Favorable trend in overall survival was also
observed
Positive high-level results from an interim analysis of the
AMPLIFY Phase III trial showed a fixed duration of AstraZeneca’s
CALQUENCE® (acalabrutinib) in combination with venetoclax, with or
without obinutuzumab, demonstrated a statistically significant and
clinically meaningful improvement in progression-free survival
(PFS) compared to standard-of-care chemoimmunotherapy in previously
untreated adult patients with chronic lymphocytic leukemia
(CLL).
For the secondary endpoint of overall survival (OS), a trend was
observed in favor of CALQUENCE in combination with venetoclax, with
or without obinutuzumab, versus standard-of-care
chemoimmunotherapy. The OS data were not mature at the time of this
analysis and the trial will continue to assess OS as a key
secondary endpoint.
CLL is caused by the abnormal production of white blood cells
and is the most prevalent type of leukemia in adults worldwide,
with numbers anticipated to grow.1-3 In the first-line setting,
approximately 40,000 patients are treated with the current standard
of care.4 Although CLL is considered an incurable cancer, patients
often live with the disease for many years, and may remain on
continuous treatment.5
Jennifer R. Brown, MD, PhD, Director of the CLL Center of the
Division of Hematologic Malignancies, Dana-Farber Cancer Institute,
and the Worthington and Margaret Collette Professor of Medicine at
Harvard Medical School, and principal investigator of the trial,
said: “The AMPLIFY results demonstrate the potential of
acalabrutinib and venetoclax with or without obinutuzumab to be
effective and well-tolerated fixed-duration treatment options for
patients with chronic lymphocytic leukemia. This is an important
advance in this setting as fixed-duration regimens allow those
living with this chronic disease to take breaks from their
treatment, thereby decreasing the possibility of long-term adverse
events and drug resistance and improving quality of life.”
Susan Galbraith, Executive Vice President, Oncology R&D,
AstraZeneca, said: “The progression-free survival and overall
survival results from the AMPLIFY Phase III trial demonstrate the
potential of including a BTK inhibitor in a fixed-duration regimen
and reinforce our leadership in advancing science for patients with
chronic lymphocytic leukemia. If approved, CALQUENCE would become
the only second-generation BTK inhibitor available as both a
treat-to-progression and fixed-duration treatment, providing more
options for patients and their healthcare providers.”
The safety and tolerability were consistent with the known
safety profile of each medicine. No new safety signals were
identified, with low rates of cardiac toxicity observed.
The data will be presented at a forthcoming medical meeting and
shared with global regulatory authorities.
INDICATIONS 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)
tablets
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 jirovecii 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.
Cardiac Arrhythmias
Serious cardiac arrhythmias have occurred in patients treated
with CALQUENCE. 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.
Grade 3 or higher ventricular arrhythmia events were reported in
0.9% of patients. The risk may be increased in patients with
cardiac risk factors, hypertension, previous arrhythmias, and acute
infection. Monitor for symptoms of arrhythmia (eg, palpitations,
dizziness, syncope, dyspnea) and manage as appropriate.
Hepatotoxicity, Including Drug-Induced Liver Injury
Hepatotoxicity, including severe, life-threatening, and
potentially fatal cases of drug-induced liver injury (DILI), has
occurred in patients treated with Bruton tyrosine kinase
inhibitors, including CALQUENCE.
Evaluate bilirubin and transaminases at baseline and throughout
treatment with CALQUENCE. For patients who develop abnormal liver
tests after CALQUENCE, monitor more frequently for liver test
abnormalities and clinical signs and symptoms of hepatic toxicity.
If DILI is suspected, withhold CALQUENCE. Upon confirmation of
DILI, discontinue CALQUENCE.
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 to 1.5 to 3 times the upper limit of normal (ULN)
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 to 1.5 to 3 times ULN 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
to 1.5 to 3 times ULN occurred in 1.3% of patients who received
CALQUENCE.
DRUG INTERACTIONS
Strong CYP3A Inhibitors: Avoid co-administration of
CALQUENCE with a strong CYP3A inhibitor. If these inhibitors will
be used short-term, interrupt CALQUENCE. After discontinuation of
strong CYP3A inhibitor for at least 24 hours, resume previous
dosage of CALQUENCE.
Moderate CYP3A Inhibitors: Reduce the dosage of CALQUENCE
to 100 mg once daily when co-administered with a moderate CYP3A
inhibitor.
Strong CYP3A Inducers: Avoid co-administration of
CALQUENCE with a strong CYP3A inducer. If co-administration is
unavoidable, increase the dosage of CALQUENCE to 200 mg
approximately every 12 hours.
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 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 2
weeks after the last dose.
Avoid use of CALQUENCE in patients with severe hepatic
impairment (Child-Pugh class C). No dosage adjustment of CALQUENCE
is recommended in patients with mild (Child-Pugh class A) or
moderate (Child-Pugh class B) hepatic impairment.
Please see full Prescribing Information,
including Patient Information.
Notes
CLL In CLL, there is an accumulation of abnormal
lymphocytes within the bone marrow and in blood and lymph nodes.1
Although some people with CLL may not experience any symptoms at
diagnosis, others may experience symptoms, such as weakness,
fatigue, weight loss, chills, fever, night sweats, swollen lymph
nodes and abdominal pain.6 As the number of abnormal cells
increases, there is less room within the marrow for the production
of normal white blood cells, red blood cells and platelets. This
could result in anemia, infection and bleeding.1 B-cell receptor
signaling through BTK is one of the essential survival pathways for
CLL.
