a0640j
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 December 2022
Commission
File Number: 001-11960
AstraZeneca PLC
1
Francis Crick Avenue
Cambridge
Biomedical Campus
Cambridge
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United
Kingdom
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AstraZeneca PLC
INDEX
TO EXHIBITS
Capivasertib PFS in HR-positive breast cancer
8 December 2022 13:30 GMT
Capivasertib
plus Faslodex reduced
the risk of disease progression or
death by
40% versus Faslodex in
advanced HR-positive breast cancer
CAPItello-291 Phase III trial
results presented at SABCS
2022
show potential of capivasertib
as first-in-class AKT inhibitor
Detailed results from the CAPItello-291 Phase III trial showed
AstraZeneca's capivasertib in combination with Faslodex (fulvestrant)
demonstrated a statistically significant and clinically meaningful
improvement in progression-free survival (PFS) versus placebo
plus Faslodex in patients with
hormone receptor (HR)-positive, HER2-low or
negative, locally advanced or metastatic breast
cancer, following recurrence or
progression on, or after, endocrine therapy (with or without a
CDK4/6 inhibitor).1 Results
will be presented today in an oral presentation at the 2022 San
Antonio Breast Cancer Symposium (SABCS).
Results showed capivasertib in
combination with Faslodex demonstrated
a 40% reduction in the risk of disease progression or death versus
placebo plus Faslodex in
the overall trial population (based on a hazard
ratio [HR] of 0.60, 95% confidence interval [CI]
0.51-0.71; p=<0.001;
median 7.2 versus 3.6
months).1 In
the AKT pathway biomarker-altered population, capivasertib
plus Faslodex reduced
the risk of disease progression or death by 50% versus placebo
plus Faslodex (HR
of 0.50, 95% CI 0.38-0.65;
p=<0.001;
median 7.3
versus 3.1
months).1 Alterations
within the AKT pathway (PI3K/AKT/PTEN) occur frequently in breast
cancer, affecting up to 50% of patients with advanced HR-positive
breast cancer.2-4
Nicholas Turner, MD, PhD, Professor of Molecular Oncology at The
Institute of Cancer Research, London, and The Royal Marsden NHS
Foundation Trust, London, UK, and principal investigator in
the CAPItello-291 Phase
III trial, said:
"These data demonstrate
the practice-changing potential of
capivasertib as a new treatment option for patients with advanced
HR-positive breast cancer.
Critically, this potentially
first-in-class treatment has shown it delays disease
progression for those who have
progressed on, or become resistant to, endocrine therapies and
CDK4/6 inhibitors."
Susan Galbraith, Executive Vice
President, Oncology R&D, AstraZeneca, said: "Capivasertib
brings important progress to an area with persistent treatment gaps
as the first therapy of its kind shown to be effective in a Phase
III trial in patients with advanced HR-positive, HER2-low or
negative breast cancer. We believe these results which showed
benefit in all-comers and biomarker positive populations can
reshape HR-positive breast cancer treatment, and that capivasertib
can become an important new option for patients."
Summary of results:
CAPItello-2911
|
Capivasertib
plus Faslodexn=355
|
Placebo plus Faslodex
n=353
|
Median PFS in overall population (months)
|
7.2
|
3.6
|
HR (95% CI)
|
0.60 (0.51-0.71)
|
p-value
|
p=<0.001
|
Median PFS in the biomarker-altered population
(months)
|
7.3
|
3.1
|
HR (95% CI)
|
0.50 (0.38-0.65)
|
p-value
|
p=<0.001
|
ORR in overall population
|
22.9%
|
12.2%
|
ORR in biomarker-altered population
|
28.8%
|
9.7%
|
HR, hazard ratio; CI, confidence interval; PFS, progression-free
survival; ORR, objective response rate
Confirmed objective response rate (ORR) was 22.9% for the
capivasertib plus Faslodex arm versus 12.2% for the placebo
plus Faslodex arm in the overall trial population, and
28.8% versus 9.7%, respectively, in the biomarker-altered
population.1 Although
the overall survival (OS) data were immature at the time of the
analysis, early data are encouraging.1 The
trial will continue to assess OS as a key secondary
endpoint.
