Two Phase III CALQUENCE trials demonstrated
superior progression-free survival across multiple settings while
maintaining favorable tolerability
CALQUENCE combined with obinutuzumab and as
monotherapy reduced the risk of disease progression or death by 90%
and 80%, respectively in ELEVATE-TN
AstraZeneca today announced that the US Food and Drug
Administration (FDA) has approved CALQUENCE® (acalabrutinib) for
adult patients with chronic lymphocytic leukemia (CLL) or small
lymphocytic lymphoma (SLL). The US approval was granted under the
FDA’s Real-Time Oncology Review and newly established Project Orbis
programs.
The approval is based on positive results from the interim
analyses of two Phase III clinical trials, ELEVATE-TN in patients
with previously untreated CLL and ASCEND in patients with relapsed
or refractory CLL. Together, the trials showed that CALQUENCE in
combination with obinutuzumab or as a monotherapy significantly
reduced the relative risk of disease progression or death versus
the comparator arms in both 1st-line and relapsed or refractory
CLL. Across both trials, the safety and tolerability of CALQUENCE
were consistent with its established profile.
Dave Fredrickson, Executive Vice President, Oncology Business
Unit said: “With over 20,000 new cases anticipated this year in the
US alone, today’s approval of CALQUENCE provides new hope for
patients with one of the most common types of adult leukemia,
offering outstanding efficacy and a favorable tolerability profile.
The chronic lymphocytic leukemia patient population is known to
face multiple comorbidities, and tolerability is a critical factor
in their treatment.”
Dr. Jeff Sharman, Director of Research at Willamette Valley
Cancer Institute, Medical Director of Hematology Research for The
US Oncology Network, and a lead author of the ELEVATE-TN trial,
said: “Tolerability remains an issue in the current treatment
landscape of chronic lymphocytic leukemia, which may require
ongoing therapy for many years. In the ELEVATE-TN and ASCEND trials
comparing CALQUENCE to commonly used treatment regimens, CALQUENCE
demonstrated a clinically meaningful improvement in
progression-free survival in patients across multiple settings,
while maintaining its favorable tolerability and safety
profile.”
The results of the interim analysis of the ELEVATE-TN trial will
be presented at the upcoming American Society of Hematology
congress.
The trial showed a statistically significant and clinically
meaningful improvement in progression-free survival (PFS) for
patients treated with either CALQUENCE in combination with
obinutuzumab or CALQUENCE monotherapy versus chlorambucil
chemotherapy plus obinutuzumab, a current standard-of-care
combination used in the control arm.
In the CALQUENCE combination arm, risk of disease progression or
death was reduced by 90% (HR 0.10; 95% CI, 0.06-0.17, p<0.0001)
and in the monotherapy arm it was reduced by 80% (HR 0.20; 95% CI,
0.13-0.30, p<0.0001).
The median time to disease progression for patients treated with
CALQUENCE in combination with obinutuzumab or as a monotherapy has
not yet been reached vs. 22.6 months (95% CI, 20-28) for
chlorambucil plus obinutuzumab.
