-- At Median Follow-Up of 24.2 Months, No
Additional Risks of Adverse Events Related to Yescarta Were
Observed --
-- Findings Also Suggest Efficacy Trend with
Median Progression-Free Survival and Durability of Response of More
Than a Year --
-- Data Presented Orally at the 2024
American Society of Clinical Oncology Annual Meeting --
Kite, a Gilead Company (Nasdaq: GILD), announced data from a
pilot study in collaboration with Dana-Farber Cancer Institute that
demonstrate Yescarta® (axicabtagene ciloleucel) is well-tolerated
in patients living with relapsed or refractory (R/R) primary or
secondary central nervous system lymphoma (PCNSL and SCNSL). The
findings, which also suggest a trend in efficacy, were presented
today in an oral session (Abstract #2006) at the 2024 American
Society of Clinical Oncology (ASCO) Annual Meeting.
Central nervous system lymphoma (CNSL) is an aggressive and rare
form of non-Hodgkin lymphoma that has either originated in
(primary) or spread to (secondary) the brain, eye, spinal cord or
cerebrospinal fluid. The prognosis of PCNSL has historically been
poor with a five-year survival rate of only 30%. More than half of
the patients experience a relapse after front-line treatment, with
a median survival of approximately two months. R/R CNSL is
considered an area of unmet clinical need with no standard of care
treatment options.
“Patients with central nervous system involvement of large
B-cell lymphoma were excluded from the studies that led to the FDA
approval of axi-cel in relapsed/refractory large B-cell lymphoma,”
said Lakshmi Nayak, MD, Associate Professor of Neurology, Harvard
Medical School and Director of the Center for CNS Lymphoma,
Dana-Farber Cancer Institute. “We conducted this pilot study to
evaluate the safety of axi-cel in CNSL patients and to see if there
would be a preliminary signal of efficacy. Not only did we see a
high response rate with axi-cel in this heavily pre-treated
population, but importantly they were durable. While we need more
data to evaluate axi-cel in a larger study, these results are
promising and represent a potential breakthrough in the treatment
of this particularly rare and aggressive brain cancer for which
there are limited options when it recurs.”
In this pilot study of 18 patients with CNSL, at a median
follow-up of 24.2 months, no treatment-limiting toxicities and no
apparent additional risk of adverse events were reported. Immune
effector cell-associated neurologic syndrome (ICANS) was observed
among 44% of patients (27.8% Grade >3).
The objective response rate was 94.4% and the complete response
rate was 66.7%. The median time to best response was three months.
The median duration of response was 13.4 months and 9 patients had
progressed. At a median follow-up of 24 months, the median
progression-free survival was 14.3 months (95% CI: 6.3-NR) and
median overall survival was 26.4 months (95% CI: 11.2-NR).
Ninety percent of patients developed grade 1 or 2 cytokine
release syndrome; two patients developed Ommaya-related meningitis
requiring explant with subsequent recovery. One patient developed
grade 3 electrographic focal status epilepticus that resolved with
anti-epileptic agents. Seven patients have died, all from disease
progression.
“We are very encouraged by the data presented today that
indicate the potential to extend the benefits of Yescarta to people
with relapsed/refractory primary and secondary central nervous
system lymphoma, whose prognoses are typically very poor,” said
Ibrahim Elhoussieny, MD, Vice President, Medical Affairs, Kite.
“These early data support that CAR T-cell therapy may potentially
offer a treatment option to these patients.”
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 Central Nervous System
Lymphoma
Central nervous system lymphoma (CNSL) is an aggressive and rare
form of non-Hodgkin lymphoma that has either originated in
(primary) or spread (secondary) to the brain, eye, spinal cord or
cerebral spinal fluid. The prognosis of PCNSL has historically been
poor with a five-year survival rate of only 30%. More than half of
the patients experience a relapse, after which the average survival
is approximately two months. R/R CNSL is considered an area of
unmet clinical need with no standard of care treatment options.
There is an estimated annual incidence of 1,500 cases of primary
CNSL in the United States. Primary CNS comprises 3% of all primary
brain tumors and 1% of all cases of non-Hodgkin lymphoma. CNSL is
most likely to be seen in the elderly and people with a compromised
immune system.
About the Study
The pilot study enrolled 18 patients (13 PCNSL, 4 SCNSL, 1
concurrent systemic and ocular lymphoma), of whom the first six
patients were observed for treatment-limiting toxicities (TLTs).
The primary endpoint was safety, measured by rate of TLTs and grade
3+ adverse events (AEs). Secondary endpoints included objective
response rate, complete response rate, duration of response,
progression-free survival and overall survival (OS).
About Yescarta
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, NEUROLOGIC
TOXICITIES, and SECONDARY HEMATOLOGICAL MALIGNANCIES
- 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.
- T-cell malignancies have occurred following treatment of
hematologic malignancies with BCMA- and CD19-directed genetically
modified autologous T cell immunotherapies, including
YESCARTA.
- 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
following treatment with YESCARTA. CRS occurred in 90% (379/422) of
patients with non-Hodgkin lymphoma (NHL), including ≥ Grade 3 CRS
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 CRS 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 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
Patients treated with YESCARTA 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
YESCARTA. Mature T-cell malignancies, including CAR-positive
tumors, may present as soon as weeks following infusion, and may
include fatal outcomes.
Monitor life-long for secondary malignancies. In the event that
a secondary malignancy 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 production, 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 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
(such as the foregoing pilot study); the possibility that Gilead
and Kite may make a strategic decision to discontinue development
of programs for indications that are currently under evaluation
and, as a result, these programs may never be successfully
commercialized for such indications; 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 March 31, 2024, 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.
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/20240603718191/en/
Jacquie Ross, Investors Investor_Relations@Gilead.com
Meaghan Smith, Gilead Media Public_Affairs@Gilead.com
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