Phase 3 TRANSFORM study shows Breyanzi
significantly improved event-free survival (EFS) vs. chemotherapy
plus autologous stem cell transplant, with a 65% reduction in risk
of EFS events in first disclosure of results presented at ASH
2021
Breyanzi showed a manageable safety profile
and no new safety signals observed, with low rates of severe
cytokine release syndrome and neurologic events
Bristol Myers Squibb (NYSE: BMY) today announced the first
disclosure of results from a prespecified interim analysis of the
pivotal TRANSFORM study, a global, randomized, multicenter, Phase 3
study evaluating Breyanzi (lisocabtagene maraleucel; liso-cel), a
CD19-directed chimeric antigen receptor (CAR) T cell therapy, as a
second-line treatment in adults with relapsed or refractory large
B-cell lymphoma (LBCL) compared to the standard of care consisting
of salvage chemotherapy followed by high-dose chemotherapy plus
autologous hematopoietic stem cell transplant (HSCT). Results show,
at a median follow up of 6.2 months, Breyanzi significantly
improved event-free survival (EFS) compared to standard of care,
the study’s primary endpoint, with a median EFS of 10.1 months (95%
CI: 6.1-NR) for Breyanzi and 2.3 months (95% CI: 2.2-4.3) for
standard of care (HR: 0.349; p<0.0001), representing a 65%
reduction in risk of EFS events with Breyanzi. The data will be
presented in an oral session during the 63rd American Society of
Hematology (ASH) Annual Meeting and Exposition (Abstract #91) and
has been selected for inclusion in the ASH Annual Meeting Press
Program.
“For more than 20 years, salvage chemotherapy followed by
high-dose chemotherapy and stem cell transplant have been the
mainstay of care for patients with second-line relapsed or
refractory LBCL, but only a small portion of patients experience
long-term benefit with this approach,” said Manali Kamdar, M.D.,
lead investigator and Associate Professor, Clinical Director of
Lymphoma Services, Division of Hematology, Hematologic Malignancies
and Stem Cell Transplantation, University of Colorado Cancer
Center. “With liso-cel outperforming the current standard of care
for patients with hard-to-treat disease in the TRANSFORM study,
these results may pave the way for a practice-changing treatment
approach where patients whose disease relapses or is refractory to
frontline therapy can be treated with a personalized CAR T cell
therapy to increase the potential for improved outcomes.”
In the TRANSFORM study, 184 patients with primary refractory
LBCL or relapsed disease within ≤12 months after first-line therapy
who were eligible for autologous HSCT were randomized to receive
Breyanzi (n=92) or salvage chemotherapy followed by high-dose
chemotherapy and autologous HSCT (n=92), which is considered the
current standard of care for these patients. In the trial, which
allowed for crossover, 50 patients switched from the standard of
care arm to receive Breyanzi following failure to achieve a
response by nine weeks post-randomization (after three cycles of
salvage chemotherapy) or after disease progression at any time.
The majority of patients (86%) treated with Breyanzi achieved a
complete or partial response, with 66% of patients achieving a
complete response. In comparison, less than half (48%) of patients
who received the standard of care achieved a response, and only 39%
of these patients achieved a complete response (p<0.0001).
Median progression-free survival was significantly longer with
Breyanzi compared to standard of care (14.8 months vs. 5.7 months
[HR: 0.406; p=0.0001]). Although overall survival data were not yet
mature, the prespecified interim analysis showed a trend favoring
Breyanzi compared with the standard of care (HR: 0.509, 95% CI:
0.258-1.004, p=0.0257).
Breyanzi exhibited a manageable 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. In the trial, no Grade 4/5 CRS or neurologic events were
reported. Any-grade CRS was reported in 49% of patients, with Grade
3 CRS reported in only one patient. Any-grade neurologic events
were reported in 12% of patients treated with Breyanzi, with Grade
3 neurologic events reported in four patients (4%).
Results from the long-term follow-up of treatment with Breyanzi
in the TRANSCEND NHL 001 study, the largest pivotal trial in
third-line plus relapsed or refractory LBCL, reinforcing durable
remissions demonstrated with Breyanzi, will also be presented at
the meeting during a poster presentation on Sunday, December 12
(Abstract #2840).
“Breyanzi, a differentiated CD-19 directed CAR T cell therapy,
has the potential to transform the treatment paradigm for relapsed
or refractory LBCL across lines of therapy, with a proven
significant clinical benefit and a consistent safety profile in the
TRANSFORM and TRANSCEND NHL 001 trials presented at this year’s ASH
Annual Meeting,” said Anne Kerber, senior vice president, Cell
Therapy Development, Bristol Myers Squibb. “We designed a
patient-centric clinical trial program for Breyanzi with the
strategic intent to improve outcomes for patients with some of the
most aggressive blood cancers, aligned with our commitment to
advancing a leading cell therapy portfolio for patients in
need.”
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 not indicated for the treatment of patients
with primary central nervous system lymphoma. The U.S. Prescribing
Information for Breyanzi has a BOXED WARNING for the risks 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 use of Breyanzi in primary
refractory or relapsed LBCL is investigational and not approved in
any geography.
About TRANSFORM
TRANSFORM (NCT03575351) is a pivotal, global, randomized,
multicenter Phase 3 trial evaluating Breyanzi compared to current
standard of care regimens in adults with high-risk,
transplant-eligible, relapsed and refractory large B-cell lymphoma
(LBCL). All enrolled patients have LBCL and were relapsed or
refractory within ≤12 months from 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 and hematopoietic stem cell transplant. The primary
endpoint of the study is 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 is a key secondary endpoint. Other
efficacy endpoints include progression-free survival, overall
survival, overall response rate and duration of response.
About TRANSCEND NHL 001
TRANSCEND NHL 001 is an open-label, multicenter, pivotal Phase 1
study to determine the safety, pharmacokinetics, and antitumor
activity of Breyanzi in patients with relapsed/refractory B-cell
non-Hodgkin lymphoma, including diffuse large B-cell lymphoma,
high-grade B-cell lymphoma, primary mediastinal B-cell lymphoma,
follicular lymphoma Grade 3B and mantle cell lymphoma. The primary
outcome measures were treatment-related adverse events,
dose-limiting toxicities and objective response rate. Secondary
outcome measures included complete response rate, duration of
response and progression-free survival.
About Breyanzi
Breyanzi is a CD-19 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.
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 not indicated for the treatment of patients
with primary central nervous system lymphoma.
Breyanzi is also approved in Japan for third-line plus relapsed
and refractory LBCL, and Marketing Authorization Applications for
Breyanzi for this indication are currently under review in the
European Union, Switzerland and Canada. 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 lymphoma. For more information,
visit clinicaltrials.gov.
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 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 Breyanzi (liso-cel) 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, 2020, 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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