An encouraging 88% of patients on CALQUENCE remained free of disease
progression after 12 months, vs. 68% of patients on rituximab combined
with idelalisib or bendamustine
AstraZeneca today announced detailed results from the interim analysis
of the Phase III ASCEND trial at the European Hematology Association
(EHA) Annual Congress in Amsterdam, showing CALQUENCE®
(acalabrutinib) significantly prolonged the time patients lived without
disease progression in relapsed or refractory chronic lymphocytic
leukemia (CLL).
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The ASCEND trial compared CALQUENCE with the investigator’s choice of
rituximab combined with idelalisib (IdR) or bendamustine (BR) in
patients with relapsed or refractory CLL.
At a median follow-up of 16.1 months, results from the trial showed a
statistically-significant and clinically-meaningful improvement in
progression-free survival (PFS) for patients treated with CALQUENCE vs.
IdR or BR, reducing the risk of disease progression or death by 69% (HR,
0.31: 95% CI, 0.20-0.49, p<0.0001). The median time without disease
progression or death for patients treated with CALQUENCE has not yet
been reached vs. 16.5 months in the control arm. At 12 months, 88% of
patients on CALQUENCE showed no disease progression compared to 68% for
the control arm. The safety and tolerability of CALQUENCE was consistent
with its established profile.
José Baselga, Executive Vice President, Oncology R&D said: “These data
add to the growing body of evidence to support the profile of CALQUENCE
as a selective BTK inhibitor that offers a chemotherapy-free treatment
option with a favorable safety profile in chronic lymphocytic leukemia,
a life-threatening disease. These data, along with our recent positive
results from the Phase III ELEVATE-TN trial in previously-untreated
chronic lymphocytic leukemia, will serve as the foundation for
regulatory submissions later this year.”
Paolo Ghia, MD, Professor, Medical Oncology, Università Vita-Salute San
Raffaele in Milan, and investigator of the ASCEND trial, said: “This is
the first randomized study to directly compare a BTK inhibitor as
monotherapy with standard chemoimmunotherapy or idelalisib and rituximab
combinations. With a significant improvement in progression-free
survival and a favorable safety profile, acalabrutinib may become an
important choice for the treatment of patients with relapsed or
refractory chronic lymphocytic leukemia.”
Safety overview:
|
|
Most common (≥15%)
AEs, n (%)
|
|
CALQUENCE (N = 154)
|
|
IdR (N = 118)
|
|
BR (N = 35)
|
|
|
Any
|
|
Grade ≥3
|
|
Any
|
|
Grade ≥3
|
|
Any
|
|
Grade ≥3
|
|
Headache
|
|
34 (22%)
|
|
1 (1%)
|
|
7 (6%)
|
|
0
|
|
0
|
|
0
|
|
Neutropenia
|
|
30 (19%)
|
|
24 (16%)
|
|
53 (45%)
|
|
47 (40%)
|
|
12 (34%)
|
|
11 (31%)
|
|
Diarrhea
|
|
28 (18%)
|
|
2 (1%)
|
|
55 (47%)
|
|
28 (24%)
|
|
5 (14%)
|
|
0
|
|
Anemia
|
|
23 (15%)
|
|
18 (12%)
|
|
11 (9%)
|
|
8 (7%)
|
|
4 (11%)
|
|
3 (9%)
|
|
Cough
|
|
23 (15%)
|
|
0
|
|
18 (15%)
|
|
1 (1%)
|
|
2 (6%)
|
|
0
|
|
Pyrexia
|
|
19 (12%)
|
|
1 (1%)
|
|
21 (18%)
|
|
8 (7%)
|
|
6 (17%)
|
|
1 (3%)
|
|
Fatigue
|
|
15 (10%)
|
|
2 (1%)
|
|
10 (8%)
|
|
0
|
|
8 (23%)
|
|
1(3%)
|
|
Nausea
|
|
11 (7%)
|
|
0
|
|
15 (13%)
|
|
1 (1%)
|
|
7 (20%)
|
|
0
|
|
IRR*
|
|
0
|
|
0
|
|
9 (8%)
|
|
2 (2%)
|
|
8 (23%)
|
|
1 (3%)
|
|
Events of clinical interest for CALQUENCE
|
|
Atrial fibrillation
|
|
8 (5%)
|
|
2 (1%)
|
|
4 (3%)
|
|
1 (1%)
|
|
1 (3%)
|
|
1 (3%)
|
|
Bleeding
|
|
40 (26%)
|
|
3 (2%)
|
|
9 (8%)
|
|
3 (3%)
|
|
2 (6%)
|
|
1(3%)
|
|
Hypertension
|
|
5 (3%)
|
|
3 (2%)
|
|
5 (4%)
|
|
1 (1%)
|
|
0
|
|
0
|
|
SPM** excluding NMSC***
|
|
10 (6%)
|
|
5 (3%)
|
|
3 (3%)
|
|
0
|
|
1 (3%)
|
|
1 (3%)
