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
2022
Commission
File Number: 001-11960
AstraZeneca PLC
1
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Kingdom
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AstraZeneca PLC
INDEX
TO EXHIBITS
1.
Enhertu efficacy results in HER2-low breast cancer
06 June 2022 07:00 BST
Enhertu reduced
the risk of disease progression or death by 50% vs. chemotherapy in
patients with HER2-low metastatic breast cancer with HR-positive
and HR-negative disease
AstraZeneca and Daiichi Sankyo's Enhertu also
improved median overall survival by more than 6 months vs.
chemotherapy in all patients evaluated in
DESTINY-Breast04
Enhertu met the primary endpoint of progression-free survival in
patients with HR-positive disease, reducing the risk of disease
progression or death by 49% vs. chemotherapy
Enhertu is the first HER2-directed therapy to demonstrate a
survival benefit in this population, potentially redefining
treatment for approximately half of all patients with breast
cancer
Detailed positive results from the pivotal DESTINY-Breast04 Phase
III trial showed that Enhertu (trastuzumab deruxtecan) demonstrated
superior and clinically meaningful progression-free survival (PFS)
and overall survival (OS) in previously treated patients with
HER2-low (immunohistochemistry (IHC) 1+ or IHC 2+/in-situ
hybridisation (ISH)-negative) unresectable and/or metastatic breast
cancer with hormone receptor (HR) positive or HR-negative disease
versus standard of care physician's choice of chemotherapy. Results
will be presented during the Plenary Session today at the 2022
American Society of Clinical Oncology (ASCO) Annual Meeting, and
have been simultaneously published in The New
England Journal of Medicine.
Enhertu is
a specifically engineered HER2-directed antibody drug
conjugate (ADC) being jointly developed and commercialised by
AstraZeneca and Daiichi Sankyo.
In the primary endpoint analysis for
DESTINY-Breast04, Enhertu demonstrated a 49% reduction in the risk of
disease progression or death versus physician's choice of
chemotherapy in patients with HER2-low metastatic breast cancer
with HR-positive disease (PFS hazard ratio [HR] 0.51; 95%
confidence interval [CI]: 0.40-0.64; p<0.001). A median PFS of
10.1 months was seen in patients treated
with Enhertu compared to 5.4 months with chemotherapy, as
assessed by blinded independent central review
(BICR).
Results also showed a 36% reduction in the risk of death
with Enhertu compared to chemotherapy in patients with
HR-positive disease (OS HR 0.64; 95% CI: 0.48-0.86; p=0.003) with a
median OS of 23.9 months with Enhertu versus 17.5 months with chemotherapy,
meeting a key secondary endpoint of the trial.
Additionally, data showed consistent efficacy
for Enhertu in the overall trial population of patients
with HER2-low metastatic breast cancer with HR-positive or
HR-negative disease and across levels of HER2 expression (IHC
1+ and IHC 2+/ISH-). In the key secondary endpoint analysis of PFS
by BICR in all patients, a similar 50% reduction in the risk of
disease progression or death was observed
between Enhertu and chemotherapy (PFS HR 0.50; 95% CI:
0.40-0.63; p<0.001). Results also showed a 36% reduction in the
risk of death with Enhertu compared to chemotherapy (OS HR 0.64; 95%
CI: 0.49-0.84; p=0.001) with a median OS of 23.4 months
for Enhertu versus 16.8 months with
chemotherapy.
Shanu Modi, MD, Medical Oncologist, Memorial Sloan Kettering Cancer
Center, US and Principal Investigator for the trial, said: "The
results of DESTINY-Breast04 show for the first time that a
HER2-directed therapy can provide a survival benefit to patients
with low HER2 expression, indicating we must reconsider the way we
categorise patients with metastatic breast cancer. The efficacy
seen with Enhertu also reinforces the potential to establish a
new standard of care for more than half of all patients with breast
cancer currently categorised as having HER2-negative disease, but
who actually have tumours with low HER2
expression."
