THOUSAND OAKS, Calif.,
Jan. 22, 2019 /PRNewswire/ -- Amgen
(NASDAQ:AMGN) today announced that the European Commission (EC) has
approved an expanded indication for BLINCYTO®
(blinatumomab) monotherapy to include adult patients with
Philadelphia chromosome negative
(Ph-) CD19 positive B-cell precursor acute lymphoblastic leukemia
(ALL) in first or second complete remission with minimal residual
disease (MRD) greater than or equal to 0.1 percent. The approval
was based on data from the Phase 2 BLAST study in frontline and
relapsed/refractory ALL, the largest prospective trial for
MRD-positive ALL ever conducted. BLINCYTO, a bispecific
CD19-directed CD3 T cell engager (BiTE®), is the first
BiTE® immunotherapy to receive regulatory approval
globally.
MRD refers to the presence of cancer cells that remain
detectable, despite a patient having achieved complete remission by
conventional assessment.1 MRD is only measurable through
the use of highly sensitive testing methods that detect cancer
cells in the bone marrow with a sensitivity of at least one cancer
cell in 10,000 cells – versus about one in 20 with a conventional
microscope-based evaluation.1-3
"This approval represents a paradigm shift in the management of
ALL in the European Union, making BLINCYTO the first and only
treatment with marketing authorization to include the presence of
MRD," said David M. Reese, M.D.,
executive vice president of Research and Development at Amgen. "We
are pleased that the European Commission has seen the value
BLINCYTO can bring to people living with ALL and are proud to
continue to deliver on our commitment to the pursuit of
breakthroughs that can transform the lives of cancer patients."
The EC approval is based on data from the Phase 2 BLAST study,
which found that BLINCYTO induced a complete MRD response, or no
detectable MRD, in 78 percent of patients within one treatment
cycle. Safety results among MRD-positive patients were consistent
with the known safety profile of BLINCYTO in relapsed or refractory
B-cell precursor ALL.
"Survival rates for patients that achieve MRD-negativity are
significantly higher than those for patients that remain
MRD-positive, underscoring the critical importance of early testing
for and eliminating residual disease in patients with ALL," said
Nicola Gökbuget, M.D., principal investigator for the BLAST study
and head of the German Multicenter Study Group for Adult ALL
located in Frankfurt, Germany.
"Data from the BLAST study demonstrated that BLINCYTO is effective
in eliminating detectable residual disease and showed the potential
to improve relapse-free survival in this patient population.
Today's approval provides physicians across Europe with a much-needed treatment option
that can potentially help prevent a relapse, which is associated
with a very unfortunate prognosis."
Approval via the centralized procedure allows for obtaining a
marketing authorization from the EC, which is valid in
all European Union (EU) and European Economic Area
(EEA)-European Free Trade Association (EFTA) states
(Norway, Iceland and Liechtenstein).
In March 2018, the U.S. Food and
Drug Administration (FDA) approved BLINCYTO for the treatment of
adults and children with B-cell precursor ALL in first or second
complete remission with MRD greater than or equal to 0.1
percent.
BLINCYTO is the first immunotherapy from Amgen's
BiTE® platform, an innovative approach that helps the
body's immune system target cancer cells. BiTE® antibody
construct technology, pioneered by Amgen, is an innovative
treatment approach that helps the body's immune system attack
cancer cells without the removal of immune cells from the patient.
Amgen is studying a number of "off-the-shelf" investigational
BiTE® immunotherapies, with distinct targets, across a
range of hematologic and solid tumors.
About the BLAST Study
The BLAST study is the largest
ever prospective trial in patients with MRD-positive ALL. It is an
open-label, multicenter, single-arm, Phase 2 study evaluating the
efficacy, safety and tolerability of BLINCYTO in adult patients
with MRD-positive B-cell precursor ALL in complete hematologic
remission after three or more cycles of intensive chemotherapy.
