– Positive Opinion Based on Landmark ZUMA-7
Study in Which 41% of Patients Demonstrated Event-Free Survival at
Two Years versus 16% for Standard of Care -
Kite, a Gilead Company (Nasdaq: GILD), today announces that the
European Medicines Agency (EMA) Committee for Medicinal Products
for Human Use (CHMP) has issued a positive opinion for Yescarta®
(axicabtagene ciloleucel) for adult patients with diffuse large
B-cell lymphoma (DLBCL) and high-grade B-cell lymphoma (HGBL) that
relapses within 12 months from completion of, or is refractory to,
first-line chemoimmunotherapy. If approved, Yescarta will be the
first Chimeric Antigen Receptor (CAR) T-cell therapy approved for
patients in Europe who do not respond to first-line treatment.
Although 60% of newly diagnosed LBCL patients will respond to their
initial treatment, 40% will relapse or will not respond and need
2nd line treatment.
“At Kite, we are committed to bringing the curative potential of
cell therapy to the world, and changing the way cancer is treated,”
said Christi Shaw, CEO, Kite. “Today’s positive CHMP opinion brings
us a step closer to utilizing cell therapy earlier in the treatment
journey, potentially transforming the standard of care for the most
common and aggressive form of non-Hodgkin lymphoma.”
The European Commission will review the CHMP opinion, and a
final decision on the marketing authorization is expected in the
coming months.
“For people with DLBCL and HGBL who do not respond to first-line
treatment or have an early relapse, outcomes are often poor and
there are limited curative treatment options for these patients,”
said Marie José Kersten, Professor of Hematology at Amsterdam
University Medical Centers, Amsterdam. “If approved, axicabtagene
ciloleucel may offer a new standard of care for patients with
relapsed or refractory DLBCL and HGBL. Importantly, in a randomized
trial of axicabtagene ciloleucel versus the current standard of
care, quality of life also showed greater improvement in the
experimental arm.”
The positive opinion for Yescarta is based on the primary
results of the landmark Phase 3 ZUMA-7 study, the largest and
longest trial of a CAR T-cell therapy versus standard of care (SOC)
in second-line LBCL. Results demonstrated that at a median
follow-up of two years, Yescarta-treated patients had a four-fold
greater improvement in the primary endpoint of event-free survival
(EFS; hazard ratio 0.40; 95% CI: 0.31-0.51, P<0.001) over the
current SOC (8.3 months v 2.0 months). Additionally, Yescarta
demonstrated a 2.5 fold increase in patients who were alive at two
years without disease progression or need for additional cancer
treatment vs SOC (41% v 16%). Improvements in EFS with Yescarta
were consistent across key patient subgroups, including elderly
patients (HR: 0.28 [95% CI: 0.16-0.46]), primary refractory
patients (HR: 0.43 [95% CI: 0.32- 0.57]), high-grade B cell
lymphoma including double-hit and triple-hit lymphoma patients
(HGBL; HR: 0.28 [95% CI: 0.14-0.59]), and double expressor lymphoma
patients (HR: 0.42 [95% CI: 0.27-0.67]).
In a separate, secondary analysis of Patient-Reported Outcomes
(PROs) published in Blood patients receiving Yescarta and eligible
for the PROs portion of the study (n=165) showed statistically
significant improvements in Quality of Life (QoL) at Day 100
compared with those who received SOC (n=131), using a pre-specified
analysis for three PRO-domains (EORTC QLQ-C30 Physical Functioning,
EORTC QLQ-C30 Global Health Status/QOL, and EQ-5D-5L visual analog
scale [VAS]). There was also a trend toward faster recovery to
baseline QoL in the Yescarta arm versus SOC.
In the ZUMA-7 trial, Yescarta had a manageable safety profile
that was consistent with previous studies. Among the 170
Yescarta-treated patients evaluable for safety, Grade ≥3 cytokine
release syndrome (CRS) and neurologic events were observed in 6%
and 21% of patients, respectively. No Grade 5 CRS or neurologic
events occurred. In the SOC arm, 83% of patients had high-grade
events, mostly cytopenias (low blood counts).
About ZUMA-7
ZUMA-7 is an ongoing, randomized, open-label, global,
multicenter (US, Australia, Canada, Europe, Israel) Phase 3 study
of 359 patients at 77 centers, evaluating the safety and efficacy
of a single-infusion of Yescarta versus current SOC for second-line
therapy (platinum-based salvage combination chemotherapy regimen
followed by high-dose chemotherapy and autologous stem cell
transplant in those who respond to salvage chemotherapy) in adult
patients with relapsed or refractory LBCL within 12 months of
first-line therapy. The primary endpoint is event free survival
(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 overall survival (OS). Additional secondary
endpoints include patient reported outcomes (PROs) and safety.
About Yescarta
Yescarta was first approved in Europe in 2018 and is currently
indicated for three types of blood cancer: Diffuse Large B-Cell
Lymphoma (DLBCL); Primary Mediastinal Large B-Cell Lymphoma
(PMBCL); and Follicular Lymphoma (FL). For the full European
Prescribing Information, please visit:
https://www.ema.europa.eu/en/medicines/human/EPAR/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 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, with manufacturing operations in
North America and Europe. Kite’s singular focus is cell therapy to
treat and potentially cure cancer. As the cell therapy leader, Kite
has more approved CAR T indications to help more patients than any
other company. For more information on Kite, please visit
www.kitepharma.com. Follow Kite on social media on Twitter
(@KitePharma) and LinkedIn.
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.
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 and
additional clinical trials, including those involving Yescarta;
uncertainties relating to regulatory applications and related
filing and approval timelines, including the risk that the European
Commission may not grant marketing authorization for Yescarta for
use in second-line DLBCL and HGBL in a timely manner or at all; the
risk that any regulatory approvals, if granted, may be subject to
significant limitations on use; the risk that physicians may not
see the benefits of prescribing Yescarta for the treatment of LBCL;
and any assumptions underlying any of the foregoing. These and
other risks, uncertainties and other factors are described in
detail in Gilead’s Quarterly Report on Form 10-Q for the quarter
ended June 30, 2022 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.
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version on businesswire.com: https://www.businesswire.com/news/home/20220916005209/en/
Jacquie Ross, Investors investor_relations@gilead.com
Anna Padula, Media apadula@kitepharma.com
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