Approval of LUMOXITI, a first-in-class medicine
for hairy cell leukemia, marks first new treatment option for
patients in over 20 years
AstraZeneca and MedImmune, its global biologics research and
development arm, announced today that the US Food and Drug
Administration (FDA) has approved LUMOXITI™ (moxetumomab
pasudotox-tdfk) for the treatment of adult patients with relapsed
or refractory hairy cell leukemia (HCL) who have received at least
two prior systemic therapies, including treatment with a purine
nucleoside analog. LUMOXITI is not recommended in patients with
severe renal impairment (CrCl ≤ 29 mL/min). The Phase III trial
results demonstrated 75% (95% confidence interval [CI]: 64, 84) of
patients receiving LUMOXITI achieved an overall response; 30% (95%
CI: 20, 41) had a durable complete response.
Dave Fredrickson, Executive Vice-President, Global Head Oncology
Business Unit, said: “Today’s FDA approval of LUMOXITI represents a
significant milestone for people living with hairy cell leukemia, a
rare blood cancer that can result in serious and life-threatening
conditions. For patients, this approval provides the first
FDA-approved medicine for this condition in more than 20
years.”
Robert J. Kreitman, MD, Senior Investigator, Head of Clinical
Immunotherapy Section, Laboratory of Molecular Biology, Center for
Cancer Research, National Cancer Institute, and Principal
Investigator of the Phase III clinical trial, said: “While many
patients with hairy cell leukemia experience a remission with
current treatments, 30% to 40% will relapse five to ten years after
their first treatment. With subsequent treatments, durations
of response diminish and toxicities accumulate, and few approved
treatment options exist. Moxetumomab pasudotox represents a
promising non-chemotherapeutic agent for HCL, addressing an unmet
medical need for physicians and their patients.”
LUMOXITI was approved under FDA Priority Review. The approval is
based on data from the Phase III single-arm, open-label ‘1053’
trial of LUMOXITI monotherapy in 80 patients who have received at
least two prior therapies, including a purine nucleoside analog.
The primary endpoint of the trial was durable complete response.
Summary of key results from the trial, as determined by a blinded
independent central review:
Efficacy Measure Result %,
(95% CI) Durable Complete Response Ratea,b 30% (20, 41)
Overall Response Ratec 75% (64, 84) Complete Responsed
41% (30, 53) Partial Responsee 34% (24, 45)
Hematologic Remissionb 80% a Durable complete
response is defined as patients who achieved complete response with
hematologic remission for a duration of more than 180 days b
Hematologic remission is defined as hemoglobin > 11g/dL,
neutrophils > 1500/mm3, and platelets > 100,000/mm3 without
transfusions or growth factor for at least 4 weeks c Overall
response rate is defined as best overall response of complete
response or partial response d Complete response is defined as
clearing of the bone marrow of hairy cells by routine Hematoxylin
and Eosin stain, radiologic resolution of preexisting
lymphadenopathy and/or organomegaly, and hematologic remission e
Partial response is defined as ≥ 50% decrease or normalization
(< 500/mm3) in peripheral blood lymphocyte count, reduction of
pre-existing lymphadenopathy and/or organomegaly, and hematologic
remission
The median time to hematologic remission was 1.1 months (range:
0.2 to 13). At data cut-off, the median duration of complete
response was not yet reached after a median 16.7 months of
follow-up.
Capillary leak syndrome (CLS) and hemolytic uremic syndrome
(HUS), including life-threatening cases of each, have been reported
among patients treated with LUMOXITI. In the combined safety
database of 129 HCL patients treated with LUMOXITI, Grade 3 or 4
CLS occurred in 1.6% and 2% of patients, respectively. Grade 3 or 4
HUS occurred in 3% and 0.8% of patients, respectively.
In the ‘1053’ trial of 80 patients, the most common Grade 3 or 4
adverse reactions (reported in at least ≥ 5% of patients) were
hypertension, febrile neutropenia, and HUS. HUS was the most common
adverse reaction leading to discontinuation (5%). The most common
adverse reactions (≥ 20%) of any grade were infusion related
reactions (50%), edema (39%), nausea (35%), fatigue (34%), headache
(33%), pyrexia (31%), constipation (23%), anemia (21%), and
diarrhea (21%). The most common laboratory abnormalities (≥ 20%) of
any grade were creatinine increased, ALT increased,
hypoalbuminemia, AST increased, hypocalcemia, hypophosphatemia,
hemoglobin decreased, neutrophil count decreased, hyponatremia,
blood bilirubin increased, hypokalemia, GGT increased,
hypomagnesemia, platelet count decreased, hyperuricemia, and
alkaline phosphate increased.