Susan Galbraith, Executive Vice President, Oncology R&D,
AstraZeneca said: "Today's results represent a pivotal moment
demonstrating the potential for Enhertu to redefine the treatment of HER2-targetable
cancers. DESTINY-Breast04 validates targeting the lower
end of the spectrum of HER2 expression,
since Enhertu reduced the risk of disease progression or
death across all types of patients in the trial by half,
and reduced the risk of death by over a third. We must now evolve
the way we classify and treat metastatic breast cancer to ensure
these patients are effectively diagnosed and
treated."
Ken Takeshita, Global Head, R&D, Daiichi Sankyo said: "As
innovative research organisations, extending the survival for
patients is one of our primary goals as we seek to identify
potentially new treatment options for patients with metastatic
breast cancer. These potentially practice-changing data show that
DESTINY-Breast04 takes us one step closer to achieving this goal,
as Enhertu is the first HER2-directed medicine to
demonstrate a survival benefit in patients with HER2-low metastatic
breast cancer. We are honoured by the recognition these important
findings are receiving at one of the world's most prominent
oncology meetings as well as in one of the leading medical
journals."
Summary of results: DESTINY-Breast04
Efficacy Measure
|
HR-Positive (n=494)i
|
All Patients (n=557)
|
HR-Negative (n=58)i
|
Enhertu (5.4
mg/kg) (n=331)
|
Chemotherapy (n=163)
|
Enhertu (5.4
mg/kg) (n=373)
|
Chemotherapy (n=184)
|
Enhertu (5.4
mg/kg) (n=40)
|
Chemotherapy (n=18)
|
PFS
|
Median PFS (months)ii
|
10.1
(9.5-11.5)
|
5.4
(4.4-7.1)
|
9.9
(9.0-11.3)
|
5.1
(4.2-6.8)
|
8.5
(4.3-11.7)
|
2.9
(1.4-5.1)
|
Hazard
Ratio (95% CI)
|
0.51 (0.40-0.64)
|
0.50 (0.40-0.63)
|
0.46 (0.24-0.89)
|
p-value
|
p<0.001
|
p<0.001
|
|
OS
|
Median
OS (months)
|
23.9 (20.8-24.8)
|
17.5
(15.2-22.4)
|
23.4
(20.0-24.8)
|
16.8
(14.5-20.0)
|
18.2
(13.6-NE)
|
8.3
(5.6-20.6)
|
Hazard
Ratio (95% CI)
|
HR 0.64 (0.48-0.86)
|
HR 0.64 (0.49-0.84)
|
HR 0.48 (0.24-0.95)
|
p-value
|
p=0.003
|
p=0.001
|
|
Confirmed ORR (%)
(95% CI)ii,iii
|
52.6% (47.0-58.0)
|
16.3%
(11.0-22.8)
|
52.3%
(47.1-57.4)
|
16.3%
(11.3-22.5)
|
50.0%
(33.8-66.2)
|
16.7%
(3.6-41.4)
|
Complete
Response (%)
|
3.6%
|
0.6%
|
3.5%
|
1.1%
|
2.5%
|
5.6%
|
Partial
Response (%)
|
49.2%
|
15.7%
|
49.1%
|
15.2%
|
47.5%
|
11.1%
|
Stable
Disease (%)
|
35.1%
|
50.0%
|
34.6%
|
49.5%
|
30.0%
|
44.4%
|
Progressive
Disease (%)
(95%
CI)
|
7.8%
|
21.1%
|
8.3%
|
22.3%
|
12.5%
|
33.3%
|
Median DoR (months)ii
|
10.7
|
6.8
|
10.7
|
6.8
|
8.6
|
4.9
|
CBR (%)ii,iv
|
71.2%
|
34.3%
|
70.2%
|
33.7%
|
62.5%
|
27.8%
|
DCR (%)iv,v
|
88.0%
|
66.3%
|
87.1%
|
65.8%
|
80.0%
|
61.1%
|
CI, confidence interval; CBR, clinical benefit rate; DCR, disease
control rate; DoR, Duration of Response; HR, hazard ratio; NE, not
evaluable; ORR, overall response rate; OS, overall survival; PFS,
progression-free survival
i For the primary end point (PFS in
the HR-positive cohort) and key secondary end points (PFS among all
patients and OS in the HR-positive cohort and among all patients),
the HR status is based on data collected with the use of the
interactive web-response and voice-response system at the time of
randomisation, which includes patients who were mis-stratified. For
the other end points, HR status is based on data from the
electronic data capture that was corrected for
mis-stratification
ii As assessed by
BICR
iii ORR is (Complete Response +
Partial Response)
iv CBR is Complete Response +
Partial Response + Stable Disease (≥ 6
months)
v DCR is (Complete Response +
Partial Response + Stable Disease)
In an exploratory analysis of patients with HR-negative disease
(n=58), median PFS was 8.5 months with Enhertu versus 2.9 months with chemotherapy (PFS HR
0.46; 95% CI: 0.24-0.89) and median OS was 18.2 months
with Enhertu versus 8.3 months with chemotherapy (OS HR
0.48; 95% CI: 0.24-0.95).
