Blueprint
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 November
2019
Commission
File Number: 001-11960
AstraZeneca PLC
1
Francis Crick Avenue
Cambridge
Biomedical Campus
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United
Kingdom
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AstraZeneca PLC
INDEX
TO EXHIBITS
1.
Calquence approved in the US for adult patients with
chronic lymphocytic leukaemia
21 November 2019 18:10 GMT
Calquence approved in the US
for adult patients with chronic lymphocytic leukaemia
Two Phase III
Calquence trials demonstrated superior
progression-free survival across multiple settings while
maintaining favourable tolerability
Calquence combined with obinutuzumab and as monotherapy
reduced
the risk of disease progression or death by 90% and
80%,
respectively in ELEVATE-TN
AstraZeneca today announced that the US Food and Drug
Administration (FDA) has approved Calquence (acalabrutinib) for adult patients with
chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma
(SLL).1 The
US approval was granted under the FDA's Real-Time Oncology Review
and newly established Project Orbis programmes.
The approval is based on positive results from the
interim analyses of two Phase III clinical trials, ELEVATE-TN
in patients with previously untreated CLL and ASCEND in patients
with relapsed or refractory CLL. Together, the trials showed
that Calquence in combination with obinutuzumab or as a
monotherapy significantly reduced the relative risk of disease
progression or death versus the comparator arms in both 1st-line
and relapsed or refractory CLL. Across both trials, the safety and
tolerability of Calquence were consistent with its established
profile.1
Dave Fredrickson, Executive Vice President, Oncology Business Unit
said: "With over 20,000 new cases anticipated this year in the US
alone, today's approval of Calquence provides new hope for patients with one of
the most common types of adult leukaemia, offering outstanding
efficacy and a favourable tolerability profile. The chronic
lymphocytic leukaemia patient population is known to face multiple
comorbidities, and tolerability is a critical factor in their
treatment."
Dr Jeff Sharman, Director of Research at Willamette Valley Cancer
Institute, Medical Director of Hematology Research for The US
Oncology Network, and a lead author of the ELEVATE-TN trial,
said: "Tolerability remains an issue in the current treatment
landscape of chronic lymphocytic leukaemia, which may require
ongoing therapy for many years. In the ELEVATE-TN and ASCEND trials
comparing Calquence to commonly used treatment
regimens, Calquence demonstrated a clinically meaningful
improvement in progression-free survival in patients across
multiple settings, while maintaining its favourable tolerability
and safety profile."
The results of the interim analysis of the ELEVATE-TN trial will be
presented at the upcoming American Society of Hematology
congress.2
The trial showed a statistically significant and clinically
meaningful improvement in progression-free survival (PFS) for
patients treated with either Calquence in combination with obinutuzumab
or Calquence monotherapy versus chlorambucil chemotherapy
plus obinutuzumab, a current standard-of-care combination used in
the control arm.1
In the Calquence combination arm, risk of disease progression
or death was reduced by 90% (HR 0.10; 95% CI, 0.06-0.17,
p<0.0001) and in the monotherapy arm it was reduced by 80% (HR
0.20; 95% CI, 0.13-0.30, p<0.0001).1
The median time to disease progression for patients treated
with Calquence in combination with obinutuzumab or as a
monotherapy has not yet been reached versus 22.6 months (95% CI,
20-28) for chlorambucil plus obinutuzumab.1
ELEVATE-TN safety overview (most common ARs,
≥15%):1
Adverse
reaction
|
Calquence plus
obinutuzumab(n=178)
|
Calquence monotherapy(n=179)
|
Chlorambucil plus obinutuzumab(n=169)
|
Any
|
Grade
≥3
|
Any
|
Grade≥3
|
Any
|
Grade≥3
|
Infection†
|
69%
|
22%
|
65%
|
14%
|
46%
|
13%
|
Neutropenia†
|
53%
|
37%
|
23%
|
13%
|
78%
|
50%
|
Anemia†
|
52%
|
12%
|
53%
|
10%
|
54%
|
14%
|
Thrombocytopenia†
|
51%
|
12%
|
32%
|
3.4%
|
61%
|
16%
|
Headache
|
40%
|
1.1%
|
39%
|
1.1%
|
12%
|
0
|
Diarrhoea
|
39%
|
4.5%
|
35%
|
0.6%
|
21%
|
1.8%
|
Musculoskeletal
pain†
|
37%
|
2.2%
|
32%
|
1.1%
|
16%
|
2.4%
|
Fatigue
|
34%
|
2.2%
|
23%
|
1.1%
|
24%
|
1.2%
|
Bruising†
|
31%
|
0
|
21%
|
0
|
5%
|
0
|
Rash†
|
26%
|
2.2%
|
25%
|
0.6%
|
9%
|
0.6%
|
Arthralgia
|
22%
|
1%
|
16%
|
0.6%
|
4.7%
|
1.2%
|
Dizziness
|
20%
|
0
|
12%
|
0
|
7%
|
0
|
Hemorrhage†
|
20%
|
1.7%
|
20%
|
1.7%
|
6%
|
0
|
Nausea
|
20%
|
0
|
22%
|
0
|
31%
|
0
|
Lymphocytosis†
|
12%
|
11%
|
16%
|
15%
|
0.6%
|
0.6%
|
†Includes multiple ADR
terms.