|
|
*Infusion related reaction **Secondary primary malignancy
***Non-melanoma skin cancer.
|
|
AstraZeneca recently announced
that the Phase III ELEVATE-TN trial met its primary endpoint at interim
analysis in patients with previously-untreated CLL and that full results
will be reported at a forthcoming medical meeting.
IMPORTANT SAFETY INFORMATION ABOUT CALQUENCE (acalabrutinib)
Hemorrhage
Serious hemorrhagic events, including fatal events, have occurred in the
combined safety database of 612 patients with hematologic malignancies
treated with CALQUENCE monotherapy. Grade 3 or higher bleeding events,
including gastrointestinal, intracranial, and epistaxis, have been
reported in 2% of patients. Overall, bleeding events, including bruising
and petechiae of any grade, occurred in approximately 50% of patients
with hematological malignancies.
The mechanism for the bleeding events is not well understood.
CALQUENCE may further increase the risk of hemorrhage in patients
receiving antiplatelet or anticoagulant therapies, and patients should
be monitored for signs of bleeding.
Consider the benefit-risk of withholding CALQUENCE for 3 to 7 days pre-
and post-surgery, depending upon the type of surgery and the risk of
bleeding.
Infection
Serious infections (bacterial, viral, or fungal), including fatal events
and opportunistic infections, have occurred in the combined safety
database of 612 patients with hematologic malignancies treated with
CALQUENCE monotherapy. Grade 3 or higher infections occurred in 18% of
these patients. The most frequently reported Grade 3 or 4 infection was
pneumonia. Infections due to hepatitis B virus (HBV) reactivation and
progressive multifocal leukoencephalopathy (PML) have occurred.
Monitor patients for signs and symptoms of infection and treat as
medically appropriate. Consider prophylaxis in patients who are at
increased risk for opportunistic infections.
Cytopenias
In the combined safety database of 612 patients with hematologic
malignancies, patients treated with CALQUENCE monotherapy experienced
Grade 3 or 4 cytopenias, including neutropenia (23%), anemia (11%), and
thrombocytopenia (8%), based on laboratory measurements. Monitor
complete blood counts monthly during treatment.
Second Primary Malignancies
Second primary malignancies, including non-skin carcinomas, have
occurred in 11% of patients with hematologic malignancies treated with
CALQUENCE monotherapy in the combined safety database of 612 patients.
The most frequent second primary malignancy was skin cancer, reported in
7% of patients. Advise protection from sun exposure.
Atrial Fibrillation and Flutter
In the combined safety database of 612 patients with hematologic
malignancies treated with CALQUENCE monotherapy, atrial fibrillation and
atrial flutter of any grade occurred in 3% of patients, and Grade 3 in
1% of patients. Monitor for atrial fibrillation and atrial flutter and
manage as appropriate.
ADVERSE REACTIONS
The most common adverse reactions (≥20%) of any grade were anemia,*
thrombocytopenia,* headache (39%), neutropenia,* diarrhea (31%), fatigue
(28%), myalgia (21%), and bruising (21%).
*Treatment-emergent decreases (all grades) of hemoglobin (46%),
platelets (44%), and neutrophils (36%) were based on laboratory
measurements and adverse reactions.
The most common Grade ≥ 3 non-hematological adverse reaction (reported
in at least 2% of patients) was diarrhea (3.2%).