The safety profile of Enhertu was consistent with previous clinical trials
with no new safety concerns identified. The most common Grade
3 or higher treatment-emergent adverse events were neutropenia
(13.7%), anaemia (8.1%), fatigue (7.5%), leukopenia (6.5%),
thrombocytopenia (5.1%), and nausea (4.6%).
Interstitial lung disease (ILD) or pneumonitis rates were
consistent with that observed in late-line HER2-positive breast
cancer trials of Enhertu with a lower rate of Grade 5 ILD observed,
as determined by an independent adjudication committee. The
majority (10%) were primarily low Grade (Grade 1 or 2) with five
Grade 3 (1.3%), no Grade 4 and three Grade 5 (0.8%) events
reported.
Notes
Breast cancer and HER2 expression
Breast cancer is the most common cancer and is one of the leading
causes of cancer-related deaths worldwide.1 More
than two million cases of breast cancer were diagnosed in 2020 with
nearly 685,000 deaths globally.1
HER2 is a tyrosine kinase receptor growth-promoting protein
expressed on the surface of many types of tumours including breast,
gastric, lung and colorectal cancers, and is one of many biomarkers
expressed in breast cancer tumours.2 HER2
expression is currently defined as either positive or negative, and
is determined by an IHC test which measures the amount of HER2
protein on a cancer cell, and/or an ISH test which counts the
copies of the HER2 gene in cancer cells.2,3 HER2-positive
cancers are defined as IHC 3+ or IHC 2+/ISH+, and HER2-negative
cancers are currently defined as IHC 0, IHC 1+ or IHC
2+/ISH-.2
Approximately half of all patients with breast cancer have tumours
with a HER2 IHC score of 1+, or 2+ in combination with a negative
ISH test, a level of HER2 expression not currently eligible for
HER2-targeted therapy.4-7 Low
HER2 expression occurs in both HR-positive and HR-negative
disease.8
HER2 testing is routinely used to determine appropriate treatment
options for patients with metastatic breast cancer. Targeting the
lower range of expression in the HER2 spectrum may offer another
approach to delay disease progression and extend survival in
patients with metastatic breast cancer.9 Currently,
patients with low HER2 expression with HR-positive tumours have
limited treatment options following progression on endocrine
(hormone) therapy.10 Few
targeted options are available for those who are
HR-negative.11
DESTINY-Breast04
DESTINY-Breast04 is a global, randomised, open-label,
registrational Phase III trial evaluating the efficacy and safety
of Enhertu (5.4mg/kg)
versus physician's choice of chemotherapy (capecitabine, eribulin,
gemcitabine, paclitaxel or nab-paclitaxel) in patients with
HR-positive or HR-negative HER2-low unresectable and/or metastatic
breast cancer previously treated with one or two prior lines of
chemotherapy. Patients were randomised 2:1 to receive
either Enhertu or chemotherapy.
