXICITIES,
AND SECONDARY HEMATOLOGICAL MALIGNANCIES
- 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.
- T cell malignancies have occurred following treatment of
hematologic malignancies with BCMA- and CD19-directed genetically
modified autologous T cell immunotherapies, including
BREYANZI.
- BREYANZI is available only through a restricted program
under a Risk Evaluation and Mitigation Strategy (REMS) called the
BREYANZI REMS.
Cytokine Release Syndrome
Cytokine release syndrome (CRS), including fatal or
life-threatening reactions, occurred following treatment with
BREYANZI. In clinical trials of BREYANZI, which enrolled a total of
702 patients with non-Hodgkin lymphoma (NHL), CRS occurred in 54%
of patients, including ≥ Grade 3 CRS in 3.2% of patients. The
median time to onset was 5 days (range: 1 to 63 days). CRS resolved
in 98% of patients with a median duration of 5 days (range: 1 to 37
days). One patient had fatal CRS and 5 patients had ongoing CRS at
the time of death. The most common manifestations of CRS (≥10%)
were fever, hypotension, tachycardia, chills, hypoxia, and
headache.
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.
Neurologic Toxicities
Neurologic toxicities that were fatal or life-threatening,
including immune effector cell-associated neurotoxicity syndrome
(ICANS), occurred following treatment with BREYANZI. Serious events
including cerebral edema and seizures occurred with BREYANZI. Fatal
and serious cases of leukoencephalopathy, some attributable to
fludarabine, also occurred.
In clinical trials of BREYANZI, CAR T cell-associated neurologic
toxicities occurred in 31% of patients, including ≥ Grade 3 cases
in 10% of patients. The median time to onset of neurotoxicity was 8
days (range: 1 to 63 days). Neurologic toxicities resolved in 88%
of patients with a median duration of 7 days (range: 1 to 119
days). Of patients developing neurotoxicity, 82% also developed
CRS.
The most common neurologic toxicities (≥5%) included
encephalopathy, tremor, aphasia, headache, dizziness, and
delirium.
CRS and Neurologic Toxicities Monitoring
Monitor patients daily for at least 7 days following BREYANZI
infusion at a REMS-certified healthcare facility for signs and
symptoms of CRS and neurologic toxicities and assess for other
causes of neurological symptoms. Monitor patients for signs and
symptoms of CRS and neurologic toxicities for at least 4 weeks
after infusion and treat promptly. At the first sign of CRS,
institute treatment with supportive care, tocilizumab, or
tocilizumab and corticosteroids as indicated. Manage neurologic
toxicity with supportive care and/or corticosteroid as needed.
Counsel patients to seek immediate medical attention should signs
or symptoms of CRS or neurologic toxicity occur at any time.
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.
Further information is available at www.BreyanziREMS.com, or
contact Bristol Myers Squibb at 1-866-340-7332.
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. In
clinical trials of BREYANZI, infections of any grade occurred in
34% of patients, with Grade 3 or higher infections occurring in 12%
of all patients. Grade 3 or higher infections with an unspecified
pathogen occurred in 7%, bacterial infections in 3.7%, viral
infections in 2%, and fungal infections in 0.7% of patients. One
patient who received 4 prior lines of therapy developed a fatal
case of John Cunningham (JC) virus progressive multifocal
leukoencephalopathy 4 months after treatment with BREYANZI. One
patient who received 3 prior lines of therapy developed a fatal
case of cryptococcal meningoencephalitis 35 days after treatment
with BREYANZI.
Febrile neutropenia developed after BREYANZI infusion in 8% of
patients. Febrile neutropenia 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.
Monitor patients for signs and symptoms of infection before and
after BREYANZI administration and treat appropriately. Administer
prophylactic antimicrobials according to standard institutional
guidelines. 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. In clinical trials of BREYANZI, 35 of 38 patients with a
prior history of HBV were treated with concurrent antiviral
suppressive therapy.
Perform screening for HBV, HCV, and HIV in accordance with
clinical guidelines before collection of cells for manufacturing.
In patients with prior history of HBV, consider concurrent
antiviral suppressive therapy to prevent HBV reactivation per
standard guidelines.
