-- Yescarta is the First and Only Treatment
in Nearly 30 Years to Demonstrate Superior Overall Survival for
Patients with Relapsed/Refractory Large B-cell Lymphoma Versus
Standard of Care as Second-Line Treatment With Curative Intent*
--
Kite, a Gilead Company (Nasdaq: GILD), today announced that the
U.S. Food and Drug Administration (FDA) has approved a label update
for Yescarta® (axicabtagene ciloleucel) to include the overall
survival (OS) primary analysis from the landmark Phase 3 ZUMA-7
study showing a statistically significant improvement for Yescarta
in OS versus standard of care (SOC) as second-line treatment with
curative intent for patients with relapsed or refractory large
B-cell lymphoma (R/R LBCL) within 12 months of completion of
first-line therapy.
The label update is based on results from the ZUMA-7 study which
demonstrated a 27.4% reduction in the risk of death with Yescarta
versus SOC, a relative 38% improvement in OS. With an estimated
median follow up of 46.7 months overall, the primary analysis of OS
showed a statistically significant improvement in the Yescarta arm
compared to the standard therapy arm, despite more than half of
patients (57%) in the SOC arm subsequently receiving cell therapy
off protocol. The estimated 39-month OS rates were 55.9% in the
Yescarta arm and 46% in the SOC arm.
“This U.S. label update for Yescarta is an important step to
reinforce healthcare provider confidence to treat eligible patients
with Yescarta, immediately following progression or relapse in
large B-cell lymphoma,” said Frank Neumann, MD, PhD, Senior Vice
President and Global Head of Clinical Development, Kite. “Our
ZUMA-7 overall survival analysis proves that when given as
second-line therapy, Yescarta is even more effective in improving
patient survival than standard of care treatment. Coupled with our
rapid and reliable manufacturing, it is our hope to provide
patients a chance to live longer lives.”
SOC therapy for this patient population has historically been a
multi-step process expected to end with stem-cell transplant. The
process starts with chemoimmunotherapy, and if a patient responds
and can tolerate further treatment, they move on to high-dose
chemotherapy (HDT), followed by autologous stem cell transplant
(ASCT). Despite this being the prior SOC, less than 40% of patients
who started this multi-step process made it through to complete
stem cell transplant, compared with 94% of patients randomized to
Yescarta in the ZUMA-7 study who received a one-time Yescarta
infusion.
Underscoring the Significance for Patients
As the first and only treatment in nearly 30 years to improve
survival for patients with R/R LBCL in this setting, Yescarta can
potentially change the standard of care for these patients who
previously had limited options for long-term remission.
“Lymphoma Research Foundation has continuously supported efforts
for the development of new treatments in large B-cell lymphoma with
the shared goal of finding a cure,” said Meghan Gutierrez, Chief
Executive Officer, Lymphoma Research Foundation. “We applaud Kite
for bringing the oncology community one step closer to eradicating
large B-cell lymphoma and offering new hope to patients.”
In November 2023, the European Medicines Agency approved an
update to the Summary of Product Characteristics (SmPC) to include
the ZUMA-7 overall survival analysis.
*Treatment of curative intent is a line of treatment
administered with the goal of achieving a durable complete
response/ remission. 2017. NIH National Library of Medicine
“Curative, Life-Extending and Palliative Chemotherapy: New Outcomes
Need New Names”
About ZUMA-7 Study
ZUMA-7 is a randomized, open-label, global, multicenter, Phase 3
study evaluating the safety and efficacy of Yescarta versus SOC for
initial treatment of adult patients with R/R LBCL within 12 months
of first-line therapy. In the study, 359 patients in 77 centers
around the world were randomized (1:1) to receive a single infusion
of Yescarta or prior SOC second-line treatment. The primary
endpoint is EFS as determined by blinded central review and defined
as the time from randomization to the earliest date of disease
progression per Lugano Classification, commencement of new lymphoma
therapy, or death from any cause. Key secondary endpoints include
objective response rate (ORR) and OS. Additional secondary
endpoints include patient reported outcomes (PROs) and safety. Per
hierarchical testing of primary and key secondary endpoints and
group sequential testing of OS, an interim analysis of OS occurred
at the time of the primary EFS analysis. The prespecified primary
OS analysis was to be conducted after 210 deaths or no later than
five years after the first patient was randomized.
