TIDMAZN
RNS Number : 9542A
AstraZeneca PLC
07 June 2021
7 June 2021 07:00 BST
Calquence demonstrated fewer incidences of atrial fibrillation
versus ibrutinib in previously treated patients with chronic
lymphocytic leukaemia and sustained patient benefit at four years
in the front-line setting
ELEVATE-RR head-to-head trial in previously treated patients
showed less cardiovascular toxicity and fewer discontinuations due
to adverse events for Calquence versus ibrutinib
Long-term follow up from ELEVATE-TN trial in front-line setting
showed Calquence maintained progression-free survival and
favourable tolerability at four years
Final results from the head-to-head ELEVATE-RR Phase III trial
of AstraZeneca's Calquence (acalabrutinib) demonstrated
non-inferior progression-free survival (PFS) and statistically
significantly fewer events of atrial fibrillation versus ibrutinib
in adults with previously treated chronic lymphocytic leukaemia
(CLL), the most common type of leukaemia in adults.(1)
Separately, updated results at four years of follow up from the
ELEVATE-TN Phase III trial continued to show a strong PFS benefit
for Calquence as combination therapy or as monotherapy in
previously untreated patients with CLL.
At a median follow up of 40.9 months, the ELEVATE-RR trial met
its primary endpoint of PFS non-inferiority versus ibrutinib with a
median PFS of 38.4 months in both arms (based on a hazard ratio
[HR] of 1.0, 95% confidence interval [CI] 0.79-1.27). Patients
treated with Calquence had a statistically significantly lower
incidence of all-grade atrial fibrillation compared with patients
treated with ibrutinib (9.4% versus 16.0%), a key secondary
endpoint.(2) Atrial fibrillation is an irregular heart rate that
can increase the risk of stroke, heart failure and other
heart-related complications.(3)
John C. Byrd, MD, Distinguished University Professor, The Ohio
State University, and lead investigator of the ELEVATE-RR trial,
said: "Cardiac adverse events are an important consideration for
treating chronic lymphocytic leukaemia patients with Bruton's
tyrosine kinase inhibitors because they can produce significant
morbidity in some cases and also lead patients to discontinue
treatment. These data provide compelling evidence that
acalabrutinib is a more tolerable option with reduced
cardiovascular toxicity and overall fewer discontinuations due to
adverse events, giving clinicians further reassurance when
prescribing this medicine that patients can stay on treatment while
maintaining ongoing control of their disease."
Dave Fredrickson, Executive Vice President, Oncology Business
Unit, said: "Tolerability is a critical factor in treating patients
with chronic lymphocytic leukaemia who often remain on medicines
for many years and experience multiple comorbidities. The totality
of the Calquence data at ASCO confirm our confidence in the
favourable benefit-risk profile of this medicine, with over 40
months of follow up in each of these two trials. Together, the
results provide strong evidence that Calquence is a preferred
option for people living with this chronic and devastating
disease."
The results of both trials were presented during the 2021
American Society of Clinical Oncology (ASCO) Annual Meeting on 7
June 2021.
ELEVATE-RR: Calquence versus ibrutinib in relapsed or refractory
CLL
ELEVATE-RR (ACE-CL-006) is the first Phase III trial to compare
two Bruton's tyrosine kinase (BTK) inhibitors in patients with
previously treated CLL with presence of 17p deletion or presence of
11q deletion.(2) The trial met the non-inferiority endpoint for PFS
defined by the trial for Calquence (n=268) versus ibrutinib (n=265)
in patients with previously treated CLL with certain high-risk
prognostic factors. (2)
Patients treated with Calquence had statistically significantly
lower incidence of all-grade atrial fibrillation, a key secondary
endpoint, compared with patients treated with ibrutinib (9.4%
[n=25/266] versus 16.0% [n=42/263]; p=0.02).(2)
A lower frequency of adverse events (AEs) was observed with
Calquence versus ibrutinib including lower common AEs, Grade 3 or
higher AEs, serious AEs, treatment discontinuations due to AEs and
overall cardiac events.(2) The safety and tolerability of Calquence
in ELEVATE-RR was consistent with the known profile of
Calquence.
