Superior safety on key secondary endpoint of
atrial fibrillation
Positive high-level results from the ELEVATE-RR Phase III trial
showed AstraZeneca’s CALQUENCE® (acalabrutinib) met the primary
endpoint demonstrating non-inferior progression-free survival (PFS)
for adults with previously treated, high-risk chronic lymphocytic
leukemia (CLL) compared to ibrutinib.
The trial also met a key secondary endpoint for safety, showing
patients treated with CALQUENCE had statistically significantly
lower incidence of atrial fibrillation compared to patients treated
with ibrutinib. Atrial fibrillation is an irregular heart rate that
can increase the risk of stroke, heart failure and other
heart-related complications.1 Further hierarchical testing revealed
no difference for Grade 3 or higher infections or Richter’s
transformation. There was a descriptive trend for numerically
favorable overall survival. Overall, the safety and tolerability of
CALQUENCE were consistent with the profile seen in the broader
CALQUENCE clinical development program.
ELEVATE-RR is the first Phase III trial to compare two Bruton’s
tyrosine kinase (BTK) inhibitors in patients with CLL, the most
common type of leukemia in adults.2 Patients diagnosed with
high-risk CLL may experience rapid worsening of their disease,
requiring treatment.3
José Baselga, Executive Vice President, Oncology R&D, said:
“With over forty months of follow-up, today’s results confirm that
CALQUENCE, a selective BTK inhibitor, displays superior safety in
atrial fibrillation without compromising efficacy. The totality of
the data confirm our confidence in the favorable benefit-risk
profile of CALQUENCE.”
The data will be presented at a forthcoming medical meeting and
shared with health authorities.
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 also 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.
CLL
CLL is the most common type of leukemia in adults, with an
estimated 114,000 new cases globally in 2017 and 21,250 new cases
in the US in 2021, and the number of people living with CLL is
expected to grow with improved treatment as patients live longer
with the disease.2,4-7 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.4 B-cell receptor signaling through BTK is one of the
essential growth pathways for CLL.
ELEVATE-RR
ELEVATE-RR (ACE-CL-006) is a randomized, multicenter, open-label
Phase III non-inferiority trial of CALQUENCE versus ibrutinib in
patients with previously treated CLL with high-risk features
(presence of 17p deletion and/or 11q deletion). In the trial, 533
patients were randomized (1:1) into two arms. Patients in the first
arm received CALQUENCE (100mg, orally, twice daily) until disease
progression or unacceptable toxicity. Patients in the second arm
received ibrutinib (420mg orally once daily) until disease
progression or unacceptable toxicity.8
The primary endpoint for the trial was PFS assessed by an
independent review committee (non-inferiority; tested after 250
events). Secondary endpoints included incidence of atrial
fibrillation, incidence of treatment-emergent Grade 3 or higher
infections, incidence of Richter’s transformation (a condition in
which CLL changes into an aggressive form of lymphoma) and overall
survival.8
CALQUENCE
CALQUENCE (acalabrutinib) is a next-generation, selective
inhibitor of BTK. CALQUENCE binds covalently to BTK, thereby
inhibiting its activity.9,10 In B-cells, BTK signaling results in
activation of pathways necessary for B-cell proliferation,
trafficking, chemotaxis, and adhesion.9
CALQUENCE is approved for the treatment of CLL and small
lymphocytic lymphoma in the US and approved for CLL in the EU and
several other countries worldwide. CALQUENCE is under regulatory
review in Japan for relapsed or refractory CLL. A Phase I trial is
currently underway in Japan for the treatment of 1st-line CLL.
In the US and several other countries, CALQUENCE is also
approved for the treatment of adult patients with mantle cell
lymphoma (MCL) who have received at least one prior therapy. The US
MCL 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 not currently approved for the
treatment of MCL in Europe or Japan.
As part of an extensive clinical development program,
AstraZeneca and Acerta Pharma are currently evaluating CALQUENCE in
more than 20 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, Waldenstr�m’s
macroglobulinaemia, follicular lymphoma, and other hematologic
malignancies.
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 medicines approved in
the US 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.
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 seven
new medicines launched between 2014 and 2020, and a broad pipeline
of small molecules and biologics in development, the Company is
committed to advance oncology as a key growth driver for
AstraZeneca focused on lung, ovarian, breast and blood cancers.
By harnessing the power of six scientific platforms -
Immuno-Oncology, Tumor Drivers and Resistance, DNA Damage Response,
Antibody Drug Conjugates, Epigenetics, and Cell Therapies - 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.
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 & Immunology. AstraZeneca operates
in over 100 countries and its innovative medicines are used by
millions of patients worldwide. For more information, please visit
astrazeneca-us.com and follow us on Twitter @AstraZenecaUS.
References 1. Mayo Clinic. Patient Care & Health
Information, Diseases & Conditions - Atrial Fibrillation.
Available at:
https://www.mayoclinic.org/diseases-conditions/atrial-fibrillation/symptoms-causes/syc-20350624.
Accessed January 2021. 2. American Cancer Society. What is Chronic
Lymphocytic Leukemia. Available at:
https://www.cancer.org/cancer/chronic-lymphocytic-leukemia/about/what-is-cll.html.
Accessed January 2021. 3. Cancer.net. Leukemia-Chronic Lymphocytic
– CLL: Stages. Available at:
https://www.cancer.net/cancer-types/leukemia-chronic-lymphocytic-cll/stages.
Accessed January 2021. 4. National Cancer Institute. Chronic
Lymphocytic Leukemia Treatment (PDQ®)–Patient Version. Available
at:
https://www.cancer.gov/types/leukemia/patient/cll-treatment-pdq.
Accessed January 2021. 5. Global Burden of Disease Cancer
Collaboration. Global, Regional, and National Cancer Incidence,
Mortality, Years of Life Lost, Years Lived With Disability, and
Disability-Adjusted Life-Years for 29 Cancer Groups, 1990 to 2017.
JAMA Oncol. 2019;5(12):1749-1768. 6. American Cancer Society.
Cancer Facts & Figures 2021. Key Statistics for Chronic
Lymphocytic Leukemia. Available at:
https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2021/cancer-facts-and-figures-2021.pdf.
Accessed January 2021. 7. Jain N, et al. Prevalence and Economic
Burden of Chronic Lymphocytic Leukemia (CLL) in the Era of Oral
Targeted Therapies. Blood. 2015;126:871.5. 8. Clinicaltrials.gov.
NCT02477696. Accessed September 18, 2020. Study started in October
2015. 9. CALQUENCE (acalabrutinib) [U.S. prescribing information].
Wilmington, DE; AstraZeneca Pharmaceuticals LP; 2019. 10. Wu J,
Zhang M & Liu D. Acalabrutinib (ACP-196): a selective
second-generation BTK inhibitor. J Hematol Oncol. 2016;9(21).
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