Application based on Phase 3 TRANSFORM study
in which Breyanzi outperformed the current standard of care with
demonstrated statistically significant improvement in event-free
survival and a well-established safety profile
Bristol Myers Squibb (NYSE: BMY) today announced that the
European Medicines Agency (EMA) has validated its type II variation
application for extension of the indication for Breyanzi
(lisocabtagene maraleucel) to treat adult patients with diffuse
large B-cell lymphoma (DLBCL), high grade B-cell lymphoma (HGBCL),
primary mediastinal large B-cell lymphoma (PMBCL) and follicular
lymphoma grade 3B (FL3B), who are refractory or have relapsed
within 12 months of initial therapy and are candidates for
haematopoietic stem cell transplant (HSCT). Validation of the
application confirms the submission is complete and begins the
EMA’s centralized review procedure.
“Rates of relapsed or refractory large B-cell lymphoma after
first-line therapy are very high and few patients are able to
benefit from stem cell transplant, which has been the second-line
standard of care for nearly 30 years,” said Anne Kerber, senior
vice president, Cell Therapy Development, Bristol Myers Squibb. “We
look forward to working with the European Medicines Agency with the
goal of establishing Breyanzi as a new second-line standard of care
for people living with relapsed or refractory large B-cell lymphoma
and, ultimately, bringing the curative potential of cell therapy to
more patients.”
The type II variation is supported by data from the pivotal
Phase 3 TRANSFORM study evaluating Breyanzi as a second-line
treatment in adults with relapsed or refractory LBCL compared to
the standard of care consisting of salvage chemotherapy followed by
high-dose chemotherapy plus HSCT. In the study, Breyanzi
significantly improved event-free survival (EFS) compared to
standard of care, the study’s primary endpoint, and demonstrated
clinically meaningful and statistically significant improvements in
complete response rates and progression-free survival compared to
standard of care. Breyanzi exhibited a well-established safety
profile with very low rates of severe cytokine release syndrome
(CRS) and neurologic events, and no new safety signals were
observed in this second-line setting, consistent with the safety
profile observed with Breyanzi in the third-line plus setting.
LBCL is an aggressive blood cancer and the most common type of
non-Hodgkin lymphoma. Approximately 40% of patients will have
disease that is refractory to or relapses after first-line
treatment. High-dose chemotherapy followed by autologous stem cell
transplant has been the mainstay of care in the second-line setting
and historically has been the only potential for cure after failure
of first-line treatment. While an estimated 50% of patients with
primary refractory or relapsed disease are considered candidates
for a stem cell transplant, only about 25% of these patients are
able to receive stem cell transplant.
A supplemental Biologics License Application for Breyanzi for
the treatment of relapsed or refractory LBCL after failure of
first-line therapy is currently under Priority Review with the U.S.
Food and Drug Administration (FDA), with an assigned Prescription
Drug User Fee Act (PDUFA) goal date of June 24, 2022. A New Drug
Application for Breyanzi for the second-line treatment of patients
with relapsed or refractory LBCL is also under review with Japan’s
Ministry of Health, Labour and Welfare.
Breyanzi, a differentiated CD-19 directed CAR T cell therapy, is
currently approved in the European Union for the treatment of adult
patients with relapsed or refractory (R/R) diffuse DLBCL, primary
mediastinal large B-cell lymphoma PMBCL, and FL3B after two or more
lines of systemic therapy. Breyanzi is not approved in any region
for the second-line treatment of LBCL.
About TRANSFORM
TRANSFORM (NCT03575351) is a pivotal, global, randomized,
multicenter Phase 3 trial evaluating Breyanzi compared to the
current standard of care (platinum-based salvage chemotherapy
followed by high-dose chemotherapy and HSCT in patients responding
to salvage chemotherapy) in patients with large B-cell lymphoma
that was primary refractory or relapsed within 12 months after
CD20-antibody and anthracycline containing first-line therapy.
Patients were randomized to receive Breyanzi or standard of care
salvage therapy, including rituximab plus dexamethasone, high-dose
cytarabine, and cisplatin (R-DHAP), rituximab plus ifosfamide,
carboplatin and etoposide (R-ICE), or rituximab plus gemcitabine,
dexamethasone and cisplatin (R-GDP) per the investigators’ choice
before proceeding to high-dose chemotherapy (HDCT) and
hematopoietic stem cell transplant (HSCT). The primary endpoint of
the study was event-free survival, defined as time from
randomization to death from any cause, progressive disease, failure
to achieve complete response or partial response, or start of new
antineoplastic therapy due to efficacy concerns, whichever occurs
first. Complete response rate was a key secondary endpoint. Other
efficacy endpoints included progression-free survival, overall
survival, overall response rate and duration of response.
About Breyanzi
Breyanzi is a CD-19 directed chimeric antigen receptor (CAR) T
cell therapy, administered as a defined composition to reduce
variability of the CD8 and CD4 component dose. Breyanzi has a 4-1BB
costimulatory domain which enhances the expansion and persistence
of the CAR T cells. Breyanzi is approved by the U.S. Food and Drug
Administration for the treatment of adult patients with relapsed or
refractory 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 also approved in the European Union, Switzerland,
Japan and Canada for relapsed and refractory LBCL after two or more
lines of systemic therapy. Bristol Myers Squibb’s clinical
development program for Breyanzi includes clinical studies in
earlier lines of treatment for patients with relapsed or refractory
LBCL and other types of lymphomas and leukemia. For more
information, visit clinicaltrials.gov.
U.S. 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.
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.
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.
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 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 may not be consistent with the results to
date, that Breyanzi (lisocabtagene maraleucel) may not receive
regulatory approval for the indication described in this release in
the currently anticipated timeline or at all, any marketing
approvals, if granted, may have significant limitations on their
use, and, if approved, whether such product candidate for such
indication 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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