Patients received continuous IV infusion of BLINCYTO 15
μg/m2/d for four weeks, followed by two weeks off.
Patients received up to four cycles of treatment and could undergo
hematopoietic stem cell transplantation at any time after the first
cycle, if eligible. Efficacy was based on achievement of
undetectable MRD within one cycle of BLINCYTO treatment and
hematological relapse-free survival (RFS). Additional
secondary endpoints included incidence and severity of adverse
events, overall survival, time to hematological remission and
duration of complete MRD response.
Results from the BLAST study were presented at the
57th American Society of Hematology (ASH) Annual Meeting
& Exposition in 2015 and published in Blood in 2018.
Long-term overall survival (OS) data results from the BLAST study
were also featured in an oral presentation during the ASH 2018
Annual Meeting & Exposition on Dec. 3,
2018.
About ALL and MRD
ALL is a rapidly progressing cancer
of the blood and bone marrow that occurs in both adults and
children.4,5 Poor outcomes have been observed in
patients who achieve first or second complete hematologic remission
but have persistent MRD, which remains detectable at the molecular
level after treatment.1,6 For more information about
MRD, please visit AmgenOncology.com.
About
BiTE® Technology
Bispecific T cell
engager (BiTE®) antibody construct is an innovative
technology that can be engineered to target any tumor antigen
expressed by any type of cancer. The protein molecules are designed
to kill malignant cells using the patient's own immune system by
bridging T cells to tumor cells. The BiTE® antibody
construct helps connect the T cells to the targeted cell, with the
intent of causing T cells to inject toxins which trigger cancer
cell death (apoptosis). Amgen is developing
BiTE® antibody constructs to uniquely (or
specifically) target numerous hematologic malignancies and solid
tumors.
About
BLINCYTO® (blinatumomab)
BLINCYTO is
a bispecific CD19-directed CD3 T cell engager (BiTE®)
immunotherapy that binds to CD19 expressed on the surface of cells
of B-lineage origin and CD3 expressed on the surface of effector T
cells. BLINCYTO was granted breakthrough therapy and priority
review designations by the FDA in 2014, and carries full
approval in the U.S. for the treatment of relapsed or
refractory B-cell precursor ALL in adults and children. In the
U.S., BLINCYTO is also approved for the treatment of adults and
children with B-cell precursor ALL in first or second complete
remission with MRD greater than or equal to 0.1 percent. This
indication is approved under accelerated approval based on MRD
response rate and hematological relapse-free survival. Continued
approval for this indication may be contingent upon verification
and description of clinical benefit in the confirmatory trials. In
the EU, BLINCYTO is indicated for the treatment of adults with Ph-
relapsed or refractory B-precursor ALL and for the treatment of Ph-
CD19 positive B-cell precursor ALL in first or second complete
remission with MRD greater than or equal to 0.1 percent.
BLINCYTO is now approved in 57 countries, including all member
countries in the EU and EEA, Canada, Japan
and Australia.
Important EU BLINCYTO® (blinatumomab) Safety
Information
This product is subject to additional monitoring in the EU.
All suspected adverse reactions should be reported in accordance
with the national reporting system.
The adverse reactions described in this section were identified
in clinical studies of patients with B-precursor ALL (N = 843). The
most serious adverse reactions that may occur during blinatumomab
treatment include: infections (24.8%), neurologic events (13.8%),
neutropenia/febrile neutropenia (10.1%), cytokine release syndrome
(3.3%), and tumour lysis syndrome (0.7%). The most common adverse
reactions were: pyrexia (69.2%), infusion-related reactions
(43.4%), infections – pathogen unspecified (42.1%), headache
(32.9%), anaemia (22.8%), thrombocytopenia (20.9%), febrile
neutropenia (20.2%), oedema (20.0%), neutropenia (19.7%), rash
(16.7%), increased liver hepatic enzymes (16.1%), bacterial
infectious disorders (15.4%), tremor (15.2%), cough (15.1%),
leukopenia (13.4%), back pain (13.3%), chills (13.0%), hypotension
(12.8%), viral infectious disorders (12.7%), decreased
immunoglobulins (12.5%), cytokine release syndrome (11.6%),
tachycardia (11.3%), insomnia (10.7%), fungal infectious disorders
(10.6%) and pain in extremity (10.2%).
