First and only BTK inhibitor to demonstrate
favorable overall survival trend vs. standard-of-care
chemoimmunotherapy in this setting
Positive results from the ECHO Phase III trial showed
AstraZeneca’s CALQUENCE® (acalabrutinib) in combination with
bendamustine and rituximab demonstrated a statistically significant
and clinically meaningful improvement in progression-free survival
(PFS) and showed a favorable trend in overall survival (OS)
compared to standard-of-care chemoimmunotherapy (bendamustine plus
rituximab) in previously untreated patients with mantle cell
lymphoma (MCL).
These results were presented today in a late-breaking oral
presentation at the European Hematology Association (EHA) 2024
Hybrid Congress in Madrid, Spain (#LBA3439).
Results showed the CALQUENCE combination regimen reduced the
risk of disease progression or death by 27% compared to
standard-of-care chemoimmunotherapy (hazard ratio [HR] 0.73; 95%
confidence interval [CI] 0.57-0.94; p=0.016). Median PFS was 66.4
months for patients treated with the CALQUENCE combination (n=299)
versus 49.6 months with standard-of-care chemoimmunotherapy
(n=299).
The secondary endpoint of OS showed a favorable trend for the
CALQUENCE combination compared to standard-of-care
chemoimmunotherapy, further supporting the clinical benefit of this
combination (HR 0.86; 95% CI 0.65-1.13; p=0.2743). 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 enrolled during the pandemic period, and a
pre-specified analysis censoring for COVID-19-related deaths was
conducted to assess the impact. 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).
Median PFS was not reached among patients treated with the
CALQUENCE combination versus 61.6 months for standard-of-care
chemoimmunotherapy (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 (HR 0.75; 95% CI 0.53-1.04; p=0.0797).
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: “For people living with mantle
cell lymphoma, a typically aggressive form of non-Hodgkin's
lymphoma, the ECHO results offer promise of a new, effective
treatment option for adults older than 65, who represent the
majority of MCL patients. The improved progression-free survival
seen in patients treated with the CALQUENCE combination compared to
chemoimmunotherapy demonstrate its potential to change the standard
of care as the only BTK inhibitor in this first-line setting.”
Susan Galbraith, Executive Vice President, Oncology R&D,
AstraZeneca, said: “The ECHO trial data demonstrate important
progress in improving outcomes for patients with mantle cell
lymphoma. The 16.8 months of additional time patients can live
without their disease progressing is highly clinically meaningful,
together with a trend to improvement in overall survival. We
therefore believe CALQUENCE plus chemoimmunotherapy will be an
important new option for patients living with this disease.”
Summary of Results: ECHO
CALQUENCE plus bendamustine and
rituximab
(n=299)
Placebo plus bendamustine and
rituximab
(n=299)
Median PFS (months)
66.4
49.6
PFS HR (95% CI)
0.73 (0.57-0.94)
PFS p-value
0.0160
OS HR (95% CI)
0.86 (0.65-1.13)
OS p-value
0.2743
Censoring for COVID-19 deaths
Median PFS
NR
61.6
PFS HR (95% CI)
0.64 (0.48-0.84)
PFS p-value
0.0017
OS HR (95% CI)
0.75 (0.53-1.04)
OS p-value
0.0797
NR=Not reached
The safety and tolerability of CALQUENCE was consistent with its
known safety profile, and no new safety signals were identified.
Grade 3 or higher adverse events (AEs) due to any cause occurred in
88.9% (n=264) of patients treated with the CALQUENCE combination
and 88.2% (n=262) of patients treated with standard-of-care
chemoimmunotherapy, including Grade 3 or higher atrial fibrillation
in 3.7% (n=11) and 1.7% (n=5) of patients, Grade 3 or higher
hypertension in 5.4% (n=16) and 8.4% (n=25), Grade 3 or higher
major bleeding in 2.0% (n=6) and 3.4% (n=10), and Grade 3 or higher
infections in 41.1% (n=122) and 34.0% (n=101), respectively.