Dosage 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.
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 twice daily.
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
There is insufficient clinical data on CALQUENCE use in pregnant women
to inform a drug-associated risk for major birth defects and
miscarriage. Advise women of the potential risk to a fetus.
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.
Please see complete Prescribing
Information including Patient Information.
– ENDS –
NOTES TO EDITORS
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.2 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). Patients in the second arm received investigator’s choice
of either rituximab in combination with idelalisib or rituximab in
combination with bendamustine.1,2
The primary endpoint is PFS assessed by an independent review committee
(IRC), and key secondary endpoints include investigator-assessed PFS,
IRC- and investigator-assessed overall response rate (ORR) and duration
of response (DOR), as well as overall survival (OS), patient reported
outcomes (PROs) and time to next treatment (TTNT).1,2
About CALQUENCE
CALQUENCE® (acalabrutinib) was granted accelerated approval
by the US Food and Drug Administration (FDA) in October 2017 for the
treatment of adult patients with MCL who have received at least one
prior therapy. Continued approval for this indication may be contingent
upon verification and description of clinical benefit in confirmatory
trials.
CALQUENCE is an inhibitor of Bruton tyrosine kinase (BTK). CALQUENCE
binds covalently to BTK, thereby inhibiting its activity.3 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 26 clinical trials
that are company sponsored. 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 multiple myeloma and other blood cancers. Beyond the
positive Phase III clinical trials ASCEND and ELEVATE-TN, other Phase
III trials in CLL are ongoing, including ELEVATE-RR (ACE-CL-006)
evaluating acalabrutinib vs. ibrutinib in previously treated high-risk
CLL and ACE-CL-311 evaluating acalabrutinib in combination with
venetoclax and with/without obinutuzumab with previously-untreated CLL
without 17p deletion or TP53 mutation.
About chronic lymphocytic leukemia (CLL)
Chronic lymphocytic leukemia (CLL) is the most common type of leukemia
in adults, with an estimated 191,000 new cases globally and 20,720 new
cases in the US annually, and prevalence that is expected to grow with
improved treatment.4-7 In CLL, too many blood stem cells in
the bone marrow become abnormal lymphocytes and these abnormal cells
have difficulty fighting infections.4 As the number of
abnormal cells grows there is less room for healthy white blood cells,
red blood cells and platelets.4 This could result in anemia,
infection and bleeding.4 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.
In October 2018, AstraZeneca
and Innate Pharma announced a global strategic collaboration that
included Innate
Pharma licensing the US commercial rights of LUMOXITI™ (moxetumomab
pasudotox-tdfk), and with support from AstraZeneca, will continue EU
development and commercialization, pending regulatory submission and
approval.
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 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 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.
References
1 Ghia P, Pluta A, Wach M, et al. ASCEND Phase 3 study of acalabrutinib
vs. investigator’s choice of rituximab plus idelalisib (IdR) or
bendamustine (BR) in patients with relapsed/refractory chronic
lymphocytic leukemia (CLL). Abstract LB2606 at: European Hematology
Association 2019 Annual Meeting. Available online. Accessed June 2019.
2 ClinicalTrials.gov. A Study of Acalabrutinib vs Investigator's Choice
of Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in R/R CLL.
NCT02970318. Available online. Accessed June 2019.
3 CALQUENCE® (acalabrutinib) Prescribing Information.
AstraZeneca Pharmaceuticals LP, Wilmington, DE.
4 National Cancer Institute. Chronic Lymphocytic Leukemia Treatment
(PDQ®)–Patient Version. Available online. Accessed June 2019.
5 Global Burden of Disease Cancer Collaboration. JAMA Oncol.
2017;3(4):524-528.
6 National Institute of Health SEER Program. Cancer Stat Facts:
Leukemia—Chronic Lymphocytic Leukemia (CLL). Available online. Accessed
June 2019.
7 Jain N, et al. Prevalence and Economic Burden of Chronic Lymphocytic
Leukemia (CLL) in the Era of Oral Targeted Therapies. Blood.
2015;126:871.
US-28693 Last Updated 5/19
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