Please refer to the Summary of Product Characteristics for
full European prescribing information.
Important Safety Information Regarding BLINCYTO®
(blinatumomab) U.S. Indication
WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGICAL
TOXICITIES
- Cytokine Release Syndrome (CRS), which may be
life-threatening or fatal, occurred in patients receiving
BLINCYTO®. Interrupt or discontinue BLINCYTO®
as recommended.
- Neurological toxicities, which may be severe,
life-threatening or fatal, occurred in patients receiving
BLINCYTO®. Interrupt or discontinue BLINCYTO®
as recommended.
Contraindications
BLINCYTO® is contraindicated in patients with a
known hypersensitivity to blinatumomab or to any component of the
product formulation.
Warnings and Precautions
- Cytokine Release Syndrome (CRS): CRS, which may be
life-threatening or fatal, occurred in patients receiving
BLINCYTO®. The median time to onset of CRS is 2 days
after the start of infusion. Closely monitor patients for signs and
symptoms of serious adverse events such as fever, headache, nausea,
asthenia, hypotension, increased alanine aminotransferase (ALT),
increased aspartate aminotransferase (AST), increased total
bilirubin (TBILI), and disseminated intravascular coagulation
(DIC). The manifestations of CRS after treatment with BLINCYTO
overlap with those of infusion reactions, capillary leak syndrome
(CLS), and hemophagocytic histiocytosis/macrophage activation
syndrome (MAS). In clinical trials of BLINCYTO, CRS was reported in
15% of patients with relapsed or refractory ALL and in 7% of
patients with MRD-positive ALL. Interrupt or discontinue
BLINCYTO® for evidence of CRS, as outlined in the
PI.
- Neurological Toxicities: Approximately 65% of patients
receiving BLINCYTO® in clinical trials experienced
neurological toxicities. The median time to the first event was
within the first 2 weeks of BLINCYTO® treatment, and the
majority of events resolved. The most common (≥ 10%) manifestations
of neurological toxicity were headache and tremor. Severe,
life‐threatening, or fatal neurological toxicities occurred in
approximately 13% of patients, including encephalopathy,
convulsions, speech disorders, disturbances in consciousness,
confusion and disorientation, and coordination and balance
disorders. Manifestations of neurological toxicity included cranial
nerve disorders. Monitor patients for signs or symptoms of
neurological toxicity and interrupt or discontinue
BLINCYTO® as outlined in the PI.
- Infections: Approximately 25% of patients receiving
BLINCYTO® in clinical trials experienced serious
infections such as sepsis, pneumonia, bacteremia, opportunistic
infections, and catheter-site infections, some of which were
life-threatening or fatal. Administer prophylactic antibiotics and
employ surveillance testing as appropriate during treatment.
Monitor patients for signs or symptoms of infection and treat
appropriately, including interruption or discontinuation of
BLINCYTO® as needed.
- Tumor Lysis Syndrome (TLS), which may be life-threatening or
fatal, has been observed. Preventive measures, including
pretreatment nontoxic cytoreduction and on-treatment hydration,
should be used during BLINCYTO® treatment. Monitor
patients for signs and symptoms of TLS and interrupt or discontinue
BLINCYTO® as needed to manage these events.
- Neutropenia and Febrile Neutropenia, including life-threatening
cases, have been observed. Monitor appropriate laboratory
parameters (including, but not limited to, white blood cell count
and absolute neutrophil count) during BLINCYTO® infusion
and interrupt BLINCYTO® if prolonged neutropenia
occurs.