In patients treated with the combination
of Calquence plus
obinutuzumab, adverse reactions (ARs) led to treatment
discontinuation in 11% of patients and a dose reduction
of Calquence in 7% of patients. In the monotherapy arm,
ARs led to discontinuation in 10% and dose reduction in 4% of
patients.1 In
the control arm, ARs led to regimen discontinuation in 14% of
patients with a dose reduction of chlorambucil in 28% of
patients.3 There
were no dose reductions for obinutuzumab.1,3
In 1,029 patients with haematologic malignancies who were treated
with Calquence 100mg approximately every 12 hours across
multiple clinical trials, where 88% received treatment for at least
six months and 79% received treatment for at least one
year, serious or Grade ≥3 infections occurred in 19%,
and Grade 3 atrial fibrillation and flutter occurred in 1.1% of
patients. In the same patient population, major
haemorrhage occurred in 3.0% (serious or Grade ≥3 bleeding or
any central nervous system bleeding), with fatal haemorrhage
occurring in 0.1% of patients. Second primary malignancies (all
grades) including skin cancers occurred in 12% of
patients.1
The US approval is among the first to be granted under Project
Orbis, an initiative of the US FDA Oncology Center of Excellence,
which provides a framework for concurrent submission and review of
oncology medicines among international partners. The FDA, the
Australian Therapeutic Goods Administration, and Health Canada
collaborated on this review. 4
About Calquence
In the US, Calquence (acalabrutinib) is indicated for the
treatment of adult patients with chronic lymphocytic leukaemia
(CLL)/small lymphocytic lymphoma (SLL). In the US, Canada,
Australia, Brazil, Qatar, the United Arab Emirates, Mexico,
Argentina, Singapore, Chile, and recently
India, Calquence is indicated for adult patients with mantle
cell lymphoma (MCL) who have received at least one prior therapy.
Approved under accelerated review in the US, continued approval for
previously treated MCL is contingent upon verification and
confirmation of clinical benefit in confirmatory
trials.
Calquence is a
next-generation selective inhibitor of Bruton's tyrosine kinase
(BTK). Calquence binds covalently to BTK, thereby inhibiting
its activity.1,5,6,7 In
B-cells, BTK signalling results in activation of pathways necessary
for B-cell proliferation, trafficking, chemotaxis, and
adhesion.1
As part of an extensive clinical development programme, AstraZeneca
and Acerta Pharma are currently evaluating Calquence in 23 company-sponsored clinical
trials. Calquence is being developed for the treatment of
multiple B-cell blood cancers including CLL, MCL, diffuse large
B-cell lymphoma, Waldenström macroglobulinaemia and follicular
lymphoma and other haematologic malignancies. Several Phase III
clinical trials in CLL are ongoing, including ASCEND, ELEVATE-TN,
ELEVATE-RR (ACE-CL-006) evaluating Calquence versus ibrutinib in patients with previously
treated high-risk CLL, and ACE-CL-311
evaluating Calquence in combination with venetoclax and
with/without obinutuzumab versus chemoimmunotherapy in patients
with previously untreated CLL without 17p deletion
or TP53 mutation.
About ELEVATE-TN
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, a CD20
monoclonal antibody, or Calquence alone versus chlorambucil, a chemotherapy,
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
or unacceptable toxicity) in combination with obinutuzumab.
Patients in the third arm received Calquence monotherapy (100mg twice daily until disease
progression or unacceptable toxicity).1,8
The primary endpoint is 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 is
IRC-assessed PFS in the Calquence monotherapy arm compared to the chlorambucil
and obinutuzumab arm. Other secondary endpoints include objective
response rate, time to next treatment and overall
survival.1,8
About ASCEND
ASCEND (ACE-CL-309) is a global, randomised, multicentre,
open-label Phase III trial evaluating the efficacy
of Calquence in previously treated patients with CLL. In
the trial, 310 patients were randomised (1:1) into two arms.
