a2736m
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 September 2021
Commission
File Number: 001-11960
AstraZeneca PLC
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AstraZeneca PLC
INDEX
TO EXHIBITS
1.
Enhertu
reduced risk of disease progression by 72%
18 September 2021 14:05 BST
Enhertu reduced
the risk of disease progression or death by 72% vs. trastuzumab
emtansine (T-DM1) in patients with
HER2-positive metastatic breast cancer
Ground-breaking Phase III head-to-head DESTINY-Breast03 results
featured at ESMO Presidential Symposium support Enhertu as the
potential new standard of care in previously treated
patients
DESTINY-Breast01 Phase II trial data also presented at ESMO showed
impressive median overall survival of 29.1 months in HER2-positive
patients following two or more HER2-based regimens
Detailed positive results from the head-to-head DESTINY-Breast03
Phase III trial showed that Enhertu (trastuzumab deruxtecan), the AstraZeneca
and Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo)
HER2-directed antibody drug conjugate (ADC), demonstrated superior
progression-free survival (PFS) versus trastuzumab emtansine
(T-DM1), a HER2-directed ADC currently approved to treat patients
with HER2-positive unresectable and/or metastatic breast cancer
previously treated with trastuzumab and a taxane. Results were
presented today in a Presidential Symposium at the European Society
for Medical Oncology (ESMO) Congress 2021.
At a prespecified interim analysis of
DESTINY-Breast03, Enhertu demonstrated a 72% reduction in the risk of
disease progression or death compared to T-DM1 (hazard ratio [HR]
0.28; 95% confidence interval [CI] 0.22-0.37;
p=7.8x10-22).
After 15.5 and 13.9 months of follow-up in
the Enhertu and T-DM1 arms respectively, the median PFS
for patients treated with Enhertu was not reached (95% CI 18.5-NE) compared to
6.8 months for T-DM1 (95% CI 5.6-8.2) as assessed by blinded
independent central review (BICR).
In the key secondary endpoint of PFS assessed by investigators,
patients treated with Enhertu experienced a three-fold improvement in PFS
of 25.1 months versus 7.2 months for T-DM1 (HR 0.26; 95% CI
0.20-0.35; p=6.5x10-24).
A consistent PFS benefit was observed in key subgroups of patients
treated with Enhertu, including those with a history of stable brain
metastases.
There was a strong trend towards improved overall survival (OS)
with Enhertu (HR 0.56; 95% CI 0.36-0.86; nominal
p=0.007172), however this analysis is not yet mature and is not
statistically significant. Nearly all patients treated
with Enhertu were alive at one year (94.1%) compared to
85.9% of patients treated with T-DM1.
Confirmed objective response rate (ORR) more than doubled in
the Enhertu arm versus the T-DM1 arm (79.7% vs. 34.2%).
Forty-two (16.1%) complete responses (CR), and 166 (63.6%) partial
responses (PR) were observed in patients treated
with Enhertu compared to 23 (8.7%) CRs and 67 (25.5%) PRs
in patients treated with T-DM1.
Javier Cortés, MD, PhD, Head, International Breast Cancer
Center (IBCC), Barcelona, said: "Patients with previously treated
HER2-positive metastatic breast cancer will typically experience
disease progression in less than a year with available
HER2-directed treatments. The high and consistent benefit seen
across efficacy endpoints and key subgroups of patients
receiving Enhertu in DESTINY-Breast03 is remarkable and
supports the potential of Enhertu to become the new standard of care for those
who have previously been treated for HER2-positive metastatic
breast cancer."
Susan Galbraith, Executive Vice President, Oncology R&D, said:
"Today's results are ground-breaking. Enhertu tripled progression-free survival as
assessed by investigators, and provided a disease control rate
exceeding 95% compared to 77% for T-DM1 in DESTINY-Breast03. In
addition, the safety profile was encouraging with no Grade 4 or 5
interstitial lung disease events in this trial. These unprecedented
data represent a potential paradigm shift in the treatment of
HER2-positive metastatic breast cancer, and illustrate the
potential for Enhertu to transform more patient lives in earlier
treatment settings."
Ken Takeshita, Global Head, R&D, Daiichi Sankyo, said: "The
early survival data, which evaluated Enhertu against another HER2-directed ADC, showed
that nearly all patients treated with Enhertu were alive after a year and is a positive
indication of the potential of this medicine to transform the
treatment of HER2-positive metastatic breast cancer. These landmark
data will form the basis of our discussions with global health
authorities to potentially bring Enhertu to patients with previously treated
HER2-positive metastatic breast cancer as a more effective
treatment option as soon as possible."