- Effects on Ability to Drive and Use Machines: Due to the
possibility of neurological events, including seizures, patients
receiving BLINCYTO® are at risk for loss of
consciousness, and should be advised against driving and engaging
in hazardous occupations or activities such as operating heavy or
potentially dangerous machinery while BLINCYTO® is being
administered.
- Elevated Liver Enzymes: Transient elevations in liver enzymes
have been associated with BLINCYTO® treatment with a
median time to onset of 3 days. In patients receiving
BLINCYTO®, although the majority of these events were
observed in the setting of CRS, some cases of elevated liver
enzymes were observed outside the setting of CRS, with a median
time to onset of 19 days. Grade 3 or greater elevations in liver
enzymes occurred in approximately 7% of patients outside the
setting of CRS and resulted in treatment discontinuation in less
than 1% of patients. Monitor ALT, AST, gamma-glutamyl transferase
(GGT), and TBILI prior to the start of and during
BLINCYTO® treatment. BLINCYTO® treatment
should be interrupted if transaminases rise to > 5 times the
upper limit of normal (ULN) or if TBILI rises to > 3 times
ULN.
- Pancreatitis: Fatal pancreatitis has been reported in patients
receiving BLINCYTO® in combination with dexamethasone in
clinical trials and the post-marketing setting. Evaluate patients
who develop signs and symptoms of pancreatitis and interrupt or
discontinue BLINCYTO® and dexamethasone as needed.
- Leukoencephalopathy: Although the clinical significance is
unknown, cranial magnetic resonance imaging (MRI) changes showing
leukoencephalopathy have been observed in patients receiving
BLINCYTO®, especially in patients previously treated
with cranial irradiation and antileukemic chemotherapy.
- Preparation and administration errors have occurred with
BLINCYTO® treatment. Follow instructions for preparation
(including admixing) and administration in the PI strictly to
minimize medication errors (including underdose and overdose).
- Immunization: Vaccination with live virus vaccines is not
recommended for at least 2 weeks prior to the start of
BLINCYTO® treatment, during treatment, and until immune
recovery following last cycle of BLINCYTO®.
- Risk of Serious Adverse Reactions in Pediatric Patients due to
Benzyl Alcohol Preservative: Serious and fatal adverse reactions
including "gasping syndrome," which is characterized by central
nervous system depression, metabolic acidosis, and gasping
respirations, can occur in neonates and infants treated with benzyl
alcohol-preserved drugs including BLINCYTO® (with
preservative). When prescribing BLINCYTO® (with
preservative) for pediatric patients, consider the combined daily
metabolic load of benzyl alcohol from all sources including
BLINCYTO® (with preservative) and other drugs containing
benzyl alcohol. The minimum amount of benzyl alcohol at which
serious adverse reactions may occur is not known. Due to the
addition of bacteriostatic saline, 7-day bags of
BLINCYTO® solution for infusion with preservative
contain benzyl alcohol and are not recommended for use in any
patients weighing < 22 kg.
Adverse Reactions
- The most common adverse reactions (≥ 20%) in clinical trial
experience of patients with MRD-positive B-cell precursor ALL
(BLAST Study) treated with BLINCYTO® were pyrexia, infusion related
reactions, headache, infections (pathogen unspecified), tremor, and
chills. Serious adverse reactions were reported in 61% of patients.
The most common serious adverse reactions (≥ 2%) included pyrexia,
tremor, encephalopathy, aphasia, lymphopenia, neutropenia,
overdose, device related infection, seizure, and staphylococcal
infection.
- The most common adverse reactions (≥ 20%) in clinical trial
experience of patients with Philadelphia chromosome-negative relapsed or
refractory B-cell precursor ALL (TOWER Study) treated with
BLINCYTO® were infections (bacterial and pathogen
unspecified), pyrexia, headache, infusion-related reactions,
anemia, febrile neutropenia, thrombocytopenia, and neutropenia.