Patients in the first arm received Calquence monotherapy (100mg twice daily until disease
progression or unacceptable toxicity). Patients in the second arm
received investigator's choice of either rituximab, a CD20
monoclonal antibody, in combination with idelalisib, a PI3K
inhibitor, or rituximab in combination with bendamustine, a
chemotherapy.1,9
The primary endpoint is PFS assessed by an IRC, and key secondary
endpoints include physician-assessed PFS, IRC- and
physician-assessed overall response rate and duration of response,
as well as overall survival, patient-reported outcomes and time to
next treatment.1,9
About CLL
Chronic lymphocytic leukaemia (CLL) is one of the most common types
of leukaemia in adults, with an estimated 105,000 new cases
globally each year and 20,720 new cases in the US in 2019, and the
number of people living with CLL is expected to grow with improved
treatment as patients live longer with the
disease.10,11,12,13 In
CLL, too many blood stem cells in the bone marrow become abnormal
lymphocytes and these abnormal cells have difficulty fighting
infections.10 As
the number of abnormal cells grows there is less room for healthy
white blood cells, red blood cells and
platelets.10 This
could result in anaemia, infection and bleeding.10 B-cell
receptor signalling through BTK is one of the essential growth
pathways for CLL.
About AstraZeneca in haematology
Leveraging its strength in oncology, AstraZeneca has established
haematology as one of four key oncology disease areas of focus. The
Company's haematology franchise includes two US FDA-approved
medicines and a robust global development programme for a broad
portfolio of potential blood cancer treatments. Acerta Pharma
serves as AstraZeneca's haematology research and development arm.
AstraZeneca partners with like-minded science-led companies to
advance the discovery and development of therapies to address unmet
need.
About AstraZeneca in oncology
AstraZeneca has a deep-rooted heritage in oncology and offers a
quickly-growing portfolio of new medicines that has the potential
to transform patients' lives and the Company's future. With at
least six new medicines to be launched between 2014 and 2020, and a
broad pipeline of small molecules and biologics in development, the
Company is committed to advance oncology as a key growth driver for
AstraZeneca focused on lung, ovarian, breast and blood cancers. In
addition to AstraZeneca's main capabilities, the Company is
actively pursuing innovative partnerships and investments that
accelerate the delivery of our strategy, as illustrated by the
investment in Acerta Pharma in haematology.
By
harnessing the power of four scientific platforms -
Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response
and Antibody Drug Conjugates - and by championing the development
of personalised combinations, AstraZeneca has the vision to
redefine cancer treatment and, one day, eliminate cancer as a cause
of death.
About AstraZeneca
AstraZeneca is a global, science-led biopharmaceutical company that
focuses on the discovery, development and commercialisation of
prescription medicines, primarily for the treatment of diseases in
three therapy areas - Oncology, Cardiovascular, Renal and
Metabolism, and Respiratory. 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.
Media
Relations
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Viña
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+44 203
749 5916
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Rob
Skelding
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Oncology
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+44 203
749 5821
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|
Oncology
|
+1 301
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BioPharmaceuticals
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749 5906
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Hursit
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References
1. CALQUENCE® (acalabrutinib)
[prescribing information]. Wilmington, DE; AstraZeneca
Pharmaceuticals LP; 2019.
2. Sharman JP, 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). Abstract 31 at: American Society of Hematology 2019
Annual Meeting and Exposition. Available online. Accessed November
2019.
3. Data on File. REF-64711. AstraZeneca Pharmaceuticals LP,
Wilmington, DE.
4. US Food and Drug Administration. Project Orbis. Available
online. Accessed November 2019.
5. Wu J, Zhang M & Liu D. Acalabrutinib (ACP-196): a selective
second-generation BTK inhibitor. J Hematol
Oncol.
2016;9(21).
6. Khan Y & O'Brien S. Acalabrutinib and its use in treatment
of chronic lymphocytic leukemia. Future
Oncol.
2018;15(6).
7. Byrd JC, et al. Acalabrutinib (ACP-196) in Relapsed Chronic
Lymphocytic Leukemia. N Engl J
Med. 2016;
374:323-332.
8. ClinicalTrials.gov. Elevate CLL TN: Study of Obinutuzumab +
Chlorambucil, Acalabrutinib (ACP-196) + Obinutuzumab, and
Acalabrutinib in Subjects With Previously Untreated CLL.
NCT02475681. Available online. Accessed November 2019.
9. ClinicalTrials.gov. A Study of Acalabrutinib vs Investigator's
Choice of Idelalisib Plus Rituximab or Bendamustine Plus Rituximab
in R/R CLL. NCT02970318. Available online. Accessed November
2019.
10. National Cancer Institute. Chronic Lymphocytic Leukemia
Treatment (PDQ®)-Patient
Version. Available online. Accessed November
2019.
11. 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
2016. JAMA Oncol. 2018;4(11):1553-1568.
12. American Cancer Society. Key Statistics for Chronic Lymphocytic
Leukemia. Available online. Accessed November 2019.
13. Jain N, et al. Prevalence and Economic Burden of Chronic
Lymphocytic Leukemia (CLL) in the Era of Oral Targeted
Therapies. Blood. 2015;126:871.
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:
21 November
2019
|
By: /s/
Adrian Kemp
|
|
Name:
Adrian Kemp
|
|
Title:
Company Secretary
|