REG - AstraZeneca PLC - Enhertu approved in EU in post-ET breast cancer

AstraZenecaAnnouncement

04/04/2025 07:00

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RNS Number : 5793D  AstraZeneca PLC  04 April 2025

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
(https://www.astrazeneca.com/media-centre/press-releases/2025/enhertu-recommended-approval-eu-chmp-patients-low-ultralow-metastatic-breast-cancer-following-least-one-endocrine-therapy.html)
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 (http://www.nejm.org/) .
(http://www.nejm.org/)

 

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
(https://www.astrazeneca.com/media-centre/press-releases/2025/enhertu-approved-in-us-for-breast-cancer-post-et.html)
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
(https://www.astrazeneca.com/media-centre/press-releases/2019/astrazeneca-and-daiichi-sankyo-enter-collaboration-for-novel-her-2-targeting-antibody-drug-conjugate.html)
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
(https://clinicaltrials.gov/study/NCT04494425) .

 

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
(https://clinicaltrials.gov/ct2/show/NCT03529110) 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 (https://clinicaltrials.gov/ct2/show/NCT03734029) 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
(https://clinicaltrials.gov/study/NCT04494425) 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
(https://www.clinicaltrials.gov/study/NCT04644237?term=DESTINY-Lung02&rank=1)
and/or DESTINY-Lung05 (https://clinicaltrials.gov/study/NCT05246514) 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 (https://clinicaltrials.gov/ct2/show/NCT03329690) ,
DESTINY-Gastric02 (https://clinicaltrials.gov/ct2/show/NCT04014075) and/or
DESTINY-Gastric06 (https://clinicaltrials.gov/study/NCT04989816) 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 (https://classic.clinicaltrials.gov/ct2/show/NCT04482309) ,
DESTINY-Lung01 (https://clinicaltrials.gov/study/NCT03505710) and
DESTINY-CRC02
(https://www.clinicaltrials.gov/study/NCT04744831?term=DESTINY-CRC02&rank=1)
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
(https://www.astrazeneca.com/media-centre/press-releases/2019/astrazeneca-and-daiichi-sankyo-enter-collaboration-for-novel-her-2-targeting-antibody-drug-conjugate.html)
and Datroway (datopotamab deruxtecan) in July 2020
(https://www.astrazeneca.com/media-centre/press-releases/2020/astrazeneca-and-daiichi-sankyo-enter-collaboration-to-develop-and-commercialise-new-antibody-drug-conjugate.html#!)
, 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 (http://www.astrazeneca.com/) and follow the
Company on social media @AstraZeneca
(https://gateway.zscalertwo.net/auD?origurl=https:%2f%2fwww.linkedin.com%2fcompany%2fastrazeneca&_ordtok=Mkk3WV5DBDPmQrD4F5MGdGDMZR)
.

 

Contacts

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(https://www.astrazeneca.com/investor-relations.html#Contacts) . For Media
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.

 

References

1.   National Cancer Institute. Surveillance, Epidemiology and End Results
Program. Available at:
https://seer.cancer.gov/statfacts/html/breast-subtypes.html
(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

 

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