AMPLIFY AMPLIFY is a randomized, global, multi-center,
open-label Phase III trial evaluating the efficacy and safety of
CALQUENCE in combination with venetoclax with and without
obinutuzumab compared to investigator's choice of
chemoimmunotherapy in adult patients with previously untreated CLL
without del(17p) or TP53 mutation.7 Patients were randomized 1:1:1
to receive either CALQUENCE in combination with venetoclax,
CALQUENCE in combination with venetoclax plus obinutuzumab for a
fixed duration or standard-of-care chemoimmunotherapy.7
The primary endpoint is PFS in the CALQUENCE and venetoclax arm
as assessed by an Independent Review Committee (IRC) and PFS in
this arm assessed by investigators (INV) is a key secondary
endpoint. IRC and INV assessed PFS in the CALQUENCE, venetoclax and
obinutuzumab arm as a key secondary endpoint. Other key secondary
endpoints include OS, event-free survival, overall response rate,
duration of response and time to next treatment.7 The trial
includes 27 countries across North and South America, Europe, Asia
and Oceania.7
The AMPLIFY trial enrolled patients from 2019 to 2021,
continuing through the COVID-19 pandemic.7 Patients with blood
cancer remain at a disproportionately high risk of severe outcomes
from COVID-19, including hospitalization and death compared to the
general population.8
CALQUENCE CALQUENCE (acalabrutinib) is a
second-generation, selective inhibitor of Bruton’s tyrosine kinase
(BTK). CALQUENCE binds covalently to BTK, thereby inhibiting its
activity.9 In B-cells, BTK signaling results in activation of
pathways necessary for B-cell proliferation, trafficking,
chemotaxis and adhesion.
CALQUENCE has been used to treat more than 80,000 patients
worldwide10 and is approved for the treatment of CLL and small
lymphocytic lymphoma (SLL) in the US and Japan, approved for CLL in
the EU and many other countries worldwide and approved in China for
relapsed or refractory CLL and SLL. CALQUENCE is also approved in
the US, China and several other countries for the treatment of
adult patients with mantle cell lymphoma (MCL) who have received at
least one prior therapy. CALQUENCE is not currently approved for
the treatment of MCL in Japan or the EU.
As part of an extensive clinical development program, CALQUENCE
is currently being evaluated as a single treatment and in
combination with standard-of-care chemoimmunotherapy for patients
with multiple B-cell blood cancers, including CLL, MCL and diffuse
large B-cell lymphoma.
AstraZeneca in hematology AstraZeneca is pushing the
boundaries of science to redefine care in hematology. Our goal is
to help transform the lives of patients living with malignant, rare
and other related hematologic diseases through innovative medicines
and approaches that are shaped by insights from patients,
caregivers and physicians.
In addition to our marketed products, we are spearheading the
development of novel therapies designed to target underlying
drivers of disease across six scientific platforms. Our recent
acquisitions of Alexion, with expertise in rare, non-malignant
blood disorders, and Gracell Biotechnologies Inc., focused on cell
therapies for hematologic malignancies, expand our hematology
pipeline and enable us to reach more patients with high unmet needs
through the end-to-end development and delivery of novel
therapies.
AstraZeneca in oncology AstraZeneca is leading a
revolution in oncology with the ambition to provide cures for
cancer in every form, following the science to understand cancer
and all its complexities to discover, develop and deliver
life-changing medicines to patients.
The Company's focus is on some of the most challenging cancers.
It is through persistent innovation that AstraZeneca has built one
of the most diverse portfolios and pipelines in the industry, with
the potential to catalyze changes in the practice of medicine and
transform the patient experience.
AstraZeneca has the vision to redefine cancer care 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 in
Oncology, Rare Diseases and BioPharmaceuticals, including
Cardiovascular, Renal & Metabolism, and Respiratory &
Immunology. Based in Cambridge, UK, AstraZeneca operates in over
125 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 social media
@AstraZeneca.
References
- National Cancer Institute. Chronic Lymphocytic Leukemia
Treatment (PDQ®)–Patient Version: General Information About Chronic
Lymphocytic Leukemia. Available online. Accessed July 2024.
- American Cancer Society. What is Chronic Lymphocytic Leukemia?
Available online. Accessed July 2024.
- Jain N, et al. Prevalence and Economic Burden of Chronic
Lymphocytic Leukemia (CLL) in the Era of Oral Targeted Therapies.
Blood. 2015;126(23):871.
- Cerner CancerMPact and DRG databases. Reflects epidemiology
estimates across G8 countries (Cerner CancerMPact for G7: US, EU,
Japan; DRG database for China). Accessed July 2024.
- American Cancer Society. After Chronic Lymphocytic Leukemia
Treatment. Available at:
https://www.cancer.org/cancer/types/chronic-lymphocytic-leukemia/after-treatment/follow-up.
Accessed July 2024.
- American Cancer Society. Signs and Symptoms of Chronic
Lymphocytic Leukemia. Available online. Accessed July 2024.
- ClinicalTrials.gov. Study of Acalabrutinib (ACP-196) in
Combination With Venetoclax (ABT-199), With and Without
Obinutuzumab (GA101) Versus Chemoimmunotherapy for Previously
Untreated CLL (AMPLIFY). Available at:
https://clinicaltrials.gov/study/NCT03836261. Accessed July
2024.
- Dube S, et al. Continued Increased Risk of COVID-19
Hospitalisation and Death in Immunocompromised Individuals Despite
Receipt of ≥4 Vaccine Doses: Updated 2023 Results from INFORM, a
Retrospective Health Database Study in England. Poster P0409 at
ECCMID 2024.
- Wu J, Zhang M, Liu D. Acalabrutinib (ACP-196): a selective
second-generation BTK inhibitor. J Hematol Oncol. 2016;9(21).
- Data on File, REF-236261. AstraZeneca Pharmaceuticals LP.
US-92135 Last Updated 7/24
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