The safety profile of capivasertib plus Faslodex was similar to that observed in previous
trials evaluating this combination.1 In
the overall trial population, the most frequent any grade adverse
events (AEs) with capivasertib plus Faslodex occurring in 20% or more of
patients were diarrhoea (72.4%), nausea (34.6%), rash (group
term including rash, rash macular, maculo-papular rash, rash
papular and rash pruritic; 38%) fatigue (20.8%) and vomiting
(20.6%).1 The
most frequent Grade 3 or higher AEs occurring in 5% or more of
patients were diarrhoea (9.3%) and rash
(12.1%).1
Notes
HR-positive breast cancer
Breast cancer is the most common cancer and is one of the leading
causes of cancer-related deaths worldwide.5 More
than two million patients were diagnosed with breast cancer in
2020, with nearly 685,000 deaths globally.5
HR-positive breast cancer (expressing estrogen or
progesterone receptors, or both), is the most common subtype
of breast cancer with approximately 70% of breast cancer tumours
considered HR-positive and HER2-low or negative.6
The growth of HR-positive breast cancer cells is often driven by
estrogen receptors (ER),7 andendocrine
therapies that target ER-driven disease are widely used as 1st-line
treatment in the advanced setting, and often paired with
cyclin-dependent kinase (CDK) 4/6 inhibitors.8,9 However,
resistance to CDK4/6 inhibitors and current endocrine therapies
develops in many patients with advanced disease.9 Once
this occurs, treatment options are limited9 -
with chemotherapy being the current standard of
care10 -
and survival rates are low with 30% of patients anticipated to live
beyond five years after diagnosis.6
Optimising endocrine therapy and overcoming resistance for
patients with ER-driven disease at all stages of treatment as well
as identifying new therapies for those who no longer have ER-driven
disease are active areas of focus for breast cancer
research.
CAPItello-291
CAPItello-291 is a Phase III, double-blind, randomised trial that
is part of a larger clinical programme focused on capivasertib, an
investigational AKT (serine/threonine kinase) inhibitor.
CAPItello-291 is evaluating the efficacy of capivasertib in
combination with Faslodex versus placebo plus Faslodex for the treatment of locally advanced
(inoperable) or metastatic HR-positive, HER2-low or negative breast
cancer.
The global trial enrolled 708 adult patients with histologically
confirmed HR-positive, HER2-low or negative breast cancer whose
disease has recurred or progressed during or after aromatase
inhibitor therapy, with or without a CDK4/6 inhibitor, and
up to one line of chemotherapy for advanced disease. The trial has
dual primary endpoints of PFS in the overall patient
population and in a population
of patients whose tumours have qualifying alterations in the AKT
pathway (PIK3CA, AKT1 or PTEN genes). In the trial, approximately
40% of tumours had these alterations.
Capivasertib
Capivasertib is an investigational oral treatment currently in
Phase III trials for the treatment of multiple subtypes of breast
cancer, prostate cancer and a Phase II trial for haematologic
malignancies. A potent, selective adenosine triphosphate
(ATP)-competitive inhibitor of all three AKT isoforms
(AKT1/2/3), capivasertib is being evaluated as a monotherapy
and in combination with existing therapies in tumours harbouring
alterations in the AKT pathway (PI3K/AKT/PTEN), and in tumours
reliant on signalling via this pathway for
survival. Capivasertib 400 mg is administered twice daily
according to an intermittent dosing schedule of four days on and
three days off. This was chosen in early phase trials based on
tolerability and the degree of target inhibition.
The capivasertib clinical research programme is investigating the
safety and efficacy of capivasertib when used alone and in
combination with established treatment regimens.
Capivasertib was discovered by AstraZeneca subsequent to a
collaboration with Astex Therapeutics (and its collaboration with
the Institute of Cancer Research and Cancer Research Technology
Limited).
AstraZeneca in breast cancer
Driven by a growing understanding of breast cancer biology,
AstraZeneca is starting to challenge, and redefine, the current
clinical paradigm for how breast cancer is classified and treated
to deliver even more effective treatments to patients in need -
with the bold ambition to one day eliminate breast cancer as a
cause of death.