Yescarta demonstrated a 2.5-fold increase in patients who were
alive at two years and did not experience cancer progression or
require the need for additional cancer treatment (40.5% vs. 16.3%)
and a four-fold greater median EFS (8.3 mo. vs. 2.0 mo.) compared
to SOC (hazard ratio 0.398; 95% CI: 0.308-0.514, P<0.0001). In
addition to being the largest and longest study of its kind, ZUMA-7
study participants on the Yescarta arm did not receive additional
bridging chemotherapy that could have potentially confounded
results.
Nearly three times as many patients randomized to Yescarta
ultimately received the definitive CAR T-cell therapy treatment
(94%) versus those randomized to SOC (35%) who received on-protocol
HDT+ASCT. More patients responded to Yescarta (ORR: 83% vs. 50%,
odds ratio: 5.31 [95% CI: 3.1-8.9; P<0.0001) and achieved a
complete response (CR) with Yescarta (CR rate: 65% vs. 32%) than
with SOC. At the time of the primary EFS analysis, more than half
of patients in the SOC arm subsequently received Yescarta off
study.
In the study, Yescarta had a safety profile that was consistent
with previous studies. Among the 168 Yescarta-treated patients
evaluable for safety, Grade ≥3 cytokine release syndrome (CRS) and
neurologic events were observed in 7% and 25% of patients,
respectively. In the SOC arm, 83% of patients had high grade
events, mostly cytopenias (low blood counts).
The Yescarta U.S. Prescribing Information has a BOXED WARNING
for the risks of CRS and neurologic toxicities, and Yescarta is
approved with a Risk Evaluation and Mitigation Strategy (REMS) due
to these risks; see below for Important Safety Information.
About Large B-Cell Lymphoma
(LBCL)
Globally, LBCL is the most common type of non-Hodgkin lymphoma
(NHL). In the United States, more than 18,000 people are diagnosed
with LBCL each year. About 30-40% of patients with LBCL will need
second-line treatment, as their cancer will either relapse (return)
or become refractory (not respond) to initial treatment.
About Yescarta (Axicabtagene
Ciloleucel)
Please see full US Prescribing Information, including BOXED
WARNING and Medication Guide.
YESCARTA is a CD19-directed genetically modified autologous T
cell immunotherapy indicated for the treatment of:
- Adult patients with large B-cell lymphoma that is refractory to
first-line chemoimmunotherapy or that relapses within 12 months of
first-line chemoimmunotherapy.
- Adult patients with relapsed or refractory large B-cell
lymphoma after two or more lines of systemic therapy, including
diffuse large B-cell lymphoma (DLBCL) not otherwise specified,
primary mediastinal large B-cell lymphoma, high-grade B-cell
lymphoma, and DLBCL arising from follicular lymphoma.
- Limitations of Use: YESCARTA is
not indicated for the treatment of patients with primary central
nervous system lymphoma.
- Adult patients with relapsed or refractory follicular lymphoma
(FL) after two or more lines of systemic therapy. This indication
is approved under accelerated approval based on the response rate.
Continued approval for this indication may be contingent upon
verification and description of clinical benefit in the
confirmatory trial(s).
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
YESCARTA. Do not administer YESCARTA to patients with active
infection or inflammatory disorders. Treat severe or
life-threatening CRS with tocilizumab or tocilizumab and
corticosteroids.
- Neurologic toxicities, including fatal or life-threatening
reactions, occurred in patients receiving YESCARTA, including
concurrently with CRS or after CRS resolution. Monitor for
neurologic toxicities after treatment with YESCARTA. Provide
supportive care and/or corticosteroids as needed.
- YESCARTA is available only through a restricted program
under a Risk Evaluation and Mitigation Strategy (REMS) called the
YESCARTA and TECARTUS REMS Program.
CYTOKINE RELEASE SYNDROME (CRS)
CRS, including fatal or life-threatening reactions, occurred.
CRS occurred in 90% (379/422) of patients with non-Hodgkin lymphoma
(NHL), including ≥ Grade 3 in 9%. CRS occurred in 93% (256/276) of
patients with large B-cell lymphoma (LBCL), including ≥ Grade 3 in
9%. Among patients with LBCL who died after receiving YESCARTA, 4
had ongoing CRS events at the time of death. For patients with LBCL
in ZUMA-1, the median time to onset of CRS was 2 days following
infusion (range: 1-12 days) and the median duration was 7 days
(range: 2-58 days). For patients with LBCL in ZUMA-7, the median
time to onset of CRS was 3 days following infusion (range: 1-10
days) and the median duration was 7 days (range: 2-43 days). CRS
occurred in 84% (123/146) of patients with indolent non-Hodgkin
lymphoma (iNHL) in ZUMA-5, including ≥ Grade 3 in 8%. Among
patients with iNHL who died after receiving YESCARTA, 1 patient had
an ongoing CRS event at the time of death. The median time to onset
of CRS was 4 days (range: 1-20 days) and the median duration was 6
days (range: 1-27 days) for patients with iNHL.