The recommended dose of LUMOXITI is 0.04 mg/kg administered as
an intravenous infusion over 30 minutes on days 1, 3, and 5 of each
28-day cycle up to 6 cycles, disease progression, or unacceptable
toxicity.
IMPORTANT SAFETY INFORMATION, INCLUDING BOXED WARNING
WARNING: CAPILLARY LEAK SYNDROME and HEMOLYTIC UREMIC
SYNDROME
- Capillary Leak Syndrome (CLS),
including life-threatening cases, occurred in patients receiving
LUMOXITI. Monitor weight and blood pressure; check labs, including
albumin, if CLS is suspected. Delay dosing or discontinue LUMOXITI
as recommended [see Dosage and Administration (2.3) and Warnings
and Precautions (5.1)].
- Hemolytic Uremic Syndrome (HUS),
including life-threatening cases, occurred in patients receiving
LUMOXITI. Monitor hemoglobin, platelet count, serum creatinine, and
ensure adequate hydration. Discontinue LUMOXITI in patients with
HUS [see Dosage and Administration (2.3) and Warnings and
Precautions (5.2)].
WARNINGS AND PRECAUTIONS
- Capillary leak syndrome (CLS),
including life-threatening cases, has been reported among patients
treated with LUMOXITI and is characterized by hypoalbuminemia,
hypotension, symptoms of fluid overload, and hemoconcentration. In
the combined safety database of HCL patients treated with LUMOXITI,
CLS occurred in 34% (44/129) of patients, including Grade 2 in 23%
(30/129), Grade 3 in 1.6% (2/129), and Grade 4 in 2% (3/129).Most
cases of CLS occurred in the first 8 days (range: 1 to 19) of a
treatment cycle, however, cases have also been reported on other
days throughout the cycle. The median time to resolution of CLS was
12 days (range: 1 to 53).Monitor patient weight and blood pressure
prior to each LUMOXITI infusion and as clinically indicated during
treatment. Assess patients for signs and symptoms of CLS, including
weight gain (increase in 5.5 pounds (2.5 kg) or ≥ 5% from Day 1 of
current cycle), hypotension, peripheral edema, shortness of breath
or cough, and pulmonary edema and/or serosal effusions. In
addition, the following changes in laboratory parameters may help
identify CLS: hypoalbuminemia, elevated hematocrit, leukocytosis,
and thrombocytosis.CLS may be life-threatening or fatal if
treatment is delayed. Counsel patients to seek immediate medical
attention should signs or symptoms of CLS occur at any time.
Patients who develop CLS should receive appropriate supportive
measures, including concomitant oral or intravenous
corticosteroids, and hospitalization as clinically indicated.
Withhold LUMOXITI for Grade 2 CLS until resolution, and permanently
discontinue for Grade ≥ 3 CLS.
- Hemolytic Uremic Syndrome (HUS),
including life threatening cases, has been reported in patients
treated with LUMOXITI and is characterized by the triad of
microangiopathic hemolytic anemia, thrombocytopenia, and
progressive renal failure. In the combined safety database of HCL
patients treated with LUMOXITI, HUS occurred in 7% (9/129) of
patients, including Grade 3 in 3% (4/129) and Grade 4 in 0.8%
(1/129).Most cases of HUS occurred in the first 9 days (range: 1 to
16) of a treatment cycle, however, cases have also been reported on
other days throughout the cycle. The median time to resolution of
HUS was 11.5 days (range: 2 to 44). All cases resolved, including
those who discontinued LUMOXITI.Avoid LUMOXITI in patients with
prior history of severe thrombotic microangiopathy (TMA) or HUS.
Administer prophylactic intravenous fluids before and after
LUMOXITI infusions. In Study 1053, patients with a platelet count ≥
100,000/mm received low-dose aspirin on Days 1 through 8 of each
28-day cycle for prophylaxis of thrombosis.Monitor blood chemistry
and complete blood counts prior to each dose and on Day 8 of each
treatment cycle. Monitoring mid-cycle is also recommended. Consider
the diagnosis of HUS in patients who develop hemolytic anemia,
worsening or sudden onset of thrombocytopenia, increase in
creatinine levels, elevation of bilirubin and/or LDH, and have
evidence of hemolysis based on peripheral blood smear
schistocytes.The events of HUS may be life-threatening if treatment
is delayed with increased risk of progressive renal failure
requiring dialysis. If HUS is suspected initiate appropriate
supportive measures, including fluid repletion, hemodynamic
monitoring, and consider hospitalization as clinically indicated.
Discontinue LUMOXITI in patients with HUS.
