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 2025
Commission
File Number: 001-11960
AstraZeneca PLC
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Kingdom
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AstraZeneca PLC
INDEX
TO EXHIBITS
1.
Enhertu approved in US for 1L HER2+ metastatic
BC
16 December 2025
Enhertu plus
pertuzumab approved in the US as first new treatment in a decade
for the 1st-line treatment of patients with HER2-positive
metastatic breast cancer
Based on DESTINY-Breast09 Phase III trial results that showed
AstraZeneca and Daiichi Sankyo's Enhertu in combination with
pertuzumab reduced the risk of disease progression or death by 44%
vs. THP with a median progression-free survival of more than three
years
AstraZeneca and Daiichi Sankyo's Enhertu (trastuzumab deruxtecan) in combination with
pertuzumab has been approved in the US for the 1st-line
treatment of adult patients with unresectable or metastatic
HER2-positive breast cancer, as determined by a Food and Drug
Administration (FDA)-approved test.
The approval follows Priority
Review and Breakthrough
Therapy Designation by the FDA and is based on the results of the
DESTINY-Breast09 Phase III trial. The data were presented at the
2025 American Society of Clinical Oncology (ASCO) Annual Meeting
and published in The
New England Journal of Medicine.1
Sara Tolaney, MD, MPH, Chief of the Division of Breast
Oncology, Dana-Farber Cancer Institute and principal investigator
for the trial, said: "Trastuzumab deruxtecan plus pertuzumab
is the only 1st-line treatment approved in more than a decade to
demonstrate a statistically significant improvement in
progression-free survival over the current standard regimen for
patients with HER2-positive metastatic breast cancer. With a
median progression-free survival exceeding three years, versus
approximately two years with THP, trastuzumab deruxtecan combined
with pertuzumab should become a new 1st-line standard of care in
this setting."
Dave Fredrickson, Executive Vice President, Oncology Haematology
Business Unit, AstraZeneca, said: "With this approval, we are
bringing Enhertu to the earliest setting for HER2-positive
metastatic breast cancer, where optimising efficacy has an
important impact on long-term outcomes. The treatment approach
with Enhertu plus pertuzumab in DESTINY-Breast09 sets a
new benchmark of more than three years without disease progression
or death for patients in this setting."
Ken Keller, Global Head of Oncology Business, and President and
CEO, Daiichi Sankyo, said: "Since its initial approval six years
ago, Enhertu has transformed the treatment of
HER2-positive metastatic breast cancer. With this approval
of Enhertu in the 1st-line HER2-positive metastatic
setting, Enhertu once again offers significant improvements
in progression-free survival and has practice-changing potential
when used in combination with pertuzumab."
In the trial, Enhertu in combination with pertuzumab reduced the
risk of disease progression or death by 44% versus a taxane,
trastuzumab and pertuzumab (THP) (based on a hazard ratio of 0.56;
95% confidence interval [CI] 0.44-0.71; p<0.0001) as a 1st-line
treatment for patients with HER2-positive metastatic breast cancer.
Median progression-free survival (PFS) was 40.7 months
with Enhertu plus pertuzumab compared to 26.9 months for
THP. The PFS benefit for Enhertu plus pertuzumab versus THP was consistent
across subgroups.1
The safety profile of Enhertu plus pertuzumab in DESTINY-Breast09 was
consistent with the known profiles of each individual therapy 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.
This application was approved under the FDA's Real-Time Oncology
Review (RTOR), an initiative by the FDA to ensure safe and
effective treatments are available to patients as early as
possible.
This US regulatory submission was also reviewed under Project
Orbis, which provides a framework for concurrent submission and
review of oncology medicines among participating international
partners. As part of Project Orbis, the Enhertu plus
pertuzumab 1st-line regimen is under review by Switzerland's
Swissmedic (SMC) and Singapore's Health Sciences Authority (HSA).
Separate regulatory applications are also under review in other
countries.
Financial considerations
Following this approval in the US, an amount of $150m is due from
AstraZeneca to Daiichi Sankyo as a milestone payment for the
1st-line unresectable or metastatic HER2-positive breast cancer
indication. Sales of Enhertu in the US are recognised by Daiichi Sankyo.
For further details on the financial arrangements, please consult
the collaboration agreement from March
2019.
Notes
HER2-positive metastatic breast cancer
Breast cancer is the second most common cancer and one of the
leading causes of cancer-related deaths
worldwide.2 More
than two million breast cancer cases were diagnosed in 2022, with
more than 665,000 deaths globally.2 In
the US, more than 300,000 cases of breast cancer are diagnosed
annually with more than 42,000 deaths.3 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.4
HER2 is a tyrosine kinase receptor growth-promoting protein
expressed on the surface of many types of tumours including breast
cancer.5 HER2
protein overexpression may occur as a result of HER2 gene
amplification.6 Approximately
one in five cases of breast cancer are considered
HER2-positive.7
HER2-positive metastatic breast cancer is an aggressive disease
driven by overexpression or amplification of
HER2.8 Approximately
10,000 patients are treated each year in the 1st-line HER2-positive
metastatic setting in the US.9 While
HER2-targeted therapies have improved outcomes, prognosis remains
poor with most patients experiencing disease progression within two
years of 1st-line treatment with THP, which has been the standard
of care for more than a decade.6,10-12 Approximately
25% to 30% of patients do not receive any treatment following
1st-line therapy due to discontinuation or
death.13-15
DESTINY-Breast09
DESTINY-Breast09 is a global, multicentre, randomised,
open-label, Phase III trial evaluating the efficacy and safety
of Enhertu (5.4 mg/kg) either alone or in combination
with pertuzumab versus standard of care THP as a 1st-line treatment
in patients with HER2-positive metastatic breast
cancer.