Key manifestations of CRS (≥ 10%) in all patients combined
included fever (85%), hypotension (40%), tachycardia (32%), chills
(22%), hypoxia (20%), headache (15%), and fatigue (12%). Serious
events that may be associated with CRS include cardiac arrhythmias
(including atrial fibrillation and ventricular tachycardia), renal
insufficiency, cardiac failure, respiratory failure, cardiac
arrest, capillary leak syndrome, multi-organ failure, and
hemophagocytic lymphohistiocytosis/macrophage activation
syndrome.
The impact of tocilizumab and/or corticosteroids on the
incidence and severity of CRS was assessed in 2 subsequent cohorts
of LBCL patients in ZUMA-1. Among patients who received tocilizumab
and/or corticosteroids for ongoing Grade 1 events, CRS occurred in
93% (38/41), including 2% (1/41) with Grade 3 CRS; no patients
experienced a Grade 4 or 5 event. The median time to onset of CRS
was 2 days (range: 1-8 days) and the median duration of CRS was 7
days (range: 2-16 days). Prophylactic treatment with
corticosteroids was administered to a cohort of 39 patients for 3
days beginning on the day of infusion of YESCARTA. Thirty-one of
the 39 patients (79%) developed CRS and were managed with
tocilizumab and/or therapeutic doses of corticosteroids with no
patients developing ≥ Grade 3 CRS. The median time to onset of CRS
was 5 days (range: 1-15 days) and the median duration of CRS was 4
days (range: 1-10 days). Although there is no known mechanistic
explanation, consider the risk and benefits of prophylactic
corticosteroids in the context of pre-existing comorbidities for
the individual patient and the potential for the risk of Grade 4
and prolonged neurologic toxicities.
Ensure that 2 doses of tocilizumab are available prior to
YESCARTA infusion. Monitor patients for signs and symptoms of CRS
at least daily for 7 days at the certified healthcare facility, and
for 4 weeks thereafter. Counsel patients to seek immediate medical
attention should signs or symptoms of CRS occur at any time. At the
first sign of CRS, institute treatment with supportive care,
tocilizumab, or tocilizumab and corticosteroids as indicated.
NEUROLOGIC TOXICITIES
Neurologic toxicities (including immune effector cell-associated
neurotoxicity syndrome) that were fatal or life-threatening
occurred. Neurologic toxicities occurred in 78% (330/422) of all
patients with NHL receiving YESCARTA, including ≥ Grade 3 in 25%.
Neurologic toxicities occurred in 87% (94/108) of patients with
LBCL in ZUMA-1, including ≥ Grade 3 in 31% and in 74% (124/168) of
patients in ZUMA-7 including ≥ Grade 3 in 25%. The median time to
onset was 4 days (range: 1-43 days) and the median duration was 17
days for patients with LBCL in ZUMA-1. The median time to onset for
neurologic toxicity was 5 days (range:1- 133 days) and the median
duration was 15 days in patients with LBCL in ZUMA-7. Neurologic
toxicities occurred in 77% (112/146) of patients with iNHL,
including ≥ Grade 3 in 21%. The median time to onset was 6 days
(range: 1-79 days) and the median duration was 16 days.
Ninety-eight percent of all neurologic toxicities in patients with
LBCL and 99% of all neurologic toxicities in patients with iNHL
occurred within the first 8 weeks of YESCARTA infusion. Neurologic
toxicities occurred within the first 7 days of infusion for 87% of
affected patients with LBCL and 74% of affected patients with
iNHL.
The most common neurologic toxicities (≥ 10%) in all patients
combined included encephalopathy (50%), headache (43%), tremor
(29%), dizziness (21%), aphasia (17%), delirium (15%), and insomnia
(10%). Prolonged encephalopathy lasting up to 173 days was noted.
Serious events, including aphasia, leukoencephalopathy, dysarthria,
lethargy, and seizures occurred. Fatal and serious cases of
cerebral edema and encephalopathy, including late-onset
encephalopathy, have occurred.
