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 April 2025
Commission
File Number: 001-11960
AstraZeneca PLC
1
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AstraZeneca PLC
INDEX
TO EXHIBITS
1.
Enhertu approved in EU in post-ET breast cancer
04 April 2025
Enhertu approved
in the EU as first HER2-directed therapy for patients with
HR-positive, HER2-low or HER2-ultralow metastatic breast cancer
following at least one endocrine therapy
Based on DESTINY-Breast06 Phase III trial results which showed
Enhertu demonstrated superiority vs. chemotherapy with a median
progression-free survival of more than one year
Approval brings AstraZeneca and Daiichi Sankyo's Enhertu earlier in
the treatment of HR-positive, HER2-low breast cancer and broadens
the eligible patient population to those with HER2-ultralow
disease
AstraZeneca and Daiichi Sankyo's Enhertu (trastuzumab deruxtecan) has been approved
in the European Union (EU) as a monotherapy for the treatment of
adult patients with unresectable or metastatic hormone receptor
(HR)-positive, HER2-low or HER2-ultralow breast cancer who have
received at least one endocrine therapy in the metastatic setting
and who are not considered suitable for endocrine therapy as the
next line of treatment.
The approval by the European Commission follows
the positive
opinion of the Committee
for Medicinal Products for Human Use and is based on results from
the DESTINY-Breast06 Phase III trial, which were presented at the
2024 American Society of Clinical Oncology (ASCO) Annual Meeting
and published in The
New England Journal of Medicine.
HR-positive, HER2-negative is the most common breast cancer
subtype, accounting for approximately 70% of all breast
cancers.1 Despite
being classified as HER2-negative, many of these tumours still have
some level of HER2 expression. Currently, regardless of HER2
expression, endocrine-based therapies are widely used in the early
lines of treatment for HR-positive metastatic breast cancer.
Following endocrine-based therapy, some patients discontinue
treatment, and others are treated with conventional chemotherapy
which is associated with poor response rates and
outcomes.2-5
Giuseppe Curigliano, MD, PhD, Professor of Medical Oncology at the
University of Milan and the Head of the Division of Early Drug
Development at the European Institute of Oncology, IRCCS, Italy and
principal investigator for the trial, said: "This approval
introduces a new treatment option for HR-positive metastatic breast
cancers that express HER2. In
DESTINY-Breast06, Enhertu outperformed chemotherapy, providing
progression-free survival of more than one year for patients with
HR-positive, HER2-low or HER2-ultralow metastatic breast cancer,
demonstrating the benefit of treating these patients
with Enhertu instead of
chemotherapy."
Dave Fredrickson, Executive Vice President, Oncology Haematology
Business Unit, AstraZeneca, said: "Enhertu continues to open up new approaches to the
diagnosis and treatment of patients with metastatic breast cancer.
This approval underscores the importance of testing metastatic
breast cancer tumours for any IHC staining to identify patients
with HR-positive, HER2-low or HER2-ultralow disease who may be
eligible for Enhertu once sustained responses are no longer
achieved with endocrine-based therapy."
Ken Keller, Global Head of Oncology Business, and President and
CEO, Daiichi Sankyo, said: "Enhertu continues to evolve what is possible with
breast cancer treatment, becoming the first HER2-directed medicine
approved in the EU for patients with HR-positive metastatic breast
cancer with HER2-low or HER2-ultralow expression following
endocrine therapy. Today's approval expands the use
of Enhertu to now include an earlier treatment setting
of HER2-low metastatic breast cancer and broadens the patient
population eligible for treatment to those with HER2-ultralow
disease."
In the trial, Enhertu showed a 38% reduction in the risk of
disease progression or death versus chemotherapy (hazard ratio [HR]
0.62; confidence interval [CI]: 0.52-0.75; p<0.0001) in patients
with chemotherapy-naïve HR-positive, HER2-low metastatic
breast cancer with a median progression-free survival (PFS) of 13.2
months versus 8.1 months.
In the overall trial population (patients with HER2-low or
HER2-ultralow metastatic breast cancer), the median PFS was 13.2
months in patients randomised to Enhertu compared to 8.1 months in those randomised
to chemotherapy (HR 0.64; 95% CI: 0.54-0.76; p<0.0001). In an
exploratory analysis, results were consistent between patients with
HER2-low expression and HER2-ultralow
expression.