Summary of results: DESTINY-Breast03
Efficacy Measure
|
Enhertu (5.4
mg/kg)
Total Evaluable
(n=261)i
|
T-DM1 (3.6 mg/kg)
Total Evaluable
(n=263)
|
PFSii (95%
CI)
|
Hazard
ratio (95% CI)
|
0.28 (0.22-0.37)
|
p-value
|
p=7.8x10-22
|
Median PFS (months) (95% CI)ii
|
NR (18.5-NE)
|
6.8 months (5.6-8.2)
|
Landmark 12-month PFS (%) (95%
CI)ii
|
75.8% (69.8-80.7)
|
34.1% (27.7-40.5)
|
PFS as assessed by investigators (95% CI)
|
Hazard
ratio (95% CI)
|
0.26 (0.20-0.35)
|
p-value
|
p=6.5x10-24
|
Median
PFS (months) (95% CI)
|
25.1 months (22.1-NE)
|
7.2 months (6.8-8.3)
|
OS
|
Hazard
ratio (95% CI)
|
0.56 (0.36-0.86)
|
p-value
|
p=0.007172iii
|
Landmark
12-month OS (%) (95% CI)
|
94.1% (90.3-96.4)
|
85.9% (80.9-89.7)
|
Median
OS (months) (95% CI)
|
NE
|
NE
|
Confirmed ORR (%) (95% CI)ii,iv
|
79.7% (74.3-84.4)
|
34.2% (28.5-40.3)
|
Complete response (%)
|
16.1% (42)
|
8.7% (23)
|
Partial response (%)
|
63.6% (166)
|
25.5% (67)
|
Stable disease (%)
|
16.9% (44)
|
42.6% (112)
|
Progressive disease (%) (95%
CI)
|
1.1% (3)
|
17.5% (46)
|
DCRv
|
96.6% (252)
|
76.8% (202)
|
i Dose used in the study
being presented
ii As assessed by blind
independent central review
iii Not statistically
significant
iv ORR is (CR +
PR)
v DCR is
(CR+PR+SD)
The safety profile of the most common adverse events
with Enhertu in DESTINY-Breast03 was consistent with
previous clinical trials with no new safety concerns identified.
The most common Grade 3 or higher treatment-emergent adverse events
in the Enhertu arm were neutropenia (19.1%),
thrombocytopenia (7.0%), leukopenia (6.6%) and nausea
(6.6%).
There were 27 cases (10.5%) of treatment-related interstitial lung
disease (ILD) or pneumonitis reported, as determined by an
independent adjudication committee. The majority (9.7%) were low
Grade (Grade 1 or Grade 2), with two Grade 3 (0.8%) events
reported. No Grade 4 or Grade 5 ILD or pneumonitis events
occurred.
DESTINY-Breast01 Updated Results
Updated results from the pivotal DESTINY-Breast01 Phase II trial
were also presented at ESMO and showed
that Enhertu (5.4
mg/kg) continued to demonstrate impressive efficacy and durable
responses in patients with HER2-positive metastatic breast cancer
following two or more prior HER2-based
regimens.
With a median duration of follow-up of 26.5 months, a continued
increase in response was seen in patients treated
with Enhertu with an updated ORR of 62.0%, including one
additional CR (7.1%). A median duration of response (DoR) of 18.2
months was also observed.
The median PFS was 19.4 months. In an exploratory analysis of OS
with a median follow-up of 31.1 months, evaluated at a greater
maturity (52%), the updated median OS was 29.1 months.
The overall safety and tolerability profile seen
with Enhertu in DESTINY-Breast01 continues to be
consistent with what has been previously observed. There has been
one new case of treatment-related Grade 1 ILD or pneumonitis
determined by an independent adjudication committee as of data
cut-off of March 26, 2021.
Enhertu is approved 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 in the metastatic setting in the US,
Japan, the EU and several other countries based on the results from
the DESTINY-Breast01 trial.
Enhertu is being further assessed in a comprehensive
clinical development programme evaluating efficacy and safety
across multiple HER2-targetable cancers, including breast, gastric,
lung and colorectal cancers.