ELEVATE-TN safety overview
(most common ARs*, ≥15%):
Adverse reaction
CALQUENCE plus obinutuzumab
(n=178)
CALQUENCE monotherapy
(n=179)
Chlorambucil plus obinutuzumab
(n=169)
Any
Grade ≥3
Any
Grade ≥3
Any
Grade ≥3
Infection†
69%
22%
65%
14%
46%
13%
Neutropenia†
53%
37%
23%
13%
78%
50%
Anemia†
52%
12%
53%
10%
54%
14%
Thrombocytopenia†
51%
12%
32%
3.4%
61%
16%
Headache
40%
1.1%
39%
1.1%
12%
0
Diarrhea
39%
4.5%
35%
0.6%
21%
1.8%
Musculoskeletal pain†
37%
2.2%
32%
1.1%
16%
2.4%
Fatigue†
34%
2.2%
23%
1.1%
24%
1.2%
Bruising†
31%
0
21%
0
5%
0
Rash†
26%
2.2%
25%
0.6%
9%
0.6%
Arthralgia
22%
1.1%
16%
0.6%
4.7%
1.2%
Dizziness
20%
0
12%
0
7%
0
Hemorrhage†
20%
1.7%
20%
1.7%
6%
0
Nausea
20%
0
22%
0
31%
0
Lymphocytosis†
12%
11%
16%
15%
0.6%
0.6%
†Includes multiple ADR terms
In patients treated with the combination of CALQUENCE plus
obinutuzumab, adverse reactions (ARs) led to treatment
discontinuation in 11% of patients and a dose reduction of
CALQUENCE in 7% of patients. In the monotherapy arm, ARs led to
discontinuation in 10% and dose reduction in 4% of patients. In the
control arm, ARs led to regimen discontinuation in 14% of patients
with a dose reduction of chlorambucil in 28% of patients. There
were no dose reductions for obinutuzumab.
In 1,029 patients with hematologic malignancies who were treated
with CALQUENCE 100mg approximately every 12 hours across multiple
clinical trials, where 88% received treatment for at least six
months and 79% received treatment for at least one year, serious or
Grade ≥3 infections occurred in 19%, and Grade 3 atrial
fibrillation and flutter occurred in 1.1% of patients. In the same
patient population, major hemorrhage occurred in 3.0% (serious or
Grade ≥3 bleeding or any central nervous system bleeding), with
fatal hemorrhage occurring in 0.1% of patients. Second primary
malignancies (all grades) including skin cancers occurred in 12% of
patients.
The US approval is among the first to be granted under Project
Orbis, an initiative of the US FDA Oncology Center of Excellence,
which provides a framework for concurrent submission and review of
oncology medicines among international partners. The FDA, the
Australian Therapeutic Goods Administration, and Health Canada
collaborated on this review.
INDICATION AND USAGE
CALQUENCE is a Bruton tyrosine kinase (BTK) inhibitor indicated
for the treatment of adult patients with mantle cell lymphoma (MCL)
who have received at least one prior therapy.
This indication is approved under accelerated
approval based on overall response rate. Continued approval for
this indication may be contingent upon verification and description
of clinical benefit in confirmatory trials.
CALQUENCE is indicated for the treatment of adult patients with
chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma
(SLL).
IMPORTANT SAFETY INFORMATION ABOUT CALQUENCE® (acalabrutinib)
capsules
Serious and Opportunistic Infections
Fatal and serious infections, including opportunistic
infections, have occurred in patients with hematologic malignancies
treated with CALQUENCE.
Serious or Grade 3 or higher infections (bacterial, viral, or
fungal) occurred in 19% of 1029 patients exposed to CALQUENCE in
clinical trials, most often due to respiratory tract infections
(11% of all patients, including pneumonia in 6%). These infections
predominantly occurred in the absence of Grade 3 or 4 neutropenia,
with neutropenic infection reported in 1.9% of all patients.
Opportunistic infections in recipients of CALQUENCE have included,
but are not limited to, hepatitis B virus reactivation, fungal
pneumonia, Pneumocystis jiroveci pneumonia, Epstein-Barr virus
reactivation, cytomegalovirus, and progressive multifocal
leukoencephalopathy (PML). Consider prophylaxis in patients who are
at increased risk for opportunistic infections. Monitor patients
for signs and symptoms of infection and treat promptly.
Hemorrhage
Fatal and serious hemorrhagic events have occurred in patients
with hematologic malignancies treated with CALQUENCE. Major
hemorrhage (serious or Grade 3 or higher bleeding or any central
nervous system bleeding) occurred in 3.0% of patients, with fatal
hemorrhage occurring in 0.1% of 1029 patients exposed to CALQUENCE
in clinical trials. Bleeding events of any grade, excluding
bruising and petechiae, occurred in 22% of patients.