- Renal Toxicity has been reported
in patients treated with LUMOXITI therapy. In the combined safety
database of HCL patients treated with LUMOXITI, 26% (34/129)
reported adverse events of renal toxicity, including acute kidney
injury (2.3%), renal failure (2.3%), renal impairment (1.6%), serum
creatinine increased (17%), and proteinuria (8%). Grade 3 acute
kidney injury occurred in 1.6% (2/129) of patients.Based on
laboratory findings, during treatment, serum creatinine increased
by two or more grades from baseline in 22% (29/129) of patients,
including increases of Grade 3 in 1.6% (2/129) of patients. At the
end of treatment, serum creatinine levels remained elevated at 1.5-
to 3-times the upper limit of normal in 5% of patients. Patients
who experience HUS, those ≥ 65 years of age, or those with baseline
renal impairment may be at increased risk for worsening of renal
function following treatment with LUMOXITI.Monitor renal function
prior to each infusion of LUMOXITI, and as clinically indicated
throughout treatment. Delay LUMOXITI dosing in patients with Grade
≥ 3 elevations in creatinine, or upon worsening from baseline by ≥
2 grades.
- Infusion Related Reactions
occurred in patients treated with LUMOXITI, and were defined as the
occurrence of any one of the following events on the day of study
drug infusion: chills, cough, dizziness, dyspnea, feeling hot,
flushing, headache, hypertension, hypotension, infusion related
reaction, myalgia nausea, pyrexia, sinus tachycardia, tachycardia,
vomiting, or wheezing. In Study 1053, infusion related reactions
occurred in 50% (40/80) of patients, including Grade 3 events in
11% (9/80) of patients. The most frequently reported infusion
related events were nausea (15%), pyrexia (14%), chills (14%),
vomiting (11%), headache (9%), and infusion related reaction
(9%).Infusion related reactions may occur during any cycle of
treatment with LUMOXITI. Premedicate with antihistamines and
antipyretics prior to each LUMOXITI dose. If a severe infusion
related reaction occurs, interrupt the LUMOXITI infusion and
institute appropriate medical management. Administer an oral or
intravenous corticosteroid approximately 30 minutes before
resuming, or before the next LUMOXITI infusion.
- Electrolyte Abnormalities: In
the combined safety database of HCL patients treated with LUMOXITI,
electrolyte abnormalities occurred in 57% (73/129) of patients with
the most common electrolyte abnormality being hypocalcemia
occurring in 25% of patients. Grade 3 electrolyte abnormalities
occurred in 14% (18/129) of patients and Grade 4 electrolyte
abnormalities occurred in 0.8% (1/129) of patients. Electrolyte
abnormalities co-occurred in the same treatment cycle with CLS,
HUS, fluid retention, or renal toxicity in 37% (48/129) of
patients.Monitor serum electrolytes prior to each dose and on Day 8
of each treatment cycle. Monitoring mid-cycle is also
recommended.
ADVERSE REACTIONS
- Most common non-laboratory adverse
reactions (≥ 20%) of any grade were infusion related reactions
(50%), edema peripheral (39%), nausea (35%), fatigue (34%),
headache (33%), pyrexia (31%), constipation (23%), anemia (21%),
and diarrhea (21%). The most common Grade 3 or 4 adverse reactions
(reported in at least ≥ 5% of patients) were hypertension, febrile
neutropenia, and HUS.
- Most common laboratory abnormalities (≥
20%) of any grade were creatinine increased, ALT increased,
hypoalbuminemia, AST increased, hypocalcemia, hypophosphatemia,
hemoglobin decreased, neutrophil count decreased, hyponatremia,
blood bilirubin increased, hypokalemia, GGT increased,
hypomagnesemia, platelet count decreased, hyperuricemia, and
alkaline phosphate increased.
- Adverse reactions resulting in
permanent discontinuation of LUMOXITI occurred in 15% (12/80) of
patients. The most common adverse reaction leading to LUMOXITI
discontinuation was HUS (5%). The most common adverse reaction
resulting in dose delays, omissions, or interruptions was pyrexia
(3.8%).
SPECIFIC POPULATIONS
- Pregnancy: There are no
available data on LUMOXITI use in pregnant women to inform a
drug-associated risk of major birth defects and miscarriage. Advise
pregnant women of the potential risk to a fetus.
- Lactation: Advise women not to
breastfeed.
- Geriatric Use: Exploratory
analyses suggest a higher incidence of adverse reactions leading to
drug discontinuation (23% versus 7%) and renal toxicity (40% versus
20%) for patients 65 years of age or older as compared to those
younger than 65 years.