HER2 testing in the trial was conducted by a central laboratory.
Approximately 85-90% of patients with HR-positive, HER2-negative
metastatic breast cancer screened were determined to be HER2-low or
HER2-ultralow.6
The safety profile of Enhertu in DESTINY-Breast06 was consistent with
previous clinical trials of Enhertu in breast cancer with no new safety concerns
identified.
Enhertu is a specifically
engineered HER2-directed DXd antibody drug conjugate (ADC)
discovered by Daiichi Sankyo and being jointly developed and
commercialised by AstraZeneca and Daiichi
Sankyo.
Enhertu was approved in the
US earlier this year based
on the DESTINY-Breast06 results. Regulatory applications are under
review in Japan and several other countries for this
indication.
Enhertu is already
approved in more than 75 countries, including the EU, for patients
with HER2-low metastatic breast cancer who have received prior
chemotherapy in the metastatic setting or developed disease
recurrence during or within six months of completing adjuvant
chemotherapy based on the results from the DESTINY-Breast04
trial.
Financial considerations
Following this approval for Enhertu in the EU, an amount of $125m is due from
AstraZeneca to Daiichi Sankyo as a milestone payment for the
HER2-low and HER2-ultralow chemotherapy-naïve breast cancer
indication. The milestone will be capitalised as an addition to the
upfront payment made by AstraZeneca to Daiichi Sankyo in 2019 and
subsequent capitalised milestones and will be amortised through the
profit and loss statement.
Sales of Enhertu in most EU territories are recognised by
Daiichi Sankyo. AstraZeneca reports its share of gross profit
margin from Enhertu sales in those territories as alliance
revenue in the Company's financial statements. AstraZeneca will
record product sales in respect of sales made in territories where
AstraZeneca is the selling party.
Further details on the financial arrangements were set out in
the March
2019 announcement of the
collaboration.
Notes
Breast cancer and HER2 expression
Breast cancer is the second most common cancer and one of the
leading causes of cancer-related deaths
worldwide.7 More
than two million breast cancer cases were diagnosed in 2022 with
more than 665,000 deaths globally.7 In
Europe, approximately 557,000 cases of breast cancer are
diagnosed annually.8 While
survival rates are high for those diagnosed with early breast
cancer, only about 30% of patients diagnosed with or who progress
to metastatic disease are expected to live five years following
diagnosis.1
HR-positive, HER2-negative is the most common breast cancer
subtype, accounting for approximately 70% of all breast
cancers.1 HER2
is a tyrosine kinase receptor growth-promoting protein expressed on
the surface of many types of tumours, including breast
cancer.9 Patients
with high levels of HER2 expression (IHC 3+ or 2+/ISH+) are
classified as HER2-positive and treated with HER2-directed
therapies, representing approximately 15-20% of all breast
cancers.10 Historically,
tumours that were not classified as HER2-positive were classified
as HER2-negative.11
Despite being classified as HER2-negative, many of these tumours
may still have some level of HER2 expression detected by
IHC.11 In
the DESTINY-Breast06 trial, approximately 85-90% of patients with
HR-positive, HER2-negative metastatic breast cancer screened were
determined to be HER2-low or HER2-ultralow.6
Prior to the approval of Enhertu in HER2-low and HER2-ultralow metastatic
breast cancer based on the DESTINY-Breast04 and DESTINY-Breast06
trials, there were no HER2-targeted therapies approved specifically
for patients with HER2-low or HER2-ultralow
expression.12,13
DESTINY-Breast06
DESTINY-Breast06 is a global, randomised, open-label Phase III
trial evaluating the efficacy and safety
of Enhertu (5.4mg/kg)
versus investigator's choice of chemotherapy (capecitabine,
paclitaxel or nab-paclitaxel) in patients with HR-positive,
HER2-low (IHC 1+ or 2+/ISH-) or HER2-ultralow (IHC 0 with membrane
staining) advanced or metastatic breast cancer. Patients in the
trial had no prior chemotherapy for advanced or metastatic disease
and received at least two lines of prior endocrine therapy in the
metastatic setting. Patients were also eligible if they had
received one prior line of endocrine therapy combined with a CDK4/6
inhibitor in the metastatic setting and experienced disease
progression within six months of starting 1st-line treatment or
received endocrine therapy as an adjuvant treatment and experienced
disease recurrence within 24 months. HER2 status in the trial was
confirmed by a central laboratory and was performed on a tumour
sample obtained at the time of initial metastatic diagnosis or
later.