Serious adverse reactions were reported in 62% of patients. The
most common serious adverse reactions (≥ 2%) included febrile
neutropenia, pyrexia, sepsis, pneumonia, overdose, septic shock,
CRS, bacterial sepsis, device related infection, and
bacteremia.
- Adverse reactions that were observed more frequently (≥ 10%) in
the pediatric population compared to the adult population were
pyrexia (80% vs. 61%), hypertension (26% vs. 8%), anemia (41% vs.
24%), infusion-related reaction (49% vs. 34%), thrombocytopenia
(34% vs. 21%), leukopenia (24% vs. 11%), and weight increase (17%
vs. 6%).
- In pediatric patients less than 2 years old (infants), the
incidence of neurologic toxicities was not significantly different
than for the other age groups, but its manifestations were
different; the only event terms reported were agitation, headache,
insomnia, somnolence, and irritability. Infants also had an
increased incidence of hypokalemia (50%) compared to other
pediatric age cohorts (15-20%) or adults (17%).
Dosage and Administration Guidelines
- BLINCYTO® is administered as a continuous
intravenous infusion at a constant flow rate using an infusion pump
which should be programmable, lockable, non-elastomeric, and have
an alarm.
- It is very important that the instructions for preparation
(including admixing) and administration provided in the full
Prescribing Information are strictly followed to minimize
medication errors (including underdose and overdose).
Please see full Prescribing Information, including Boxed
WARNINGS and Medication Guide, for BLINCYTO®.
About Amgen's Commitment to Oncology
Amgen
Oncology is committed to helping patients take on some of the
toughest cancers, such as those that have been resistant to drugs,
those that progress rapidly through the body and those where
limited treatment options exist. Amgen's supportive care
treatments help patients combat certain side effects of strong
chemotherapy, and our targeted medicines and immunotherapies focus
on more than a dozen different malignancies, ranging from blood
cancers to solid tumors. With decades of experience providing
therapies for cancer patients, Amgen continues to grow
its portfolio of innovative and biosimilar oncology medicines.
For more information, follow us on
www.twitter.com/amgenoncology.
About Amgen
Amgen is committed to unlocking
the potential of biology for patients suffering from serious
illnesses by discovering, developing, manufacturing and delivering
innovative human therapeutics. This approach begins by using tools
like advanced human genetics to unravel the complexities of disease
and understand the fundamentals of human biology.
Amgen focuses on areas of high unmet medical need and
leverages its expertise to strive for solutions that improve health
outcomes and dramatically improve people's lives. A biotechnology
pioneer since 1980, Amgen has grown to be one of the
world's leading independent biotechnology companies, has reached
millions of patients around the world and is developing a pipeline
of medicines with breakaway potential.
For more information, visit www.amgen.com and follow
us on www.twitter.com/amgen.
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CONTACT: Amgen, Thousand
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Kristen Davis, 805-447-3008
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Emma Gilbert, +41 413692542
References:
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leukemia: a changing definition and concept? Bone Marrow
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- Gökbuget N, et al. Adult patients with acute lymphoblastic
leukemia and molecular failure display a poor prognosis and are
candidates for stem cell transplantation and targeted therapies.
Blood. 2012;120:1868-1876.
- Brüggemann M, et al. Has MRD monitoring superseded other
prognostic factors in adult ALL? Blood.
2012;120:4470-4481.
- Cancer Research UK. About acute lymphoblastic leukaemia (ALL).
http://www.cancerresearchuk.org/about-cancer/acute-lymphoblastic-leukaemia-all/about.
Accessed Nov. 1, 2018.
- Mayo Clinic. Acute lymphocytic leukemia.
http://www.mayoclinic.org/diseases-conditions/acute-lymphocytic-leukemia/basics/definition/con-20042915.
Accessed Nov. 1, 2018.
- Bassan R, Spinelli O, Oldani E, et al. Improved risk
classification for risk-specific therapy based on the molecular
study of minimal residual disease (MRD) in adult acute
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