Prolonged Cytopenias
Patients may exhibit cytopenias not resolved for several weeks
following lymphodepleting chemotherapy and BREYANZI infusion. In
clinical trials of BREYANZI, Grade 3 or higher cytopenias persisted
at Day 29 following BREYANZI infusion in 35% of patients, and
included thrombocytopenia in 25%, neutropenia in 22%, and anemia in
6% of patients. Monitor complete blood counts prior to and after
BREYANZI administration.
Hypogammaglobulinemia
B-cell aplasia and hypogammaglobulinemia can occur in patients
receiving BREYANZI. In clinical trials of BREYANZI,
hypogammaglobulinemia was reported as an adverse reaction in 10% of
patients. Hypogammaglobulinemia, either as an adverse reaction or
laboratory IgG level below 500 mg/dL after infusion, was reported
in 30% 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. T cell malignancies have occurred following treatment
of hematologic malignancies with BCMA- and CD19-directed
genetically modified autologous T cell immunotherapies, including
BREYANZI. Mature T cell malignancies, including CAR-positive
tumors, may present as soon as weeks following infusion, and may
include fatal outcomes. 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 developing 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, for at least 8 weeks.
Immune Effector Cell-Associated Hemophagocytic
Lymphohistiocytosis-Like Syndrome (IEC-HS)
Immune Effector Cell-Associated Hemophagocytic
Lymphohistiocytosis-Like Syndrome (IEC-HS), including fatal or
life-threatening reactions, occurred following treatment with
BREYANZI. Three of 89 (3%) safety evaluable patients with R/R
CLL/SLL developed IEC-HS. Time to onset of IEC-HS ranged from 7 to
18 days. Two of the 3 patients developed IEC-HS in the setting of
ongoing CRS and 1 in the setting of ongoing neurotoxicity. IEC-HS
was fatal in 2 of 3 patients. One patient had fatal IEC-HS and one
had ongoing IEC-HS at time of death. IEC-HS is a life-threatening
condition with a high mortality rate if not recognized and treated
early. Treatment of IEC-HS should be administered per current
practice guidelines.
Adverse Reactions
The most common adverse reaction(s) (incidence ≥30%) in:
- LBCL are fever, cytokine release syndrome, fatigue,
musculoskeletal pain, and nausea. The most common Grade 3-4
laboratory abnormalities include lymphocyte count decrease,
neutrophil count decrease, platelet count decrease, and hemoglobin
decrease.
- CLL/SLL are cytokine release syndrome, encephalopathy, fatigue,
musculoskeletal pain, nausea, edema, and diarrhea. The most common
Grade 3-4 laboratory abnormalities include neutrophil count
decrease, white blood cell decrease, hemoglobin decrease, platelet
count decrease, and lymphocyte count decrease.
- FL is cytokine release syndrome. The most common Grade 3-4
laboratory abnormalities include lymphocyte count decrease,
neutrophil count decrease, and white blood cell decrease.
- MCL are cytokine release syndrome, fatigue, musculoskeletal
pain, and encephalopathy. The most common Grade 3-4 laboratory
abnormalities include neutrophil count decrease, white blood cell
decrease, and platelet count decrease.
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 understanding of causal human biology,
cutting-edge capabilities and differentiated research platforms
uniquely position the company to approach 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. As a
leader in cancer care, Bristol Myers Squibb is working to empower
all people with cancer to have a better future.
Learn more about the science behind cell therapy and ongoing
research at Bristol Myers Squibb here.
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.
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 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 Breyanzi (lisocabtagene maraleucel) may not receive EMA
regulatory approval for the additional indication described in this
release in the currently anticipated timeline or at all, that any
marketing approvals, if granted, may have significant limitations
on their use, including that continued approval for such additional
indication may be contingent upon verification and description of
clinical benefit in confirmatory trials, and, if approved, whether
Breyanzi for such additional indication described in this release
will be commercially successful. No forward-looking statement can
be guaranteed. It should also be noted that the validation by the
EMA of the application does not change the standards for EMA
approval. 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, 2023, 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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