The primary endpoint is PFS in the HR-positive, HER2-low patient
population as measured by blinded independent central review
(BICR). Key secondary endpoints include PFS by BICR in the overall
trial population (HER2-low and HER2-ultralow), overall survival
(OS) in the HER2-low patient population and OS in the overall trial
population. Other secondary endpoints include objective response
rate, duration of response, time to first subsequent treatment or
death, time to second subsequent treatment or death and
safety.
DESTINY-Breast06 enrolled 866 patients (n=713 for HER2-low and
n=153 for HER2-ultralow) in Asia, Europe, North America, Oceania
and South 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 number of topoisomerase I inhibitor payloads (an
exatecan derivative, DXd) via tetrapeptide-based cleavable
linkers.
Enhertu (5.4mg/kg) is
approved in more than 75 countries worldwide for the treatment of
adult patients with unresectable or metastatic HER2-positive
(immunohistochemistry [IHC 3+ or in-situ hybridisation [ISH]+)
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 the results from
the DESTINY-Breast03 trial.
Enhertu (5.4mg/kg) is
approved in more than 75 countries worldwide for the treatment of
adult patients with unresectable or metastatic HER2-low (IHC 1+ or
IHC 2+/ ISH-) 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 from the DESTINY-Breast04 trial.
Enhertu (5.4mg/kg) is
approved in more than 30 countries for the treatment of adult
patients with unresectable or metastatic HR-positive, HER2-low (IHC
1+ or IHC 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining)
breast cancer, as determined by a locally or regionally approved
test, that have progressed on one or more endocrine therapies in
the metastatic setting based on the results from
the DESTINY-Breast06 trial.
Enhertu (5.4mg/kg) is
approved in more than 50 countries worldwide for the treatment of
adult patients with unresectable or metastatic non-small cell lung
cancer (NSCLC) whose tumours have
activating HER2 (ERBB2) mutations, as detected by a locally or
regionally approved test, and who have received a prior systemic
therapy based on the results from the DESTINY-Lung02 and/or DESTINY-Lung05 trials.
Continued approval in China and the US for this indication may be
contingent upon verification and description of clinical benefit in
a confirmatory trial.
Enhertu (6.4mg/kg) is
approved in more than 65 countries worldwide for the treatment of
adult patients with locally advanced or metastatic HER2-positive
(IHC 3+ or 2+/ISH+) gastric or gastroesophageal junction (GEJ)
adenocarcinoma who have received a prior trastuzumab-based regimen
based on the results from the DESTINY-Gastric01, DESTINY-Gastric02 and/or DESTINY-Gastric06 trials.
Continued approval in China for this indication may be contingent
upon verification and description of clinical benefit in a
confirmatory trial.
Enhertu (5.4mg/kg) is
approved in Brazil, Isreal, Russia and the US for the treatment of
adult patients with unresectable or metastatic HER2-positive (IHC
3+) solid tumours who have received prior systemic treatment and
have no satisfactory alternative treatment options based on the
results from the DESTINY-PanTumor02, DESTINY-Lung01 and DESTINY-CRC02 trials.
Continued approval for this indication in the US may be contingent
upon verification and description of clinical benefit in a
confirmatory trial.
Enhertu development programme
A comprehensive global clinical development programme is underway
evaluating the efficacy and safety of Enhertu monotherapy across multiple HER2-targetable
cancers. Trials in combination with other anti-cancer treatments,
such as immunotherapy, also are underway.
Daiichi Sankyo collaboration
AstraZeneca and Daiichi Sankyo entered into a global collaboration
to jointly develop and commercialise Enhertu in March
2019 and Datroway (datopotamab deruxtecan)
in July
2020, except in Japan where
Daiichi Sankyo maintains exclusive rights for each ADC. Daiichi
Sankyo is responsible for the manufacturing and supply
of Enhertu and Datroway.