The impact of tocilizumab and/or corticosteroids on the
incidence and severity of neurologic toxicities was assessed in 2
subsequent cohorts of LBCL patients in ZUMA-1. Among patients who
received corticosteroids at the onset of Grade 1 toxicities,
neurologic toxicities occurred in 78% (32/41), and 20% (8/41) had
Grade 3 neurologic toxicities; no patients experienced a Grade 4 or
5 event. The median time to onset of neurologic toxicities was 6
days (range: 1-93 days) with a median duration of 8 days (range:
1-144 days). Prophylactic treatment with corticosteroids was
administered to a cohort of 39 patients for 3 days beginning on the
day of infusion of YESCARTA. Of those patients, 85% (33/39)
developed neurologic toxicities, 8% (3/39) developed Grade 3, and
5% (2/39) developed Grade 4 neurologic toxicities. The median time
to onset of neurologic toxicities was 6 days (range: 1-274 days)
with a median duration of 12 days (range: 1-107 days). Prophylactic
corticosteroids for management of CRS and neurologic toxicities may
result in a higher grade of neurologic toxicities or prolongation
of neurologic toxicities, delay the onset of and decrease the
duration of CRS.
Monitor patients for signs and symptoms of neurologic toxicities
at least daily for 7 days at the certified healthcare facility, and
for 4 weeks thereafter, and treat promptly.
REMS
Because of the risk of CRS and neurologic toxicities, YESCARTA
is available only through a restricted program called the YESCARTA
and TECARTUS REMS Program which requires that: Healthcare
facilities that dispense and administer YESCARTA must be enrolled
and comply with the REMS requirements and must have on-site,
immediate access to a minimum of 2 doses of tocilizumab for each
patient for infusion within 2 hours after YESCARTA infusion, if
needed for treatment of CRS. Certified healthcare facilities must
ensure that healthcare providers who prescribe, dispense, or
administer YESCARTA are trained in the management of CRS and
neurologic toxicities. Further information is available at
www.YescartaTecartusREMS.com or 1-844-454-KITE (5483).
HYPERSENSITIVITY REACTIONS
Allergic reactions, including serious hypersensitivity reactions
or anaphylaxis, may occur with the infusion of YESCARTA.
SERIOUS INFECTIONS
Severe or life-threatening infections occurred. Infections (all
grades) occurred in 45% of patients with NHL; ≥ Grade 3 infections
occurred in 17% of patients, including ≥ Grade 3 infections with an
unspecified pathogen in 12%, bacterial infections in 5%, viral
infections in 3%, and fungal infections in 1%. YESCARTA should not
be administered to patients with clinically significant active
systemic infections. Monitor patients for signs and symptoms of
infection before and after infusion and treat appropriately.
Administer prophylactic antimicrobials according to local
guidelines.
Febrile neutropenia was observed in 36% of all patients with NHL
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.
In immunosuppressed patients, including those who have received
YESCARTA, life-threatening and fatal opportunistic infections
including disseminated fungal infections (e.g., candida sepsis and
aspergillus infections) and viral reactivation (e.g., human herpes
virus-6 [HHV-6] encephalitis and JC virus progressive multifocal
leukoencephalopathy [PML]) have been reported. The possibility of
HHV-6 encephalitis and PML should be considered in immunosuppressed
patients with neurologic events and appropriate diagnostic
evaluations should be performed.
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, including
YESCARTA. Perform screening for HBV, HCV, and HIV in accordance
with clinical guidelines before collection of cells for
manufacturing.
PROLONGED CYTOPENIAS
Patients may exhibit cytopenias for several weeks following
lymphodepleting chemotherapy and YESCARTA infusion. ≥ Grade 3
cytopenias not resolved by Day 30 following YESCARTA infusion
occurred in 39% of all patients with NHL and included neutropenia
(33%), thrombocytopenia (13%), and anemia (8%). Monitor blood
counts after infusion.
HYPOGAMMAGLOBULINEMIA
B-cell aplasia and hypogammaglobulinemia can occur.
Hypogammaglobulinemia was reported as an adverse reaction in 14% of
all patients with NHL. Monitor immunoglobulin levels after
treatment and manage using infection precautions, antibiotic
prophylaxis, and immunoglobulin replacement. The safety of
immunization with live viral vaccines during or following YESCARTA
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 YESCARTA treatment, and
until immune recovery following treatment.
SECONDARY MALIGNANCIES
Secondary malignancies may develop. Monitor life-long for
secondary malignancies. In the event that one occurs, contact Kite
at 1-844-454-KITE (5483) to obtain instructions on patient samples
to collect for testing.