Adverse events led to treatment discontinuation in 14.7% of
patients on Calquence and 21.3% of patients on ibrutinib. AEs of
clinical interest for Calquence versus ibrutinib included cardiac
events (all grade, 24.1%, and 30.0%, respectively), bleeding events
(all grade, 38.0% and 51.3%, respectively), hypertension (all
grade, 9.4% and 23.2%, respectively), infections (all grade, 78.2%
and 81.4%, respectively), interstitial lung disease/pneumonitis
(all grade, 2.6% and 6.5%, respectively) and second primary
malignancies excluding non-melanoma skin cancer (all-grade, 9.0%
and 7.6%, respectively).(2) Serious AEs (any grade) occurred in
53.8% of patients on Calquence versus 58.6% of patients receiving
ibrutinib.(2)
Median overall survival (OS) was not reached in either arm, with
63 (23.5%) patients in the Calquence arm, and 73 (27.5%) patients
in the ibrutinib arm experiencing an event (HR of 0.82, 95% CI
0.59-1.15).(2)
ELEVATE-TN: Four-year follow up for Calquence in previously
untreated CLL
ELEVATE-TN (ACE-CL-007) is a randomised, multicentre, open-label
Phase III trial evaluating the safety and efficacy of Calquence in
combination with obinutuzumab or alone versus chlorambucil in
combination with obinutuzumab in previously untreated patients with
CLL.(4) The trial met its primary endpoint (IRC-assessed PFS with
Calquence plus obinutuzumab versus chlorambucil plus obinutuzumab)
at the data cut-off for the interim analysis after a median follow
up of 28.3 months.(5)
After a median follow up of 46.9 months, the ELEVATE-TN Phase
III trial showed Calquence plus obinutuzumab reduced the risk of
disease progression or death by 90% (HR 0.10, 95% CI 0.07-0.17) and
as a monotherapy by 81% (HR 0.19, 95% CI 0.13-0.28) compared with
chlorambucil plus obinutuzumab.(4) Estimated PFS rates at 48 months
for Calquence plus obinutuzumab or as monotherapy were 87% and 78%,
respectively, versus 25% for chlorambucil plus obinutuzumab.(4) PFS
findings were consistent across high-risk subgroups.(4) Median PFS
was not yet reached for either Calquence arm at four years of
follow up. Median OS was not reached in any treatment arm with a
trend toward significance in the Calquence plus obinutuzumab group
(p=0.0604).(4)
Summary of key efficacy results from the ELEVATE-TN trial(4)
Median follow up of 46.9 months (range: 0.0-59.4)
Efficacy measure Calquence plus Calquence monotherapy Chlorambucil
obinutuzumab N=179 plus obinutuzumab
N=179 N=177
PFS*: Overall population
Median (HR, 95% CI), NR NR
months (0.10; 0.07-0.17) (0.19; 0.13-0.28) 27.8
------------------- ---------------------- -------------------
p-value <0.0001 <0.0001 -
------------------- ---------------------- -------------------
Estimated PFS at
48 months, % 87 78 25
------------------- ---------------------- -------------------
PFS*: Patients with del(17p) and/or mutated TP53
Median (HR, 95% CI), NR NR
months (0.17; 0.07-0.42) (0.18; 0.07-0.46) 17.5
------------------- ---------------------- -------------------
p-value <0.0001 <0.0001
------------------- ---------------------- -------------------
Estimated PFS at
48 months, % 75 76 18
------------------- ---------------------- -------------------
ORR*
ORR, % (95% CI) 96.1 89.9 82.5
(92.1-98.1) (84.7-93.5) (76.2-87.4)
------------------- ---------------------- -------------------
p-value <0.0001 0.035 -
------------------- ---------------------- -------------------
OS
Median (HR, 95% CI), NR NR NR
months (0.50; 0.25-1.02) (0.95; 0.52-1.74)
------------------- ---------------------- -------------------
p-value 0.0604 0.9164 -
------------------- ---------------------- -------------------
Estimated OS at 48
months, % 93 88 88
------------------- ---------------------- -------------------
CI, confidence interval; NR, not reached; ORR, overall response
rate; OS, overall survival
*Investigator-assessed.
The safety profile remained largely unchanged from the interim
analysis at 24 months, with similar treatment discontinuation rates
across arms (25.1%, 30.7% and 22.6% for Calquence plus
obinutuzumab, Calquence monotherapy and chlorambucil plus
obinutuzumab, respectively).(4) The most common reasons for
treatment discontinuation were AEs (12.8%, 12.34% and 14.7%,
respectively) and progressive disease (4.5%, 7.8% and 1.7%,
respectively).(4)
Selected AEs of interest of any grade in the Calquence
combination arm (n=178), Calquence monotherapy arm (n=179) and
chlorambucil plus obinutuzumab arm (n=169) included cardiac events
(20.8%, 19.0% and 7.7%, respectively), bleeding (47.2%, 41.9% and
11.8%, respectively), hypertension (7.9%, 7.3% and 4.1%,
respectively), infections (75.3%, 73.7% and 44.4%, respectively)
and second primary malignancies (15.7%, 13.4% and 4.1%,
respectively).(4)
CLL
Chronic lymphocytic leukaemia is the most common type of
leukaemia in adults, with an estimated 114,000 new cases globally
in 2017, and the number of people living with CLL is expected to
grow with improved treatment as patients live longer with the
disease.(1,6-8) In CLL, too many blood stem cells in the bone
marrow become abnormal lymphocytes and these abnormal cells have
difficulty fighting infections. As the number of abnormal cells
grows there is less room for healthy white blood cells, red blood
cells and platelets. This could result in anaemia, infection and
bleeding.(6) B-cell receptor signalling through Bruton's tyrosine
kinase is one of the essential growth pathways for CLL.