The primary endpoint of DESTINY-Breast04 is PFS in patients with
HR-positive disease based on blinded independent central review
(BICR). Key secondary endpoints include PFS based on BICR in all
randomised patients (HR-positive and HR-negative disease), OS in
patients with HR-positive disease and OS in all randomised patients
(HR-positive and HR-negative disease). Other secondary endpoints
include PFS based on investigator assessment, objective response
rate based on BICR and on investigator assessment, duration of
response based on BICR and safety.
DESTINY-Breast04 enrolled approximately 557 patients at multiple
sites in Asia, Europe and North America. For more information about
the trial, visit ClinicalTrials.gov.
Enhertu
Enhertu is a HER2-directed
ADC. Designed using Daiichi Sankyo's proprietary DXd ADC
technology, Enhertu is the lead ADC in the oncology portfolio of
Daiichi Sankyo and the most advanced programme in AstraZeneca's ADC
scientific platform. Enhertu consists of a HER2 monoclonal antibody
attached to a topoisomerase I inhibitor payload, an exatecan
derivative, via a stable tetrapeptide-based cleavable
linker.
Enhertu (5.4mg/kg) is
approved in the US and Israel for the treatment of adult patients
with unresectable or metastatic HER2-positive breast cancer who
have received a prior anti-HER2-based regimen either in the
metastatic setting, or in the neoadjuvant or adjuvant setting and
have developed disease recurrence during or within six months of
completing therapy, based on results from the DESTINY-Breast03
trial.
Enhertu (5.4mg/kg) is
also approved in approximately 40 countries for the treatment of
adult patients with unresectable or metastatic HER2-positive breast
cancer who have received two or more prior anti-HER2-based regimens
based on the results from the DESTINY-Breast01
trial.
Enhertu (6.4mg/kg) is
approved in several countries for the treatment of adult patients
with locally advanced or metastatic HER2-positive gastric or
gastroesophageal junction (GEJ) adenocarcinoma who have received a
prior trastuzumab-based regimen based on the results from the
DESTINY-Gastric01 trial.
Enhertu development programme
A comprehensive development programme is underway globally,
evaluating the efficacy and safety of Enhertu monotherapy
across multiple HER2-targetable cancers, including breast, gastric,
lung and colorectal cancers. Trials in combination with other
anticancer treatments, such as immunotherapy, are also
underway.
Regulatory applications for Enhertu are currently under review in China, Europe,
Japan and several other countries for the treatment of adult
patients with unresectable or metastatic HER2-positive breast
cancer who have received a prior anti-HER2 based regimen based on
the results from the DESTINY-Breast03 trial.
Enhertu was granted
Breakthrough Therapy Designation in the US for the treatment of
adult patients with unresectable or metastatic HER2-low (IHC 1+ or
IHC 2+/ISH-negative) breast cancer who have received a prior
systemic therapy in the metastatic setting or developed disease
recurrence during or within six months of completing adjuvant
chemotherapy, based on the results of the DESTINY-Breast04 trial.
Patients with hormone receptor (HR) positive breast cancer should
additionally have received or be ineligible for endocrine
therapy.
Enhertu is also currently
under review in the US for the treatment of adult patients with
unresectable or metastatic non-small cell lung cancer (NSCLC) whose
tumours have a HER2 (ERBB2) mutation and who have received a prior
systemic therapy, based on the DESTINY-Lung01 trial, and in Europe
for the treatment of adult patients with locally advanced or
metastatic HER2-positive gastric or GEJ adenocarcinoma who have
received a prior anti-HER2-based regimen based on the
DESTINY-Gastric01 and DESTINY-Gastric02 trials.
Daiichi Sankyo collaboration
Daiichi Sankyo Company, Limited (TSE: 4568) [referred to as Daiichi
Sankyo] and AstraZeneca entered into a global collaboration to
jointly develop and commercialise Enhertu (a HER2-directed ADC) in March 2019, and
datopotamab deruxtecan (DS-1062; a TROP2-directed ADC) in July
2020, except in Japan where Daiichi Sankyo maintains exclusive
rights. Daiichi Sankyo is responsible for the manufacturing and
supply of Enhertu and datopotamab
deruxtecan.
