29 July 2024
Fixed-duration Calquence plus venetoclax,
with or without obinutuzumab, significantly improved
progression-free survival in 1st-line chronic lymphocytic leukaemia
in AMPLIFY Phase III trial
Favourable 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 leukaemia (CLL).
For the secondary endpoint of
overall survival (OS), a trend was observed in favour 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
leukaemia 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 leukaemia. 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 leukaemia. 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.
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 anaemia, infection and
bleeding.1 B-cell receptor signalling through BTK is one
of the essential survival pathways for CLL.
AMPLIFY
AMPLIFY is a randomised, global,
multi-centre, 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 randomised 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 hospitalisation 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 signalling 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 programme, 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
haematology
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In addition to our marketed products, we are
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unmet needs through the end-to-end development and delivery of
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in oncology with the ambition to provide cures for cancer in every
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the most challenging cancers. It is through persistent innovation
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References
1. National Cancer
Institute. Chronic Lymphocytic Leukemia Treatment (PDQ®)-Patient
Version: General Information About Chronic Lymphocytic Leukemia.
Available online. Accessed July 2024.
2. American Cancer
Society. What is Chronic Lymphocytic Leukemia? Available online.
Accessed July 2024.
3. 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.
4. 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.
5. 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.
6. American Cancer
Society. Signs and Symptoms of Chronic Lymphocytic Leukemia.
Available online. Accessed July 2024.
7. 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.
8. 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.
9. Wu J, Zhang M, Liu D.
Acalabrutinib (ACP-196): a selective second-generation BTK
inhibitor. J Hematol
Oncol. 2016;9(21).
10. Data on File, REF-236261.
AstraZeneca Pharmaceuticals LP.
Adrian Kemp
Company Secretary
AstraZeneca PLC