a9573a
FORM 6-K
SECURITIES
AND EXCHANGE COMMISSION
Washington,
D.C. 20549
Report
of Foreign Issuer
Pursuant
to Rule 13a-16 or 15d-16 of
the
Securities Exchange Act of 1934
For the
month of June 2021
Commission
File Number: 001-11960
AstraZeneca PLC
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AstraZeneca PLC
INDEX
TO EXHIBITS
1.
Calquence
head-to-head results versus ibrutinib
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 trial4
Median follow up of 46.9 months (range: 0.0-59.4)
Efficacy measure
|
Calquence plus
obinutuzumab
N=179
|
Calquence monotherapy
N=179
|
Chlorambucil plus obinutuzumab
N=177
|
PFS*: Overall population
|
Median (HR, 95% CI), months
|
NR
(0.10; 0.07-0.17)
|
NR
(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), months
|
NR
(0.17; 0.07-0.42)
|
NR
(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
(92.1-98.1)
|
89.9
(84.7-93.5)
|
82.5
(76.2-87.4)
|
p-value
|
<0.0001
|
0.035
|
-
|
OS
|
Median (HR, 95% CI), months
|
NR
(0.50; 0.25-1.02)
|
NR
(0.95; 0.52-1.74)
|
NR
|
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
ASCEND 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
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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®)-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
SIGNATURES
Pursuant
to the requirements of the Securities Exchange Act of 1934, the
Registrant has duly caused this report to be signed on its behalf
by the undersigned, thereunto duly authorized.
Date:
07 June 2021
|
By: /s/
Adrian Kemp
|
|
Name:
Adrian Kemp
|
|
Title:
Company Secretary
|