Patients were randomised 1:1:1 to receive
either Enhertu monotherapy with a pertuzumab matching
placebo; Enhertu in combination with pertuzumab; or THP.
Randomisation was stratified by prior treatment
(de
novo metastatic disease
versus progression from early-stage disease), hormone receptor (HR)
status and PIK3CA mutation status.
The primary endpoint of DESTINY-Breast09 is PFS as assessed by
blinded-independent central review in the Enhertu monotherapy
and Enhertu combination
arms. Secondary endpoints include investigator-assessed PFS,
overall survival, objective response rate, duration of
response, pharmacokinetics and
safety. The investigational arm assessing Enhertu monotherapy
versus THP remains blinded to patients and investigators and will
continue to the final PFS analysis.
DESTINY-Breast09 enrolled 1,157 patients across multiple sites in
Africa, Asia, Europe, North America 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) in combination
with pertuzumab is approved in the US as a 1st-line treatment for
adult patients with unresectable or metastatic HER2-positive (IHC
3+ or ISH+) breast cancer, as determined by an FDA-approved test
based on the results from the DESTINY-Breast09 trial.
Enhertu (5.4mg/kg) is approved in
more than 90 countries/regions worldwide for the treatment of adult
patients with unresectable or metastatic HER2-positive (IHC 3+ or
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 85 countries/regions 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 55 countries/regions worldwide for the treatment of adult
patients with unresectable or metastatic hormone receptor
(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 60 countries/regions 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 70 countries/regions worldwide for the treatment of adult
patients with locally advanced or metastatic HER2-positive (IHC 3+
or IHC 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 more than 10 countries/regions worldwide 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 efficacy results from the DESTINY-PanTumor02, DESTINY-Lung01 and DESTINY-CRC02 trials.
Continued approval for this indication 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 as a monotherapy, in combination or
sequentially with other cancer medicines across multiple
HER2-targetable cancers.
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 patients with 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. 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. Tolaney SM, et al.
Trastuzumab Deruxtecan plus Pertuzumab for HER2-Positive Metastatic
Breast Cancer. N Engl J
Med. 2025; DOI:
10.1056/NEJMoa2508668.
2. 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;10.3322/caac.21834.
3. American Cancer
Society. Key Statistics for Breast Cancer. Available
at: https://www.cancer.org/cancer/types/breast-cancer/about/how-common-is-breast-cancer.html.
Accessed December 2025.
4. National Cancer
Institute. SEER Cancer Stat Facts: Female Breast Cancer Subtypes.
Available at: https://seer.cancer.gov/statfacts/html/breast-subtypes.html.
Accessed December 2025.
5. Iqbal N, et al. Human Epidermal
Growth Factor Receptor 2 (HER2) in Cancers: Overexpression and
Therapeutic Implications. Mol Biol
Int.
2014;852748.
6. Pillai R, et al. HER2 mutations in
lung adenocarcinomas: A report from the Lung Cancer Mutation
Consortium. Cancer. 2017;1;123(21):4099-4105.
7. Ahn S, et al. HER2 status in breast
cancer: changes in guidelines and complicating factors for
interpretation. J Pathol Transl
Med.
2019;54(1):34-44.
8. Tarantino P, et al. ESMO expert
consensus statements (ECS) on the definition, diagnosis, and
management of HER2-low breast cancer. Ann
Onc.
2023;34(8):645-659.
9. AstraZeneca.
Investor Relations: Epidemiology. Available at: https://www.astrazeneca.com/content/dam/az/Investor_Relations/Epidemiology-data-2024.xlsx.
Accessed December 2025.
10. Swain SM, et al. Pertuzumab,
trastuzumab, and docetaxel for HER2-positive metastatic breast
cancer (CLEOPATRA): end-of-study results from a double-blind,
randomised, placebo-controlled, Phase III
study. Lancet
Oncol. 2020;21(4):519-530.
11. Blumenthal G, et al. First FDA Approval
of Dual Anti-HER2 Regimen: Pertuzumab in Combination with
Trastuzumab and Docetaxel for HER2-Positive Metastatic Breast
Cancer. Clin Can
Res. 2013;19(18).
12. Tripathy D, et al. De Novo Versus
Recurrent HER2-Positive Metastatic Breast Cancer: Patient
Characteristics, Treatment, and Survival from the SystHERs
Registry. Oncologist. 2020;25(2):e214-e222.
13. Hartkopt AD, et al. Attrition in the
First Three Therapy Lines in Patients with Advanced Breast Cancer
in the German Real-World PRAEGNANT
Registry. Geburtshilfe
Frauenheilkd. 2024;84(5):459-469.
14. Cottu P, et al. Attrition between lines
of therapy and real-world outcomes of patients with HER2-positive
metastatic breast cancer in Europe: a cohort study leveraging
electronic medical records. Breast Cancer Res
Treat.
2025;209:419-430.
15. Lam C, et al. Treatment patterns and
associated outcomes among patients with HER2+ metastatic breast
cancer in the United States: an observational cohort
study. Oncologist. 2025;30(4).
Matthew Bowden
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: 16 December 2025
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By: /s/
Matthew Bowden
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Name:
Matthew Bowden
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Title:
Company Secretary
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