First BTK inhibitor to show favorable trend
in overall survival vs. standard-of-care chemoimmunotherapy
in this setting
Positive high-level results from an interim analysis of the ECHO
Phase III trial showed AstraZeneca’s CALQUENCE® (acalabrutinib) in
combination with standard-of-care chemoimmunotherapy, bendamustine
and rituximab, demonstrated a statistically significant and
clinically meaningful improvement in progression-free survival
(PFS) versus standard of care in previously untreated adult
patients with mantle cell lymphoma (MCL).
A trend was observed in favor of CALQUENCE plus
chemoimmunotherapy for the secondary endpoint of overall survival
(OS). The OS data were not mature at the time of this analysis and
the trial will continue to assess OS.
MCL is a rare and typically aggressive form of non-Hodgkin
lymphoma (NHL), often diagnosed as a late-stage disease, resulting
when B-lymphocytes mutate into malignant cells within a region of
the lymph node known as the mantle zone.1,2 It is estimated that
there are more than 27,500 patients diagnosed with MCL
worldwide.3,4
Michael Wang, MD, Puddin Clarke Endowed Professor, Director of
Mantle Cell Lymphoma Program of Excellence, Co-Director of Clinical
Trials at MD Anderson Cancer Center in Houston, US and principal
investigator in the trial, said: “These positive progression-free
survival results from the ECHO Phase III trial could provide a new
standard of care for patients with mantle cell lymphoma.
Incorporating CALQUENCE into the first-line mantle cell lymphoma
setting would give many more patients the opportunity to benefit
from the robust efficacy and strong safety profile we’ve seen with
this medicine.”
Susan Galbraith, Executive Vice President, Oncology R&D,
AstraZeneca, said: “These impactful results in mantle cell lymphoma
show that bringing CALQUENCE to the first-line setting
significantly delays disease progression and, for the first time,
shows potential to extend survival. The improvement in
progression-free survival together with the differentiated safety
profile of CALQUENCE are both important as we strive to transform
outcomes earlier in the course of disease treatment.”
The safety and tolerability of CALQUENCE was consistent with its
known safety profile, and no new safety signals were
identified.
The data will be presented at a forthcoming medical meeting and
shared with global regulatory authorities.
As part of an extensive clinical development program,
AstraZeneca is currently evaluating CALQUENCE alone and in
combination for the treatment of multiple B-cell blood cancers,
including chronic lymphocytic leukemia (CLL), MCL, and diffuse
large B-cell lymphoma.
CALQUENCE has been used to treat more than 80,000 patients
worldwide and is approved for the treatment of CLL and small
lymphocytic lymphoma (SLL) in the US, approved for CLL in the EU
and many other countries worldwide and approved in Japan and 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 MCL who have received at least one prior
therapy. CALQUENCE is not currently approved for the treatment of
MCL in Japan or the EU.
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.
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 (eg, 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 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
Mantle cell lymphoma MCL is an uncommon subtype of B-cell
non-Hodgkin lymphoma.5 MCL comprises about 3-6% of non-Hodgkin
lymphomas, with an annual incidence of 0.5 per 100,000 population
in Western countries; in the US, it is estimated that approximately
4,000 new cases of MCL are diagnosed each year.5,6 While MCL
patients initially respond to treatment, patients do tend to
relapse.5
ECHO ECHO is a randomized, double-blind,
placebo-controlled, multi-center Phase III trial evaluating the
efficacy and safety of CALQUENCE plus bendamustine and rituximab
compared to standard of care chemoimmunotherapy (bendamustine and
rituximab) in adult patients at or over 65 years of age (n=598)
with previously untreated MCL.7 In the experimental arms, patients
were randomized 1:1 to receive either CALQUENCE or placebo
administered orally twice per day, on days 1 and 2 of each 28 day
treatment cycle, plus bendamustine on days 1 and 2 and rituximab on
day 1. After six cycles of CALQUENCE or placebo in combination with
bendamustine and rituximab, patients receive CALQUENCE or placebo
plus maintenance rituximab for two years and then either CALQUENCE
or placebo only until disease progression.7
The primary endpoint is PFS and key secondary endpoints include
OS, overall response rate (ORR), duration of response (DoR) and
time to response (TTR).7 The trial includes 27 countries across
North and South America, Europe, Asia and Oceania.7
The ECHO trial was conducted from 2017 to 2023 continuing
through the COVID-19 pandemic. 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 next-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.
AstraZeneca in hematology AstraZeneca is pushing the
boundaries of science to redefine care in hematology. We have
expanded our commitment to patients with hematologic conditions,
not only in oncology but also in rare diseases with the acquisition
of Alexion, allowing us to reach more patients with high unmet
needs. By applying our deep understanding of blood cancers,
leveraging our strength in solid tumor oncology and delivering on
Alexion’s pioneering legacy in complement science to provide
innovative medicines for rare diseases, we are pursuing the
end-to-end development of novel therapies designed to target
underlying drivers of disease. Following AstraZeneca’s recent
acquisition of Gracell Biotechnologies Inc., we have broadened our
pipeline of innovative cell therapies with a differentiated
manufacturing process to potentially further address hematologic
malignancies.
By targeting hematologic conditions with high unmet medical
needs, we aim to deliver innovative medicines and approaches to
improve patient outcomes. Our goal is to help transform the lives
of patients living with malignant, rare and other related
hematologic diseases, shaped by insights from patients, caregivers
and physicians to have the most meaningful impact.
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 (LSE/STO/Nasdaq: AZN) 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 100 countries and its innovative medicines are used by
millions of patients worldwide. Please visit www.astrazeneca-us.com
and follow the Company on social media @AstraZeneca.
References
- Lymphoma Research Foundation. Mantle Cell Lymphoma. Available
at: https://lymphoma.org/aboutlymphoma/nhl/mcl/. Accessed April
2024.
- National Organization for Rare Disorders. Mantle Cell Lymphoma.
Available at:
https://rarediseases.org/rare-diseases/mantle-cell-lymphoma/.
Accessed April 2024.
- GLOBOCAN. Non-Hodgkin Lymphoma. Available at:
https://gco.iarc.who.int/media/globocan/factsheets/cancers/34-non-hodgkin-lymphoma-fact-sheet.pdf.
Accessed April 2024.
- Lynch DT, Koya S, Acharya U, et al. Mantle Cell Lymphoma.
Available at: https://www.ncbi.nlm.nih.gov/books/NBK536985/.
Accessed April 2024.
- Cheah C, Seymour J, Wang ML. Mantle cell lymphoma. J Clin
Oncol. 2016;34(11):1256-1269. doi: 10.1200/JCO.2015.63.5904.
- MD Anderson Cancer Center. What to know about mantle cell
lymphoma. Available at:
https://www.mdanderson.org/cancerwise/what-to-know-about-mantle-cell-lymphoma-symptoms-diagnosis-and-treatment.h00-159385101.html.
Accessed April 2024.
- ClinicalTrials.gov. A Study of BR Alone Versus in Combination
With Acalabrutinib in Subjects With Previously Untreated MCL.
Available at: https://clinicaltrials.gov/study/NCT02972840.
Accessed April 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).
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