Use of antithrombotic agents concomitantly with CALQUENCE may
further increase the risk of hemorrhage. In clinical trials, major
hemorrhage occurred in 2.7% of patients taking CALQUENCE without
antithrombotic agents and 3.6% of patients taking CALQUENCE with
antithrombotic agents. Consider the risks and benefits of
antithrombotic agents when co-administered with CALQUENCE. Monitor
patients for signs of bleeding.
Consider the benefit-risk of withholding CALQUENCE for 3-7 days
pre- and post-surgery depending upon the type of surgery and the
risk of bleeding.
Cytopenias
Grade 3 or 4 cytopenias, including neutropenia (23%), anemia
(8%), thrombocytopenia (7%), and lymphopenia (7%), developed in
patients with hematologic malignancies treated with CALQUENCE.
Grade 4 neutropenia developed in 12% of patients. Monitor complete
blood counts regularly during treatment. Interrupt treatment,
reduce the dose, or discontinue treatment as warranted.
Second Primary Malignancies
Second primary malignancies, including skin cancers and other
solid tumors, occurred in 12% of 1029 patients exposed to CALQUENCE
in clinical trials. The most frequent second primary malignancy was
skin cancer, reported in 6% of patients. Monitor patients for skin
cancers and advise protection from sun exposure.
Atrial Fibrillation and Flutter
Grade 3 atrial fibrillation or flutter occurred in 1.1% of 1029
patients treated with CALQUENCE, with all grades of atrial
fibrillation or flutter reported in 4.1% of all patients. The risk
may be increased in patients with cardiac risk factors,
hypertension, previous arrhythmias, and acute infection. Monitor
for symptoms of arrhythmia (e.g., palpitations, dizziness, syncope,
dyspnea) and manage as appropriate.
ADVERSE REACTIONS
The most common adverse reactions (≥ 20%) of any grade in
patients with relapsed or refractory MCL were anemia,*
thrombocytopenia,* headache (39%), neutropenia,* diarrhea (31%),
fatigue (28%), myalgia (21%), and bruising (21%). The most common
Grade ≥ 3 non-hematological adverse reaction (reported in at least
2% of patients) was diarrhea (3.2%).
*Treatment-emergent decreases (all grades) of hemoglobin (46%),
platelets (44%), and neutrophils (36%) were based on laboratory
measurements and adverse reactions.
Dose reductions or discontinuations due to any adverse reaction
were reported in 1.6% and 6.5% of patients, respectively. Increases
in creatinine 1.5 to 3 times the upper limit of normal occurred in
4.8% of patients.
The most common adverse reactions (≥ 30%) of any grade in
patients with CLL were anemia,* neutropenia,* thrombocytopenia,*
headache, upper respiratory tract infection, and diarrhea.
*Treatment-emergent decreases (all grades) of hemoglobin,
platelets, and neutrophils were based on laboratory measurements
and adverse reactions.
In patients with previously untreated CLL exposed to CALQUENCE,
fatal adverse reactions that occurred in the absence of disease
progression and with onset within 30 days of the last study
treatment were reported in 2% for each treatment arm, most often
from infection. Serious adverse reactions were reported in 39% of
patients in the CALQUENCE plus obinutuzumab arm and 32% in the
CALQUENCE monotherapy arm, most often due to events of pneumonia
(7% and 2.8%, respectively).
Adverse reactions led to CALQUENCE dose reduction in 7% and 4%
of patients in the CALQUENCE plus obinutuzumab arm (N=178) and
CALQUENCE monotherapy arm (N=179), respectively. Adverse events led
to discontinuation in 11% and 10% of patients, respectively.
Increases in creatinine 1.5 to 3 times the upper limit of normal
occurred in 3.9% and 2.8% of patients in the CALQUENCE combination
arm and monotherapy arm, respectively.