Serious AEs and Grade 5 events were balanced across arms (69%
[n=205] versus 62% [n=184], and 12.1% [n=36] versus 10.1% [n=30],
respectively). AEs leading to discontinuation were observed in
10.4% (n=31) and 6.4% (n=19) of patients for the CALQUENCE
combination and placebo arms respectively. AEs related to COVID-19
were seen in the trial, including Grade 5 events which occurred in
9.4% (n=28) of patients treated with the CALQUENCE combination and
6.7% (n=20) of patients treated with standard-of-care
chemoimmunotherapy.
Additional AstraZeneca data at
EHA
In addition to these compelling data, AstraZeneca data at EHA
2024 shows how the Company is advancing a diverse and innovative
pipeline spanning multiple modalities including next-generation T
cell engagers, cell therapy and antibody drug conjugates, to enable
the creation of novel combination regimens across a range of blood
cancers.
Results from the ongoing Phase I, dose-escalation trial of
AZD0486, a novel CD19xCD3 T cell engager, showed durable responses
in patients with heavily pretreated relapsed/refractory follicular
lymphoma with a median follow up of 11 months. Complete response
rates of 84% were seen at doses of AZD0486 of 2.4 mg and above.
Data also showed how cytokine release syndrome (CRS) events were
effectively mitigated by the double step-up dosing schedule and no
immune effector cell-associated neurotoxicity syndrome (ICANS)
events were observed.
In an oral presentation, preliminary data was shared from an
investigator-initiated trial of AstraZeneca’s first hematology cell
therapy, GC012F (AZD0120), in patients with transplant-eligible
high-risk, newly diagnosed multiple myeloma. Early results showed
that GC012F had an overall response rate of 100%, a minimal
residual disease-negative stringent complete response rate of 95%,
and was well tolerated. Grade 1-2 CRS was experienced by 27% (6/22)
of patients and no ICANS or neurotoxicity was observed. GC012F is a
novel BCMAxCD19 dual-targeting autologous chimeric antigen receptor
T therapy (CAR-T) created using the next-day FasTCAR manufacturing
platform pioneered by Gracell Biotechnologies, a wholly owned
subsidiary of AstraZeneca.
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
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 While MCL patients
initially respond to treatment, patients do tend to relapse.3 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.3,4 It is estimated that there are
more than 27,500 people living with MCL worldwide.5,6
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=635) with previously
untreated MCL.7 Patients were randomized 1:1 to receive either
CALQUENCE or placebo administered orally twice per day, on 28 day
treatment cycles, plus bendamustine on days 1 and 2 and rituximab
on day 1 of each cycle. After six cycles of induction therapy, all
patients continued 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 assessed by an Independent Review
Committee 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 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.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.
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 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, diffuse
large B-cell lymphoma and follicular 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's innovative medicines are sold in more than 125
countries and 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 May
2024.
- National Organization for Rare Disorders. Mantle Cell Lymphoma.
Available at:
https://rarediseases.org/rare-diseases/mantle-cell-lymphoma/.
Accessed May 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 May 2024.
- GLOBOCAN. Non-Hodgkin Lymphoma. Available at:
https://gco.iarc.who.int/media/globocan/factsheets/cancers/34-non-hodgkin-lymphoma-fact-sheet.pdf.
Accessed May 2024.
- Lynch DT, Koya S, Acharya U, et al. Mantle Cell Lymphoma.
Available at: https://www.ncbi.nlm.nih.gov/books/NBK536985/.
Accessed May 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 May 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).
US-90789 Last Updated 6/24
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Media Inquiries Brendan McEvoy +1 302 885 2677
US Media Mailbox: usmediateam@astrazeneca.com
AstraZeneca (NASDAQ:AZN)
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AstraZeneca (NASDAQ:AZN)
過去 株価チャート
から 6 2023 まで 6 2024