ELEVATE-RR
ELEVATE-RR (ACE-CL-006) is a randomised, multicentre, open-label
Phase III non-inferiority trial of Calquence versus ibrutinib in
patients with relapsed or refractory CLL after at least one prior
therapy, and at least one of the following prognostic factors:
presence of 17p deletion, or presence of 11q deletion. In the
trial, 533 patients were randomised (1:1) into two arms. Patients
in the first arm received Calquence (100mg orally twice daily)
until disease progression or unacceptable toxicity. Patients in the
second arm received ibrutinib (420mg orally once daily) until
disease progression or unacceptable toxicity.(2)
The primary endpoint for the trial was PFS assessed by an
independent review committee (non-inferiority; tested after 250
events, HR upper margin of <1.429).(2) Secondary endpoints
included incidence of atrial fibrillation, incidence of Grade 3 or
higher infections, incidence of Richter's transformation (a
condition in which CLL changes into an aggressive form of lymphoma)
and OS.(2,9)
ELEVATE-TN
ELEVATE-TN (ACE-CL-007) is a randomised, multicentre, open-label
Phase III trial evaluating the safety and efficacy of Calquence
alone or in combination with obinutuzumab versus chlorambucil in
combination with obinutuzumab in previously untreated patients with
CLL. In the trial, 535 patients were randomised (1:1:1) into three
arms. Patients in the first arm received chlorambucil in
combination with obinutuzumab. Patients in the second arm received
Calquence (100mg twice daily until disease progression) in
combination with obinutuzumab. Patients in the third arm received
Calquence monotherapy (100mg twice daily until disease
progression).(4)
The primary endpoint was PFS in the Calquence and obinutuzumab
arm compared to the chlorambucil and obinutuzumab arm, assessed by
an independent review committee (IRC), and a key secondary endpoint
was IRC-assessed PFS in the Calquence monotherapy arm compared to
the chlorambucil and obinutuzumab arm. Other secondary endpoints
included objective response rate, time to next treatment, OS and
investigator-assessed PFS.(4) After interim analysis, assessments
were by investigator only.(4)
Initial results from the ELEVATE-TN Phase III trial were
presented in December 2019 at the American Society of Hematology
Annual Meeting and Exhibition.(10) The findings, along with
previously reported data from the Phase III ASC trial in relapsed
or refractory CLL, supported the approvals of Calquence by the US
FDA and the Australian Therapeutic Goods Administration for the
treatment of adult patients with CLL or small lymphocytic lymphoma
(SLL) and by the European Union and Health Canada for CLL.
Calquence
Calquence (acalabrutinib) is a next-generation, selective
inhibitor of BTK. Calquence binds covalently to BTK, thereby
inhibiting its activity.(11,12) In B-cells, BTK signalling results
in activation of pathways necessary for B-cell proliferation,
trafficking, chemotaxis, and adhesion.(11)
Calquence is approved for the treatment of CLL and SLL in the
US, approved for CLL in the EU and several other countries
worldwide, and approved in Japan for relapsed or refractory CLL and
SLL. A Phase I trial is currently underway in Japan for the
treatment of front-line CLL.
In the US and several other countries, Calquence is also
approved for the treatment of adult patients with mantle cell
lymphoma (MCL) who have received at least one prior therapy. The US
MCL 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 not currently approved for the
treatment of MCL in Europe or Japan.
As part of an extensive clinical development programme,
AstraZeneca and Acerta Pharma are currently evaluating Calquence in
more than 20 company-sponsored clinical trials. Calquence is being
evaluated for the treatment of multiple B-cell blood cancers
including CLL, MCL, diffuse large B-cell lymphoma, Waldenström's
macroglobulinaemia, follicular lymphoma and other haematologic
malignancies.