In patients with relapsed/refractory CLL exposed to CALQUENCE,
serious adverse reactions occurred in 29% of patients. Serious
adverse reactions in > 5% of patients who received CALQUENCE
included lower respiratory tract infection (6%). Fatal adverse
reactions within 30 days of the last dose of CALQUENCE occurred in
2.6% of patients, including from second primary malignancies and
infection.
Adverse reactions led to CALQUENCE dose reduction in 3.9% of
patients (N=154), dose interruptions in 34% of patients, most often
due to respiratory tract infections followed by neutropenia, and
discontinuation in 10% of patients, most frequently due to second
primary malignancies followed by infection. Increases in creatinine
1.5 to 3 times the upper limit of normal occurred in 1.3% of
patients who received CALQUENCE.
DRUG INTERACTIONS
Strong CYP3A Inhibitors: Avoid co-administration with a
strong CYP3A inhibitor. If a strong CYP3A inhibitor will be used
short-term, interrupt CALQUENCE.
Moderate CYP3A Inhibitors: When CALQUENCE is
co-administered with a moderate CYP3A inhibitor, reduce CALQUENCE
dose to 100 mg once daily.
Strong CYP3A Inducers: Avoid co-administration with a
strong CYP3A inducer. If a strong CYP3A inducer cannot be avoided,
increase the CALQUENCE dose to 200 mg approximately every 12
hours.
Gastric Acid Reducing Agents: If treatment with a gastric
acid reducing agent is required, consider using an H2-receptor
antagonist or an antacid. Take CALQUENCE 2 hours before taking an
H2-receptor antagonist. Separate dosing with an antacid by at least
2 hours.
Avoid co-administration with proton pump inhibitors. Due to the
long-lasting effect of proton pump inhibitors, separation of doses
may not eliminate the interaction with CALQUENCE.
SPECIFIC POPULATIONS
Based on findings in animals, CALQUENCE may cause fetal harm and
dystocia when administered to a pregnant woman. There are no
available data in pregnant women to inform the drug-associated
risk. Advise pregnant women of the potential risk to a fetus.
Pregnancy testing is recommended for females of reproductive
potential prior to initiating CALQUENCE therapy. Advise female
patients of reproductive potential to use effective contraception
during treatment with CALQUENCE and for at least 1 week following
the last dose of CALQUENCE.
It is not known if CALQUENCE is present in human milk. Advise
lactating women not to breastfeed while taking CALQUENCE and for at
least 2 weeks after the final dose.
Avoid administration of CALQUENCE in patients with severe
hepatic impairment. Dose modifications are not required for
patients with mild or moderate hepatic impairment.
Please see full Prescribing Information including Patient
Information.
– ENDS –
NOTES TO EDITORS
About CALQUENCE
In the US, CALQUENCE® (acalabrutinib) is indicated for the
treatment of adult patients with chronic lymphocytic leukemia (CLL)
or small lymphocytic lymphoma (SLL). In the US, Canada, Brazil,
Qatar, the United Arab Emirates, Mexico, Argentina, Singapore,
Chile, and recently India, CALQUENCE is indicated for adult
patients with mantle cell lymphoma (MCL) who have received at least
one prior therapy. Approved under accelerated review in the US,
continued approval for previously-treated MCL is contingent upon
verification and confirmation of clinical benefit in confirmatory
trials.
CALQUENCE is a next-generation selective inhibitor of Bruton
tyrosine kinase (BTK). CALQUENCE binds covalently to BTK, thereby
inhibiting its activity. In B-cells, BTK signaling results in
activation of pathways necessary for B-cell proliferation,
trafficking, chemotaxis, and adhesion.