AstraZeneca in breast cancer
Driven by a growing understanding of breast cancer biology,
AstraZeneca is challenging, and redefining, 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, AstraZeneca and Daiichi Sankyo are aiming to
improve outcomes in previously treated HER2-positive, HER2-low and
HER2-ultralow 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 first-in-class AKT
inhibitor, Truqap (capivasertib), the TROP2-directed
ADC, Datroway (datopotamab deruxtecan) and next-generation
oral SERD and potential new medicine
camizestrant.
PARP inhibitor Lynparza (olaparib) is a targeted treatment option
that has been studied in 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 these settings and to explore its
potential in earlier disease. AstraZeneca is also exploring the
potential of saruparib, a potent and selective inhibitor of PARP1,
in combination with camizestrant in BRCA-mutated, HR-positive, HER2-negative advanced
breast cancer.
To bring much-needed treatment options to patients with
triple-negative breast cancer, an aggressive form of breast cancer,
AstraZeneca is collaborating with Daiichi Sankyo to evaluate the
potential of Datroway alone and in combination with
immunotherapy Imfinzi (durvalumab).
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's innovative
medicines are sold in more than 125 countries and used by millions
of patients worldwide. Please visit astrazeneca.com and
follow the Company on social media @AstraZeneca.
Contacts
For details on how to contact the
Investor Relations Team, please
click here.
For Media contacts, click here.
References
1. National Cancer Institute.
Surveillance, Epidemiology and End Results Program. Available
at: https://seer.cancer.gov/statfacts/html/breast-subtypes.html. Accessed
April 2025.
2. Manohar
P, et al. Updates in endocrine therapy for metastatic breast
cancer. Cancer Biol Med. 2022 Feb 12; 19(2): 2020-212
3. Cortes J, et al. Eribulin
monotherapy versus treatment of physician's choice in patients with
metastatic breast cancer (EMBRACE): a phase 3 open-label randomised
study. Lancet. 2011;377:914-923.
4. Yuan P, et al. Eribulin
mesilate versus vinorelbine in women with locally recurrent or
metastatic breast cancer: A randomised clinical
trial. Eur J
Cancer.
2019;112:57-65.
5. Jerusalem G, et al. Everolimus
Plus Exemestane vs Everolimus or Capecitabine Monotherapy for
Estrogen Receptor-Positive, HER2-Negative Advanced Breast
Cancer. JAMA Oncol. 2018;4(10):1367-1374.
6. Salgado RF, et al. LBA21 - Human epidermal growth
factor receptor 2 (HER2)-low and HER2-ultralow status determination
in tumors of patients (pts) with hormone receptor-positive (HR+)
metastatic breast cancer (mBC) in DESTINY-Breast06
(DB-06). Annals of
Oncology. (2024) 35 (suppl_2):
1-72. 10.1016/annonc/annonc1623.
7. Bray F, et
al. Global cancer statistics 2022:
GLOBOCAN estimates of incidence and mortality worldwide for 36
cancers in 185 countries. CA Cancer J
Clin.
2024;74(3):229-263.
8. WHO.
International Agency of Cancer Research. Cancer Today. Breast.
2022. Available at:
https://gco.iarc.who.int/media/globocan/factsheets/cancers/20-breast-fact-sheet.pdf.
Accessed April 2025.
9. Iqbal N, et al. Human
Epidermal Growth Factor Receptor 2 (HER2) in Cancers:
Overexpression and Therapeutic
Implications. Mol Biol
Int.
2014;852748.
10. 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.
11. Sajjadi E, et al. Improving HER2
testing reproducibility in HER2-low breast
cancer. Cancer Drug
Resist.
2022;5(4):882-888.
12. Modi S, et al. Trastuzumab
Deruxtecan in Previously Treated HER2-Low Advanced Breast
Cancer. N Engl J
Med. 2022;387:9-20.
13. Eiger D, et al. The Exciting New Field
of HER2-Low Breast Cancer Treatment. Cancers. 2021;13:1015.
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.
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AstraZeneca
PLC
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Date:
04 April 2025
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By: /s/
Adrian Kemp
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Name:
Adrian Kemp
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Title:
Company Secretary
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