AstraZeneca in haematology
AstraZeneca is pushing the boundaries of science to redefine
care in haematology. Applying our deep understanding of blood
cancers and leveraging our strength in solid tumour oncology, we
are driving the development of novel therapies designed to target
underlying drivers of disease across six scientific platforms. By
addressing blood cancers with high unmet medical needs, our aim is
to deliver innovative medicines and approaches to healthcare
services that have a meaningful impact on patients and caregivers,
transforming the haematologic cancer care experience.
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 catalyse 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 commercialisation of prescription medicines in
Oncology 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 astrazeneca.com and follow the Company on Twitter
@AstraZeneca.
Contacts
For details on how to contact the Investor Relations Team,
please click here. For Media contacts, click here.
References
1. American Cancer Society. What is Chronic Lymphocytic
Leukemia. Available online . Accessed June 2021.
2. Byrd JC, Hillmen P, Ghia P, et al. First Results of a
Head-to-Head Trial of Acalabrutinib versus Ibrutinib in Previously
Treated Chronic Lymphocytic Leukemia. Oral presentation at:
American Society for Clinical Oncology (ASCO) Annual Meeting; June
4-8, 2021; virtual. Abstract ID: 7500.
3. Mayo Clinic. Patient Care & Health Information, Diseases
& Conditions - Atrial Fibrillation. Available online . Accessed
June 2021.
4. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib +/-
Obinutuzumab vs Obinutuzumab + Chlorambucil in Treatment-Naïve
Chronic Lymphocytic Leukemia: ELEVATE-TN 4-Year Follow-up [abstract
and poster]. Presented at: American Society for Clinical Oncology
(ASCO) Annual Meeting; June 4-8, 2021; virtual. Abstract ID: 7509.
Accessed June 2021.
5. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or
without obinutuzumab versus chlorambucil and obinutuzumab for
treatment-naive chronic lymphocytic leukaemia (ELEVATE-TN): a
randomised, controlled, phase 3 trial. Lancet. 2020;395:1278-1291.
doi:10.1182/blood-2019-128404.
6. National Cancer Institute. Chronic Lymphocytic Leukemia
Treatment (PDQ(R) )-Patient Version. Available online . Accessed
June 2021.
7. Global Burden of Disease Cancer Collaboration. Global,
Regional, and National Cancer Incidence, Mortality, Years of Life
Lost, Years Lived With Disability, and Disability-Adjusted
Life-Years for 29 Cancer Groups, 1990 to 2017. JAMA Oncol.
2019;5(12):1749-1768.
8. Jain N, et al. Prevalence and Economic Burden of Chronic
Lymphocytic Leukemia (CLL) in the Era of Oral Targeted Therapies.
Blood. 2015;126:871.5.
9. Leukaemia Foundation. Richter's Syndrome. Available online . Accessed June 2021.
10. Sharman JP, Egyed M, Jurczak W, et al. ELEVATE TN: Phase 3
Study of Acalabrutinib Combined with Obinutuzumab (O) or Alone vs O
Plus Chlorambucil (Clb) in Patients (Pts) With Treatment-Naive
Chronic Lymphocytic Leukemia (CLL). Oral presentation at: American
Society of Hematology 2019 Annual Meeting and Exposition; December
7-10, 2019; Orlando, FL.
11. CALQUENCE (acalabrutinib) [U.S. prescribing information].
Wilmington, DE; AstraZeneca Pharmaceuticals LP; 2019.
12. Wu J, Zhang M & Liu D. Acalabrutinib (ACP-196): a
selective second-generation BTK inhibitor. J Hematol Oncol.
2016;9(21).
Adrian Kemp
Company Secretary
AstraZeneca PLC
, the news service of the London Stock Exchange. RNS is approved by
the Financial Conduct Authority to act as a Primary Information
Provider in the United Kingdom. Terms and conditions relating to
the use and distribution of this information may apply. For further
information, please contact rns@lseg.com or visit www.rns.com.
RNS may use your IP address to confirm compliance with the terms
and conditions, to analyse how you engage with the information
contained in this communication, and to share such analysis on an
anonymised basis with others as part of our commercial services.
For further information about how RNS and the London Stock Exchange
use the personal data you provide us, please see our Privacy
Policy.
END
MSCDKABQFBKDAAK
(END) Dow Jones Newswires
June 07, 2021 02:00 ET (06:00 GMT)
Astrazeneca (LSE:AZN)
Historical Stock Chart
From Mar 2024 to Apr 2024
Astrazeneca (LSE:AZN)
Historical Stock Chart
From Apr 2023 to Apr 2024