Based on ECHO Phase III trial which
demonstrated CALQUENCE combination reduced risk of disease
progression or death by 27% compared to standard-of-care
chemoimmunotherapy
Submission to be reviewed under Project
Orbis
AstraZeneca’s supplemental New Drug Application (sNDA) for
CALQUENCE® (acalabrutinib) has been accepted and granted Priority
Review in the US for the treatment of adult patients with
previously untreated mantle cell lymphoma (MCL).
The Food and Drug Administration (FDA) grants Priority Review to
applications for medicines that, if approved, would offer
significant improvements over available options by demonstrating
safety or efficacy improvements, preventing serious conditions or
enhancing patient compliance.1 The Prescription Drug User Fee Act
date, the FDA action date for their regulatory decision, is
anticipated during the first quarter of 2025.
MCL is a rare and typically aggressive form of non-Hodgkin
lymphoma (NHL), resulting when B-lymphocytes mutate into malignant
cells within a region of the lymph node known as the mantle
zone.2,3 The disease is often diagnosed at advanced stages and
remains largely incurable. It is estimated that there are more than
27,500 people living with MCL worldwide.4,5
Susan Galbraith, Executive Vice President, Oncology R&D,
AstraZeneca, said: “Today’s Priority Review acceptance reinforces
the potential of CALQUENCE to transform outcomes in untreated
mantle cell lymphoma. Data from the ECHO trial showed CALQUENCE
plus chemoimmunotherapy significantly delayed disease progression
and showed a trend to improved survival in patients with this
currently incurable blood cancer. We are working closely with the
FDA to provide patients this potential new treatment as soon as
possible.”
The sNDA is being reviewed under Project Orbis, an initiative of
the FDA which provides a framework for concurrent submission and
review of oncology medicines among participating international
partners to bring cancer treatments to patients around the world as
early as possible.
Results from the ECHO Phase III trial recently were presented
during the late-breaking oral session at the European Hematology
Association (EHA) 2024 Hybrid Congress.
In the trial, CALQUENCE plus bendamustine and rituximab reduced
the risk of disease progression or death by 27% compared to
standard-of-care (SoC) chemoimmunotherapy (hazard ratio [HR] 0.73;
95% confidence interval [CI] 0.57-0.94; p=0.016). The addition of
CALQUENCE to SoC provided almost 1.5 years of additional median
progression free survival (mPFS) with mPFS of 66.4 months for
patients treated with the CALQUENCE combination versus 49.6 months
with SoC.
Overall survival (OS) showed a favorable trend for the CALQUENCE
combination compared to SoC chemoimmunotherapy (HR 0.86; 95% CI
0.65-1.13; p=0.2743). The OS trend was sustained over time,
although most patients in the SoC arm who needed subsequent therapy
received a BTK inhibitor, mainly CALQUENCE. 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.
The ECHO trial was conducted during the COVID-19 pandemic, and
prespecified PFS and OS analyses censoring for COVID-19 deaths were
conducted to assess the impact of COVID-19 on the study outcome in
alignment with FDA. After censoring for COVID-19 deaths, the PFS
was further improved in both arms, with the CALQUENCE combination
reducing the risk of disease progression or death by 36% (HR 0.64;
95% CI; 0.48-0.84; p=0.0017). A favorable trend was seen for OS in
this analysis for the CALQUENCE combination, but OS data were not
mature at the time of this analysis (HR 0.75; 95% CI 0.53-1.04;
p=0.0797).
The safety and tolerability of CALQUENCE was consistent with its
known safety profile, and no new safety signals were
identified.
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
Mantle cell lymphoma
While MCL patients initially respond to treatment, patients do
tend to relapse.6 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 patients are diagnosed with MCL each year.6,7
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 SoC
chemoimmunotherapy (bendamustine and rituximab) in adult patients
at or over 65 years of age (n=635) with previously untreated MCL.8
Patients were randomized 1:1 to receive either CALQUENCE or placebo
administered orally twice per day, continuously, until disease
progression or unacceptable toxicity. Additionally, all patients
received six 28-day cycles of bendamustine on days 1 and 2 and
rituximab on day 1 of each cycle, followed by rituximab maintenance
for two years if patients achieved a response after induction
therapy.8
The primary endpoint is PFS assessed by an Independent Review
Committee; other efficacy endpoints include OS, overall response
rate (ORR), duration of response (DoR) and time to response (TTR).8
The trial was conducted in 27 countries across North and South
America, Europe, Asia and Oceania.8
The ECHO trial enrolled patients from May 2017 to March 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.9
CALQUENCE
CALQUENCE (acalabrutinib) is a second-generation, selective
inhibitor of Bruton’s tyrosine kinase (BTK). CALQUENCE binds
covalently to BTK, thereby inhibiting its activity.10 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 85,000 patients
worldwide11 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 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 multiple scientific platforms. Our
acquisitions of Alexion, with expertise in rare, non-malignant
blood disorders, and Gracell Biotechnologies Inc., pioneers of
autologous cell therapies, expand our hematology pipeline and
enable us to reach more patients with high unmet needs through the
end-to-end discovery, 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
- FDA. Priority Review. January 4, 2018. FDA website. Accessed
October 2, 2024.
https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/priority-review.
- Lymphoma Research Foundation (LRF). Mantle Cell Lymphoma. LRF
website. Accessed October 2, 2024.
https://lymphoma.org/understanding-lymphoma/aboutlymphoma/nhl/mantle-cell-lymphoma/.
- National Organization for Rare Disorders (NORD). Mantle Cell
Lymphoma. June 5, 2024. NORD website. Accessed October 2, 2024.
https://rarediseases.org/rare-diseases/mantle-cell-lymphoma/.
- World Health Organization. Non-Hodgkin Lymphoma. Global Cancer
Observatory: Cancer Today website. Accessed October 2, 2024.
https://gco.iarc.who.int/media/globocan/factsheets/cancers/34-non-hodgkin-lymphoma-fact-sheet.pdf.
- Lynch DT, Koya S, Acharya U, et al. Mantle Cell Lymphoma.
Treasure Island (FL): StatPearls; 2023.
https://www.ncbi.nlm.nih.gov/books/NBK536985/. Accessed October 2,
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.
- Adams M. What to know about mantle cell lymphoma. September 28,
2020. MD Anderson Cancer Center website. Accessed October 2, 2024.
https://www.mdanderson.org/cancerwise/what-to-know-about-mantle-cell-lymphoma-symptoms-diagnosis-and-treatment.h00-159385101.html.
- ClinicalTrials.gov. A Study of BR Alone Versus in Combination
With Acalabrutinib in Subjects With Previously Untreated MCL.
ClinicalTrials.gov website. Accessed October 2, 2024.
https://clinicaltrials.gov/study/NCT02972840.
- Dube S, lu Y, McNulty R, et al. Continued Increased Risk of
COVID-19 Hospitalization 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).
doi:10.1186/s13045-016-0250-9.
- Data on File, REF-236261. AstraZeneca Pharmaceuticals LP.
View source
version on businesswire.com: https://www.businesswire.com/news/home/20241003958806/en/
Media Inquiries Brendan McEvoy +1 302 885 2677
US Media Mailbox: usmediateam@astrazeneca.com
AstraZeneca (NASDAQ:AZN)
Historical Stock Chart
From Feb 2025 to Mar 2025
AstraZeneca (NASDAQ:AZN)
Historical Stock Chart
From Mar 2024 to Mar 2025