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.
AstraZeneca aims to continue to transform outcomes for HR-positive
breast cancer with foundational medicines Faslodex (fulvestrant) and Zoladex (goserelin) and the next-generation oral
selective oestrogen receptor degrader (SERD) and potential new
medicine camizestrant.
PARP inhibitor Lynparza (olaparib) is a targeted treatment option
that has been studied in HER2-negative early and metastatic breast
cancer patients with an inherited BRCA mutation. AstraZeneca with
MSD (Merck & Co., Inc. in the US and Canada) continue to
research Lynparza in metastatic breast cancer patients with an
inherited BRCA mutation and are exploring new opportunities to
treat these patients earlier in their disease.
Building on the initial approvals of Enhertu, a HER2-directed ADC, in previously treated
HER2-positive metastatic breast cancer, AstraZeneca and Daiichi
Sankyo are exploring its potential in earlier lines of treatment
and in new breast cancer settings.
To bring much-needed treatment options to patients with
triple-negative breast cancer, an aggressive form of breast cancer,
AstraZeneca is testing immunotherapy Imfinzi (durvalumab) in combination with other
oncology medicines, including Lynparza and Enhertu, evaluating the potential of AKT kinase
inhibitor, capivasertib, in combination with chemotherapy, and
collaborating with Daiichi Sankyo to explore the potential of
TROP2-directed ADC, datopotamab deruxtecan.
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. 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.
2. Iqbal N, et al. Human Epidermal Growth Factor Receptor 2 (HER2)
in Cancers: Overexpression and Therapeutic
Implications. Mol Biol
Int.
2014;852748.
3. Wolff A, et al. Human Epidermal Growth Factor Receptor 2 Testing
in Breast Cancer: American Society of Clinical Oncology/College of
American Pathologists Clinical Practice Guideline Focused
Update. Arch Pathol Lab
Med. 2018; 142 (11):
1364-1382.
4. Ahn S, et al. HER2 status in breast cancer: changes in
guidelines and complicating factors for
interpretation. J Pathol Transl
Med. 2020; 54(1):
34-44.
5. Schalper K, et al. A retrospective population-based comparison
of HER2 immunohistochemistry and fluorescence in situ hybridization
in breast carcinomas. Arch Pathol Lab
Med. 2014;
138:213-219.
6. Schettini F, et al. Clinical, pathological, and PAM50 gene
expression features of HER2-low breast
cancer. npj Breast
Cancer. 2021; 7:1 ;
https://doi.org/10.1038/s41523-020-00208-2.
7. Denkert C, et al. Clinical and molecular characteristics of
HER2-low-positive breast cancer: pooled analysis of individual
patient data from four prospective, neoadjuvant clinical trials.
2021. Lancet
Oncol; 22:
1151-61.
8. Miglietta F, et al. Evolution of HER2-low expression from
primary to recurrent breast cancer. NPJ Breast
Cancer. 2021; 7:137;
10.1038/s41523-021-00343-4.
9. Eiger D, et al. The Exciting New Field of HER2-Low Breast Cancer
Treatment. Cancers. 2021;
10.3390/cancers13051015.
10. Matutino A, et al. Hormone receptor-positive,
HER2-negative metastatic breast cancer: redrawing the lines.
Current Oncology. 2018; 25(S1):S131-S141.
11. American Cancer Society. Breast Cancer Hormone Receptor Status.
Available at:
https://www.cancer.org/cancer/breast-cancer/understanding-a-breast-cancer-diagnosis/breast-cancer-hormone-receptor-status.html.
Accessed June 2022.
Dr. Modi has financial interests related to AstraZeneca and Daiichi
Sankyo.
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:
06 June
2022
|
By: /s/
Adrian Kemp
|
|
Name:
Adrian Kemp
|
|
Title:
Company Secretary
|
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