Several presentations featured during the ESMO
Congress 2021 will showcase the strength and depth
of Enhertu data across multiple tumour types,
including gastric, lung and
breast cancers, reinforcing the transformational potential of this
medicine in the treatment of HER2-targetable
cancers.
HER2-positive breast cancer
Breast cancer remains the most common cancer and is one of the
leading causes of cancer-related deaths in women
worldwide.1 More
than two million patients with breast cancer were diagnosed in
2020, resulting in nearly 685,000 deaths
globally.1 Approximately
one in five cases of breast cancer are considered
HER2-positive.2
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.3 HER2
protein overexpression may occur as a result of HER2 gene
amplification and is often associated with aggressive disease and a
poor prognosis in breast cancer.4
Despite initial treatment with trastuzumab and a taxane, people
with HER2-positive metastatic breast cancer will often experience
disease progression.5 More
effective options are needed to further delay progression and
extend survival.5-7
DESTINY-Breast03
DESTINY-Breast03 is a global head-to-head, randomised, open-label,
registrational Phase III trial evaluating the safety and efficacy
of Enhertu (5.4mg/kg) versus T-DM1 in patients with
HER2-positive unresectable and/or metastatic breast cancer
previously treated with trastuzumab and a
taxane.
The primary efficacy endpoint of DESTINY-Breast03 is PFS based on
blinded independent central review. Secondary efficacy endpoints
include OS, objective response rate, duration of response, clinical
benefit rate, PFS based on investigator assessment and
safety.
DESTINY-Breast03 enrolled approximately 500 patients at
multiple sites in Asia, Europe, North America, Oceania and South
America. For more information about the trial,
visit ClinicalTrials.gov.
DESTINY-Breast01
DESTINY-Breast01 is a registrational Phase II, single-arm,
open-label, global, multi-centre, two-part trial evaluating the
safety and efficacy of Enhertu in patients with HER2-positive unresectable
and/or metastatic breast cancer previously treated with
T-DM1.
The primary endpoint of the trial is ORR, as determined by ICR.
Secondary objectives include DoR, disease control rate, clinical
benefit rate, PFS and OS.
DESTINY-Breast01 enrolled 253 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 Canada, the EU, Israel, Japan, the UK and the US 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 in the metastatic setting based on the
results from the DESTINY-Breast01 trial.
Enhertu (6.4mg/kg) is also
approved in Israel, Japan and the US for the treatment of adult
patients with locally advanced or metastatic HER2-positive gastric
or gastroesophageal junction 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.
Enhertu was highlighted in
the Clinical Cancer Advances 2021 report as one of two significant
advancements in the "ASCO Clinical Advance of the Year: Molecular
Profiling Driving Progress in GI Cancers," based on data from both
the DESTINY-CRC01 and DESTINY-Gastric01 trials, as well as one of
the targeted therapy advances of the year in non-small cell lung
cancer (NSCLC), based on the interim results of the HER2-mutated
cohort of the DESTINY-Lung01 trial.
In May 2020, Enhertu also received Breakthrough Therapy
Designation for the treatment of patients with metastatic NSCLC
whose tumours have a HER2-mutation and with disease progression on
or after platinum-based therapy.
Daiichi Sankyo collaboration
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 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
SERD and potential new medicine AZD9833.
PARP inhibitor, Lynparza (olaparib) is a targeted treatment option
for 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 first approval 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, investigating 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. 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.
3. Iqbal N, et al. Human Epidermal Growth Factor Receptor 2 (HER2)
in Cancers: Overexpression and Therapeutic
Implications. Mol Biol
Int.
2014;852748.
4. Pillai R, et al. HER2 mutations in lung adenocarcinomas: A report
from the Lung Cancer Mutation Consortium. Cancer. 2017;1;123(21):4099-4105.
5. Barok M, et al. Trastuzumab emtansine: mechanism of action and
drug resistance. Breast Cancer
Res. 2014;
16(2):209.
6. Mounsey, L et al. Changing Natural History of HER2-Positive Breast
Cancer Metastatic to the Brain in the Era of New Targeted
Therapies. Clin Breast
Cancer. 2018;
18(1):29-37.
7. Martinez-S Sáez O, et al. Current and Future Management of HER2-Positive
Metastatic Breast Cancer. JCO Oncol
Pract. 2021.
10.1200/OP.21.00172.
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:
20 September
2021
|
By: /s/
Adrian Kemp
|
|
Name:
Adrian Kemp
|
|
Title:
Company Secretary
|