CALQUENCE plus venetoclax with obinutuzumab
reduced the risk of disease progression or death by 58% versus
standard of care in this setting
CALQUENCE plus venetoclax poised to become
first all-oral fixed-duration regimen of a second-generation
BTK inhibitor plus venetoclax in 1st-line CLL
Positive results from the AMPLIFY Phase III trial showed
AstraZeneca’s CALQUENCE® (acalabrutinib) in combination with
venetoclax 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).
These results will be presented at the American Society of
Hematology (ASH) 2024 Annual Meeting in San Diego, CA.
At a median follow up of 41 months, results showed CALQUENCE
plus venetoclax reduced the risk of disease progression or death by
35% compared to standard-of-care chemoimmunotherapy (hazard ratio
[HR] 0.65; 95% confidence interval [CI] 0.49-0.87; p=0.0038).
CALQUENCE plus venetoclax with obinutuzumab demonstrated a 58%
reduction in the risk of disease progression or death compared to
standard-of-care chemoimmunotherapy (HR 0.42; 95% CI 0.30-0.59;
p<0.0001). Median PFS was not reached for either experimental
arm versus median PFS of 47.6 months for chemoimmunotherapy.
Interim overall survival (OS) data demonstrated a favorable
trend which was nominally statistically significant for CALQUENCE
plus venetoclax (HR 0.33; 95% CI 0.18-0.56; p<0.0001), however
the OS data were immature at the time of this analysis and the
trial will continue to assess OS as a key secondary endpoint.
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: “Chronic lymphocytic leukemia is considered an incurable
cancer and patients live with the disease and the long-term effects
of their treatments for many years. The AMPLIFY results show the
promise of a new all-oral fixed-duration therapy approach which
would allow patients to take breaks from treatment, reducing the
risk of long-term adverse events and drug resistance.”
Susan Galbraith, Executive Vice President, Oncology R&D,
AstraZeneca, said: “Based on these impressive data from the AMPLIFY
trial, CALQUENCE is the only second-generation BTK inhibitor to
demonstrate efficacy in the front-line treatment of patients with
chronic lymphocytic leukemia as both a treat-to-progression and a
fixed-duration approach. This advance is an important development
for patients and their physicians who seek new options and more
flexibility in managing this disease in the long term.”
Both investigational arms demonstrated durable responses, with
estimated 36-month PFS rates of 76.5% for CALQUENCE plus venetoclax
and 83.1% with the addition of obinutuzumab compared to 66.5% for
chemoimmunotherapy. Patients also demonstrated a robust response in
both investigational arms with an overall response rate (ORR) of
92.8% for CALQUENCE plus venetoclax and 92.7% with the addition of
obinutuzumab, compared to 75.2% for chemoimmunotherapy.
Summary of Results: AMPLIFY
CALQUENCE plus venetoclax
CALQUENCE plus venetoclax and
obinutuzumab
Control arm
Patient population (n)
291
286
290
Median PFS
(months)
NR
NR
47.6
PFS HR vs. control
(95% CI)
0.65
p=0.0038
0.42
p<0.0001
Reference
36-month PFS rate
76.5%
83.1%
66.5%
ORR (95% CI)
92.8% (89.4-95.4)
p<0.0001
92.7% (89.2-95.3)
p<0.0001
75.2% (70.0-79.9)
OS HR vs. control (95% CI)
0.33 (0.18-0.56)
p<0.0001
0.76 (0.49-1.18)
p=0.2224
Reference
NR=Not reached
Control arm = Investigator’s choice of
fludarabine-cyclophosphamide-rituximab or
bendamustine-rituximab
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) occurred in 53.6% of
patients treated with CALQUENCE plus venetoclax, 69.4% of patients
treated with CALQUENCE plus venetoclax with obinutuzumab and 60.6%
for patients treated with standard-of-care chemoimmunotherapy. The
most common Grade 3 or higher AE was neutropenia across all arms,
seen in 26.8%, 35.2% and 32.4% of patients respectively. There were
over twice as many COVID-19 related deaths in the CALQUENCE plus
venetoclax with obinutuzumab arm compared with the CALQUENCE plus
venetoclax arm.
Notably, low rates of tumor lysis syndrome (TLS) were observed
in both CALQUENCE arms with events of any grade seen in 0.3% of
patients treated with CALQUENCE plus venetoclax and 0.4% with the
addition of obinutuzumab, compared to 3.1% for patients treated
with chemoimmunotherapy. No cases of clinical TLS were observed
across CALQUENCE treatment arms.
CALQUENCE has been used to treat more than 85,000 patients
worldwide1 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.
INDICATION AND USAGE
CALQUENCE is a Bruton tyrosine kinase (BTK) inhibitor 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 (≥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 the upper limit of normal
(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
Chronic Lymphocytic Leukemia (CLL)
CLL is the most prevalent type of leukemia in adults, with over
100,000 new cases globally in 2019.2 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.3 In CLL,
there is an accumulation of abnormal lymphocytes within the blood,
bone marrow and lymph nodes. 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.4 This
could result in infection, anemia and bleeding. B-cell receptor
signaling through BTK is one of the essential growth 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
(fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab)
in adult patients with previously untreated CLL without del(17p) or
TP53 mutation.5 Patients were randomized 1:1:1 to receive either
CALQUENCE plus venetoclax, CALQUENCE plus venetoclax with
obinutuzumab for a fixed duration or standard-of-care
chemoimmunotherapy.5 Both the CALQUENCE containing arms were
administered for a fixed duration of 14 cycles (each 28 days), and
the standard-of-care chemoimmunotherapy was for 6 cycles.5
The primary endpoint is PFS in the CALQUENCE and venetoclax arm
as assessed by an Independent Review Committee and PFS in the
CALQUENCE plus venetoclax with obinutuzumab is a key secondary
endpoint. Other key secondary endpoints include OS and undetectable
measurable residual disease.5 The trial includes 27 countries
across North and South America, Europe, Asia and Oceania.5
The AMPLIFY trial enrolled patients from 2019 to 2021,
continuing through the COVID-19 pandemic.5 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.6
CALQUENCE®
CALQUENCE (acalabrutinib) is a second-generation, selective
inhibitor of Bruton’s tyrosine kinase (BTK). CALQUENCE binds
covalently to BTK, thereby inhibiting its activity.7 In B-cells,
BTK signaling results in activation of pathways necessary for
B-cell proliferation, trafficking, chemotaxis and adhesion.
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 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
- Data on File, REF-236261. AstraZeneca Pharmaceuticals LP.
- Yao Y, et al. The global burden and attributable risk factors
of chronic lymphocytic leukemia in 204 countries and territories
from 1990 to 2019: analysis based on the global burden of disease
study 2019. Biomed Eng Online. 2022;1:4.
- American Cancer Society. Signs and Symptoms of Chronic
Lymphocytic Leukemia. Accessed November 2024. Available at:
https://www.cancer.org/cancer/types/chronic-lymphocytic-leukemia/detection-diagnosis-staging/signs-symptoms.html.
- National Cancer Institute. Chronic lymphocytic leukemia
treatment (PDQ®)–Patient version. Accessed November 2024. Available
at:
https://www.cancer.gov/types/leukemia/patient/cll-treatment-pdq.
- 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). Accessed November 2024. Available at:
https://clinicaltrials.gov/study/NCT03836261.
- Dube S, 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, et al. Acalabrutinib (ACP-196): a selective
second-generation BTK inhibitor. J Hematol Oncol. 2016;9(21).
US-96571 Last Updated 12/24
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