EFFECTS ON ABILITY TO DRIVE AND USE MACHINES
Due to the potential for neurologic events, including altered
mental status or seizures, patients are at risk for altered or
decreased consciousness or coordination in the 8 weeks following
YESCARTA infusion. Advise patients to refrain from driving and
engaging in hazardous occupations or activities, such as operating
heavy or potentially dangerous machinery, during this initial
period.
ADVERSE REACTIONS
The most common non-laboratory adverse reactions (incidence ≥
20%) in patients with LBCL in ZUMA-7 included fever, CRS, fatigue,
hypotension, encephalopathy, tachycardia, diarrhea, headache,
musculoskeletal pain, nausea, febrile neutropenia, chills, cough,
infection with an unspecified pathogen, dizziness, tremor,
decreased appetite, edema, hypoxia, abdominal pain, aphasia,
constipation, and vomiting.
The most common adverse reactions (incidence ≥ 20%) in patients
with LBCL in ZUMA-1 included CRS, fever, hypotension,
encephalopathy, tachycardia, fatigue, headache, decreased appetite,
chills, diarrhea, febrile neutropenia, infections with an
unspecified, nausea, hypoxia, tremor, cough, vomiting, dizziness,
constipation, and cardiac arrhythmias.
The most common non-laboratory adverse reactions (incidence ≥
20%) in patients with iNHL in ZUMA-5 included fever, CRS,
hypotension, encephalopathy, fatigue, headache, infections with an
unspecified, tachycardia, febrile neutropenia, musculoskeletal
pain, nausea, tremor, chills, diarrhea, constipation, decreased
appetite, cough, vomiting, hypoxia, arrhythmia, and dizziness.
About Kite
Kite, a Gilead Company, is a global biopharmaceutical company
based in Santa Monica, California, focused on cell therapy to treat
and potentially cure cancer. As the global cell therapy leader,
Kite has treated more patients with CAR T-cell therapy than any
other company. Kite has the largest in-house cell therapy
manufacturing network in the world, spanning process development,
vector manufacturing, clinical trial supply and commercial product
manufacturing.
About Gilead Sciences
Gilead Sciences, Inc. is a biopharmaceutical company that has
pursued and achieved breakthroughs in medicine for more than three
decades, with the goal of creating a healthier world for all
people. The company is committed to advancing innovative medicines
to prevent and treat life-threatening diseases, including HIV,
viral hepatitis and cancer. Gilead operates in more than 35
countries worldwide, with headquarters in Foster City, California.
Gilead Sciences acquired Kite in 2017.
Forward-Looking
Statements
This press release includes forward-looking statements, within
the meaning of the Private Securities Litigation Reform Act of 1995
that are subject to risks, uncertainties and other factors,
including the ability of Gilead and Kite to initiate, progress or
complete clinical trials within currently anticipated timelines or
at all, and the possibility of unfavorable results from ongoing or
additional clinical studies, including those involving Yescarta;
the possibility that Gilead and Kite may make a strategic decision
to discontinue development of any programs for indications
currently under evaluation and, as a result, these programs and/or
indications may never be successfully commercialized; the risk that
physicians may not see the benefits of prescribing Yescarta; and
any assumptions underlying any of the foregoing. These and other
risks, uncertainties and factors are described in detail in
Gilead’s Quarterly Report on Form 10-Q for the quarter ended
September 30, 2023, as filed with the U.S. Securities and Exchange
Commission. These risks, uncertainties and other factors could
cause actual results to differ materially from those referred to in
the forward-looking statements. All statements other than
statements of historical fact are statements that could be deemed
forward-looking statements. The reader is cautioned that any such
forward-looking statements are not guarantees of future performance
and involve risks and uncertainties, and is cautioned not to place
undue reliance on these forward-looking statements. All
forward-looking statements are based on information currently
available to Gilead and Kite, and Gilead and Kite assume no
obligation and disclaim any intent to update any such
forward-looking statements.
U.S. Prescribing Information for Yescarta
including BOXED WARNING, is available at www.kitepharma.com and
www.gilead.com .
Kite, the Kite logo, Yescarta, and GILEAD are
trademarks of Gilead Sciences, Inc. or its related companies.
For more information on Kite, please visit the
company’s website at www.kitepharma.com. Follow Kite on social
media on X ( @KitePharma ) and LinkedIn.
View source
version on businesswire.com: https://www.businesswire.com/news/home/20231220595740/en/
Jacquie Ross, Investors investor_relations@gilead.com
Meaghan Smith, Gilead Media msmith@gilead.com
Anna Padula, Kite Media apadula@kitepharma.com
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