Please see complete Prescribing Information,
including Boxed WARNING, Patient Information (Medication Guide),
and Instructions for Use
NOTES TO EDITORS
About Hairy Cell Leukemia
Hairy cell leukemia (HCL) is a rare, chronic, and slow-growing
leukemia in which the bone marrow overproduces abnormal B cell
lymphocytes. HCL can result in serious conditions, including
infections, bleeding and anemia. Approximately 1,000 people are
diagnosed with HCL in the US each year. HCL accounts for up to 3%
of all adult leukemias. While many patients initially respond to
treatment, 30% to 40% will relapse five to ten years after their
first treatment. With no established standard of care and very few
treatments available, there remains significant unmet medical need
for people with relapsed or refractory HCL.
About LUMOXITI
LUMOXITI™ (moxetumomab pasudotox-tdfk, formerly CAT8015 or HA22)
is a CD22-directed cytotoxin and a first-in-class treatment in the
US for adult patients with relapsed or refractory hairy cell
leukemia (HCL) who have received at least two prior systemic
therapies, including treatment with a purine nucleoside analog.
LUMOXITI is not recommended in patients with severe renal
impairment (CrCl ≤ 29 mL/min). It comprises the CD22 binding
portion of an antibody fused to a truncated bacterial toxin; the
toxin inhibits protein synthesis and ultimately triggers apoptotic
cell death. LUMOXITI has been granted Orphan Drug Designation by
the FDA for the treatment of HCL.
About the ‘1053’ Phase III Trial
The ‘1053’ trial is a single-arm, multicenter Phase III clinical
trial assessing the efficacy, safety, immunogenicity and
pharmacokinetics of moxetumomab pasudotox monotherapy in patients
with relapsed or refractory HCL who have received at least two
prior therapies, including one purine nucleoside analog. The trial
was conducted in 80 patients across 34 sites in 14
countries. The primary endpoint was durable complete response
(CR), defined as CR with hematologic remission (blood count
normalization) for >180 days. Secondary outcome measures
included overall response rate, relapse free survival,
progression-free survival, time to response, safety,
pharmacokinetic and immunogenic potential.
Early discovery of moxetumomab pasudotox was led by Dr. Ira
Pastan and colleagues at the National Cancer Institute (NCI). The
collaboration between NCI and MedImmune, AstraZeneca’s global
biologics research and development arm, is an example of how
scientific partnerships can lead to important advances for cancer
patients.
About AstraZeneca in Hematology
Leveraging its strength in oncology, AstraZeneca has established
hematology as one of four key oncology disease areas of focus and
is accelerating development of a broad portfolio of potential blood
cancer treatments. AstraZeneca and Acerta Pharma, its hematology
research and development center of excellence, received US FDA
approval for the first medicine in this franchise in 2017.
About AstraZeneca in Oncology
AstraZeneca has a deep-rooted heritage in Oncology and offers a
quickly-growing portfolio of new medicines that has the potential
to transform patients’ lives and the Company’s future. With at
least six new medicines to be launched between 2014 and 2020, and a
broad pipeline of small molecules and biologics in development, we
are committed to advance Oncology as a growth driver for
AstraZeneca focused on lung, ovarian, breast and blood cancers. In
addition to our core capabilities, we actively pursue innovative
partnerships and investments that accelerate the delivery of our
strategy, as illustrated by our investment in Acerta Pharma in
hematology.
By harnessing the power of four scientific platforms –
Immuno-Oncology, Tumor Drivers and Resistance, DNA Damage Response
and Antibody Drug Conjugates – and by championing the development
of personalized combinations, AstraZeneca has the vision to
redefine cancer treatment and one day eliminate cancer as a cause
of death.
About MedImmune
MedImmune is the global biologics research and development arm
of AstraZeneca, a global, innovation-driven biopharmaceutical
business that focuses on the discovery, development and
commercialization of small molecule and biologic prescription
medicines. MedImmune is pioneering innovative research and
exploring novel pathways across Oncology, Respiratory,
Cardiovascular, Renal & Metabolic Diseases, and Infection and
Vaccines. The MedImmune headquarters is located in Gaithersburg,
Md., one of AstraZeneca’s three global R&D centers, with
additional sites in Cambridge, UK and South San Francisco, CA. For
more information, please visit www.medimmune.com.
About AstraZeneca
AstraZeneca is a global, science-led biopharmaceutical company
that focuses on the discovery, development and commercialization of
prescription medicines, primarily for the treatment of diseases in
three therapy areas – Oncology, Cardiovascular, Renal &
Metabolism and Respiratory. AstraZeneca operates in over 100
countries and its innovative medicines are used by millions of
patients worldwide.
For more information, please visit www.astrazeneca-us.com and
follow us on Twitter @AstraZenecaUS.
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