As part of an extensive clinical development program,
AstraZeneca and Acerta Pharma are currently evaluating CALQUENCE in
23 company-sponsored clinical trials. CALQUENCE is being developed
for the treatment of multiple B-cell blood cancers including CLL,
MCL, diffuse large B-cell lymphoma, Waldenstrom macroglobulinemia,
follicular lymphoma, and other hematologic malignancies. Several
Phase III clinical trials in CLL are ongoing, including ASCEND,
ELEVATE-TN, ELEVATE-RR (ACE-CL-006) evaluating acalabrutinib vs.
ibrutinib in patients with previously-treated high-risk CLL, and
ACE-CL-311 evaluating acalabrutinib in combination with venetoclax
and with/without obinutuzumab vs. chemoimmunotherapy in patients
with previously-untreated CLL without 17p deletion or TP53
mutation.
About ELEVATE-TN
ELEVATE-TN (ACE-CL-007) is a randomized, multicenter, open-label
Phase III trial evaluating the safety and efficacy of CALQUENCE in
combination with obinutuzumab, a CD20 monoclonal antibody, or
CALQUENCE alone vs. chlorambucil, a chemotherapy, in combination
with obinutuzumab in previously-untreated patients with CLL. In the
trial, 535 patients were randomized (1:1:1) into three arms.
Patients in the first arm received chlorambucil in combination with
obinutuzumab. Patients in the second arm received CALQUENCE (100mg
twice daily until disease progression or unacceptable toxicity) in
combination with obinutuzumab. Patients in the third arm received
CALQUENCE monotherapy (100mg twice daily until disease progression
or unacceptable toxicity).
The primary endpoint is PFS in the CALQUENCE and obinutuzumab
arm compared to the chlorambucil and obinutuzumab arm, assessed by
an independent review committee (IRC), and a key secondary endpoint
is IRC-assessed PFS in the CALQUENCE monotherapy arm compared to
the chlorambucil and obinutuzumab arm. Other secondary endpoints
include objective response rate, time to next treatment and overall
survival.
About ASCEND
ASCEND (ACE-CL-309) is a global, randomized, multicenter,
open-label Phase III trial evaluating the efficacy of CALQUENCE in
previously treated patients with CLL. In the trial, 310 patients
were randomized (1:1) into two arms. Patients in the first arm
received CALQUENCE monotherapy (100mg twice daily until disease
progression or unacceptable toxicity). Patients in the second arm
received investigator’s choice of either rituximab, a CD20
monoclonal antibody, in combination with idelalisib, a PI3K
inhibitor, or rituximab in combination with bendamustine, a
chemotherapy.
The primary endpoint is PFS assessed by an IRC, and key
secondary endpoints include physician-assessed PFS, IRC- and
physician-assessed overall response rate and duration of response,
as well as overall survival, patient-reported outcomes and time to
next treatment.
About CLL
Chronic lymphocytic leukemia (CLL) is one of the most common
types of leukemia in adults, with an estimated 105,000 new cases
globally and 20,720 new cases in the US in 2019, and the number of
people living with CLL is expected to grow with improved treatment
as patients live longer with disease. In CLL, too many blood stem
cells in the bone marrow become abnormal lymphocytes and these
abnormal cells have difficulty fighting infections. As the number
of abnormal cells grows there is less room for healthy white blood
cells, red blood cells and platelets. This could result in anemia,
infection and bleeding. B-cell receptor signaling through BTK is
one of the essential growth pathways for CLL.
About AstraZeneca in hematology
Leveraging its strength in oncology, AstraZeneca has established
hematology as one of four key oncology disease areas of focus. The
Company’s hematology franchise includes two US FDA-approved
medicines and a robust global development program for a broad
portfolio of potential blood cancer treatments. Acerta Pharma
serves as AstraZeneca’s hematology research and development arm.
AstraZeneca partners with like-minded science-led companies to
advance the discovery and development of therapies to address unmet
need.
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 key growth driver for
AstraZeneca focused on lung, ovarian, breast and blood cancers. In
addition to AstraZeneca’s main capabilities, the Company is
actively pursuing 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 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. Please visit www.astrazeneca-us.com and follow
the Company on Twitter @AstraZenecaUS.
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