AstraZeneca has a comprehensive portfolio of approved and promising
compounds in development that leverage different mechanisms of
action to address the biologically diverse breast cancer tumour
environment.
With Enhertu (trastuzumab deruxtecan), a HER2-directed
ADC, AstraZeneca and Daiichi Sankyo are aiming to improve outcomes
in previously treated HER2-positive and HER2-low metastatic breast
cancer and are exploring its potential in earlier lines of
treatment and in new breast cancer settings.
In HR-positive breast cancer, AstraZeneca continues to improve
outcomes with foundational medicines Faslodex (fulvestrant) and Zoladex (goserelin) and aims to reshape the
HR-positive space with next-generation SERD and potential new
medicine camizestrant as well as a potential first-in-class AKT
kinase inhibitor, capivasertib. AstraZeneca is also collaborating
with Daiichi Sankyo to explore the potential of TROP2-directed ADC,
datopotamab deruxtecan, in this setting.
PARP inhibitor Lynparza (olaparib) is a targeted treatment option
that has been studied in early and metastatic breast cancer with an
inherited BRCA mutation. AstraZeneca with MSD (Merck & Co.,
Inc. in the US and Canada) continue to
research Lynparza in these settings and to explore its
potential in earlier disease.
To bring much-needed treatment options to patients with
triple-negative breast cancer, an aggressive form of breast cancer,
AstraZeneca is evaluating the potential of datopotamab deruxtecan
alone and in combination with
immunotherapy Imfinzi (durvalumab),
capivasertib in combination with chemotherapy, and Imfinzi in
combination with other oncology medicines,
including Lynparza and Enhertu.
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, Rare Diseases, 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.
Turner,
et al. Capivasertib and fulvestrant for patients with aromatase
inhibitor-resistant hormone receptor-positive/human epidermal
growth factor receptor 2-negative advanced breast cancer: results
from the Phase III CAPItello-291 trial. Presented at: San Antonio
Breast Cancer Symposium, 6-10 December 2022, San Antonio, Texas,
USA.
2.
Howell S J, et al. Fulvestrant plus capivasertib
versus placebo after relapse or progression on an aromatase
inhibitor in metastatic, oestrogen receptor-positive, HER2-negative
breast cancer (FAKTION). J Clin
Oncol. 2022;
23:851-64.
3.
Hortobagyi G N, et al. Correlative Analysis of
Genetic Alterations and Everolimus Benefit in Hormone
Receptor-Positive, Human Epidermal Growth Factor Receptor
2-Negative Advanced Breast Cancer: Results From
BOLERO-2. J Clin
Oncol. 2016;
34:419-26.
4.
Millis S Z, et al. Landscape of
phosphatidylinositol-3-kinase pathway alterations across 19784
diverse solid tumors. JAMA Oncol. 2016;2(12):1565-73.
5.
Sung H, et al. Global Cancer Statistics 2020:
GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36
Cancers in 185 Countries. CA Cancer J
Clin. 2021;
10.3322/caac.21660.
6.
National Cancer Institute. Surveillance,
Epidemiology and End Results Program. https://seer.cancer.gov/statfacts/html/breast-subtypes.html.
Accessed December 2022.
7.
Scabia V, et al. Estrogen receptor positive breast
cancers have patient specific hormone sensitivities and rely on
progesterone receptor. Nat Commun. 2022;
10.1038/s41467-022-30898-0.
8.
Lin M, et al. Comparative Overall Survival of
CDK4/6 Inhibitors Plus Endocrine Therapy vs. Endocrine Therapy
Alone for Hormone receptor-positive, HER2-negative metastatic
breast cancer. J Cancer. 2020; 10.7150/jca.48944.
9.
Lloyd M R, et al. Mechanisms of Resistance to
CDK4/6 Blockade in Advanced Hormone Receptor-positive,
HER2-negative Breast Cancer and Emerging Therapeutic
Opportunities. Clin Cancer
Res. 2022;28(5):821-30.
10.
National Comprehensive Cancer Network. Clinical
Practice Guidelines in Oncology (NCCN Guidelines). Available
at: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1419.
Accessed December 2022.
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:
08 December
2022
|
By: /s/
Adrian Kemp
|
|
Name:
Adrian Kemp
|
|
Title:
Company Secretary
|